@article {pmid31119293, year = {2019}, author = {Shaw, DA and Dinh, VC and Matsen, FA}, title = {Joint maximum likelihood of phylogeny and ancestral states is not consistent.}, journal = {Molecular biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/molbev/msz128}, pmid = {31119293}, issn = {1537-1719}, abstract = {Maximum likelihood estimation in phylogenetics requires a means of handling unknown ancestral states. Classical maximum likelihood averages over these unknown intermediate states, leading to provably consistent estimation of the topology and continuous model parameters. Recently, a computationally-efficient approach has been proposed to jointly maximize over these unknown states and phylogenetic parameters. Although this method of joint maximum likelihood estimation can obtain estimates more quickly, its properties as an estimator are not yet clear. In this paper, we show that this method of jointly estimating phylogenetic parameters along with ancestral states is not consistent in general. We find a sizeable region of parameter space that generates data on a four-taxon tree for which this joint method estimates the internal branch length to be exactly zero, even in the limit of infinite-length sequences. More generally, we show that this joint method only estimates branch lengths correctly on a set of measure zero. We show empirically that branch length estimates are systematically biased downward, even for short branches.}, }
@article {pmid31119044, year = {2019}, author = {Chen, J and Zhu, J and Wang, G and Groopman, JD and Kensler, TW}, title = {Qidong: a crucible for studies on liver cancer etiology and prevention.}, journal = {Cancer biology & medicine}, volume = {16}, number = {1}, pages = {24-37}, doi = {10.20892/j.issn.2095-3941.2018.0394}, pmid = {31119044}, issn = {2095-3941}, abstract = {Qidong (Jiangsu, China) has been of interest to cancer epidemiologists and biologists because, until recently, it was an endemic area for liver cancer, having amongst the highest incidence rates in the world. The establishment of the Qidong Cancer Registry together with the Qidong Liver Cancer Institute in 1972 has charted the patterns of liver cancer incidence and mortality in a stable population throughout a period of enormous economic, social, and environmental changes as well as of improvements in health care delivery. Updated incidence trends in Qidong are described. Notably, the China age-standardized incidence rate for liver cancer has dropped by over 50% in the past several decades. Molecular epidemiologic and genomic deep sequencing studies have affirmed that infection with hepatitis B virus as well as dietary exposure to aflatoxins through contamination of dietary staples such as corn, and to microcystins - blue-green algal toxins found in ditch and pond water - were likely important etiologic factors that account for the high incidence of liver cancer in this region. Public health initiatives to facilitate universal vaccination of newborns against HBV and to improve drinking water sources in this rural area, as well as economic and social mandates serendipitously facilitating dietary diversity, have led to precipitous declines in exposures to these etiologic factors, concomitantly driving substantive declines in the liver cancer incidence seen now in Qidong. In this regard, Qidong serves as a template for the global impact that a package of intervention strategies may exert on cancer burden.}, }
@article {pmid31118087, year = {2019}, author = {Vachon, CM and Scott, CG and Tamimi, RM and Thompson, DJ and Fasching, PA and Stone, J and Southey, MC and Winham, S and Lindström, S and Lilyquist, J and Giles, GG and Milne, RL and MacInnis, RJ and Baglietto, L and Li, J and Czene, K and Bolla, MK and Wang, Q and Dennis, J and Haeberle, L and Eriksson, M and Kraft, P and Luben, R and Wareham, N and Olson, JE and Norman, A and Polley, EC and Maskarinec, G and Le Marchand, L and Haiman, CA and Hopper, JL and Couch, FJ and Easton, DF and Hall, P and Chatterjee, N and Garcia-Closas, M}, title = {Joint association of mammographic density adjusted for age and body mass index and polygenic risk score with breast cancer risk.}, journal = {Breast cancer research : BCR}, volume = {21}, number = {1}, pages = {68}, doi = {10.1186/s13058-019-1138-8}, pmid = {31118087}, issn = {1465-542X}, support = {R01CA128931//National Cancer Institute/ ; R01CA122340//National Cancer Institute/ ; R01CA128978//National Cancer Institute/ ; R01CA097396//National Cancer Institute/ ; P50CA116201//National Cancer Institute/ ; K24CA169004//National Cancer Institute/ ; R21CA179442//National Cancer Institute/ ; P01CA154292//National Cancer Institute/ ; P01CA087969//National Cancer Institute/ ; R01CA085265//National Cancer Institute/ ; UM1CA176726//National Cancer Institute/ ; UM1CA186107//National Cancer Institute/ ; U01CA164973//National Cancer Institute/ ; R01CA240386//National Cancer Institute/ ; R01CA058427//National Institutes of Health (US)/ ; }, abstract = {BACKGROUND: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk.<br><br>METHODS: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies.<br><br>RESULTS: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile.<br><br>CONCLUSIONS: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.}, }
@article {pmid31117986, year = {2019}, author = {Gilbert, PB and Fong, Y and Juraska, M and Carpp, LN and Monto, AS and Martin, ET and Petrie, JG}, title = {HAI and NAI titer correlates of inactivated and live attenuated influenza vaccine efficacy.}, journal = {BMC infectious diseases}, volume = {19}, number = {1}, pages = {453}, doi = {10.1186/s12879-019-4049-5}, pmid = {31117986}, issn = {1471-2334}, support = {R37AI054165//National Institute of Allergy and Infectious Diseases/ ; R01AI122991//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {BACKGROUND: High hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk. While repeated influenza vaccination reduces seroresponse, vaccine effectiveness is not always reduced.<br><br>METHODS: During the 2007-2008 influenza season, a randomized, placebo-controlled trial (FLUVACS) evaluated the efficacies of live-attenuated (LAIV) and inactivated influenza vaccines (IIV) among healthy adults aged 18-49 in Michigan; IIV vaccine efficacy (VE) and LAIV VE against influenza disease were estimated at 68% and 36%. Using the principal stratification/VE moderation framework, we analyzed data from this trial to assess how each VE varied by HAI or NAI responses to vaccination observed for vaccinated individuals and predicted counterfactually for placebo recipients. We also assessed how each VE varied with pre-vaccination/baseline variables including HAI titer, NAI titer, and vaccination history.<br><br>RESULTS: IIV VE appeared to increase with Day 30 post-vaccination HAI titer, albeit not significantly (p=0.20 and estimated VE 14.4%, 70.5%, and 85.5% at titer below the assay lower quantification limit, 512, and 4096 (maximum)). Moreover, IIV VE increased significantly with Day 30 post-vaccination NAI titer (p=0.040), with estimated VE zero at titer 10 and 92.2% at highest titer 640. There was no evidence that fold-change in post-vaccination HAI or NAI titer associated with IIV VE (p=0.76, 0.38). For LAIV, there was no evidence that VE associated with post-vaccination or fold-rise HAI or NAI titers (p-values >0.40). For IIV, VE increased with increasing baseline NAI titer in those previously vaccinated, but VE decreased with increasing baseline NAI titer in those previously unvaccinated. In contrast, for LAIV, VE did not depend on previous vaccination or baseline HAI or NAI titer.<br><br>CONCLUSIONS: Future efficacy trials should measure baseline and post-vaccination antibody titers in both vaccine and control/placebo recipients, enabling analyses to better elucidate correlates of vaccine- and natural-protection.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT00538512. October 1, 2007.}, }
@article {pmid31116975, year = {2019}, author = {Sharon, N and Vanderhooft, J and Straubhaar, J and Mueller, J and Chawla, R and Zhou, Q and Engquist, EN and Trapnell, C and Gifford, DK and Melton, DA}, title = {Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development.}, journal = {Cell reports}, volume = {27}, number = {8}, pages = {2281-2291.e5}, doi = {10.1016/j.celrep.2019.04.083}, pmid = {31116975}, issn = {2211-1247}, abstract = {In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.}, }
@article {pmid31115618, year = {2019}, author = {Wu, W and Pierce, LA and Zhang, Y and Pipavath, SNJ and Randolph, TW and Lastwika, KJ and Lampe, PD and Houghton, AM and Liu, H and Xia, L and Kinahan, PE}, title = {Comparison of prediction models with radiological semantic features and radiomics in lung cancer diagnosis of the pulmonary nodules: a case-control study.}, journal = {European radiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00330-019-06213-9}, pmid = {31115618}, issn = {1432-1084}, support = {U01CA148131//National Institutes of Health/ ; U01185097//National Institutes of Health/ ; U01186157//National Institutes of Health/ ; F32 CA200265//National Institutes of Health/ ; P30CA015704//National Institutes of Health/ ; 81471637//National Natural Science Foundation of China/ ; }, abstract = {PURPOSE: To compare the ability of radiological semantic and quantitative texture features in lung cancer diagnosis of pulmonary nodules.<br><br>MATERIALS AND METHODS: A total of N = 121 subjects with confirmed non-small-cell lung cancer were matched with 117 controls based on age and gender. Radiological semantic and quantitative texture features were extracted from CT images with or without contrast enhancement. Three different models were compared using LASSO logistic regression: &quot;CS&quot; using clinical and semantic variables, &quot;T&quot; using texture features, and &quot;CST&quot; using clinical, semantic, and texture variables. For each model, we performed 100 trials of fivefold cross-validation and the average receiver operating curve was accessed. The AUC of the cross-validation study (AUCCV) was calculated together with its 95% confidence interval.<br><br>RESULTS: The AUCCV (and 95% confidence interval) for models T, CS, and CST was 0.85 (0.71-0.96), 0.88 (0.77-0.96), and 0.88 (0.77-0.97), respectively. After separating the data into two groups with or without contrast enhancement, the AUC (without cross-validation) of the model T was 0.86 both for images with and without contrast enhancement, suggesting that contrast enhancement did not impact the utility of texture analysis.<br><br>CONCLUSIONS: The models with semantic and texture features provided cross-validated AUCs of 0.85-0.88 for classification of benign versus cancerous nodules, showing potential in aiding the management of patients.<br><br>KEY POINTS: • Pretest probability of cancer can aid and direct the physician in the diagnosis and management of pulmonary nodules in a cost-effective way. • Semantic features (qualitative features reported by radiologists to characterize lung lesions) and radiomic (e.g., texture) features can be extracted from CT images. • Input of these variables into a model can generate a pretest likelihood of cancer to aid clinical decision and management of pulmonary nodules.}, }
@article {pmid31115304, year = {2019}, author = {Gilbert, PB and Huang, Y and Juraska, M and Moodie, Z and Fong, Y and Luedtke, A and Zhuang, Y and Shao, J and Carpp, LN and Jackson, N and Chambonneau, L and Bouckenooghe, A and Zambrano, B and Frago, C and Pallardy, S and Noriega, F}, title = {Bridging Efficacy of a Tetravalent Dengue Vaccine from Children/Adolescents to Adults in Highly Endemic Countries Based on Neutralizing Antibody Response.}, journal = {The American journal of tropical medicine and hygiene}, volume = {}, number = {}, pages = {}, doi = {10.4269/ajtmh.18-0534}, pmid = {31115304}, issn = {1476-1645}, abstract = {The CYD-TDV vaccine is licensed in multiple endemic countries based on vaccine efficacy (VE) against symptomatic, virologically confirmed dengue demonstrated in two phase 3 trials (CYD14, 2- to 14-year-olds, Asia; CYD15, 9- to 16-year-olds, Latin America). 50% plaque reduction neutralization test (PRNT50) titers at baseline and month 13 (post-vaccination) were associated with VE and may enable bridging VE to adults. Two phase 2 trials of CYD-TDV measured baseline and month 13 PRNT50 titers: CYD22 (9- to 45-year-olds, Vietnam) and CYD47 (18- to 45-year-olds, India). 50% plaque reduction neutralization test distributions were compared between age cohorts, and four versions of an epidemiological bridging method were used to estimate VE against any serotype (dengue virus [DENV]-Any) and against each serotype over 25 months post first vaccination in a hypothetical CYD14 + CYD15 18- to 45-year-old cohort (bridging population 1) and in the actual CYD47 18- to 45-year-old cohort (bridging population 2). Baseline and month 13 geometric mean PRNT50 titers to each serotype were significantly greater in 18- to 45-year-olds than 9- to 16-year-olds for all comparisons. The four methods estimated VE against DENV-Any at 75.3-86.0% (95% CIs spanning 52.5-100%) for bridging population 1 and 68.4-77.5% (95% CIs spanning 42.3-88.5%) for bridging population 2. The vaccine efficacy against serotype 1, 2, 3, and 4 was estimated at 56.9-76.9%, 68.3-85.8%, 91.4-95.0%, and 93.2-100% (bridging population 1) and 44.5-66.9%, 53.2-69.2%, 79.8-92.0%, and 90.6-95.0% (bridging population 2), respectively; thus, CYD-TDV would likely confer improved efficacy in adults than 9- to 16-year-olds. Using the same methods, we predicted VE against hospitalized DENV-Any over 72 months of follow-up, with estimates 59.1-73.5% (95% CIs spanning 40.9-92.2%) for bridging population 1 and 50.9-65.9% (95% CIs spanning 38.1-82.1%) for bridging population 2.}, }
@article {pmid31113932, year = {2019}, author = {Rafiee, R and Chauhan, L and Alonzo, TA and Wang, YC and Elmasry, A and Loken, MR and Pollard, J and Aplenc, R and Raimondi, S and Hirsch, BA and Bernstein, ID and Gamis, AS and Meshinchi, S and Lamba, JK}, title = {ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.}, journal = {Blood cancer journal}, volume = {9}, number = {6}, pages = {51}, doi = {10.1038/s41408-019-0211-y}, pmid = {31113932}, issn = {2044-5385}, abstract = {Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.}, }
@article {pmid31113819, year = {2019}, author = {Jackson, SS and Van Dyke, AL and Zhu, B and Pfeiffer, RM and Petrick, JL and Adami, HO and Albanes, D and Andreotti, G and Beane Freeman, LE and Berrington de Gonzalez, A and Buring, JE and Chan, AT and Chen, Y and Fraser, GE and Freedman, ND and Gao, YT and Gapstur, SM and Gaziano, JM and Giles, GG and Grant, EJ and Grodstein, F and Hartge, P and Jenab, M and Kitahara, CM and Knutsen, SF and Koh, WP and Larsson, SC and Lee, IM and Liao, LM and Luo, J and McGee, EE and Milne, RL and Monroe, KR and Neuhouser, ML and O'Brien, KM and Peters, U and Poynter, JN and Purdue, MP and Robien, K and Sandler, DP and Sawada, N and Schairer, C and Sesso, HD and Simon, TG and Sinha, R and Stolzenberg-Solomon, RZ and Tsugane, S and Wang, R and Weiderpass, E and Weinstein, SJ and White, E and Wolk, A and Yuan, JM and Zeleniuch-Jacquotte, A and Zhang, X and McGlynn, KA and Campbell, PT and Koshiol, J}, title = {Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-19-0459}, pmid = {31113819}, issn = {1538-7445}, abstract = {Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index, waist circumference, hip circumference, waist-to-hip and waist-to-height ratios. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in body mass index there were risk increases for GBC (HR: 1.27 [95% CI: 1.19, 1.36]), IHBDC (HR: 1.32 [95% CI: 1.21, 1.45]), and EHBDC (HR: 1.13 [95% CI: 1.03, 1.23]), but not AVC (HR: 0.99 [95% CI: 0.88, 1.11]). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.}, }
@article {pmid31112280, year = {2019}, author = {Limaye, AP and Green, ML and Edmison, BC and Stevens-Ayers, T and Chatterton-Kirchmeier, S and Geballe, AP and Singh, N and Boeckh, M}, title = {Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz181}, pmid = {31112280}, issn = {1537-6613}, abstract = {The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.}, }
@article {pmid31112106, year = {2019}, author = {Gulati, R and Psutka, SP and Etzioni, R}, title = {Personalized risks of overdiagnosis for screen-detected prostate cancer incorporating patient comorbidities: Estimation and communication.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000000346}, doi = {10.1097/JU.0000000000000346}, pmid = {31112106}, issn = {1527-3792}, abstract = {PURPOSE: Shared patient-physician decision-making regarding treatment for prostate cancer detected by prostate-specific antigen screening involves a complex calculus weighing the risk of the cancer and patient life expectancy. We investigated quantifying these competing risks using the probability that the cancer was &quot;overdiagnosed&quot;-i.e., would not have been clinically diagnosed (diagnosed without screening) during the patient's remaining lifetime.<br><br>MATERIALS AND METHODS: Using an established model of prostate cancer screening and clinical diagnosis, we simulated screen-detected cases and determined whether modeled clinical diagnosis would occur before non-cancer death, which was based on comorbidity-adjusted population lifetables. Logistic regression models were fitted to the simulated data and used to estimate overdiagnosis probabilities given patient age, PSA level, Gleason sum, and comorbidity category. An online calculator was developed to communicate overdiagnosis estimates; face validity and ease of use was assessed by surveying 32 clinical experts.<br><br>RESULTS: Estimated probabilities of overdiagnosis ranged 4%-78% across clinicopathologic variables and comorbidity status. Ignoring comorbidity, the estimated probability for a 70-year-old man with PSA 9.4 ng/mL and Gleason 6 is 34%; if he has severe comorbidities, the estimate increases to 51%, a personalization that may help inform the choice between active surveillance and definitive treatment. Based on responses from 20/32 experts, we modified the online calculator's explanation of overdiagnosis and input method for comorbid conditions.<br><br>CONCLUSIONS: The probability of overdiagnosis is strongly influenced by comorbidity status in addition to age. Personalized estimates incorporating comorbidity may contribute to shared decision-making between patients and providers regarding personalized treatment selection.}, }
@article {pmid31111901, year = {2019}, author = {Little, RF and Uldrick, TS}, title = {Are There Clues to Oral KSHV Shedding and Kaposi Sarcoma Oncogenesis in the Oral Microbiome?.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz250}, pmid = {31111901}, issn = {1537-6613}, }
@article {pmid31110328, year = {2019}, author = {Bien, SA and Peters, U}, title = {Moving from one to many: insights from the growing list of pleiotropic cancer risk genes.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41416-019-0475-9}, pmid = {31110328}, issn = {1532-1827}, abstract = {Pleiotropy, a phenomenon in which a single gene affects multiple phenotypes, is becoming very common among different cancer types and cancer-related phenotypes, such as those in hormonal, cardiometabolic and inflammatory/immune conditions. The discovery of pleiotropic associations can improve our understanding of cancer and help to target investigation of genes with greater clinical relevance.}, }
@article {pmid31109923, year = {2019}, author = {Goyal, L and Shi, L and Liu, LY and Fece de la Cruz, F and Lennerz, JK and Raghavan, S and Leshchiner, I and Elagina, L and Siravegna, G and Ng, RWS and Vu, P and Patra, KC and Saha, SK and Uppot, RN and Arellano, R and Reyes, S and Sagara, T and Otsuki, S and Nadres, B and Shahzade, HA and Dey-Guha, I and Fetter, IJ and Baiev, I and Van Seventer, EE and Murphy, JE and Ferrone, CR and Tanabe, KK and Deshpande, V and Harding, JJ and Yaeger, R and Kelley, RK and Bardelli, A and Iafrate, AJ and Hahn, WC and Benes, CH and Ting, DT and Hirai, H and Getz, G and Juric, D and Zhu, AX and Corcoran, RB and Bardeesy, N}, title = {TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-19-0182}, pmid = {31109923}, issn = {2159-8290}, abstract = {ATP-competitive Fibroblast Growth Factor Receptor (FGFR) kinase inhibitors, including BGJ398 and Debio1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor, TAS-120, demonstrated efficacy in four patients with FGFR2-fusion-positive ICC who developed resistance to BGJ398 or Debio1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsies and ctDNA, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC.}, }
@article {pmid31106344, year = {2019}, author = {Evans, WD and Andrade, EL and Barrett, N and Snider, J and Cleary, S and Edberg, M}, title = {Outcomes of the Adelante community social marketing campaign for Latino youth.}, journal = {Health education research}, volume = {}, number = {}, pages = {}, doi = {10.1093/her/cyz016}, pmid = {31106344}, issn = {1465-3648}, abstract = {The authors designed and evaluated an innovative, branded campaign called 'Adelante' to promote positive youth development (PYD) and reduce risk behaviors among Latino youth near Washington, DC. Repeated cross-sectional surveys were conducted in the intervention and a comparison community to evaluate campaign exposure and changes in PYD outcomes. The sample consisted of 1549 Latino and immigrant adolescents surveyed at three time points in intervention and comparison communities. A social marketing campaign was implemented using outdoor advertising, Web, video and social media channels to promote PYD and health outcomes over a 1-year period from 2015 to 2016. Measures included media use; self-reported exposure to campaign promotions; Adelante message receptivity; validated PYD scales; substance use, sexual risk taking, violence-related knowledge, attitudes, beliefs, intentions and risk behavior. Outcomes were regressed first on campaign exposure to examine dose-response effects of the Adelante campaign over time. Second, we compared outcomes between the Adelante and comparison communities. We observed a positive effect of self-reported exposure on multiple outcomes, including improvements in pro-violence and sexual risk outcomes and lower pro-violence attitudes and lower risky attitudes toward sex. Adelante was effective in improving youth risk outcomes and offers a promising model for future health promotion with Latino and immigrant populations.}, }
@article {pmid31104561, year = {2019}, author = {Kerr, KF and Marsh, TL and Janes, H}, title = {The Importance of Uncertainty and Opt-In v. Opt-Out: Best Practices for Decision Curve Analysis.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {}, number = {}, pages = {272989X19849436}, doi = {10.1177/0272989X19849436}, pmid = {31104561}, issn = {1552-681X}, }
@article {pmid31103694, year = {2019}, author = {Cohen, O and Strizich, GM and Ramos, AR and Zee, PC and Reid, KJ and Mani, V and Rapoport, DM and Redline, S and Kaplan, RC and Shah, NA}, title = {Sex Differences in the Association Between Smoking and Sleep Disordered Breathing in the Hispanic Community Health Study/ Study of Latinos.}, journal = {Chest}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chest.2019.04.106}, pmid = {31103694}, issn = {1931-3543}, abstract = {BACKGROUND: Previous studies examining associations between cigarette smoking and sleep disordered breathing (SDB) are inconsistent. We therefore investigated this association in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).<br><br>METHODS: 13,863 US Hispanics/Latinos, 18-76 years old, provided smoking histories and underwent home SDB testing. Logistic regression analyses were conducted to assess the independent association of smoking and SDB with covariate adjustment. Sex and age stratified analyses were done.<br><br>RESULTS: The weighted prevalence of moderate-to-severe SDB was 9.7% (95%CI: 9.0, 10.5). No independent and statistically significant association was observed between ever smoking (defined as minimum lifetime cigarette use of 100) and moderate-to-severe SDB (defined as apnea-hypopnea index ≥15) (OR 1.02, 95%CI: 0.85, 1.22; p=0.85). Sex and age were effect modifiers of the aforementioned association. Stratification by age and sex revealed that younger (35-54 years old) female smokers had 83% higher odds of SDB compared to younger female never smokers (OR 1.83, 95%CI: 1.19, 2.81; p=0.01). A significant dose response relationship was noted between smoking intensity and SDB in younger female smokers (p<0.01). Lastly, use of ≥10 cigarettes a day was associated with a nearly 3-fold increase in SDB odds in younger female ever smokers. The above associations were not observed in younger males.<br><br>CONCLUSIONS: In the HCHS/SOL, we found no independent and statistically significant association between smoking and SDB. Sex and age stratification revealed a novel statistically significant association between smoking and SDB in younger (35-54 years old) female smokers. Our findings highlight the importance of investigating sex and age specific associations of SDB risk factors.}, }
@article {pmid31103365, year = {2019}, author = {Bernstein, DI and Flechtner, JB and McNeil, LK and Heineman, T and Oliphant, T and Tasker, S and Wald, A and Hetherington, S and , }, title = {Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2019.05.009}, pmid = {31103365}, issn = {1873-2518}, abstract = {BACKGROUND: Genital herpes simplex virus (HSV) type 2 is a common persistent infection that frequently reactivates to cause recurrent lesions and recurrent viral shedding which is incompletely controlled by antiviral therapy. GEN-003 is a candidate therapeutic vaccine containing 2 HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant (M2).<br><br>METHODS: HSV-2 seropositive persons with genital herpes were randomized into three dose cohorts of Gen-003 (60 µg antigen/50 µg M2, 60 µg/75 µg M2 or Placebo). Three intramuscular doses 21 days apart of GEN-003 or placebo were administered. Participants obtained genital area swabs twice-daily for HSV-2 detection and monitored genital lesions for 12 months. The rates of virus shedding and lesion rates before vaccination were compared to 3 defined periods after vaccination; Days 43-71, Month 6 and Month 12.<br><br>RESULTS: GEN-003 at a dose of 60 µg each antigen/50 µg M2 reduced HSV shedding immediately after dosing with a rate ratio of 0.58, compared to 0.75 for the GEN-003 60 µg/75 µg M2 and 1.06 for placebo. Lesion rates, recurrence rates, and duration of recurrences were also reduced. Reactogenicity was higher with the 75 µg M2 dose than the 50 µg M2 dose, specifically for pain, tenderness, malaise and fatigue. Antibody and cellular immune responses were stimulated by both doses and persisted to 12 months.<br><br>CONCLUSIONS: GEN-003 vaccine manufactured with a scalable process gave results similar to those observed in prior clinical trials. GEN-003 had an acceptable safety profile and stimulated both humoral and cellular immune responses. The 60 µg antigen/50 µg M2 provided the maximal effect on virologic and clinical measures and warrants further development. (Funded by Genocea; ClinicalTrials.gov number NCT02515175).}, }
@article {pmid31101673, year = {2019}, author = {Moffett, HF and Harms, CK and Fitzpatrick, KS and Tooley, MR and Boonyaratanakornkit, J and Taylor, JJ}, title = {B cells engineered to express pathogen-specific antibodies protect against infection.}, journal = {Science immunology}, volume = {4}, number = {35}, pages = {}, doi = {10.1126/sciimmunol.aax0644}, pmid = {31101673}, issn = {2470-9468}, abstract = {Effective vaccines inducing lifelong protection against many important infections such as respiratory syncytial virus (RSV), HIV, influenza virus, and Epstein-Barr virus (EBV) are not yet available despite decades of research. As an alternative to a protective vaccine, we developed a genetic engineering strategy in which CRISPR-Cas9 was used to replace endogenously encoded antibodies with antibodies targeting RSV, HIV, influenza virus, or EBV in primary human B cells. The engineered antibodies were expressed efficiently in primary B cells under the control of endogenous regulatory elements, which maintained normal antibody expression and secretion. Using engineered mouse B cells, we demonstrated that a single transfer of B cells engineered to express an antibody against RSV resulted in potent and durable protection against RSV infection in RAG1-deficient mice. This approach offers the opportunity to achieve sterilizing immunity against pathogens for which traditional vaccination has failed to induce or maintain protective antibody responses.}, }
@article {pmid31101617, year = {2019}, author = {Xi, LF and Schiffman, M and Hughes, JP and Galloway, DA and Koutsky, LA and Kiviat, NB}, title = {Changes in DNA Level of Oncogenic Human Papillomaviruses Other Than Types 16 and 18 in Relation to Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-18-0802}, pmid = {31101617}, issn = {1538-7755}, abstract = {BACKGROUND: Epidemiologic data addressing clinical relevance of viral load fluctuation of oncogenic types other than human papillomavirus (HPV) types 16 and 18 are limited.<br><br>METHODS: A type-stratified set of infections by non-HPV16/18 oncogenic types that were detected at ≥2 visits was randomly selected from women who were enrolled in a clinical trial and followed every 6 months for 2 years for detection of HPV and cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3). Type-specific viral load was measured on both first and last HPV-positive cervical swab samples.<br><br>RESULTS: CIN2/3 was initially confirmed at the last HPV-positive visit for 67 of 439 infections. The increase in risk of CIN2/3 was associated with high, relative to low, viral load at both first and last positive visits (OR adjusted=3.67; 95% CI, 1.19-11.32) and marginally associated with a change of viral load from low to high levels (OR adjusted=3.15; 95% CI, 0.96-10.35) for infection by species group alpha-9 non-HPV16 oncogenic types but not species group alpha-5-7 non-HPV18 oncogenic types. Among women with an initial diagnosis of CIN2/3 at the first positive visit, CIN2/3 was more frequently redetected at the last positive visit for infections with, compared to without, high DNA load of species group alpha-9 non-HPV16 oncogenic types at both visits (P exact=0.04).<br><br>CONCLUSIONS: In agreement with data on baseline viral load, the viral load change-associated risk of CIN2/3 differs by HPV species groups.<br><br>IMPACT: These findings underscore the importance of distinguishing species groups in future studies of clinical relevance of HPV DNA load.}, }
@article {pmid31099956, year = {2019}, author = {Corey, L and Gray, GE and Buchbinder, SP}, title = {The aspirational necessity of HIV prevention.}, journal = {Journal of the International AIDS Society}, volume = {22}, number = {5}, pages = {e25289}, doi = {10.1002/jia2.25289}, pmid = {31099956}, issn = {1758-2652}, support = {UM1 AI068614//National Institute of Allergy and Infectious Diseases/ ; }, }
@article {pmid31099684, year = {2019}, author = {Grivas, P and Drakaki, A and Friedlander, TW and Sonpavde, G}, title = {Conceptual Framework for Therapeutic Development Beyond Anti-PD-1/PD-L1 in Urothelial Cancer.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {}, number = {39}, pages = {284-300}, doi = {10.1200/EDBK_237449}, pmid = {31099684}, issn = {1548-8756}, abstract = {Platinum-based chemotherapy has been the standard of care in advanced urothelial cancer, but long-term outcomes have remained poor. Immune checkpoint inhibitors, with their favorable toxicity profiles and noteworthy efficacy, have steered a new era in advanced urothelial cancer, with five agents targeting the PD-1/PD-L1 pathway approved by the U.S. Food and Drug Administration (FDA). However, most patients do not achieve response, whereas immunotherapy-related adverse events may cause morbidity, increased health care use, and-rarely-mortality. Therefore, there is an urgent need for additional therapeutic modalities across the disease spectrum. A plethora of clinical trials are ongoing in various disease settings, including chemotherapy regimens, radiotherapy, antibody-drug conjugates, agents targeting additional immune checkpoint pathways, vaccine, cytokines, adoptive cell therapies, as well as targeted and anti-angiogenic agents. Two agents, enfortumab vedotin and erdafitinib, have breakthrough designation by the FDA but are not approved yet (at the time of this paper's preparation). Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials. Evaluation of new treatments has met with substantial challenges for many reasons, for example, molecular heterogeneity, clonal evolution, and genomic instability. In the era of precision molecular medicine, and because patients do not respond uniformly to current therapies, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. Here, we review current updates and future directions of experimental therapeutics in urothelial cancer, including examples (but not an exhaustive list) of ongoing clinical trials.}, }
@article {pmid31099627, year = {2019}, author = {Klepin, HD and Estey, E and Kadia, T}, title = {More Versus Less Therapy for Older Adults With Acute Myeloid Leukemia: New Perspectives on an Old Debate.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {}, number = {39}, pages = {421-432}, doi = {10.1200/EDBK_239097}, pmid = {31099627}, issn = {1548-8756}, abstract = {Most patients with newly diagnosed acute myeloid leukemia (AML) are at least age 65 and continue to have short survival, with many patients receiving no specific anti-AML therapy, particularly if they are older than age 75. Although consensus regarding optimal treatment of this growing population is lacking, treatment options are expanding even for the oldest patients. A fundamental question when seeing an older patient with AML is whether to recommend &quot;more intensive&quot; or &quot;less intensive&quot; induction therapy. Existing data can support more intensive treatment strategies for selected older adults, although there is growing evidence to support less intensive therapies as well. Randomized trials to provide clear comparisons between treatment strategies among well-characterized older adult populations are lacking. Reliance on age alone to determine treatment choice is problematic, as &quot;fitness&quot; or &quot;unfitness&quot; varies dramatically among patients of the same chronologic age and remains poorly characterized in existing studies. This article will provide differing perspectives on the &quot;more&quot; versus &quot;less&quot; question, with particular attention to recent drug approvals. Issues relevant to both treatment decision-making in practice and alternative trial design to inform gaps in knowledge will be discussed. Given the heterogeneity, an important conclusion will be that there is unlikely to be a single best approach and that appropriate decision-making requires considerations of many factors specific to individual patients.}, }
@article {pmid31097697, year = {2019}, author = {Simonich, CA and Doepker, L and Ralph, D and Williams, JA and Dhar, A and Yaffe, Z and Gentles, L and Small, CT and Oliver, B and Vigdorovich, V and Mangala Prasad, V and Nduati, R and Sather, DN and Lee, KK and Matsen Iv, FA and Overbaugh, J}, title = {Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {2190}, doi = {10.1038/s41467-019-09481-7}, pmid = {31097697}, issn = {2041-1723}, abstract = {HIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. Here we reconstruct the developmental lineage of BF520.1, an infant-derived HIV-specific broadly neutralizing antibody (bnAb), using computational methods developed specifically for this purpose. We find that the BF520.1 inferred naive precursor binds HIV Env. We also show that heterologous cross-clade neutralizing activity evolved in the infant within six months of infection and that, ultimately, only 2% SHM is needed to achieve the full breadth of the mature antibody. Mutagenesis and structural analyses reveal that, for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses.}, }
@article {pmid31097593, year = {2019}, author = {Johnston, CD and Cotton, SL and Rittling, SR and Starr, JR and Borisy, GG and Dewhirst, FE and Lemon, KP}, title = {Systematic evasion of the restriction-modification barrier in bacteria.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {}, number = {}, pages = {}, doi = {10.1073/pnas.1820256116}, pmid = {31097593}, issn = {1091-6490}, abstract = {Bacteria that are recalcitrant to genetic manipulation using modern in vitro techniques are termed genetically intractable. Genetic intractability is a fundamental barrier to progress that hinders basic, synthetic, and translational microbiology research and development beyond a few model organisms. The most common underlying causes of genetic intractability are restriction-modification (RM) systems, ubiquitous defense mechanisms against xenogeneic DNA that hinder the use of genetic approaches in the vast majority of bacteria and exhibit strain-level variation. Here, we describe a systematic approach to overcome RM systems. Our approach was inspired by a simple hypothesis: if a synthetic piece of DNA lacks the highly specific target recognition motifs for a host's RM systems, then it is invisible to these systems and will not be degraded during artificial transformation. Accordingly, in this process, we determine the genome and methylome of an individual bacterial strain and use this information to define the bacterium's RM target motifs. We then synonymously eliminate RM targets from the nucleotide sequence of a genetic tool in silico, synthesize an RM-silent &quot;SyngenicDNA&quot; tool, and propagate the tool as minicircle plasmids, termed SyMPL (SyngenicDNA Minicircle Plasmid) tools, before transformation. In a proof-of-principle of our approach, we demonstrate a profound improvement (five orders of magnitude) in the transformation of a clinically relevant USA300 strain of Staphylococcus aureus This stealth-by-engineering SyngenicDNA approach is effective, flexible, and we expect in future applications could enable microbial genetics free of the restraints of restriction-modification barriers.}, }
@article {pmid31096572, year = {2019}, author = {Dingens, AS and Arenz, D and Overbaugh, J and Bloom, JD}, title = {Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide.}, journal = {Viruses}, volume = {11}, number = {5}, pages = {}, doi = {10.3390/v11050439}, pmid = {31096572}, issn = {1999-4915}, support = {R01AI127893//National Institutes of Health/ ; DA039543//National Institutes of Health/ ; DGE-1256082//National Science Foundation/ ; }, abstract = {Identifying drug resistance mutations is important for the clinical use of antivirals and can help define both a drug's mechanism of action and the mechanistic basis of resistance. Resistance mutations are often identified one-at-a-time by studying viral evolution within treated patients or during viral growth in the presence of a drug in cell culture. Such approaches have previously mapped resistance to enfuvirtide, the only clinically approved HIV-1 fusion inhibitor, to enfuvirtide's binding site in the N-terminal heptad repeat (NHR) of the Envelope (Env) transmembrane domain as well as a limited number of allosteric sites. Here, we sought to better delineate the genotypic determinants of resistance throughout Env. We used deep mutational scanning to quantify the effect of all single-amino-acid mutations to the subtype A BG505 Env on resistance to enfuvirtide. We identified both previously characterized and numerous novel resistance mutations in the NHR. Additional resistance mutations clustered in other regions of Env conformational intermediates, suggesting they may act during different fusion steps by altering fusion kinetics and/or exposure of the enfuvirtide binding site. This complete map of resistance sheds light on the diverse mechanisms of enfuvirtide resistance and highlights the utility of using deep mutational scanning to comprehensively map potential drug resistance mutations.}, }
@article {pmid31096148, year = {2019}, author = {Lloyd, EC and Haase, AM and Foster, CE and Verplanken, B}, title = {A systematic review of studies probing longitudinal associations between anxiety and anorexia nervosa.}, journal = {Psychiatry research}, volume = {276}, number = {}, pages = {175-185}, doi = {10.1016/j.psychres.2019.05.010}, pmid = {31096148}, issn = {1872-7123}, abstract = {The current study aimed to establish whether anxiety predicts subsequent anorexia nervosa onset and maintenance. A systematic review of longitudinal studies assessing the association between stable anxiety exposures (e.g. trait anxiety/anxiety disorder pathology) and anorexia nervosa development or maintenance was undertaken. Eight studies met inclusion criteria. Seven probed the association between anxiety and anorexia nervosa onset, and one assessed the association between anxiety and anorexia nervosa maintenance. Individuals with anorexia nervosa were more likely to report childhood anxiety compared to healthy individuals, but whether childhood anxiety explains unique variance in anorexia nervosa development is unclear. Current evidence does not support longitudinal associations between specific anxiety disorders (independently of other anxiety disorders) and subsequent anorexia nervosa onset, however anxiety disorder diagnosis in general may predict increased anorexia nervosa risk. The single study probing the association between anxiety and anorexia nervosa maintenance did not find evidence supporting a relationship. The quality of individual studies was fair to high, however the body of evidence was of low quality. Further research that minimises bias, allowing for strong conclusions concerning longitudinal associations between anxiety and subsequent anorexia nervosa outcomes, is required to inform anorexia nervosa aetiology. This in turn may promote improved prevention and treatment.}, }
@article {pmid31095276, year = {2019}, author = {Krantz, EM and Zier, J and Stohs, E and Ogimi, C and Sweet, A and Marquis, S and Klaassen, J and Pergam, SA and Liu, C}, title = {Antibiotic Prescribing and Respiratory Viral Testing for Acute Upper Respiratory Infections Among Adult Patients at an Ambulatory Cancer Center.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciz409}, pmid = {31095276}, issn = {1537-6591}, abstract = {BACKGROUND: Outpatient antibiotic prescribing for acute upper respiratory infections (URI) is a high priority target for antimicrobial stewardship that has not been described for cancer patients.<br><br>METHODS: We conducted a retrospective cohort study of adult patients at an ambulatory cancer center with ICD-10 diagnosis code consistent with URI from October 1, 2015 to September 30, 2016. We obtained antimicrobial prescribing, respiratory viral testing, and other clinical data at first encounter for the URI through day 14. We used generalized estimating equations to test associations of baseline factors with antibiotic prescribing.<br><br>RESULTS: Of 341 charts reviewed, 251 (74%) patients were eligible for analysis. Nearly one-third (32%) of patients were prescribed antibiotics for URI. Respiratory viruses were detected among 85 (75%) of 113 patients tested. Antibiotic prescribing (p=0.001) and viral testing (p<0.001) varied by clinical service. Sputum production or chest congestion was associated with higher risk of antibiotic prescribing (RR=2.3, 95% CI 1.4-3.8, p<0.001). Viral testing on day 0 was associated with lower risk of antibiotic prescribing (RR=0.4, 95% CI 0.2-0.8, p=0.01) though collinearity between viral testing and clinical service limited our ability to separate these effects on prescribing. Antibiotic prescribing was not associated with subsequent URI-related healthcare visits (p=0.89).<br><br>CONCLUSIONS: Nearly one-third of hematology-oncology outpatients were prescribed antibiotics for URI, despite viral etiologies identified among 75% of those tested. Antibiotic prescribing was significantly lower among patients receiving an initial respiratory viral test. The role of viral testing in antibiotic prescribing for URI in outpatient oncology settings merits further study.}, }
@article {pmid31095246, year = {2019}, author = {Sorror, ML and Storer, BE and Nyland, J and Estey, EH}, title = {Revised Acute Myeloid Leukemia Composite Model Using the 2017 European LeukemiaNet Risk Classification.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2019.0902}, pmid = {31095246}, issn = {2374-2445}, }
@article {pmid31095088, year = {2019}, author = {Pescatello, LS and Buchner, DM and Jakicic, JM and Powell, KE and Kraus, WE and Bloodgood, B and Campbell, WW and Dietz, S and Dipietro, L and George, SM and Macko, RF and McTiernan, A and Pate, RR and Piercy, KL and , }, title = {Physical Activity to Prevent and Treat Hypertension: A Systematic Review.}, journal = {Medicine and science in sports and exercise}, volume = {51}, number = {6}, pages = {1314-1323}, doi = {10.1249/MSS.0000000000001943}, pmid = {31095088}, issn = {1530-0315}, abstract = {PURPOSE: This systematic umbrella review examines and updates the evidence on the relationship between physical activity (PA) and blood pressure (BP) presented in the 2008 Physical Activity Guidelines Advisory Committee Scientific Report.<br><br>METHODS: We performed a systematic review to identify systematic reviews and meta-analyses involving adults with normal BP, prehypertension, and hypertension published from 2006 to February 2018.<br><br>RESULTS: In total, 17 meta-analyses and one systematic review with 594,129 adults ≥18 yr qualified. Strong evidence demonstrates: 1) an inverse dose-response relationship between PA and incident hypertension among adults with normal BP; 2) PA reduces the risk of cardiovascular disease (CVD) progression among adults with hypertension; 3) PA reduces BP among adults with normal BP, prehypertension, and hypertension; and 4) the magnitude of the BP response to PA varies by resting BP, with greater benefits among adults with prehypertension than normal BP. Moderate evidence indicates the relationship between resting BP and the magnitude of benefit does not vary by PA type among adults with normal BP, prehypertension, and hypertension. Limited evidence suggests the magnitude of the BP response to PA varies by resting BP among adults with hypertension. Insufficient evidence is available to determine if factors such as sex, age, race/ethnicity, socioeconomic status, and weight status or the frequency, intensity, time, and duration of PA influence the associations between PA and BP.<br><br>CONCLUSIONS: Future research is needed that adheres to standard BP measurement protocols and classification schemes to better understand the influence of PA on the risk of comorbid conditions, health-related quality of life, and CVD progression and mortality; the interactive effects between PA and antihypertensive medication use; and the immediate BP-lowering benefits of PA.}, }
@article {pmid31095082, year = {2019}, author = {McTiernan, A and Friedenreich, CM and Katzmarzyk, PT and Powell, KE and Macko, R and Buchner, D and Pescatello, LS and Bloodgood, B and Tennant, B and Vaux-Bjerke, A and George, SM and Troiano, RP and Piercy, KL and , }, title = {Physical Activity in Cancer Prevention and Survival: A Systematic Review.}, journal = {Medicine and science in sports and exercise}, volume = {51}, number = {6}, pages = {1252-1261}, doi = {10.1249/MSS.0000000000001937}, pmid = {31095082}, issn = {1530-0315}, abstract = {PURPOSE: This article reviews and updates the evidence on the associations between physical activity and risk for cancer, and for mortality in persons with cancer, as presented in the 2018 Physical Activity Guidelines Advisory Committee Scientific Report.<br><br>METHODS: Systematic reviews of meta-analyses, systematic reviews, and pooled analyses were conducted through December 2016. An updated systematic review of such reports plus original research through February 2018 was conducted. This article also identifies future research needs.<br><br>RESULTS: In reviewing 45 reports comprising hundreds of epidemiologic studies with several million study participants, the report found strong evidence for an association between highest versus lowest physical activity levels and reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal, and gastric cancers. Relative risk reductions ranged from approximately 10% to 20%. Based on 18 systematic reviews and meta-analyses, the report also found moderate or limited associations between greater amounts of physical activity and decreased all-cause and cancer-specific mortality in individuals with a diagnosis of breast, colorectal, or prostate cancer, with relative risk reductions ranging almost up to 40% to 50%. The updated search, with five meta-analyses and 25 source articles reviewed, confirmed these findings.<br><br>CONCLUSIONS: Levels of physical activity recommended in the 2018 Guidelines are associated with reduced risk and improved survival for several cancers. More research is needed to determine the associations between physical activity and incidence for less common cancers and associations with survival for other cancers. Future studies of cancer incidence and mortality should consider these associations for population subgroups, to determine dose-response relationships between physical activity and cancer risk and prognosis, and to establish mechanisms to explain these associations.}, }
@article {pmid31095007, year = {2019}, author = {Lemos, MP and Lazarus, E and Isaacs, A and Dietrich, J and Morgan, C and Huang, Y and Grove, D and Andrasik, M and Laher, F and Hural, J and Chung, E and Dragavon, J and Puren, A and Gulati, RK and Coombs, R and McElrath, MJ and Gray, G and Kublin, JG}, title = {Daily Vaginal Swabs and Mobile Phone Sex Report for Assessing HIV Virion Exposure Prospectively Among a Cohort of Young Sexually Active Women in South Africa (HVTN 915).}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {81}, number = {2}, pages = {e39-e48}, doi = {10.1097/QAI.0000000000002015}, pmid = {31095007}, issn = {1944-7884}, abstract = {BACKGROUND: Measurements of HIV exposure could help identify subpopulations at highest risk of acquisition and improve the design of HIV prevention efficacy trials and public health interventions. The HVTN 915 study evaluated the feasibility of self-administered vaginal swabs for detection of HIV virions to assess exposure.<br><br>METHODS: Fifty 18- to 25-year-old sexually active HIV-seronegative women using contraception were enrolled in Soweto, South Africa. Participants self-administered daily vaginal swabs and answered sexual behavior questions through mobile phone for 90 days. Clinician-administered vaginal swabs, behavioral questionnaires, HIV diagnostic testing, and counseling were performed at 8 clinic visits. Glycogen concentrations assessed adherence to swabbing. Y-chromosome DNA (Yc-DNA) assessed the accuracy of reported condom use. HIV exposure was measured by virion polymerase chain reaction in swabs from 41 women who reported unprotected vaginal sex during follow-up.<br><br>RESULTS: Glycogen was detected in 315/336 (93.8%) participant-collected and in all clinician-collected swabs. Approximately 20/39 daily swabs (51.3%) linked to mobile reports of unprotected sex tested positive for Yc-DNA, whereas 10/187 swabs collected after 3 days of abstinence or protected sex (5.3%) had detectable Yc-DNA. No participant became HIV infected during the study; yet, exposure to HIV was detected by nucleic acids in 2 vaginal swabs from 1 participant, collected less than 1 hour after coitus.<br><br>CONCLUSION: There was high adherence to daily vaginal swabbing. Daily mobile surveys had accurate reporting of unprotected sex. Detection of HIV in self-collected vaginal swabs from an uninfected participant demonstrated it was possible to measure HIV exposure, but the detection rate was lower than expected.}, }
@article {pmid31093677, year = {2019}, author = {Su, Y and Huang, J and Wang, S and Unger, JM and Arias-Fuenzalida, J and Shi, Y and Li, J and Gao, Y and Shi, W and Wang, X and Peng, R and Xu, F and An, X and Xue, C and Xia, W and Hong, R and Zhong, Y and Lin, Y and Huang, H and Zhang, A and Zhang, L and Cai, L and Zhang, J}, title = {The Effects of Ganglioside-Monosialic Acid in Taxane-induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djz086}, pmid = {31093677}, issn = {1460-2105}, abstract = {BACKGROUND: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients.<br><br>METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomized to receive GM1 (80 mg, Day -1 to Day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity (FACT-Ntx) subscale score after 4-cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by CTCAE Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale (ENS). All statistical tests were two-sided.<br><br>RESULTS: In 183 evaluable patients, GM1 group reported better mean FACT-Ntx subscale scores than patients in the placebo group after 4-cycles of chemotherapy (43.27 [95% CI = 43.05 to 43.49] vs 34.34 [95% CI = 33.78 to 34.89]; mean difference = 8.96 [95% CI = 8.38 to 9.54], P < .001). Grade ≥ 1 peripheral neurotoxicity in CTCAE v4.0 scale was statistically significantly lower in GM1 group (14.3% vs 100.0%, P < .001). Additionally, GM1 group reported a statistically significantly lower incidence of grade ≥ 1 neurotoxicity assessed by ENS sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001).<br><br>CONCLUSIONS: The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after 4-cycles of taxane-containing chemotherapy in patients with breast cancer.}, }
@article {pmid31093519, year = {2019}, author = {Jiang, Y and Girard, EJ and Pakiam, F and Seibel, EJ}, title = {Calibration of fluorescence imaging for tumor surgical margin delineation: multistep registration of fluorescence and histological images.}, journal = {Journal of medical imaging (Bellingham, Wash.)}, volume = {6}, number = {2}, pages = {025005}, doi = {10.1117/1.JMI.6.2.025005}, pmid = {31093519}, issn = {2329-4302}, abstract = {Although a greater extent of tumor resection is important for patients' survival, complete tumor removal, especially tumor margins, remains challenging due to the lack of sensitivity and specificity of current surgical guidance techniques at the margins. Intraoperative fluorescence imaging with targeted fluorophores is promising for tumor margin delineation. To verify the tumor margins detected by the fluorescence images, it is necessary to register fluorescence with histological images, which provide the ground truth for tumor regions. However, current registration methods compare fluorescence images to a single-layer histological slide, which is selected subjectively and represents a single plane of the three-dimensional tumor. A multistep pipeline is established to correlate fluorescence images to stacked histological images, including fluorescence calibration and multistep registration. Multiple histological slices are integrated as a two-dimensional (2-D) tumor map using optical attenuation model and average intensity projection. A BLZ-100-labeled medulloblastoma mouse model is used to test the whole framework. On average, the synthesized 2-D tumor map outperforms the selected best slide as ground truth [Dice similarity coefficient (DSC): 0.582 versus 0.398, with significant differences; mean area under the curve (AUC) of the receiver operating characteristic curve: 88% versus 85.5%] and the randomly selected slide as ground truth (DSC: 0.582 versus 0.396 with significant differences; mean AUC: 88% versus 84.1% with significant differences), which indicates our pipeline is reliable and can be applied to investigate targeted fluorescence probes in tumor margin detection. Following this proposed pipeline, BLZ-100 shows enhancement in both tumor cores and tumor margins (mean target-to-background ratio: 8.64 ± 5.76 and 4.82 ± 2.79 , respectively).}, }
@article {pmid31092901, year = {2019}, author = {Martins, F and Sofiya, L and Sykiotis, GP and Lamine, F and Maillard, M and Fraga, M and Shabafrouz, K and Ribi, C and Cairoli, A and Guex-Crosier, Y and Kuntzer, T and Michielin, O and Peters, S and Coukos, G and Spertini, F and Thompson, JA and Obeid, M}, title = {Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.}, journal = {Nature reviews. Clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41571-019-0218-0}, pmid = {31092901}, issn = {1759-4782}, abstract = {Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.}, }
@article {pmid31092900, year = {2019}, author = {Kansagra, AJ and Frey, NV and Bar, M and Laetsch, TW and Carpenter, PA and Savani, BN and Heslop, HE and Bollard, CM and Komanduri, KV and Gastineau, DA and Chabannon, C and Perales, MA and Hudecek, M and Aljurf, M and Andritsos, L and Barrett, JA and Bachanova, V and Bonini, C and Ghobadi, A and Gill, SI and Hill, JA and Kenderian, S and Kebriaei, P and Nagler, A and Maloney, D and Liu, HD and Shah, NN and Kharfan-Dabaja, MA and Shpall, EJ and Mufti, GJ and Johnston, L and Jacoby, E and Bazarbachi, A and DiPersio, JF and Pavletic, SZ and Porter, DL and Grupp, SA and Sadelain, M and Litzow, MR and Mohty, M and Hashmi, SK}, title = {Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT).}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0451-2}, pmid = {31092900}, issn = {1476-5365}, abstract = {On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.}, }
@article {pmid31091066, year = {2016}, author = {Sundar, H and Radich, J}, title = {Optimizing Patient Care in Chronic Phase Chronic Myelogenous Leukemia: A Multidisciplinary Approach.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {14}, number = {14 Suppl 1}, pages = {S1-S6}, doi = {10.6004/jnccn.2016.0197}, pmid = {31091066}, issn = {1540-1413}, abstract = {Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome arising from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation results in the formation of the BCR-ABL fusion gene. The product of this fusion gene, p210, a protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. Tyrosine kinase inhibitor (TKI) therapy with small molecule inhibitors of BCR-ABL tyrosine kinase has significantly reduced the annual mortality rate among patients with CML. Although most of these patients respond to first-line TKI therapy, the use of TKIs is complicated by the development of resistance or intolerance in some patients, resulting in a loss of response or discontinuation of treatment. Inadequate response to TKI therapy is associated with poor long-term outcome, and the cases of patients with resistance or intolerance should be carefully evaluated for alternative treatment options. This report discusses the challenges associated with the management of newly diagnosed chronic phase CML in a patient with intolerance to multiple TKI therapies.}, }
@article {pmid31013172, year = {2019}, author = {Davis, LE and Bolejack, V and Ryan, CW and Ganjoo, KN and Loggers, ET and Chawla, S and Agulnik, M and Livingston, MB and Reed, D and Keedy, V and Rushing, D and Okuno, S and Reinke, DK and Riedel, RF and Attia, S and Mascarenhas, L and Maki, RG}, title = {Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO1802374}, doi = {10.1200/JCO.18.02374}, pmid = {31013172}, issn = {1527-7755}, abstract = {PURPOSE: SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort.<br><br>PATIENTS AND METHODS: This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS.<br><br>RESULTS: Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation.<br><br>CONCLUSION: The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.}, }
@article {pmid31091400, year = {2019}, author = {Goodman, PJ and Tangen, CM and Thompson, IM}, title = {More on Long-Term Effects of Finasteride on Prostate Cancer Mortality. Reply.}, journal = {The New England journal of medicine}, volume = {380}, number = {20}, pages = {e38}, doi = {10.1056/NEJMc1902700}, pmid = {31091400}, issn = {1533-4406}, }
@article {pmid31089142, year = {2019}, author = {Law, PJ and Timofeeva, M and Fernandez-Rozadilla, C and Broderick, P and Studd, J and Fernandez-Tajes, J and Farrington, S and Svinti, V and Palles, C and Orlando, G and Sud, A and Holroyd, A and Penegar, S and Theodoratou, E and Vaughan-Shaw, P and Campbell, H and Zgaga, L and Hayward, C and Campbell, A and Harris, S and Deary, IJ and Starr, J and Gatcombe, L and Pinna, M and Briggs, S and Martin, L and Jaeger, E and Sharma-Oates, A and East, J and Leedham, S and Arnold, R and Johnstone, E and Wang, H and Kerr, D and Kerr, R and Maughan, T and Kaplan, R and Al-Tassan, N and Palin, K and Hänninen, UA and Cajuso, T and Tanskanen, T and Kondelin, J and Kaasinen, E and Sarin, AP and Eriksson, JG and Rissanen, H and Knekt, P and Pukkala, E and Jousilahti, P and Salomaa, V and Ripatti, S and Palotie, A and Renkonen-Sinisalo, L and Lepistö, A and Böhm, J and Mecklin, JP and Buchanan, DD and Win, AK and Hopper, J and Jenkins, ME and Lindor, NM and Newcomb, PA and Gallinger, S and Duggan, D and Casey, G and Hoffmann, P and Nöthen, MM and Jöckel, KH and Easton, DF and Pharoah, PDP and Peto, J and Canzian, F and Swerdlow, A and Eeles, RA and Kote-Jarai, Z and Muir, K and Pashayan, N and ,  and Harkin, A and Allan, K and McQueen, J and Paul, J and Iveson, T and Saunders, M and Butterbach, K and Chang-Claude, J and Hoffmeister, M and Brenner, H and Kirac, I and Matošević, P and Hofer, P and Brezina, S and Gsur, A and Cheadle, JP and Aaltonen, LA and Tomlinson, I and Houlston, RS and Dunlop, MG}, title = {Association analyses identify 31 new risk loci for colorectal cancer susceptibility.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {2154}, doi = {10.1038/s41467-019-09775-w}, pmid = {31089142}, issn = {2041-1723}, abstract = {Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.}, }
@article {pmid31085765, year = {2019}, author = {Cheng, HH and Sokolova, AO and Schaeffer, EM and Small, EJ and Higano, CS}, title = {Germline and Somatic Mutations in Prostate Cancer for the Clinician.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {17}, number = {5}, pages = {515-521}, doi = {10.6004/jnccn.2019.7307}, pmid = {31085765}, issn = {1540-1413}, abstract = {It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.}, }
@article {pmid31085057, year = {2019}, author = {Heath, EI and Nanus, DM and Slovin, S and Strand, C and Higano, C and Simons, VH and Johnson, C and Kyriakopoulos, CE and Reichert, ZR and Lory, S and George, DJ and Mucci, LA and Marcus, JD and Trendel, JA and Bock, CH}, title = {Prostate Cancer National Summit's Call to Action.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2019.04.002}, pmid = {31085057}, issn = {1938-0682}, }
@article {pmid31084888, year = {2019}, author = {Graves, SS and Gyurkocza, B and Stone, DM and Parker, MH and Abrams, K and Jochum, C and Gallo, S and Saad, M and Johnson, MM and Rosinski, SL and Storb, R}, title = {Development and characterization of a canine-specific anti-CD94 (KLRD-1) monoclonal antibody.}, journal = {Veterinary immunology and immunopathology}, volume = {211}, number = {}, pages = {10-18}, doi = {10.1016/j.vetimm.2019.03.005}, pmid = {31084888}, issn = {1873-2534}, abstract = {Natural killer (NK) cells are non-T, non-B lymphocytes are part of the innate immune system and function without prior activation. The human NK cell surface determinant, CD94, plays a critical role in regulation of NK cell activity as a heterodimer with NKG2 subclasses. Canine NK cells are not as well defined as the human and murine equivalents, due in part to the paucity of reagents specific to cell surface markers. Canines possess NK/NKT cells that have similar morphological characteristics to those found in humans, yet little is known about their functional characteristics nor of cell surface expression of CD94. Here, we describe the development and function of a monoclonal antibody (mAb) to canine (ca) CD94. Freshly isolated canine CD94+ cells were CD3+/-, CD8+/-, CD4-, CD21-, CD5low, NKp46+, and were cytotoxic against a canine target cell line. Anti-caCD94 mAb proved useful in enriching NK/NKT cells from PBMC for expansion on CTAC feeder cells in the presence of IL-2 and IL-15. The cultured cells were highly cytolytic with co-expression of NKp46 and reduced expression of CD3. Transmission electron microscopy revealed expanded CD94+ lymphocytes were morphologically large granular lymphocytes with large electron dense granules. Anti-caCD94 (mAb) can serve to enrich NK/NKT cells from dog peripheral blood for ex vivo expansion for HCT and is a potentially valuable reagent for studying NK/NKT regulation in the dog.}, }
@article {pmid31084545, year = {2019}, author = {Shaw, BE and D'Souza, A and Lee, SJ}, title = {Importance of Assessing Patient-Reported Outcomes With Salvage Autologous Transplantation in Relapsed Multiple Myeloma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO1900865}, doi = {10.1200/JCO.19.00865}, pmid = {31084545}, issn = {1527-7755}, }
@article {pmid31059230, year = {2019}, author = {Paudel, L and Nagana Gowda, GA and Raftery, D}, title = {Extractive Ratio Analysis NMR Spectroscopy for Metabolite Identification in Complex Biological Mixtures.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.9b01235}, pmid = {31059230}, issn = {1520-6882}, abstract = {The complexity of biological mixtures continues to challenge efforts aimed at unknown metabolite identification in the metabolomics field. To address this challenge, we provide a new method to identify related peaks from individual metabolites in complex NMR spectra. Extractive ratio analysis NMR spectroscopy (E-RANSY) builds on our previously described ratio analysis method [ Wei et al. Anal. Chem. 2011 , 83 , 7616 - 7623 ] and exploits the simplified NMR spectra provided by the extraction of metabolites under varied pH conditions. Under such conditions, metabolites from the same biological specimen are extracted differentially, and the resulting NMR spectra exhibit characteristics favorable for unraveling unknown metabolite peaks using ratio analysis. We demonstrate the utility of the E-RANSY method by extracting carboxylic acid containing metabolites from human urine, one of the highly complex biological mixtures encountered in the metabolomics field. E-RANSY performs better than STOCSY and the original RANSY method and offers new avenues to identify unknown metabolites in complex biological mixtures.}, }
@article {pmid31083663, year = {2019}, author = {Foss, EJ and Gatbonton-Schwager, T and Thiesen, AH and Taylor, E and Soriano, R and Lao, U and MacAlpine, DM and Bedalov, A}, title = {Sir2 suppresses transcription-mediated displacement of Mcm2-7 replicative helicases at the ribosomal DNA repeats.}, journal = {PLoS genetics}, volume = {15}, number = {5}, pages = {e1008138}, doi = {10.1371/journal.pgen.1008138}, pmid = {31083663}, issn = {1553-7404}, abstract = {Repetitive DNA sequences within eukaryotic heterochromatin are poorly transcribed and replicate late in S-phase. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). Despite the widespread association between transcription and replication, it remains unclear how transcription might impinge on replication, or vice versa. Here we show that, when silencing of an RNA polymerase II (RNA Pol II)-transcribed non-coding RNA at the rDNA is disrupted by SIR2 deletion, RNA polymerase pushes and thereby relocalizes replicative Mcm2-7 helicases away from their loading sites to an adjacent region with low nucleosome occupancy, and this relocalization is associated with increased rDNA origin efficiency. Our results suggest a model in which two of the major defining features of heterochromatin, transcriptional silencing and late replication, are mechanistically linked through suppression of polymerase-mediated displacement of replication initiation complexes.}, }
@article {pmid31082669, year = {2019}, author = {Morris, MJ and Loriot, Y and Sweeney, CJ and Fizazi, K and Ryan, CJ and Shevrin, DH and Antonarakis, ES and Pandit-Taskar, N and Deandreis, D and Jacene, HA and Vesselle, H and Petrenciuc, O and Lu, C and Carrasquillo, JA and Higano, CS}, title = {Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {114}, number = {}, pages = {107-116}, doi = {10.1016/j.ejca.2019.04.007}, pmid = {31082669}, issn = {1879-0852}, abstract = {PURPOSE: Radium 223 dichloride (radium-223) is an alpha particle-emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective.<br><br>PATIENTS AND METHODS: Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers.<br><br>RESULTS: Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers.<br><br>CONCLUSIONS: Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.}, }
@article {pmid31079354, year = {2019}, author = {Vaughn, JE and Shankaran, V and Walter, RB}, title = {Trends in Clinical Benefits and Costs of Novel Therapeutics in AML: at What Price Does Progress Come?.}, journal = {Current hematologic malignancy reports}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11899-019-00510-2}, pmid = {31079354}, issn = {1558-822X}, abstract = {PURPOSE OF REVIEW: Since 2017, eight novel agents have been approved for the treatment of acute myeloid leukemia (AML) in the USA. Here, we review the clinical benefits and costs associated with these drugs.<br><br>RECENT FINDINGS: For some of the newly-approved drugs, clinical benefit has been documented in randomized trials. Others received accelerated approval based on surrogate endpoints in early phase trials. All, however, carry significant costs and toxicities. Cost-effectiveness analyses are so far only available for midostaurin, CPX-351, and gemtuzumab ozogamicin. Recently approved drugs for AML have varying levels of evidence for clinical effectiveness and because of associated high costs may further increase the overall economic burden of AML care. This issue is complex and whether novel AML drugs will cost-effective will depend on multiple factors, including their ability to improve survival and quality of life while simultaneously reducing the costs of healthcare resource utilization.}, }
@article {pmid31078451, year = {2019}, author = {Janes, H and Donnell, D and Gilbert, PB and Brown, ER and Nason, M}, title = {Taking stock of the present and looking ahead: envisioning challenges in the design of future HIV prevention efficacy trials.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(19)30133-X}, pmid = {31078451}, issn = {2352-3018}, abstract = {Despite the recent success of antiretrovirals for HIV prevention, additional, more effective, or more acceptable biomedical interventions will ultimately be needed to end the HIV epidemic. Designing clinical trials to evaluate the efficacy of new products that reduce HIV infection risk is challenging because of the existence of highly effective interventions to prevent HIV. However, the implementation of these interventions is uneven, and the fact that multiple HIV prevention efficacy trials are currently evaluating new products means the field confronts uncertainty in the emerging standard of prevention. In this Viewpoint, we take stock of the current state of HIV prevention, and subsequently discuss the key challenges in designing future trials to evaluate the next generation of HIV prevention products. We also highlight gaps in the knowledge base that need to be addressed to advance the design of research. Future trials are tenable, even in the context of existing and effective interventions, and should involve careful statistical approaches and multidisciplinary collaborative design.}, }
@article {pmid31077105, year = {2019}, author = {Simoni, Y and Fehlings, M and Newell, EW}, title = {Multiplex MHC Class I Tetramer Combined with Intranuclear Staining by Mass Cytometry.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1989}, number = {}, pages = {147-158}, doi = {10.1007/978-1-4939-9454-0_11}, pmid = {31077105}, issn = {1940-6029}, abstract = {Antigen-specific CD8+ T cells play a crucial role in the host protective immune response against viruses, tumors, and other diseases. Major histocompatibility complex (MHC) class I tetramers allow for a direct detection of such antigen-specific CD8+ T cells. Using mass cytometry together with multiplex MHC class I tetramer staining, we are able to screen more than 1000 different antigen candidates simultaneously across tissues in health and disease, while retaining the possibility to deliver an in-depth characterization of antigen-specific CD8+ T cells and associated phenotypes. Here we describe the method for a MHC class I tetramer multiplexing approach together with intracellular antibody staining for a parallel phenotypic cell characterization using mass cytometry in human specimens.}, }
@article {pmid31076446, year = {2019}, author = {Garg, S and Reyes-Palomares, A and He, L and Bergeron, A and Lavallée, VP and Lemieux, S and Gendron, P and Rohde, C and Xia, J and Jagdhane, P and Müller-Tidow, C and Lipka, DB and Imren, S and Humphries, RK and Waskow, C and Vick, B and Jeremias, I and Richard-Carpentier, G and Hébert, J and Sauvageau, G and Zaugg, J and Barabé, F and Pabst, C}, title = {Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2018862383}, pmid = {31076446}, issn = {1528-0020}, abstract = {FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon co-occurrence. Here we show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia specific GPR56highCD34low immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC marker GPR56 allowed isolation of triple mutated from DNMT3A/NPM1 double-mutated subclones. Moreover, in DNMT3A R882 mutated patients, CpG hypomethylation at the HLF transcription start site correlated with high HLF mRNA expression, which was itself associated with poor survival. Loss of HLF 3 via CRISPR/Cas9 significantly reduced the CD34+GPR56+ LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when re-introduced in culture. RNA-sequencing (RNA-Seq) of primary human triple-mutated AML cells after shRNA mediated HLF knockdown revealed the NOTCH target Hairy And Enhancer Of Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel targets of HLF potentially mediating these effects. Overall our data establish HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.}, }
@article {pmid31074843, year = {2019}, author = {Hwang, V and Mendez, E and Chow, LQM and Futran, ND and Andersen, P and Li, R and Divi, V and Rodriguez, CP}, title = {Wound Complications in Head and Neck Squamous Cell Carcinomas After Anti-PD-1 Therapy.}, journal = {The Laryngoscope}, volume = {}, number = {}, pages = {}, doi = {10.1002/lary.27902}, pmid = {31074843}, issn = {1531-4995}, abstract = {Immune checkpoint inhibitors have demonstrated activity in recurrent/metastatic head and neck squamous cell cancer, but less is known regarding their long-term sequelae. We describe four patients who, after complete responses to anti-PD-1 therapy, developed complications requiring surgical intervention. Patient 1 is a 57-year-old female whose marked tumor regression exposed some mandibular hardware. Patient 2 is a 39-year-old male who developed an ulcerated buccal lesion with exposed mandible. Patient 3 is a 66-year-old male with craniofacial osteoradionecrosis. Patient 4 is a 71-year-old male who developed an exposed and fractured mandible. All patients successfully underwent surgical intervention and remain disease free. Laryngoscope, 2019.}, }
@article {pmid31073153, year = {2019}, author = {Ustun, C and Le-Rademacher, J and Wang, HL and Othus, M and Sun, Z and Major, B and Zhang, MJ and Storrick, E and Lafky, JM and Chow, S and Mrózek, K and Attar, EC and Nand, S and Bloomfield, CD and Cripe, LD and Tallman, MS and Appelbaum, F and Larson, RA and Marcucci, G and Roboz, GJ and Uy, GL and Stone, RM and Jatoi, A and Shea, TC and de Lima, M and Foran, JM and Sandmaier, BM and Litzow, MR and Erba, HP and Hurria, A and Weisdorf, DJ and Artz, AS}, title = {Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-019-0477-x}, pmid = {31073153}, issn = {1476-5551}, abstract = {The preferred post-remission therapy for older patients with acute myeloid leukemia (AML) in first complete remission (CR1) remains uncertain. In this retrospective, multicenter study, we compared the outcomes for older AML patients (age 60-77 years) receiving allogeneic hematopoietic cell transplantation (alloHCT) (n = 431) with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy (CT) consolidation trials (n = 211). AlloHCT patients were younger (median age: 64.2 versus 67.9 years, p < 0.001), but more frequently had high-risk AML (high WBC, secondary AML, and unfavorable cytogenetics). Overall survival (OS) was worse in alloHCT during the first 9 months after CR1 (HR = 1.52, p = 0.02), but was significantly better thereafter (HR = 0.53, p < 0.0001) relative to CT. Treatment-related mortality (TRM) following HCT was worse in the first 9 months (HR = 2.8, 95% CI: 1.5-5.2, p = 0.0009), while post-HCT relapse was significantly less frequent beyond 9 months (HR = 0.42, 95% CI: 0.29-0.61, p < 0.0001). Despite higher early TRM, alloHCT recipients had superior long-term OS [29% (24-34%) versus CT 13.8% (9-21%) at 5 years]. Although this is a retrospective analysis with potential biases, it indicates that alloHCT led to heightened early risks from TRM, yet reduced relapse and superior long-term survival relative to CT in older AML patients in CR1.}, }
@article {pmid31072965, year = {2019}, author = {Panaite, L and Shadman, M}, title = {Concurrent diagnosis of classical Hodgkin lymphoma and Langerhans cell histiocytosis.}, journal = {Blood}, volume = {133}, number = {19}, pages = {2109}, doi = {10.1182/blood-2019-01-891937}, pmid = {31072965}, issn = {1528-0020}, }
@article {pmid31071066, year = {2017}, author = {Coronato-Nunes, B and Calegar, DA and Monteiro, KJL and Hubert-Jaeger, L and Reis, ERC and Xavier, SCDC and Carpp, LN and Lima, MM and Bóia, MN and Carvalho-Costa, FA}, title = {Giardia intestinalis infection associated with malnutrition in children living in northeastern Brazil.}, journal = {Journal of infection in developing countries}, volume = {11}, number = {7}, pages = {563-570}, doi = {10.3855/jidc.8410}, pmid = {31071066}, issn = {1972-2680}, abstract = {INTRODUCTION: The present study aimed to determine the prevalence and factors associated with Giardia intestinalis infection, verifying its impact on the nutritional status of children in northeastern Brazil.<br><br>METHODOLOGY: A cross-sectional study was conducted to obtain parasitological, sociodemographic, and anthropometric data in two municipalities in the states of Piauí and Ceará, northeastern Brazil.<br><br>RESULTS: Prevalence of giardiasis was 55/511 (10.8%). G. intestinalis was more frequent in people living in poverty (30/209 [14.4%], p = 0.041), performing open evacuation (26/173 [15%], p = 0.034), and drinking rainwater stored in cisterns (9/56 [16.1%], p = 0.005). The proportion of stunting and being underweight in children infected with G. intestinalis was significantly higher than that in uninfected children (5/23 [21.7%] vs. 10/179 [5.6%], p = 0.017, OR = 4.69, 95% confidence interval [CI] = 1.44-15.25 and 5/23 [21.7%] vs. 13/179 [7.3%], p = 0.038, OR = 3.54, 95% CI = 1.13-11.09, respectively). Infection with G. intestinalis remained significantly associated with stunting and being underweight after adjustment for poverty, municipality, sex, and age in a logistic regression multivariate model.<br><br>CONCLUSIONS: In rural areas in northeastern Brazil, giardiasis has acquired great public health importance in the soil-transmitted helminths control era, impacting the nutritional status of children and requiring new approaches to diagnosis and treatment and translational research that could generate applicable solutions at the community level.}, }
@article {pmid31070753, year = {2019}, author = {Kummer, K and Jensen, PN and Kratz, M and Lemaitre, RN and Howard, BV and Cole, SA and Fretts, AM}, title = {Full-Fat Dairy Food Intake is Associated with a Lower Risk of Incident Diabetes Among American Indians with Low Total Dairy Food Intake.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/jn/nxz058}, pmid = {31070753}, issn = {1541-6100}, abstract = {BACKGROUND: Diet plays a key role in development of diabetes, and there has been recent interest in better understanding the association of dairy food intake with diabetes.<br><br>OBJECTIVE: This study examined the associations of full-fat and low-fat dairy food intake with incident diabetes among American Indians-a population with a high burden of diabetes.<br><br>METHODS: The study included participants from the Strong Heart Family Study (SHFS), a family-based study of cardiovascular disease in American Indians, free of diabetes at baseline (2001-2003) (n = 1623). Participants were 14-86-y-old at baseline and 60.8% were female. Dairy food intake was assessed using a Block food frequency questionnaire. Incident diabetes was defined using American Diabetes Association criteria. Parametric survival models with a Weibull distribution were used to evaluate the associations of full-fat and low-fat dairy food intake with incident diabetes. Serving sizes were defined as 250 mL for milk and 42.5 g for cheese.<br><br>RESULTS: We identified 277 cases of diabetes during a mean follow-up of 11 y. Reported intake of dairy foods was low [median full-fat dairy food intake: 0.11 serving/1000 kcal; median low-fat dairy food intake: 0.03 serving/1000 kcal]. Participants who reported the highest full-fat dairy food intake had a lower risk of diabetes compared to those who reported the lowest full-fat food dairy intake [HR (95% CI): 0.79 (0.59, 1.06); P-trend = 0.03, comparing extreme tertiles, after adjustment for age, sex, site, physical activity, education, smoking, diet quality, and low-fat dairy food intake]. Low-fat dairy food intake was not associated with diabetes.<br><br>CONCLUSIONS: American Indians who participated in the SHFS reported low dairy food intake. Participants who reported higher full-fat dairy food intake had a lower risk of diabetes than participants who reported lower intake. These findings may be of interest to populations with low dairy food intake.}, }
@article {pmid31050286, year = {2019}, author = {Qin, Y and Wu, L and Wang, J and Han, R and Shen, J and Wang, J and Xu, S and Paguirigan, AL and Smith, JL and Radich, JP and Chiu, DT}, title = {A Fluorescence-Activated Single-Droplet Dispenser for High Accuracy Single-Droplet and Single-Cell Sorting and Dispensing.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.9b01017}, pmid = {31050286}, issn = {1520-6882}, abstract = {The ability to sort and dispense droplets accurately is essential to droplet-based single-cell analysis. Here, we describe a fluorescence-activated single-droplet dispenser (FASD) that is analogous to a conventional fluorescence-activated cell sorter, but sorts droplets containing single cells within an oil emulsion. The FASD system uses cytometric detection and electrohydrodynamic actuation-based single-droplet manipulation, allowing droplet isolation and dispensing with high efficiency and accuracy. The system is compatible with multiwell plates and can be integrated with existing microfluidic devices and large-scale screening systems. By enabling sorting based on single-cell reactions such as PCR, this platform will help expand the basis of cell sorting from mainly protein biomarkers to nucleic acid sequences and secreted biomolecules.}, }
@article {pmid31067357, year = {2019}, author = {Tonorezos, ES and Ford, JS and Wang, L and Ness, KK and Yasui, Y and Leisenring, W and Sklar, CA and Robison, LL and Oeffinger, KC and Nathan, PC and Armstrong, GT and Krull, K and Jones, LW}, title = {Impact of exercise on psychological burden in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.32173}, pmid = {31067357}, issn = {1097-0142}, support = {//American Lebanese-Syrian Associated Charities/ ; //AKTIV Against Cancer/ ; CA55727, CA21765//National Cancer Institute/ ; //Kavli Trust/ ; }, abstract = {BACKGROUND: Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown.<br><br>METHODS: In total, 6199 participants in the Childhood Cancer Survivor Study (median age, 34.3 years [range, 22.0-54.0 years]; median age at diagnosis, 10.0 years [range, 0-21.0 years]) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median of 7.8 years (range, 0.1-10.0 years) later and were defined as: symptom level above the 90th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory-18; cancer-related pain; cognitive impairment using a validated self-report neurocognitive questionnaire; or poor health-related quality of life. Log-binomial regression estimated associations between exercise (metabolic equivalent [MET]-hours per week-1) and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions.<br><br>RESULTS: The prevalence of depression at follow-up was 11.4% (95% CI, 10.6%-12.3%), anxiety 7.4% (95% CI, 6.7%-8.2%) and somatization 13.9% (95% CI, 13.0%-14.9%). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio for depression was 0.87 (95% CI, 0.72-1.05) for 3 to 6 MET hours per week-1 , 0.76 (95% CI, 0.62-0.94) for 9 to 12 MET-hours per week-1 , and 0.74 (95% CI, 0.58-0.95) for 15 to 21 MET-hours per week-1 . Compared with 0 MET hours per week-1 , 15 to 21 MET-hours per week-1 were associated with an adjusted prevalence ratio of 0.79 (95% CI, 0.62-1.00) for somatization. Vigorous exercise also was associated with less impairment in the physical functioning, general health and vitality (Ptrend < .001), emotional role limitations (Ptrend = .02), and mental health (Ptrend = .02) domains as well as higher cognitive function in the domains of task completion, organization, and working memory (P < .05 for all), but not in the domain of cancer pain.<br><br>CONCLUSIONS: Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors.}, }
@article {pmid31067356, year = {2019}, author = {Mascarenhas, L and Lyden, ER and Breitfeld, PP and Walterhouse, DO and Donaldson, SS and Rodeberg, DA and Parham, DM and Anderson, JR and Meyer, WH and Hawkins, DS}, title = {Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.32122}, pmid = {31067356}, issn = {1097-0142}, support = {U10CA98413//National Cancer Institute/ ; U10CA180886//National Cancer Institute/ ; U10CA180899//National Cancer Institute/ ; U10CA98543//National Cancer Institute/ ; }, abstract = {BACKGROUND: The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse.<br><br>METHODS: Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31 weeks of the same multi-agent chemotherapy without VI and TPZ.<br><br>RESULTS: One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities.<br><br>CONCLUSIONS: Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy.}, }
@article {pmid31066029, year = {2019}, author = {Zhou, J and Han, J and Nutescu, EA and Galanter, WL and Walton, SM and Gordeuk, VR and Saraf, SL and Calip, GS}, title = {Type 2 diabetes in adults with sickle cell disease: can we dive deeper? Response to Skinner et al.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.15949}, pmid = {31066029}, issn = {1365-2141}, }
@article {pmid31064850, year = {2019}, author = {Gordon, JA and Noble, JW and Midha, A and Derakhshan, F and Wang, G and Adomat, HH and Tomlinson Guns, ES and Lin, YY and Ren, S and Collins, CC and Nelson, PS and Morrisey, C and Wasan, KM and Cox, ME}, title = {Upregulation of Scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-18-2529}, pmid = {31064850}, issn = {1538-7445}, abstract = {Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer (PCa) initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary PCa. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in PCa relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice-variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small molecule SR-BI antagonist Block Lipid Transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and non-steroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.}, }
@article {pmid31064833, year = {2019}, author = {Porotto, M and Ferren, M and Chen, YW and Siu, Y and Makhsous, N and Rima, B and Briese, T and Greninger, AL and Snoeck, HW and Moscona, A}, title = {Authentic Modeling of Human Respiratory Virus Infection in Human Pluripotent Stem Cell-Derived Lung Organoids.}, journal = {mBio}, volume = {10}, number = {3}, pages = {}, doi = {10.1128/mBio.00723-19}, pmid = {31064833}, issn = {2150-7511}, abstract = {Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host.IMPORTANCE Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.}, }
@article {pmid31061986, year = {2018}, author = {Prentice, RL and Huang, Y}, title = {RESPONSE TO DISCUSSION OF 'NUTRITIONAL EPIDEMIOLOGY METHODS AND RELATED STATISTICAL CHALLENGES AND OPPORTUNITIES'.}, journal = {Statistical theory and related fields}, volume = {2}, number = {1}, pages = {23-26}, doi = {10.1080/24754269.2018.1493633}, pmid = {31061986}, issn = {2475-4277}, }
@article {pmid31062632, year = {2019}, author = {Deng, N and Sun, Y and Liu, M and He, Q and Wang, L and Zhang, Y and Sun, W and Lei, N and Liu, Y and Luo, Y and Shen, F}, title = {Alpha-momorcharin regulates cytokine expression and induces apoptosis in monocytes.}, journal = {Immunopharmacology and immunotoxicology}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/08923973.2019.1610430}, pmid = {31062632}, issn = {1532-2513}, abstract = {BACKGROUND AND AIM: Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein (RIP) that is purified from Momordica charantia. Despite its strong antitumor activities, α-MMC exerts the undesirable immunotoxicity effects of hypersensitivity or immunosuppression. Since α-MMC is a plant protein, its application in vivo can easily induce hypersensitivity, but its immunosuppressive mechanism is still unclear.<br><br>MATERIALS AND METHODS: The toxicity of α-MMC to peripheral blood cells and the cytokine expression in peripheral blood mononuclear cells (PBMCs) and spleen immune cells were measured in rats. For further confirmation, experiments were performed in vitro with the mononuclear cell line THP-1, B lymphocyte cell line WIL2-S and T lymphocyte cell line Jurkat.<br><br>RESULTS: High doses of α-MMC (3.0 mg/kg) resulted in weight loss in rats, a decreased percentage of monocytes, and increased percentages of eosinophils and basophils. Both high-dose and low-dose (1.0 mg/kg) α-MMC inhibited cytokine expression in PBMCs and increased cytokine expression in spleen T cells. In in vitro, α-MMC mainly acted on THP-1 cells, with effects including high dose-induced apoptosis and low dose-induced regulation of inhibitory cytokine expression.<br><br>CONCLUSIONS: The action of α-MMC on immune cells mainly affects monocytes, thereby eliciting its immunosuppressive effect. Its mode of action is to guide functional immunosuppressive regulation at low doses and induce apoptosis at high doses. As the monocytes would be recruited into tumor tissues and are polarized into tumor-associated macrophages, the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes may be an important mechanism of its antitumor effects.}, }
@article {pmid31061142, year = {2019}, author = {Martínez, LE and O'Brien, VP and Leverich, CK and Knoblaugh, SE and Salama, NR}, title = {Non-helical Helicobacter pylori show altered gland colonization and elicit less gastric pathology during chronic infection.}, journal = {Infection and immunity}, volume = {}, number = {}, pages = {}, doi = {10.1128/IAI.00904-18}, pmid = {31061142}, issn = {1098-5522}, abstract = {Half of all humans harbor Helicobacter pylori in their stomachs. Helical cell shape is thought to facilitate H. pylori's ability to bore into the protective mucus layer in a corkscrew-like motion, thus enhancing colonization of the stomach. H. pylori cell shape mutants show impaired colonization of the mouse stomach, highlighting the importance of cell shape in infection. To gain a deeper understanding of how helical cell morphology promotes host colonization by H. pylori, we used 3D-confocal microscopy to visualize the clinical isolate PMSS1 and an isogenic straight rod mutant (Δcsd6) within thick longitudinal mouse stomach sections and performed volumetric image analysis to quantify the number of bacteria residing within corpus and antral glands in addition to measuring total colony forming units (CFU). We found that straight rods show attenuation during acute colonization of the stomach (one day or one week post-infection) as measured by total CFU. Our quantitative imaging revealed that wild-type bacteria extensively colonized antral glands at one week post-infection, while csd6 mutants showed variable colonization of the antrum at this timepoint. During chronic infection (one or three months post-infection), total CFU were highly variable, but similar for wild-type and straight rods. Both wild-type and straight rods persisted and expanded in corpus glands during chronic infection. However, the straight rods showed reduced inflammation and disease progression. Thus, helical cell shape contributes to tissue interactions that promote inflammation during chronic infection, in addition to facilitating niche acquisition during acute infection.}, }
@article {pmid31061129, year = {2019}, author = {Abida, W and Cyrta, J and Heller, G and Prandi, D and Armenia, J and Coleman, I and Cieslik, M and Benelli, M and Robinson, D and Van Allen, EM and Sboner, A and Fedrizzi, T and Mosquera, JM and Robinson, BD and De Sarkar, N and Kunju, LP and Tomlins, S and Wu, YM and Nava Rodrigues, D and Loda, M and Gopalan, A and Reuter, VE and Pritchard, CC and Mateo, J and Bianchini, D and Miranda, S and Carreira, S and Rescigno, P and Filipenko, J and Vinson, J and Montgomery, RB and Beltran, H and Heath, EI and Scher, HI and Kantoff, PW and Taplin, ME and Schultz, N and deBono, JS and Demichelis, F and Nelson, PS and Rubin, MA and Chinnaiyan, AM and Sawyers, CL}, title = {Genomic correlates of clinical outcome in advanced prostate cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {}, number = {}, pages = {}, doi = {10.1073/pnas.1902651116}, pmid = {31061129}, issn = {1091-6490}, abstract = {Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.}, }
@article {pmid31060607, year = {2019}, author = {Green, D and Kharono, B and Tordoff, DM and Akullian, A and Bershteyn, A and Morrison, M and Garnett, G and Duerr, A and Drain, P}, title = {Demographic and risk group heterogeneity across the UNAIDS 90-90-90 targets: a systematic review and meta-analysis protocol.}, journal = {Systematic reviews}, volume = {8}, number = {1}, pages = {110}, doi = {10.1186/s13643-019-1024-6}, pmid = {31060607}, issn = {2046-4053}, abstract = {BACKGROUND: Despite policies for universal HIV testing and treatment (UTT) regardless of CD4 count, there are still 1.8 million new HIV infections and 1 million AIDS-related deaths annually. The UNAIDS 90-90-90 goals target suppression of HIV viral load in 73% of all HIV-infected people worldwide by 2030. However, achieving these targets may not lead to expected reductions in HIV incidence if the remaining 27% (persons with unsuppressed viral load) are the drivers of HIV transmission through high-risk behaviors. We aim to conduct a systematic review and meta-analysis to understand the demographics, mobility, geographic distribution, and risk profile of adults who are not virologically suppressed in sub-Saharan Africa in the era of UTT.<br><br>METHODS: We will review the published and grey literature for study sources that contain data on demographic and behavioral strata of virologically suppressed and unsuppressed populations since 2014. We will search PubMed and Embase using four sets of search terms tailored to identify characteristics associated with virological suppression (or lack thereof) and each of the individual 90-90-90 goals. Record screening and data abstraction will be done independently and in duplicate. We will use random effects meta-regression analyses to estimate the distribution of demographic and risk features among groups not virologically suppressed and for each individual 90-90-90 goal.<br><br>DISCUSSION: The results of our review will help elucidate factors associated with failure to achieve virological suppression in sub-Saharan Africa, as well as factors associated with failure to achieve each of the 90-90-90 goals. These data will help quantify the population-level effects of current HIV treatment interventions to improve strategies for maximizing virological suppression and ending the HIV epidemic.<br><br>PROSPERO CRD42018089505 .}, }
@article {pmid31058977, year = {2019}, author = {Dropulic, LK and Oestreich, MC and Pietz, HL and Laing, KJ and Hunsberger, S and Lumbard, K and Garabedian, D and Turk, SP and Chen, A and Hornung, RL and Seshadri, C and Smith, MT and Hosken, NA and Phogat, S and Chang, LJ and Koelle, DM and Wang, K and Cohen, JI}, title = {A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus 2 Vaccine, HSV529, in Adults With or Without HSV Infection.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz225}, pmid = {31058977}, issn = {1537-6613}, abstract = {BACKGROUND: Herpes simplex virus 2 (HSV2) causes genital herpes in over 400 million persons worldwide.<br><br>METHODS: We conducted a randomized, double-blind, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults each enrolled in three serogroups, HSV1 /HSV2 , HSV1 /HSV2 , and HSV1 /HSV2 , received vaccine or placebo at 0, 1, and 6 months. The primary endpoint was the frequency of solicited local and systemic reactions to vaccination.<br><br>RESULTS: Eighty-nine percent of vaccinees experienced mild to moderate solicited injection site reactions compared with 47% of placebo recipients (p = 0.006, 95% CI 0.129, 0.676). Sixty-four percent of vaccinees experienced systemic reactions compared with 53% of placebo recipients (p = 0.44, 95%CI -0.179, 0.402). Seventy-eight percent of HSV1 /HSV2 vaccine recipients had > 4-fold rises in neutralizing antibody titer after three doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36% 46%, and 27%, of HSV1 /HSV2 , HSV1 /HSV2 , and HSV1 /HSV2 participants, respectively, one month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants in each group, respectively.<br><br>CONCLUSIONS: HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV seronegative vaccinees.Clinical Trials Registration. NCT01915212.}, }
@article {pmid31058542, year = {2019}, author = {Goulart, BHL and Silgard, ET and Baik, CS and Bansal, A and Sun, Q and Durbin, EB and Hands, I and Shah, D and Arnold, SM and Ramsey, SD and Kavuluru, R and Schwartz, SM}, title = {Validity of Natural Language Processing for Ascertainment of EGFR and ALK Test Results in SEER Cases of Stage IV Non-Small-Cell Lung Cancer.}, journal = {JCO clinical cancer informatics}, volume = {3}, number = {}, pages = {1-15}, doi = {10.1200/CCI.18.00098}, pmid = {31058542}, issn = {2473-4276}, abstract = {PURPOSE: SEER registries do not report results of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutation tests. To facilitate population-based research in molecularly defined subgroups of non-small-cell lung cancer (NSCLC), we assessed the validity of natural language processing (NLP) for the ascertainment of EGFR and ALK testing from electronic pathology (e-path) reports of NSCLC cases included in two SEER registries: the Cancer Surveillance System (CSS) and the Kentucky Cancer Registry (KCR).<br><br>METHODS: We obtained 4,278 e-path reports from 1,634 patients who were diagnosed with stage IV nonsquamous NSCLC from September 1, 2011, to December 31, 2013, included in CSS. We used 855 CSS reports to train NLP systems for the ascertainment of EGFR and ALK test status (reported v not reported) and test results (positive v negative). We assessed sensitivity, specificity, and positive and negative predictive values in an internal validation sample of 3,423 CSS e-path reports and repeated the analysis in an external sample of 1,041 e-path reports from 565 KCR patients. Two oncologists manually reviewed all e-path reports to generate gold-standard data sets.<br><br>RESULTS: NLP systems yielded internal validity metrics that ranged from 0.95 to 1.00 for EGFR and ALK test status and results in CSS e-path reports. NLP showed high internal accuracy for the ascertainment of EGFR and ALK in CSS patients-F scores of 0.95 and 0.96, respectively. In the external validation analysis, NLP yielded metrics that ranged from 0.02 to 0.96 in KCR reports and F scores of 0.70 and 0.72, respectively, in KCR patients.<br><br>CONCLUSION: NLP is an internally valid method for the ascertainment of EGFR and ALK test information from e-path reports available in SEER registries, but future work is necessary to increase NLP external validity.}, }
@article {pmid31056762, year = {2019}, author = {Chow, VA and Gopal, AK and Maloney, DG and Turtle, CJ and Smith, SD and Ujjani, CS and Shadman, M and Cassaday, RD and Till, BG and Tseng, YD and Warren, EH and Shustov, AR and Menon, MP and Bhark, S and Acharya, UH and Mullane, E and Hannan, LM and Voutsinas, JM and Gooley, TA and Lynch, RC}, title = {Outcomes of Patients with Large B-Cell Lymphomas and Progressive Disease Following CD19-Specific CAR T-Cell Therapy.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.25505}, pmid = {31056762}, issn = {1096-8652}, }
@article {pmid31056688, year = {2019}, author = {Ortiz, JR and Sugimoto, JD and Neuzil, KM and Halloran, ME and Victor, JC}, title = {Reply to Skowronski and De Serres.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciz352}, pmid = {31056688}, issn = {1537-6591}, }
@article {pmid31056675, year = {2019}, author = {Matrajt, L and Halloran, ME and Antia, R}, title = {Successes and failures of the live-attenuated influenza vaccine: can we do better?.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciz358}, pmid = {31056675}, issn = {1537-6591}, abstract = {BACKGROUND: The effectiveness of the live attenuated influenza vaccine (LAIV) can vary widely, ranging from 0 - 50%. The reasons for these discrepancies remain largely unclear.<br><br>METHODS: We use mathematical models to explore how the efficacy of LAIV is affected by the degree of mismatch with the currently circulating influenza strain and interference with pre-existing immunity. The models incorporate three key antigenic distances: the distances between the vaccine strain, pre-existing immunity, and the challenge strain.<br><br>RESULTS: Our models show that a LAIV that is matched with the currently circulating strain is likely to have only modest efficacy. Our results suggest that the efficacy of the vaccine would be increased (optimized) if, rather than being matched to the circulating strain, it is antigenically slightly further from pre-existing immunity compared with the circulating strain. The models also suggest two regimes in which LAIV that is matched to circulating strains may be protective: in children before they have built immunity to circulating strains, and in response to novel strains (such as antigenic shifts) which are at substantial antigenic distance from previously circulating strains. We provide an explanation for the variation in vaccine effectiveness between studies and countries of vaccine effectiveness observed during the 2014-15 influenza season.<br><br>CONCLUSIONS: LAIV is offered to children across the world, however, its effectiveness significantly varies between studies. Here, we propose a mechanistic explanation to understand these differences. We further propose a way to select the LAIV strain that would have a higher chance of being protective.}, }
@article {pmid31055949, year = {2019}, author = {Guthrie, KA and Caan, B and Diem, S and Ensrud, KE and Greaves, SR and Larson, JC and Newton, KM and Reed, SD and LaCroix, AZ}, title = {Facebook advertising for recruitment of midlife women with bothersome vaginal symptoms: A pilot study.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {1740774519846862}, doi = {10.1177/1740774519846862}, pmid = {31055949}, issn = {1740-7753}, abstract = {BACKGROUND: The MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) Network recruited into five randomized clinical trials (n = 100-350) through mass mailings. The fifth trial tested two interventions for postmenopausal vulvovaginal symptoms (itching, pain, irritation, dryness, or pain with sex) and thus required a high level of sensitivity to privacy concerns. For this trial, in addition to mass mailings we pilot tested a social media recruitment approach. We aimed to evaluate the feasibility of recruiting healthy midlife women with bothersome vulvovaginal symptoms to participate in the Vaginal Health Trial through Facebook advertising.<br><br>METHODS: As part of a larger advertising campaign that enrolled 302 postmenopausal women for the 12-week randomized, double-blind, placebo-controlled Vaginal Health Trial from April 2016 to February 2017, Facebook advertising was used to recruit 25 participants. The target population for recruitment by mailings and by Facebook ads included women aged 50-70 years and living within 20 miles of study sites in Minneapolis, MN and Seattle, WA. Design of recruitment letters and Facebook advertisements was informed by focus group feedback. Facebook ads were displayed in the &quot;newsfeed&quot; of targeted users and included a link to the study website. Response rates and costs are described for both online ads and mailing.<br><br>RESULTS: Facebook ads ran in Minneapolis for 28 days and in Seattle for 15 days, with ads posted and removed from the site as needed based on clinic flow and a set budget limit. Our estimated Facebook advertising reach was over 200,000 women; 461 women responded and 25 were enrolled at a cost of US$14,813. The response rate per estimated reach was 0.22%; costs were US$32 per response and US$593 per randomized participant. The social media recruitment results varied by site, showing greater effectiveness in Seattle than in Minneapolis. We mailed 277,000 recruitment letters; 2166 women responded and 277 were randomized at a cost of US$98,682. The response rate per letter sent was 0.78%; costs were US$46 per response and US$356 per randomized participant. Results varied little across sites.<br><br>CONCLUSION: Recruitment to a clinical trial testing interventions for postmenopausal vaginal symptoms is feasible through social media advertising. Variability in observed effectiveness and costs may reflect the small sample sizes and limited budget of the pilot recruitment study.}, }
@article {pmid31055637, year = {2019}, author = {Swygert, SG and Tsukiyama, T}, title = {Unraveling quiescence-specific repressive chromatin domains.}, journal = {Current genetics}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00294-019-00985-9}, pmid = {31055637}, issn = {1432-0983}, support = {F32GM120962//Foundation for the National Institutes of Health/ ; T32CA009657//Foundation for the National Institutes of Health/ ; R01GM111428//Foundation for the National Institutes of Health/ ; }, abstract = {Quiescence is a highly conserved inactive life stage in which the cell reversibly exits the cell cycle in response to external cues. Quiescence is essential for diverse processes such as the maintenance of adult stem cell stores, stress resistance, and longevity, and its misregulation has been implicated in cancer. Although the non-cycling nature of quiescent cells has made obtaining sufficient quantities of quiescent cells for study difficult, the development of a Saccharomyces cerevisiae model of quiescence has recently enabled detailed investigation into mechanisms underlying the quiescent state. Like their metazoan counterparts, quiescent budding yeast exhibit widespread transcriptional silencing and dramatic chromatin condensation. We have recently found that the structural maintenance of chromosomes (SMC) complex condensin binds throughout the quiescent budding yeast genome and induces the formation of large chromatin loop domains. In the absence of condensin, quiescent cell chromatin is decondensed and transcription is de-repressed. Here, we briefly discuss our findings in the larger context of the genome organization field.}, }
@article {pmid31053707, year = {2019}, author = {Niehaus, L and Boland, I and Liu, M and Chen, K and Fu, D and Henckel, C and Chaung, K and Miranda, SE and Dyckman, S and Crum, M and Dedrick, S and Shou, W and Momeni, B}, title = {Microbial coexistence through chemical-mediated interactions.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {2052}, doi = {10.1038/s41467-019-10062-x}, pmid = {31053707}, issn = {2041-1723}, support = {T32 HL 7427//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, abstract = {Many microbial functions happen within communities of interacting species. Explaining how species with disparate growth rates can coexist is important for applications such as manipulating host-associated microbiota or engineering industrial communities. Here, we ask how microbes interacting through their chemical environment can achieve coexistence in a continuous growth setup (similar to an industrial bioreactor or gut microbiota) where external resources are being supplied. We formulate and experimentally constrain a model in which mediators of interactions (e.g. metabolites or waste-products) are explicitly incorporated. Our model highlights facilitation and self-restraint as interactions that contribute to coexistence, consistent with our intuition. When interactions are strong, we observe that coexistence is determined primarily by the topology of facilitation and inhibition influences not their strengths. Importantly, we show that consumption or degradation of chemical mediators moderates interaction strengths and promotes coexistence. Our results offer insights into how to build or restructure microbial communities of interest.}, }
@article {pmid31051132, year = {2019}, author = {Peterson, CW and Kiem, HP}, title = {Lessons from London and Berlin: Designing A Scalable Gene Therapy Approach for HIV Cure.}, journal = {Cell stem cell}, volume = {24}, number = {5}, pages = {685-687}, doi = {10.1016/j.stem.2019.04.010}, pmid = {31051132}, issn = {1875-9777}, abstract = {Recently in Nature, Gupta et al. (2019) reported that a second patient has achieved HIV-1 remission/functional cure after allogeneic hematopoietic stem cell transplantation from a donor carrying a mutation in the CCR5 coreceptor. We highlight both patients' treatments and summarize efforts to develop a broader, more patient-friendly approach.}, }
@article {pmid31048629, year = {2019}, author = {Sabo, MC and Richardson, BA and Lavreys, L and Martin, HL and Jaoko, W and Mandaliya, K and Baeten, JM and Overbaugh, J and McClelland, RS}, title = {Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion.}, journal = {AIDS (London, England)}, volume = {33}, number = {7}, pages = {1225-1230}, doi = {10.1097/QAD.0000000000002167}, pmid = {31048629}, issn = {1473-5571}, abstract = {OBJECTIVES: A recent study of HIV serodiscordant couples found that depot medroxyprogesterone acetate (DMPA) and oral contraceptive pills (OCPs) were associated with increased HIV risk in the presence, but not in the absence, of bacterial vaginosis. We assessed whether bacterial vaginosis is an effect modifier of the association between hormonal contraception and HIV seroconversion in female sex workers (FSWs) in Mombasa, Kenya.<br><br>DESIGN: Prospective cohort study.<br><br>METHODS: Data collected from HIV-negative FSWs from 1993 to 2017 were analyzed. Cox proportional hazards models were used to assess the relationship between HIV seroconversion and use of DMPA, OCPs, or hormonal contraceptive implants (Norplant, Jadelle).<br><br>RESULTS: A total of 1985 women contributed 7127 person-years of follow-up; 307 women seroconverted to HIV (4.32/100 person-years). DMPA was significantly associated with elevated risk of HIV seroconversion in women with [aHR 1.56, 95% confidence interval (CI) 1.08-2.25; P = 0.02] and without (aHR 2.08, 95% CI 1.46-2.97; P < 0.001) bacterial vaginosis (interaction P = 0.4). Similarly, OCP use was associated with increased HIV risk both in the presence (aHR 1.50, 95% CI 0.94-2.39; P = 0.09) and absence (aHR 1.61, 95% CI 0.99-2.64; P = 0.06) of bacterial vaginosis (interaction P = 0.9), though neither stratum reached statistical significance. Implants were not associated with HIV seroconversion overall (aHR 0.99, 95% CI 0.40-2.45; P = 0.9), or in women with (aHR 0.65, 95% CI 0.16-2.72; P = 0.6) and without (aHR 1.39, 95% CI 0.43-4.46; P = 0.6) bacterial vaginosis (interaction P = 0.5).<br><br>CONCLUSION: Bacterial vaginosis had no effect on the associations between hormonal contraceptives and HIV seroconversion in this cohort. Contraceptive implants were not associated with increased HIV risk compared with no contraception.}, }
@article {pmid31044423, year = {2019}, author = {Geer, M and Roberts, E and Shango, M and Till, BG and Smith, SD and Abbas, H and Hill, BT and Kaplan, J and Barr, PM and Caimi, P and Stephens, DM and Lin, E and Herrera, AF and Rosenbaum, E and Amengual, JE and Boonstra, PS and Devata, S and Wilcox, RA and Kaminski, MS and Phillips, TJ}, title = {Multicentre retrospective study of intravascular large B-cell lymphoma treated at academic institutions within the United States.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.15923}, pmid = {31044423}, issn = {1365-2141}, abstract = {Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.}, }
@article {pmid31043533, year = {2019}, author = {Hanson, DJ and Tsvetkova, O and Rerolle, G and Greninger, AL and Sette, A and Jing, L and Campbell, V and Koelle, DM}, title = {Genome-wide approach to the CD4 T-cell response to HHV-6B.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {}, doi = {10.1128/JVI.00321-19}, pmid = {31043533}, issn = {1098-5514}, abstract = {HHV-6 and CMV are population-prevalent betaherpesviruses with intermittent lytic replication that can be pathogenic in immunocompromised hosts. Elucidation of the adaptive immune response is valuable for understanding pathogenesis and designing novel treatments. Knowledge of T-cell antigens has reached the genome-wide level for CMV and other human herpesviruses, but study of HHV-6 is at an earlier stage. Using rare cell enrichment combined with an HLA-agnostic, proteome-wide approach, we queried HHV-6B-specific CD4 T cells from 18 healthy donors with each known HHV-6B protein. We detect low abundance of HHV-6-specific CD4 T cells in blood; however, the within-person CD4 T-cell response is quite broad: the median number of ORF products recognized was nine per person. Overall, the data expands the number of documented HHV-6B CD4 T-cell antigens from approximately 11 to 60. Epitopes in the proteins encoded by U14, U90, and U95 were mapped with synthetic peptides and HLA restriction defined for some responses. Intriguingly, CD4 T-cell antigens newly described in this report are among the most population-prevalent, including U73, U72, U95 and U30. Our results indicate that selection of HHV-6B ORFs for immunotherapy should consider this expanded panel of HHV-6B antigens.IMPORTANCE Human herpesvirus 6 is highly prevalent and maintains chronic infection in immunocompetent individuals with the potential to replicate widely in settings of immunosuppression, leading to clinical disease. Antiviral compounds may be ineffective and/or pose dose-limiting toxicity, and therefore immune-based therapies have garnered increased interest in recent years. Attempts at addressing this unmet medical need begin with understanding the cellular response to HHV-6 at the individual and population level. The current study provides a comprehensive assessment of HHV-6-specific T-cell responses that may inform development of cell-based therapies directed at this virus.}, }
@article {pmid31043415, year = {2019}, author = {Veatch, JR and Jesernig, B and Kargl, J and Fitzgibbon, MP and Lee, SM and Baik, CS and Martins, R and Houghton, AM and Riddell, S}, title = {Endogenous CD4+ T cells recognize neoantigens in lung cancer patients, including recurrent oncogenic KRAS and ERBB2 (Her2) driver mutations.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-18-0402}, pmid = {31043415}, issn = {2326-6074}, abstract = {T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8+ T cells by class I MHC. However, CD4+ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8+ or CD4+ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 NSCLC patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1-7 antigens identified per patient. A majority of responses were to random, patient-specific mutations. However, CD4+ T cells that recognized the recurrent KRASG12V and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wildtype sequences, were identified in two patients. Two different T-cell receptors (TCRs) specific for KRASG12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITD-specific TCR in the tumor but not non-adjacent lung. Our results showed that CD4+ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4+ neoantigen-specific T cells and elucidate their role in human antitumor immunity.}, }
@article {pmid31043412, year = {2019}, author = {Hiatt, JB and MacPherson, D}, title = {Delivering a STINGing Blow to Small Cell Lung Cancer via Synergistic Inhibition of DNA-Damage Response and Immune-Checkpoint Pathways.}, journal = {Cancer discovery}, volume = {9}, number = {5}, pages = {584-586}, doi = {10.1158/2159-8290.CD-19-0234}, pmid = {31043412}, issn = {2159-8290}, abstract = {Small cell lung cancer (SCLC) has demonstrated modest responses to immune-checkpoint blockade despite harboring a high mutational burden. In this issue, Sen and colleagues show remarkable synergy between inhibition of the DNA-damage response and the PD-1 axis, resulting in striking tumor regressions in SCLC mouse models.See related article by Sen et al., p. 646.}, }
@article {pmid31040439, year = {2019}, author = {Higano, C}, title = {Enzalutamide, apalutamide, or darolutamide: are apples or bananas best for patients?.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41585-019-0186-2}, pmid = {31040439}, issn = {1759-4820}, }
@article {pmid31039409, year = {2019}, author = {Marks, DI and Kebriaei, P and Stelljes, M and Gökbuget, N and Kantarjian, H and Advani, AS and Merchant, A and Stock, W and Cassaday, RD and Wang, T and Zhang, H and Loberiza, F and Vandendries, E and DeAngelo, DJ}, title = {Outcomes of allogeneic stem cell transplantation after inotuzumab ozogamicin treatment for relapsed or refractory acute lymphoblastic leukemia.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.04.020}, pmid = {31039409}, issn = {1523-6536}, abstract = {BACKGROUND: Attaining complete remission of acute lymphoblastic leukemia (ALL) before hematopoietic stem cell transplantation (HSCT) correlates with better post-transplant outcomes. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher rates of remission, minimal residual disease negativity, and HSCT versus standard chemotherapy in treating relapsed/refractory (R/R) ALL. We investigated the role of previous transplant, and proceeding directly to HSCT after remission, as factors in determining post-transplant survival in the setting of InO treatment for R/R ALL.<br><br>METHODS: The analyzed population comprised InO-treated patients who proceeded to allogeneic HSCT in two clinical trials (phase 1/2: NCT01363297 and phase 3: NCT01564784). Overall survival (OS) was defined as time from HSCT to death (any cause).<br><br>RESULTS: Of 236 InO-treated patients, 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Most received InO as first salvage (62%); 85% had no previous HSCT. Median (95% CI) post-transplant OS was 9.2 months (5.1, not estimable) with 2-year survival probability (95% CI) of 41% (32-51%). In first-HSCT patients (n=86), median (95% CI) post-transplant OS was 11.8 months (5.9, not estimable) with 2-year survival probability (95% CI) of 46% (35-56%); some patients relapsed and needed additional treatment before HSCT (n=28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (n=73) fared best: median post-transplant OS was not reached with 2-year survival probability (95% CI) of 51% (39-62%).<br><br>CONCLUSION: In patients with R/R ALL, InO followed by allogeneic HSCT provided optimal long-term survival benefit among those with no previous HSCT who went directly to transplant after remission.}, }
@article {pmid31038671, year = {2019}, author = {Hang, D and Joshi, AD and He, X and Chan, AT and Jovani, M and Gala, MK and Ogino, S and Kraft, P and Turman, C and Peters, U and Bien, SA and Lin, Y and Hu, Z and Shen, H and Wu, K and Giovannucci, EL and Song, M}, title = {Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies.}, journal = {International journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ije/dyz096}, pmid = {31038671}, issn = {1464-3685}, abstract = {BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.<br><br>METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.<br><br>RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).<br><br>CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.}, }
@article {pmid31038123, year = {2019}, author = {Soh, YS and Moncla, LH and Eguia, R and Bedford, T and Bloom, JD}, title = {Comprehensive mapping of adaptation of the avian influenza polymerase protein PB2 to humans.}, journal = {eLife}, volume = {8}, number = {}, pages = {}, doi = {10.7554/eLife.45079}, pmid = {31038123}, issn = {2050-084X}, support = {R01 AI127893//National Institute of Allergy and Infectious Diseases/ ; R35 GM119774-01//National Institute of General Medical Sciences/ ; DRG-2271-16//Damon Runyon Cancer Research Foundation/United States ; }, abstract = {Viruses like influenza are infamous for their ability to adapt to new hosts. Retrospective studies of natural zoonoses and passaging in the lab have identified a modest number of host-adaptive mutations. However, it is unclear if these mutations represent all ways that influenza can adapt to a new host. Here we take a prospective approach to this question by completely mapping amino-acid mutations to the avian influenza virus polymerase protein PB2 that enhance growth in human cells. We identify numerous previously uncharacterized human-adaptive mutations. These mutations cluster on PB2's surface, highlighting potential interfaces with host factors. Some previously uncharacterized adaptive mutations occur in avian-to-human transmission of H7N9 influenza, showing their importance for natural virus evolution. But other adaptive mutations do not occur in nature because they are inaccessible via single-nucleotide mutations. Overall, our work shows how selection at key molecular surfaces combines with evolutionary accessibility to shape viral host adaptation.}, }
@article {pmid31037736, year = {2019}, author = {McNabb, S and Harrison, TA and Albanes, D and Berndt, SI and Brenner, H and Caan, BJ and Campbell, PT and Cao, Y and Chang-Claude, J and Chan, A and Chen, Z and English, DR and Giles, GG and Giovannucci, EL and Goodman, PJ and Hayes, RB and Hoffmeister, M and Jacobs, EJ and Joshi, AD and Larsson, SC and Le Marchand, L and Li, L and Lin, Y and Männistö, S and Milne, RL and Nan, H and Newton, C and Ogino, S and Parfrey, PS and Petersen, PS and Potter, JD and Schoen, RE and Slattery, ML and Su, YR and Tangen, CM and Tucker, TC and Weinstein, SJ and White, E and Wolk, A and Woods, MO and Phipps, AI and Peters, U}, title = {Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.32377}, pmid = {31037736}, issn = {1097-0215}, abstract = {Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from five case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (OR: 0.92, 95% CI: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08), and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage. This article is protected by copyright. All rights reserved.}, }
@article {pmid31037296, year = {2019}, author = {Roble, G and Pullium, J and Hester, T and Harvey, S}, title = {Disaster Planning for Animals in Hazardous Agent Containment Units.}, journal = {ILAR journal}, volume = {}, number = {}, pages = {}, doi = {10.1093/ilar/ily022}, pmid = {31037296}, issn = {1930-6180}, abstract = {Disaster response planning for laboratory animal facilities is a time- and personnel-intensive undertaking. This article outlines numerous considerations in formulating a plan for disaster response in a high containment animal unit. The planning process is discussed around a set of elements: planning team formation, situational understanding, goal and objective determination, plan development, preparation, and rehearsal or implementation. The importance of an appropriate planning team and personnel development is explored in relationship to exemplary disaster scenarios such as natural disaster and terrorism. Specific risks such as hazardous agent and animal species type serve to delineate goal-setting methods. These goals provide the framework for an institutional disaster plan. The review further uses elements of the planning process to explore the difficulties of euthanasia of animals treated with hazardous agents. Ultimately, the pitfalls of handling media relations following disaster are examined. Proactive measures for preparing to speak to the media and mitigate negative perceptions of research are presented.}, }
@article {pmid31036827, year = {2019}, author = {Kaya-Okur, HS and Wu, SJ and Codomo, CA and Pledger, ES and Bryson, TD and Henikoff, JG and Ahmad, K and Henikoff, S}, title = {CUT&amp;Tag for efficient epigenomic profiling of small samples and single cells.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {1930}, doi = {10.1038/s41467-019-09982-5}, pmid = {31036827}, issn = {2041-1723}, support = {4DN TCPA A093//U.S. Department of Health &amp; Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/International ; R01 GM108699/GM/NIGMS NIH HHS/United States ; }, abstract = {Many chromatin features play critical roles in regulating gene expression. A complete understanding of gene regulation will require the mapping of specific chromatin features in small samples of cells at high resolution. Here we describe Cleavage Under Targets and Tagmentation (CUT&amp;Tag), an enzyme-tethering strategy that provides efficient high-resolution sequencing libraries for profiling diverse chromatin components. In CUT&amp;Tag, a chromatin protein is bound in situ by a specific antibody, which then tethers a protein A-Tn5 transposase fusion protein. Activation of the transposase efficiently generates fragment libraries with high resolution and exceptionally low background. All steps from live cells to sequencing-ready libraries can be performed in a single tube on the benchtop or a microwell in a high-throughput pipeline, and the entire procedure can be performed in one day. We demonstrate the utility of CUT&amp;Tag by profiling histone modifications, RNA Polymerase II and transcription factors on low cell numbers and single cells.}, }
@article {pmid31036730, year = {2019}, author = {Yang, DC and Blair, KM and Taylor, JA and Petersen, TW and Sessler, T and Tull, CM and Leverich, C and Collar, AL and Wyckoff, TJ and Biboy, J and Vollmer, W and Salama, NR}, title = {A genome-wide Helicobacter pylori morphology screen uncovers a membrane spanning helical cell shape complex.}, journal = {Journal of bacteriology}, volume = {}, number = {}, pages = {}, doi = {10.1128/JB.00724-18}, pmid = {31036730}, issn = {1098-5530}, abstract = {Evident in its name, the gastric pathogen Helicobacter pylori has helical cell morphology which facilitates efficient colonization of the human stomach. An improved light focusing strategy allowed us to robustly distinguish even subtle perturbations of H. pylori cell morphology by deviations in light scattering properties measured by flow cytometry. Profiling of an arrayed genome-wide deletion library identified 28 genes that influence different aspects of cell shape including properties of the helix, cell length or width, cell filament formation, cell shape heterogeneity and cell branching. Included in this mutant collection were two that failed to form any helical cells, a soluble lytic transglycosylase and a previously uncharacterized putative multi-pass inner membrane protein HPG27_0728, renamed Csd7. A combination of cell fractionation, mutational and immunoprecipitation experiments show that Csd7 and Csd2 collaborate to stabilize the Csd1 peptidoglycan (PG) endopeptidase. Thus, both csd2 and csd7 mutants show the same enhancement of PG tetra-pentapeptide crosslinking as csd1 mutants. Csd7 also links Csd1 with the bactofilin CcmA via protein-protein interactions. Although Csd1 is stable in ccmA mutants, these mutants show altered PG tetra-pentapeptide crosslinking, suggesting that Csd7 may directly or indirectly activate as well as stabilize Csd1. These data begin to illuminate a highly orchestrated program to regulate PG modifications that promote helical shape, which includes nine non-essential, non-redundant genes required for helical shape and 26 additional genes that further modify H. pylori's cell morphology.ImportanceThe stomach ulcer and cancer-causing pathogen Helicobacter pylori has helical cell shape which facilitates stomach infection. Using light scattering to measure perturbations of cell morphology, we identified 28 genes that influence different aspects of cell shape. A mutant in a previously uncharacterized protein renamed Csd7 failed to form any helical cells. Biochemical analyses showed that Csd7 collaborates with other proteins to stabilize the cell wall degrading enzyme Csd1. Csd7 also links Csd1 with a putative filament forming protein via protein-protein interactions. These data suggest that helical cell shape arises from a a highly orchestrated program to regulate cell wall modifications. Targeting of this helical cell shape promoting program could offer new ways to block infectivity of this important human pathogen.}, }
@article {pmid31036644, year = {2019}, author = {Da Costa, AS and Graham, JB and Swarts, JL and Lund, JM}, title = {Regulatory T cells limit unconventional memory to preserve the capacity to mount protective CD8 memory responses to pathogens.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {}, number = {}, pages = {}, doi = {10.1073/pnas.1818327116}, pmid = {31036644}, issn = {1091-6490}, abstract = {Immunological memory exists so that following infection an expanded population of pathogen-specific lymphocytes can rapidly and efficiently control infection in the case of reexposure. However, in the case of CD8+ T lymphocytes, a population of unconventional CD44+CD122+ virtual memory T cells (TVM) has been described that possesses many, though not all, features of &quot;true memory&quot; T cells, without the requirement of first encountering cognate antigen. Here, we demonstrate a role for regulatory T cell-mediated restraint of TVM at least in part through limiting IL-15 trans-presentation by CD11b+ dendritic cells. Further, we show that keeping TVM in check ensures development of functional, antigen-specific &quot;true&quot; memory phenotype CD8+ T cells that can assist in pathogen control upon reexposure.}, }
@article {pmid31031411, year = {2019}, author = {Bellettiere, J and LaMonte, MJ and Evenson, KR and Rillamas-Sun, E and Kerr, J and Lee, IM and Di, C and Rosenberg, DE and Stefanick, M and Buchner, DM and Hovell, MF and LaCroix, AZ}, title = {Sedentary behavior and cardiovascular disease in older women: The Objective Physical Activity and Cardiovascular Health (OPACH) Study.}, journal = {Circulation}, volume = {139}, number = {8}, pages = {1036-1046}, doi = {10.1161/CIRCULATIONAHA.118.035312}, pmid = {31031411}, issn = {1524-4539}, abstract = {Background: Evidence that higher sedentary time is associated with higher risk for cardiovascular disease (CVD) is based mainly on self-reported measures. Few studies have examined whether patterns of sedentary time are associated with higher risk for CVD.<br><br>Methods: Women from the Objective Physical Activity and Cardiovascular Health (OPACH) Study (n=5638, aged 63-97, mean age=79±7) with no history of myocardial infarction (MI) or stroke wore accelerometers for 4-to-7 days and were followed for up to 4.9 years for CVD events. Average daily sedentary time and mean sedentary bout duration were the exposures of interest. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CVD using models adjusted for covariates and subsequently adjusted for potential mediators (body mass index (BMI), diabetes, hypertension, and CVD-risk biomarkers [fasting glucose, high-density lipoprotein, triglycerides, and systolic blood pressure]). Restricted cubic spline regression characterized dose-response relationships.<br><br>Results: There were 545 CVD events during 19,350 person-years. Adjusting for covariates, women in the highest (≥ ~11 hr/day) vs. the lowest (≤ ~9 hr/day) quartile of sedentary time had higher risk for CVD (HR=1.62; CI=1.21-2.17; p-trend <0.001). Further adjustment for potential mediators attenuated but did not eliminate significance of these associations (p-trend<.05, each). Longer vs. shorter mean bout duration was associated with higher risks for CVD (HR=1.54; CI=1.27-2.02; p-trend=0.003) after adjustment for covariates. Additional adjustment for CVD-risk biomarkers attenuated associations resulting in a quartile 4 vs. quartile 1 HR=1.36; CI=1.01-1.83; p-trend=0.10). Dose-response associations of sedentary time and bout duration with CVD were linear (P-nonlinear >0.05, each). Women jointly classified as having high sedentary time and long bout durations had significantly higher risk for CVD (HR=1.34; CI=1.08-1.65) than women with both low sedentary time and short bout duration. All analyses were repeated for incident coronary heart disease (MI or CVD death) and associations were similar with notably stronger hazard ratios.<br><br>Conclusions: Both high sedentary time and long mean bout durations were associated in a dose-response manner with increased CVD risk in older women, suggesting that efforts to reduce CVD burden may benefit from addressing either or both component(s) of sedentary behavior.}, }
@article {pmid31029691, year = {2019}, author = {Mathewson, AW and Berman, D and Moens, CB}, title = {Microtubules are required for the maintenance of planar cell polarity in monociliated floorplate cells.}, journal = {Developmental biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ydbio.2019.04.007}, pmid = {31029691}, issn = {1095-564X}, abstract = {The asymmetric localization of planar cell polarity (PCP) proteins is essential for the establishment of many planar polarized cellular processes, but the mechanisms that maintain these asymmetric distributions remain poorly understood. A body of evidence has tied oriented subapical microtubules (MTs) to the establishment of PCP protein polarity, yet recent studies have suggested that the MT cytoskeleton is later dispensable for the maintenance of this asymmetry. As MTs underlie the vesicular trafficking of membrane-bound proteins within cells, the requirement for MTs in the maintenance of PCP merited further investigation. We investigated the complex interactions between PCP proteins and the MT cytoskeleton in the polarized context of the floorplate of the zebrafish neural tube. We demonstrated that the progressive posterior polarization of the primary cilia of floorplate cells requires not only Vangl2 but also Fzd3a. We determined that GFP-Vangl2 asymmetrically localizes to anterior membranes whereas Fzd3a-GFP does not polarize on anterior or posterior membranes but maintains a cytosolic enrichment at the base of the primary cilium. Vesicular Fzd3a-GFP is rapidly trafficked along MTs primarily toward the apical membrane during a period of PCP maintenance, whereas vesicular GFP-Vangl2 is less frequently observed. Nocodazole-induced loss of MT polymerization disrupts basal body positioning as well as GFP-Vangl2 localization and reduces cytosolic Fzd3a-GFP movements. Removal of nocodazole after MT disruption restores MT polymerization but does not restore basal body polarity. Interestingly, GFP-Vangl2 repolarizes to anterior membranes and vesicular Fzd3a-GFP dynamics recover after multiple hours of recovery, even in the context of unpolarized basal bodies. Together our findings challenge previous work by revealing an ongoing role for MT-dependent transport of PCP proteins in maintaining both cellular and PCP protein asymmetry during development.}, }
@article {pmid31029171, year = {2019}, author = {Sherr, K and Ásbjörnsdóttir, K and Crocker, J and Coutinho, J and de Fatima Cuembelo, M and Tavede, E and Manaca, N and Ronen, K and Murgorgo, F and Barnabas, R and John-Stewart, G and Holte, S and Weiner, BJ and Pfeiffer, J and Gimbel, S}, title = {Scaling-up the Systems Analysis and Improvement Approach for prevention of mother-to-child HIV transmission in Mozambique (SAIA-SCALE): a stepped-wedge cluster randomized trial.}, journal = {Implementation science : IS}, volume = {14}, number = {1}, pages = {41}, doi = {10.1186/s13012-019-0889-z}, pmid = {31029171}, issn = {1748-5908}, support = {R01MH113435//National Institute of Mental Health/ ; P30AI027757//National Institutes of Health/ ; }, abstract = {BACKGROUND: The introduction of option B+-rapid initiation of lifelong antiretroviral therapy regardless of disease status for HIV-infected pregnant and breastfeeding women-can dramatically reduce HIV transmission during pregnancy, birth, and breastfeeding. Despite significant investments to scale-up Option B+, results have been mixed, with high rates of loss to follow-up, sub-optimal viral suppression, continued pediatric HIV transmission, and HIV-associated maternal morbidity. The Systems Analysis and Improvement Approach (SAIA) cluster randomized trial demonstrated that a package of systems engineering tools improved flow through the prevention of mother-to-child HIV transmission (PMTCT) cascade. This five-step, facility-level intervention is designed to improve understanding of gaps (cascade analysis), guide identification and prioritization of low-cost workflow modifications (process mapping), and iteratively test and redesign these modifications (continuous quality improvement). This protocol describes a novel model for SAIA delivery (SAIA-SCALE) led by district nurse supervisors (rather than research nurses), and evaluation procedures, to serve as a foundation for national scale-up.<br><br>METHODS: The SAIA-SCALE stepped wedge trial includes three implementation waves, each 12 months in duration. Districts are the unit of assignment, with four districts randomly assigned per wave, covering all 12 districts in Manica province, Mozambique. In each district, the three highest volume health facilities will receive the SAIA-SCALE intervention (totaling 36 intervention facilities). The RE-AIM framework will guide SAIA-SCALE's evaluation. Reach describes the proportion of clinics and population in Manica province reached, and sub-groups not reached. Effectiveness assesses impact on PMTCT process measures and patient-level outcomes. Adoption describes the proportion of districts/clinics adopting SAIA-SCALE, and determinants of adoption using the Organizational Readiness for Implementing Change (ORIC) tool. Implementation will identify SAIA-SCALE core elements and determinants of successful implementation using the Consolidated Framework for Implementation Research (CFIR). Maintenance describes the proportion of districts sustaining the intervention. We will also estimate the budget and program impact from the payer perspective for national scale-up.<br><br>DISCUSSION: SAIA packages user-friendly systems engineering tools to guide decision-making by frontline health workers, and to identify low-cost, contextually appropriate PMTCT improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial is designed to test a model for national intervention scale-up.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03425136 (registered 02/06/2018).}, }
@article {pmid31028033, year = {2019}, author = {Stromnes, IM and Burrack, AL and Hulbert, A and Bonson, P and Black, C and Brockenbrough, JS and Raynor, JF and Spartz, EJ and Pierce, RH and Greenberg, PD and Hingorani, SR}, title = {Differential effects of depleting versus programming tumor-associated macrophages on engineered T cells in pancreatic ductal adenocarcinoma.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-18-0448}, pmid = {31028033}, issn = {2326-6074}, abstract = {Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to therapies, including immune checkpoint blockade. We investigated two distinct strategies to modulate tumor-associated macrophages (TAMs) to enhance cellular therapy targeting mesothelin in an autochthonous PDA mouse model. Administration of an antibody to colony-stimulating factor (anti-Csf1R) depleted Ly6Clow pro-tumorigenic TAMs and significantly enhanced endogenous T-cell intratumoral accumulation. Despite increasing the number of endogenous T cells at the tumor site, as previously reported, TAM depletion had only minimal impact on intratumoral accumulation and persistence of T cells engineered to express a murine mesothelin-specific T-cell receptor (TCR). TAM depletion interfered with the antitumor activity of the infused T cells in PDA, evidenced by reduced tumor cell apoptosis. In contrast, TAM programming with agonistic anti-CD40 increased both Ly6Chigh TAMs and the intratumoral accumulation and longevity of TCR-engineered T cells. Anti-CD40 significantly increased the frequency and number of proliferating and granzyme B+ engineered T cells, and increased tumor cell apoptosis. However, anti-CD40 failed to rescue intratumoral engineered T-cell IFNγ production. Thus, although functional modulation, rather than TAM depletion, enhanced the longevity of engineered T cells and increased tumor cell apoptosis, ultimately, anti-CD40 modulation was insufficient to rescue key effector defects in tumor-reactive T cells. This study highlights critical distinctions between how endogenous T cells that evolve in vivo, and engineered T cells with previously acquired effector activity, respond to modifications of the tumor microenvironment.}, }
@article {pmid31013271, year = {2019}, author = {Mewes, JC and Pulia, MS and Mansour, MK and Broyles, MR and Nguyen, HB and Steuten, LM}, title = {The cost impact of PCT-guided antibiotic stewardship versus usual care for hospitalised patients with suspected sepsis or lower respiratory tract infections in the US: A health economic model analysis.}, journal = {PloS one}, volume = {14}, number = {4}, pages = {e0214222}, doi = {10.1371/journal.pone.0214222}, pmid = {31013271}, issn = {1932-6203}, abstract = {BACKGROUND: Procalcitonin is a biomarker that supports clinical decision-making on when to initiate and discontinue antibiotic therapy. Several cost (-effectiveness) analyses have been conducted on Procalcitonin-guided antibiotic stewardship, but none mainly based on US originated data.<br><br>OBJECTIVE: To compare effectiveness and costs of a Procalcitonin-algorithm versus standard care to guide antibiotic prescription for patients hospitalized with a diagnosis of suspected sepsis or lower respiratory tract infection in the US.<br><br>METHODS: A previously published health economic decision model was used to compare the costs and effects of Procalcitonin-guided care. The analysis considered the societal and hospital perspective with a time horizon covering the length of hospital stay. The main outcomes were total costs per patient, including treatment costs and productivity losses, the number of patients with antibiotic resistance or C.difficile infections, and costs per antibiotic day avoided.<br><br>RESULTS: Procalcitonin -guided care for hospitalized patients with suspected sepsis and lower respiratory tract infection is associated with a reduction in antibiotic days, a shorter length of stay on the regular ward and the intensive care unit, shorter duration of mechanical ventilation, and fewer patients at risk for antibiotic resistant or C.difficile infection. Total costs in the Procalcitonin-group compared to standard care were reduced by 26.0% in sepsis and 17.7% in lower respiratory tract infection (total incremental costs of -$11,311 per patient and -$2,867 per patient respectively).<br><br>CONCLUSIONS: Using a Procalcitonin-algorithm to guide antibiotic use in sepsis and hospitalised lower respiratory tract infection patients is expected to generate cost-savings to the hospital and lower rates of antibiotic resistance and C.difficile infections.}, }
@article {pmid31025025, year = {2019}, author = {Dimitrov, D and Wood, D and Ulrich, A and Swan, DA and Adamson, B and Lama, JR and Sanchez, J and Duerr, A}, title = {Projected effectiveness of HIV detection during early infection and rapid ART initiation among MSM and transgender women in Peru: A modeling study.}, journal = {Infectious Disease Modelling}, volume = {4}, number = {}, pages = {73-82}, doi = {10.1016/j.idm.2019.04.001}, pmid = {31025025}, issn = {2468-0427}, abstract = {Background: The Sabes study, a treatment as prevention intervention in Peru, tested the hypothesis that initiating antiretroviral therapy (ART) early in HIV infection when viral load is high, would markedly reduce onward HIV transmission among high-risk men who have sex with men (MSM) and transgender women (TW). We investigated the potential population-level benefits of detection of HIV early after acquisition and rapid initiation of ART.<br><br>Methods: We designed a transmission dynamic model to simulate the HIV epidemic among MSM and TW in Peru, calibrated to data on HIV prevalence and ART coverage from 2004 to 2011. We assessed the impact of an intervention starting in 2018 in which up to 50% of the new infections were diagnosed within three months of acquisition and initiated on ART within 1 month of diagnosis. We estimated the impact of the intervention over 20 years using the cumulative prevented fraction of new HIV infections compared to scenarios without intervention.<br><br>Findings: Our model suggests that only 19% of the infected MSM and TW are virally suppressed in 2018 and 35%-40% of the new HIV infections are transmitted from contacts with acutely-infected partners. An intervention reaching 10% of all acutely infected MSM and TW is projected to prevent 13.3% [Uncertainty interval: 11.9%-14.3%] of the new infections over 20 years and reduce HIV incidence in 2038 by 24%. Reaching 50% of all acutely infected MSM and TW will increase the prevalence of viral suppression in 2038 to 59% and prevent 41% of expected infections over 20 years. Reaching 50% of the high-risk MSM and TW in acute phase would reduce HIV incidence in 2038 by 60% and prevent 36% of new infections between 2018 and 2038.<br><br>Conclusions: Early detection of HIV infections and rapid initiation of ART among MSM is desirable as it would increase the effectiveness of the HIV prevention program in Peru. Targeting high-risk MSM and TW will be highly efficient.}, }
@article {pmid31024219, year = {2019}, author = {Luedtke, AR and Carone, M and van der Laan, MJ}, title = {An omnibus non-parametric test of equality in distribution for unknown functions.}, journal = {Journal of the Royal Statistical Society. Series B, Statistical methodology}, volume = {81}, number = {1}, pages = {75-99}, doi = {10.1111/rssb.12299}, pmid = {31024219}, issn = {1369-7412}, abstract = {We present a novel family of nonparametric omnibus tests of the hypothesis that two unknown but estimable functions are equal in distribution when applied to the observed data structure. We developed these tests, which represent a generalization of the maximum mean discrepancy tests described in Gretton et al. [2006], using recent developments from the higher-order pathwise differentiability literature. Despite their complex derivation, the associated test statistics can be expressed rather simply as U-statistics. We study the asymptotic behavior of the proposed tests under the null hypothesis and under both fixed and local alternatives. We provide examples to which our tests can be applied and show that they perform well in a simulation study. As an important special case, our proposed tests can be used to determine whether an unknown function, such as the conditional average treatment effect, is equal to zero almost surely.}, }
@article {pmid31019050, year = {2019}, author = {Hom, N and Gentles, L and Bloom, JD and Lee, KK}, title = {Deep mutational scan of the highly conserved influenza A M1 matrix protein reveals substantial intrinsic mutational tolerance.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {}, doi = {10.1128/JVI.00161-19}, pmid = {31019050}, issn = {1098-5514}, abstract = {Influenza A virus matrix protein M1 is involved in multiple stages of the viral infectious cycle. Despite its functional importance, our present understanding of this essential viral protein is limited. The roles of a small subset of specific amino acids have been reported, but a more comprehensive understanding of the relationship between M1 sequence, structure, and virus fitness remains elusive. Here, we use deep mutational scanning to measure the effect of every amino-acid substitution in M1 on viral replication in cell culture. The map of amino-acid mutational tolerance we have generated allows us to identify sites that are functionally constrained in cell-culture as well as sites that are less constrained. Several sites that exhibit low tolerance to mutation have been found to be critical for M1 function and production of viable virions. Surprisingly, significant portions of the M1 sequence, especially in the C-terminal domain whose structure is undetermined, were found to be highly tolerant of amino acid variation, despite having extremely low levels of sequence diversity among natural influenza strains. This unexpected discrepancy indicates that not all sites in M1 that exhibit high sequence conservation in nature are under strong constraint during selection for viral replication in cell culture.IMPORTANCE The M1 matrix protein is critical for many stages of the influenza infection cycle. Currently, we have an incomplete understanding of this highly conserved protein's function and structure. Key regions of M1, particularly in the C-terminus of the protein, remain poorly characterized. Here we used deep mutational scanning to determine the extent of M1's tolerance to mutation. Surprisingly, nearly two-thirds of the M1 sequence exhibits a high tolerance for substitutions, contrary to the extremely low sequence diversity observed across naturally occurring M1 isolates. Sites with low mutational tolerance were also identified, suggesting that they likely play critical functional roles and are under selective pressure. These results reveal the intrinsic mutational tolerance throughout M1, and shape future inquiries probing the function of this essential influenza A virus protein.}, }
@article {pmid31018977, year = {2019}, author = {Godavarthy, PS and Kumar, R and Herkt, SC and Pereira, RS and Hayduk, N and Weissenberger, ES and Aggoune, D and Manavski, Y and Lucas, T and Pan, KT and Voutsinas, JM and Wu, Q and Müller, MC and Saussele, S and Oellerich, T and Oehler, VG and Lausen, J and Krause, DS}, title = {The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.212365}, pmid = {31018977}, issn = {1592-8721}, abstract = {The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries to leukemic cells. In murine chronic myeloid leukemia CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of chronic myeloid leukemia-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in chronic myeloid leukemia after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with chronic myeloid leukemia via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and protooncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human chronic myeloid leukemia. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - a strategy therapeutically exploitable in future.}, }
@article {pmid31018921, year = {2019}, author = {Ligibel, J and Dillon, DA and Giobbie-Hurder, A and McTiernan, A and Frank, ES and Cornwell, M and Pun, M and Campbell, N and Dowling, RJO and Chang, MC and Tolaney, SM and Chagpar, AB and Yung, R and Freedman, RA and Dominici, LS and Golshan, M and Rhei, E and Taneja, K and Huang, Y and Brown, M and Winer, EP and Jeselsohn, R and Irwin, ML}, title = {Impact of a pre-operative exercise intervention on breast cancer proliferation and gene expression: Results from the Pre-Operative Health and Body (PreHAB) Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-18-3143}, pmid = {31018921}, issn = {1078-0432}, abstract = {PURPOSE: Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window of opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.<br><br>EXPERIMENTAL DESIGN: Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind-body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.<br><br>RESULTS: Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2kg/m2 and exercise was 49 min/wk. Exercise participants significantly increased exercise vs. controls (203 vs. 23 min/week, p<0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants vs controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q<0.1). Top ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise vs control participants over the intervention period (p=0.08).<br><br>CONCLUSIONS: A window of opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer.}, }
@article {pmid31018183, year = {2019}, author = {Bellettiere, J and Zhang, Y and Berardi, V and Full, KM and Kerr, J and LaMonte, MJ and Evenson, KR and Hovell, MF and LaCroix, AZ and Di, C}, title = {Parameterizing and validating existing algorithms for identifying out-of-bed time using hip-worn accelerometer data from older women.}, journal = {Physiological measurement}, volume = {}, number = {}, pages = {}, doi = {10.1088/1361-6579/ab1c04}, pmid = {31018183}, issn = {1361-6579}, abstract = {OBJECTIVE: To parameterize and validate two existing algorithms for identifying out-of-bed time using 24-hour hip-worn accelerometer data from older women. &#13; &#13; Approach: Overall, 628 women (80±6 years old) wore ActiGraph GT3X+ accelerometers 24 hours/day for up to 7 days and concurrently completed sleep-logs. Trained staff used a validated visual analysis protocol to measure in-bed periods on accelerometer tracings (criterion). The Tracy and McVeigh algorithms were adapted for optimal use in older adults. A training set of 314 women was used to choose two key thresholds by maximizing the sum of sensitivity and specificity for each algorithm and data (vertical axis, VA, and vector magnitude, VM) combination. Data from the remaining 314 women were then used to test agreement in waking wear time (i.e., out-of-bed time while wearing the accelerometer) by computing sensitivity, specificity, and kappa comparing the algorithm output with the criterion. Waking wear time-adjusted means of sedentary time, light-intensity physical activity (light PA) and moderate-to-vigorous-intensity physical activity (MVPA) were then estimated and compared. &#13; &#13; Main results: Waking wear time agreement with the criterion was high for Tracy_VA, Tracy_VM, McVeigh_VA, and highest for McVeigh_VM. Compared to the criterion, McVeigh_VM had mean sensitivity=0.92, specificity=0.87, kappa=0.80, and overall mean difference (±SD) of -0.04±2.5 hours/day. Minutes of sedentary time, light PA, and MVPA adjusted for waking wear time using the criterion measure and McVeigh_VM were not statistically different (p >0.43 | all).&#13; &#13; Significance: The McVeigh algorithm with optimal parameters using VM performed best compared to criterion sleep-log assisted visual analysis and is suitable for automated identification of waking wear time in older women when visual analysis is not feasible.&amp;#13.}, }
@article {pmid31017084, year = {2019}, author = {Seilie, AM and Chang, M and Hanron, AE and Billman, ZP and Stone, BC and Zhou, K and Olsen, TM and Daza, G and Ortega, J and Cruz, K and Smith, N and Healy, SA and Neal, J and Wallis, CK and Shelton, L and Mankowski, TV and Wong-Madden, S and Mikolajczak, SA and Vaughan, AM and Kappe, SHI and Fishbaugher, M and Betz, W and Kennedy, M and Hume, JC and Talley, AK and Hoffman, SL and Chakravarty, S and Lee Sim, BK and Richie, TL and Wald, A and Plowe, CV and Lyke, KE and Matthew, A and Fahle, GA and Cowan, EP and Duffy, PE and Kublin, JG and Murphy, SC}, title = {Beyond Blood Smears-Qualification of the Plasmodium 18S rRNA as a Biomarker for Controlled Human Malaria Infections.}, journal = {The American journal of tropical medicine and hygiene}, volume = {}, number = {}, pages = {}, doi = {10.4269/ajtmh.19-0094}, pmid = {31017084}, issn = {1476-1645}, abstract = {18S rRNA is a biomarker that provides an alternative to thick blood smears in controlled human malaria infection (CHMI) trials. We reviewed data from CHMI trials at non-endemic sites that used blood smears and Plasmodium 18S rRNA/rDNA biomarker nucleic acid tests (NATs) for time to positivity. We validated a multiplex quantitative reverse transcription-PCR (qRT-PCR) for Plasmodium 18S rRNA, prospectively compared blood smears and qRT-PCR for three trials, and modeled treatment effects at different biomarker-defined parasite densities to assess the impact on infection detection, symptom reduction, and measured intervention efficacy. Literature review demonstrated accelerated NAT-based infection detection compared with blood smears (mean acceleration: 3.2-3.6 days). For prospectively tested trials, the validated Plasmodium 18S rRNA qRT-PCR positivity was earlier (7.6 days; 95% CI: 7.1-8.1 days) than blood smears (11.0 days; 95% CI: 10.3-11.8 days) and significantly preceded the onset of grade 2 malaria-related symptoms (12.2 days; 95% CI: 10.6-13.3 days). Discrepant analysis showed that the risk of a blood smear-positive, biomarker-negative result was negligible. Data modeling predicted that treatment triggered by specific biomarker-defined thresholds can differentiate complete, partial, and non-protective outcomes and eliminate many grade 2 and most grade 3 malaria-related symptoms post-CHMI. Plasmodium 18S rRNA is a sensitive and specific biomarker that can justifiably replace blood smears for infection detection in CHMI trials in non-endemic settings. This study led to biomarker qualification through the U.S. Food and Drug Administration for use in CHMI studies at non-endemic sites, which will facilitate biomarker use for the qualified context of use in drug and vaccine trials.}, }
@article {pmid31016321, year = {2019}, author = {Casto, AM and Roychoudhury, P and Xie, H and Selke, S and Perchetti, GA and Wofford, H and Huang, ML and Verjans, GMGM and Gottlieb, GS and Wald, A and Jerome, KR and Koelle, DM and Johnston, C and Greninger, AL}, title = {Large, stable, contemporary interspecies recombination events in circulating human herpes simplex viruses.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz199}, pmid = {31016321}, issn = {1537-6613}, abstract = {The ubiquitous human pathogens, HSV-1 and HSV-2, are distinct viral species that diverged about six million years ago. At least four small, ancient HSV-1 x HSV-2 interspecies recombination events have affected the HSV-2 genome, with recombinants and non-recombinants at each locus circulating today. However, it is unknown if interspecies recombination can affect other loci and if new recombinants continue to be generated. Using 255 newly sequenced and 230 existing HSV genome sequences, we comprehensively assessed interspecies recombination in HSV. Our findings show that the sizes and locations of interspecies recombination events in HSV-2 are significantly more variable than previously appreciated and that they can impact species-specific T-cell recognition of HSV. We describe two large (>5kb) recombination events, one of which arose in its current host, demonstrating that interspecies recombination continues to occur today. These results raise concerns about the use of live attenuated HSV-2 vaccines in high HSV-1 prevalence areas.}, }
@article {pmid31015278, year = {2019}, author = {Chan, YH and Teo, TH and Utt, A and Tan, JJ and Amrun, SN and Abu Bakar, F and Yee, WX and Becht, E and Lee, CY and Lee, B and Rajarethinam, R and Newell, E and Merits, A and Carissimo, G and Lum, FM and Ng, LF}, title = {Mutating chikungunya virus non-structural protein produces potent live-attenuated vaccine candidate.}, journal = {EMBO molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.15252/emmm.201810092}, pmid = {31015278}, issn = {1757-4684}, abstract = {Currently, there are no commercially available live-attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non-structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type-I IFN response compared to WT-CHIKV Adult mice infected with this nsP-mutant exhibited a mild joint phenotype with low-level viremia that rapidly cleared. Mechanistically, ingenuity pathway analyses revealed a tilt in the anti-inflammatory IL-10 versus pro-inflammatory IL-1β and IL-18 balance during CHIKV nsP-mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP-mutant-infected mice with WT-CHIKV or the closely related O'nyong-nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Challenged mice showed high antibody titers with efficient neutralizing capacity, indicative of immunological memory. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection.}, }
@article {pmid31014151, year = {2019}, author = {Bezerra, ED and Flowers, ME and Onstad, LE and Chielens, D and Radich, J and Higano, CS}, title = {A phase 2 study of alpha interferon for molecularly measurable residual disease in chronic myeloid leukemia after allogeneic hematopoietic cell transplantation.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/10428194.2019.1605508}, pmid = {31014151}, issn = {1029-2403}, abstract = {CML therapy has improved dramatically with the development of tyrosine kinase inhibitors (TKIs). Prior to the TKI era, we conducted two trials of alpha-interferon (IFN) for post-transplant hematologic and cytogenetic relapse. The complete cytogenetic response rate was 33% and 57% respectively. This report describes a third trial in which 40 patients with molecular relapse between 6 and 12 months post-transplant were treated with IFN. The projected cytogenetic relapse at 4.5 years was 12.6% compared with 42% in the historical control group. Although this data may not apply to most patients with CML today due to the availability of multiple TKIs, the effectiveness of short term IFN in post-transplant molecular relapse is supported by long-term treatment-free-survival in 75% of patients after a median follow-up of 15.6 years. This report suggests that alpha-interferon is potentially useful in the rare patient who has post-transplant molecular relapse who does not tolerate, or is resistant to TKIs.}, }
@article {pmid31013472, year = {2018}, author = {Radich, J}, title = {Is DNA a better assay for residual disease in chronic myeloid leukemia?.}, journal = {Haematologica}, volume = {103}, number = {12}, pages = {1942-1944}, doi = {10.3324/haematol.2018.205583}, pmid = {31013472}, issn = {1592-8721}, }
@article {pmid31009236, year = {2019}, author = {Liang, X and Young, WC and Hung, LH and Raftery, AE and Yeung, KY}, title = {Integration of Multiple Data Sources for Gene Network Inference Using Genetic Perturbation Data.}, journal = {Journal of computational biology : a journal of computational molecular cell biology}, volume = {}, number = {}, pages = {}, doi = {10.1089/cmb.2019.0036}, pmid = {31009236}, issn = {1557-8666}, abstract = {The inference of gene networks from large-scale human genomic data is challenging due to the difficulty in identifying correct regulators for each gene in a high-dimensional search space. We present a Bayesian approach integrating external data sources with knockdown data from human cell lines to infer gene regulatory networks. In particular, we assemble multiple data sources, including gene expression data, genome-wide binding data, gene ontology, and known pathways, and use a supervised learning framework to compute prior probabilities of regulatory relationships. We show that our integrated method improves the accuracy of inferred gene networks as well as extends some previous Bayesian frameworks both in theory and applications. We apply our method to two different human cell lines, namely skin melanoma cell line A375 and lung cancer cell line A549, to illustrate the capabilities of our method. Our results show that the improvement in performance could vary from cell line to cell line and that we might need to choose different external data sources serving as prior knowledge if we hope to obtain better accuracy for different cell lines.}, }
@article {pmid31008438, year = {2019}, author = {Beresford, SA and Bowen, DJ and Littman, AJ and Albano, DL and Chan, KG and Langer, SL and Barrington, WE and Patrick, DL}, title = {Relationship of Socioeconomic Status Indicators to Obesity in Hispanic and Non-Hispanic White Middle-Aged Women: A Population Study.}, journal = {International journal of women's health and wellness}, volume = {5}, number = {1}, pages = {}, doi = {10.23937/2474-1353/1510090}, pmid = {31008438}, issn = {2474-1353}, abstract = {Background: Obesity rates differ between Hispanic and White (non-Hispanic) women in the United States, with higher rates among Hispanic women. Socioeconomic processes contribute to this disparity both at the individual and the environmental level. Understanding these complex relationships requires multilevel analyses within cohorts of women that have a shared environment. In population-based samples of Hispanic and White (non-Hispanic) women from the same neighborhoods, we evaluated within each ethnic group a) The association of individual-level socioeconomic status (SES) with body mass index (BMI); and b) The additional contribution of neighborhood-level measures of SES.<br><br>Methods: Using population-based multi-stage sampling methods, we oversampled low SES and Hispanic block groups. During household screening, we identified women aged 30 to 50 years. Among White women, we specifically oversampled women with low educational levels. 515 Hispanic and 503 White women completed baseline. Height and weight were measured. Baseline surveys, in Spanish and English, included four measures of SES. Three measures of area-level SES were examined. Analysis of loge BMI on each SES measure used linear mixed models, incorporating design effects.<br><br>Results: Among White women, low education, social status, and neighborhood SES were associated with higher BMI (p < 0.001, p < 0.0001, and p < 0.05, respectively), independent of other SES measures. Although the highest grouped category of education, income and subjective social status within the Hispanic cohort had the lowest mean estimated BMI, the point estimates across categories were not monotonic, and had wide confidence intervals. As a result, in contrast to the findings among White women, no statistically significant associations were found between BMI and measures of SES among Hispanic women.<br><br>Discussion: Neighborhood and individual measures of SES operate differently in Hispanic compared with White women. We had assumed the measures we included to be most salient and operate similarly for both groups of women. Rather the salient factors for Hispanic women have yet to be identified. Improved understanding may ultimately inform the design of culturally-relevant multilevel obesity prevention strategies.}, }
@article {pmid31006650, year = {2019}, author = {Zhang, P and Holowatyj, AN and Roy, T and Pronovost, SM and Marchetti, M and Liu, H and Ulrich, CM and Edgar, BA}, title = {An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling.}, journal = {Developmental cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.devcel.2019.03.029}, pmid = {31006650}, issn = {1878-1551}, abstract = {The effect of intracellular vesicle trafficking on stem-cell behavior is largely unexplored. We screened the Drosophila sorting nexins (SNXs) and discovered that one, SH3PX1, profoundly affects gut homeostasis and lifespan. SH3PX1 restrains intestinal stem cell (ISC) division through an endocytosis-autophagy network that includes Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. Blockages in this network stabilize ligand-activated EGFRs, recycling them via Rab11-dependent endosomes to the plasma membrane. This hyperactivated ERK, calcium signaling, and ER stress, autonomously stimulating ISC proliferation. The excess divisions induced epithelial stress, Yki activity, and Upd3 and Rhomboid production in enterocytes, catalyzing feedforward ISC hyperplasia. Similarly, blocking autophagy increased ERK activity in human cells. Many endocytosis-autophagy genes are mutated in cancers, most notably those enriched in microsatellite instable-high and KRAS-wild-type colorectal cancers. Disruptions in endocytosis and autophagy may provide an alternative route to RAS-ERK activation, resulting in EGFR-dependent cancers.}, }
@article {pmid31004014, year = {2019}, author = {Kayser, S and Hills, RK and Luskin, MR and Brunner, AM and Terré, C and Westermann, J and Menghrajani, K and Shaw, C and Baer, MR and Elliott, MA and Perl, AE and Ráčil, Z and Mayer, J and Zak, P and Szotkowski, T and de Botton, S and Grimwade, D and Mayer, K and Walter, RB and Krämer, A and Burnett, AK and Ho, AD and Platzbecker, U and Thiede, C and Ehninger, G and Stone, RM and Röllig, C and Tallman, MS and Estey, EH and Müller-Tidow, C and Russell, NH and Schlenk, RF and Levis, MJ}, title = {Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia - results from an international collaborative study.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.208678}, pmid = {31004014}, issn = {1592-8721}, abstract = {Acute myeloid leukemia with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of acute myeloid leukemia cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation may improve survival if applied early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 (range: 16-76) years, acute myeloid leukemia was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow-up of 5.43 years, estimated overall survival at 5 years was 38% (95%-CI, 31-47%). Allogeneic hematopoietic cell transplantation was performed in 117 (66%) patients, including 89 in first complete remission. Allogeneic hematopoietic cell transplantation in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy (45% [95%-CI, 35-59%] and 53% [95%-CI, 42-66%], vs. 7% [95%-CI, 3-19%] and 23% [95%-CI, 13-38%]. For patients undergoing allogeneic hematopoietic cell transplantation, overall survival rates at 5 years did not differ whether performed in first (53% [95%-CI, 42-66%]), or second complete remission (58% [95%-CI, 31-100%]; n=10) or with active disease/relapse (54% [95%-CI, 34-84%]; n=18) (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) acute myeloid leukemias are poor with chemotherapy, and can be substantially improved with allogeneic hematopoietic cell transplantation.}, }
@article {pmid31004001, year = {2019}, author = {Roeker, LE and Fox, CP and Eyre, TA and Brander, D and Allan, JN and Schuster, SJ and Nabhan, C and Hill, BT and Shah, NN and Lansigan, F and Sarraf Yazdy, M and Cheson, BD and Lamanna, N and Singavi, AK and Coombs, CC and Barr, PM and Skarbnik, AP and Shadman, M and Ujjani, CS and Tuncer, HH and Winter, AM and Rhodes, J and Dorsey, C and Morse, H and Kabel, C and Pagel, JM and Williams, AM and Jacobs, R and Goy, A and Muralikrishnan, S and Pearson, LK and Sitlinger, A and Bailey, N and Schuh, A and Kirkwood, AA and Mato, AR}, title = {Tumor lysis, adverse events, and dose adjustments in 297 venetoclax treated CLL in routine clinical practice.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-19-0361}, pmid = {31004001}, issn = {1078-0432}, abstract = {PURPOSE: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AEs), and impact of dosing modifications in routine clinical practice.<br><br>EXPERIMENTAL DESIGN: This retrospective cohort study included 297 CLL venetoclax treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.<br><br>RESULTS: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). 22 patients (7.4%) discontinued venetoclax due to an AE. PFS was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.<br><br>CONCLUSION: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.}, }
@article {pmid31003603, year = {2019}, author = {Breen, N and Skinner, CS and Zheng, Y and Inrig, S and Corley, DA and Beaber, EF and Garcia, M and Chubak, J and Doubeni, C and Quinn, VP and Haas, JS and Li, CI and Wernli, KJ and Klabunde, CN and , }, title = {Time to Follow-up After Colorectal Cancer Screening by Health Insurance Type.}, journal = {American journal of preventive medicine}, volume = {56}, number = {5}, pages = {e143-e152}, doi = {10.1016/j.amepre.2019.01.005}, pmid = {31003603}, issn = {1873-2607}, abstract = {INTRODUCTION: The purpose of this study was to test the hypothesis that patients with Medicaid insurance or Medicaid-like coverage would have longer times to follow-up and be less likely to complete colonoscopy compared with patients with commercial insurance within the same healthcare systems.<br><br>METHODS: A total of 35,009 patients aged 50-64years with a positive fecal immunochemical test were evaluated in Northern and Southern California Kaiser Permanente systems and in a North Texas safety-net system between 2011 and 2012. Kaplan-Meier estimation was used between 2016 and 2017 to calculate the probability of having follow-up colonoscopy by coverage type. Among Kaiser Permanente patients, Cox regression was used to estimate hazard ratios and 95% CIs for the association between coverage type and receipt of follow-up, adjusting for sociodemographics and health status.<br><br>RESULTS: Even within the same integrated system with organized follow-up, patients with Medicaid were 24% less likely to complete follow-up as those with commercial insurance. Percentage receiving colonoscopy within 3 months after a positive fecal immunochemical test was 74.6% for commercial insurance, 63.10% for Medicaid only, and 37.5% for patients served by the integrated safety-net system.<br><br>CONCLUSIONS: This study found that patients with Medicaid were less likely than those with commercial insurance to complete follow-up colonoscopy after a positive fecal immunochemical test and had longer average times to follow-up. With the future of coverage mechanisms uncertain, it is important and timely to assess influences of health insurance coverage on likelihood of follow-up colonoscopy and identify potential disparities in screening completion.}, }
@article {pmid31002955, year = {2019}, author = {Schenk, JM and Neuhouser, ML and Beatty, SJ and VanDoren, M and Lin, DW and Porter, M and Gore, JL and Gulati, R and Plymate, SR and Wright, JL}, title = {Randomized trial evaluating the role of weight loss in overweight and obese men with early stage prostate Cancer on active surveillance: Rationale and design of the Prostate Cancer Active Lifestyle Study (PALS).}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cct.2019.04.004}, pmid = {31002955}, issn = {1559-2030}, abstract = {Active surveillance (AS) is increasingly used to monitor patients with low-risk prostate cancer; however, approximately 50% of AS patients experience disease reclassification requiring definitive treatment and little is known about patient characteristics that modify the risk of reclassification. Obesity may be one of the major contributing factors. The Prostate Cancer Active Lifestyle Study (PALS) is a clinical trial evaluating the impact of weight loss among overweight/obese (Body Mass Index (BMI) ≥ 25 kg/m2) men with clinically localized prostate cancer on AS. Two hundred participants will be randomized to either the PALS intervention, a 6-month structured diet and exercise program adapted from the Diabetes Prevention Program followed by 6 months of maintenance, or control (general diet and physical activity guidelines delivered in a single session). The PALS intervention involves one-on-one instruction with a registered dietitian and exercise physiologist to achieve the study goal of loss of 7% of baseline weight. Participation is coordinated so that the 6-month time point coincides with the participants' standard-of-care AS prostate biopsy. Primary outcomes will evaluate the intervention effects on circulating and tissue markers of glucose and insulin regulation, health-related quality of life and pathologic upgrading on follow-up prostate biopsies. Additional analyses will determine whether changes in weight and glucose regulation can be sustained for 6 months after the end of instruction. Findings from this trial may have wide reaching implications for men diagnosed with clinically-localized prostate cancer by providing an active lifestyle-based approach to improve prostate cancer patient outcomes.}, }
@article {pmid31002583, year = {2019}, author = {Sugarman, J and Lin, L and Baeten, JM and Palanee-Phillips, T and Brown, ER and Matovu Kiweewa, F and Mgodi, NM and Nair, G and Siva, S and Seils, DM and Weinfurt, KP and , }, title = {Preventive Misconception and Risk Behaviors in a Multinational HIV Prevention Trial.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/23294515.2019.1593257}, pmid = {31002583}, issn = {2329-4523}, abstract = {BACKGROUND: Some HIV prevention research participants may hold a &quot;preventive misconception&quot; (PM), an overestimate of the probability or level of personal protection afforded by trial participation. However, these reports typically rely upon small, retrospective qualitative assessments that did not use a standardized approach.<br><br>METHODS: We administered a measure of PM called PREMIS, during Microbicide Trials Network 020-A Study to Prevent Infection with a Ring for Extended Use, a large, multicenter, placebo-controlled, phase III trial evaluating the safety and efficacy of a dapivirine vaginal ring among women at risk for HIV infection in Malawi, South Africa, Uganda, and Zimbabwe. The maximum follow-up period was 2.6 years.<br><br>RESULTS: One thousand two hundred sixty-one respondents completed PREMIS at their month 3 visit (M3); 2085 at their month 12 visit (M12); and 1010 at both visits. Most participants expressed high expectations of personal benefit (EPB) and that at least one of the rings used in the trial would reduce the risk of getting HIV (expectation of maximum aggregate benefit or EMAB). There was a moderate positive correlation between EPB and EMAB at M3 (r = .43, 95% CI: .37, .47) and M12 (r = .44, 95% CI: .40, .48). However, there was variability among sites in the strength of the relationship. There was no relationship between either expectation variable and condom use, adherence, or HIV infection.<br><br>CONCLUSIONS: A majority of trial participants expressed some belief that their risk of HIV infection would be reduced by using a vaginal ring, which may signal PM. However, such beliefs were not associated with adherence, condom use, or subsequent HIV infection, and there was variability across sites. Further work is needed to understand these findings.}, }
@article {pmid31002328, year = {2019}, author = {Yang, JJ and Yu, D and Wen, W and Saito, E and Rahman, S and Shu, XO and Chen, Y and Gupta, PC and Gu, D and Tsugane, S and Xiang, YB and Gao, YT and Yuan, JM and Tamakoshi, A and Irie, F and Sadakane, A and Tomata, Y and Kanemura, S and Tsuji, I and Matsuo, K and Nagata, C and Chen, CJ and Koh, WP and Shin, MH and Park, SK and Wu, PE and Qiao, YL and Pednekar, MS and He, J and Sawada, N and Li, HL and Gao, J and Cai, H and Wang, R and Sairenchi, T and Grant, E and Sugawara, Y and Zhang, S and Ito, H and Wada, K and Shen, CY and Pan, WH and Ahn, YO and You, SL and Fan, JH and Yoo, KY and Ashan, H and Chia, KS and Boffetta, P and Inoue, M and Kang, D and Potter, JD and Zheng, W}, title = {Association of Diabetes With All-Cause and Cause-Specific Mortality in Asia: A Pooled Analysis of More Than 1 Million Participants.}, journal = {JAMA network open}, volume = {2}, number = {4}, pages = {e192696}, doi = {10.1001/jamanetworkopen.2019.2696}, pmid = {31002328}, issn = {2574-3805}, abstract = {Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations.<br><br>Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status.<br><br>This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018.<br><br>Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status.<br><br>Main Outcomes and Measures: All-cause and cause-specific mortality.<br><br>Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age.<br><br>Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.}, }
@article {pmid31001917, year = {2019}, author = {Grant, DJ and Manichaikul, A and Alberg, AJ and Bandera, EV and Barnholtz-Sloan, J and Bondy, M and Cote, ML and Funkhouser, E and Moorman, PG and Peres, LC and Peters, ES and Schwartz, AG and Terry, PD and Wang, XQ and Keku, TO and Hoyo, C and Berchuck, A and Sandler, DP and Taylor, JA and O'Brien, KM and Velez Edwards, DR and Edwards, TL and Beeghly-Fadiel, A and Wentzensen, N and Pearce, CL and Wu, AH and Whittemore, AS and McGuire, V and Sieh, W and Rothstein, JH and Modugno, F and Ness, R and Moysich, K and Rossing, MA and Doherty, JA and Sellers, TA and Permuth-Way, JB and Monteiro, AN and Levine, DA and Setiawan, VW and Haiman, CA and LeMarchand, L and Wilkens, LR and Karlan, BY and Menon, U and Ramus, S and Gayther, S and Gentry-Maharaj, A and Terry, KL and Cramer, DW and Goode, EL and Larson, MC and Kaufmann, SH and Cannioto, R and Odunsi, K and Etter, JL and Huang, RY and Bernardini, MQ and Tone, AA and May, T and Goodman, MT and Thompson, PJ and Carney, ME and Tworoger, SS and Poole, EM and Lambrechts, D and Vergote, I and Vanderstichele, A and Van Nieuwenhuysen, E and Anton-Culver, H and Ziogas, A and Brenton, JD and Bjorge, L and Salvensen, HB and Kiemeney, LA and Massuger, LFAG and Pejovic, T and Bruegl, A and Moffitt, M and Cook, L and Le, ND and Brooks-Wilson, A and Kelemen, LE and Pharoah, PDP and Song, H and Campbell, I and Eccles, D and DeFazio, A and Kennedy, CJ and Schildkraut, JM}, title = {Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.1996}, pmid = {31001917}, issn = {2045-7634}, support = {//National Institues of Health/ ; //Mayo Foundation, the Minnesota Ovarian Cancer Alliance and the Katherine B. Andersen Foundation/ ; //Radboud University Medical Centre/ ; //Princess Margaret Cancer Centre Foundation-Bridge for the Cure/ ; //American Cancer Society/ ; //The Eve Appeal (The Oak Foundation) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre/ ; //Department of Defense, CDMRP/ ; //UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge/ ; //Lon V Smith Foundation/ ; //Canadian Institutes of Health Research/ ; //National Center for Advancing Translational Sciences/ ; //National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK/ ; //Royal Marsden Hospital/ ; //Merck Pharmaceuticals, the state of Florida, Hillsborough County and the city of Tampa/ ; //National Health and Medical Research Council of Australia/ ; //Helse Vest, the Norwegian Cancer Society, and the Research Council of Norway/ ; //California Cancer Research Program/ ; //OHSU Foundation/ ; //National Institute of Environmental Health Sciences/ ; //Cancer Institute NSW/ ; //Cambridge Cancer Centre/ ; //Ovarian Cancer Research Fund/ ; //Research Centers in Minority Institutes (RCMI)/ ; //North Carolina Central University/University of North Carolina at Chapel Hill/ ; //U54 Cooperative Agreement Grant/ ; //National Cancer Institute/ ; }, abstract = {An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.}, }
@article {pmid30988301, year = {2019}, author = {Ferreira, MA and Gamazon, ER and Al-Ejeh, F and Aittomäki, K and Andrulis, IL and Anton-Culver, H and Arason, A and Arndt, V and Aronson, KJ and Arun, BK and Asseryanis, E and Azzollini, J and Balmaña, J and Barnes, DR and Barrowdale, D and Beckmann, MW and Behrens, S and Benitez, J and Bermisheva, M and Białkowska, K and Blomqvist, C and Bogdanova, NV and Bojesen, SE and Bolla, MK and Borg, A and Brauch, H and Brenner, H and Broeks, A and Burwinkel, B and Caldés, T and Caligo, MA and Campa, D and Campbell, I and Canzian, F and Carter, J and Carter, BD and Castelao, JE and Chang-Claude, J and Chanock, SJ and Christiansen, H and Chung, WK and Claes, KBM and Clarke, CL and ,  and ,  and ,  and Couch, FJ and Cox, A and Cross, SS and Czene, K and Daly, MB and de la Hoya, M and Dennis, J and Devilee, P and Diez, O and Dörk, T and Dunning, AM and Dwek, M and Eccles, DM and Ejlertsen, B and Ellberg, C and Engel, C and Eriksson, M and Fasching, PA and Fletcher, O and Flyger, H and Friedman, E and Frost, D and Gabrielson, M and Gago-Dominguez, M and Ganz, PA and Gapstur, SM and Garber, J and García-Closas, M and García-Sáenz, JA and Gaudet, MM and Giles, GG and Glendon, G and Godwin, AK and Goldberg, MS and Goldgar, DE and González-Neira, A and Greene, MH and Gronwald, J and Guénel, P and Haiman, CA and Hall, P and Hamann, U and He, W and Heyworth, J and Hogervorst, FBL and Hollestelle, A and Hoover, RN and Hopper, JL and Hulick, PJ and Humphreys, K and Imyanitov, EN and ,  and ,  and ,  and Isaacs, C and Jakimovska, M and Jakubowska, A and James, PA and Janavicius, R and Jankowitz, RC and John, EM and Johnson, N and Joseph, V and Karlan, BY and Khusnutdinova, E and Kiiski, JI and Ko, YD and Jones, ME and Konstantopoulou, I and Kristensen, VN and Laitman, Y and Lambrechts, D and Lazaro, C and Leslie, G and Lester, J and Lesueur, F and Lindström, S and Long, J and Loud, JT and Lubiński, J and Makalic, E and Mannermaa, A and Manoochehri, M and Margolin, S and Maurer, T and Mavroudis, D and McGuffog, L and Meindl, A and Menon, U and Michailidou, K and Miller, A and Montagna, M and Moreno, F and Moserle, L and Mulligan, AM and Nathanson, KL and Neuhausen, SL and Nevanlinna, H and Nevelsteen, I and Nielsen, FC and Nikitina-Zake, L and Nussbaum, RL and Offit, K and Olah, E and Olopade, OI and Olsson, H and Osorio, A and Papp, J and Park-Simon, TW and Parsons, MT and Pedersen, IS and Peixoto, A and Peterlongo, P and Pharoah, PDP and Plaseska-Karanfilska, D and Poppe, B and Presneau, N and Radice, P and Rantala, J and Rennert, G and Risch, HA and Saloustros, E and Sanden, K and Sawyer, EJ and Schmidt, MK and Schmutzler, RK and Sharma, P and Shu, XO and Simard, J and Singer, CF and Soucy, P and Southey, MC and Spinelli, JJ and Spurdle, AB and Stone, J and Swerdlow, AJ and Tapper, WJ and Taylor, JA and Teixeira, MR and Terry, MB and Teulé, A and Thomassen, M and Thöne, K and Thull, DL and Tischkowitz, M and Toland, AE and Torres, D and Truong, T and Tung, N and Vachon, CM and van Asperen, CJ and van den Ouweland, AMW and van Rensburg, EJ and Vega, A and Viel, A and Wang, Q and Wappenschmidt, B and Weitzel, JN and Wendt, C and Winqvist, R and Yang, XR and Yannoukakos, D and Ziogas, A and Kraft, P and Antoniou, AC and Zheng, W and Easton, DF and Milne, RL and Beesley, J and Chenevix-Trench, G}, title = {Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {1741}, doi = {10.1038/s41467-018-08053-5}, pmid = {30988301}, issn = {2041-1723}, abstract = {Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.}, }
@article {pmid30996101, year = {2019}, author = {Williams-Wietzikoski, CA and Campbell, MS and Payant, R and Lam, A and Zhao, H and Huang, H and Wald, A and Stevens, W and Gray, G and Farquhar, C and Rees, H and Celum, C and Mullins, JI and Lingappa, JR and Frenkel, LM}, title = {Comparisons of human immunodeficiency virus type 1 envelope variants in blood and genital fluids near the time of male-to-female transmission.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {}, doi = {10.1128/JVI.01769-18}, pmid = {30996101}, issn = {1098-5514}, abstract = {To better understand the transmission of human immunodeficiency virus type-1 (HIV-1), the genetic characteristics of male blood and genital viruses were compared to the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genitial specimens near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1 env gp160. Eight of twenty-nine couples examined yielded viral sequences from both tissues. Analysis of these couples' sequences demonstrated, with one exception, that the women's founding viral populations arose from a single viral variant, and were CCR5-tropic despite X4-variants detected within four males. The median genetic distance of the imputed MRCA of the women's founder viruses was closer to the semen than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the males' blood and genital viruses were consistently compartmentalized in only two of eight men. No distinct amino acid signatures in the men's viruses were found to link to the women's founders, nor did the women's env have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for co-receptor tropism, is consistent with others' findings in male-to-female and high-risk transmissions. The infrequent compartmentization between transmitters' blood and semen viruses suggest that cell-free blood virus likely includes HIV-1 sequences representative of semen.Importance Mucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that males' genital tract viruses were rarely distinct from blood variants. The imputed founder viruses in women were genetically similar to both blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.}, }
@article {pmid30995984, year = {2019}, author = {Barker, JN and Kempenich, J and Kurtzberg, J and Brunstein, CG and Delaney, C and Milano, F and Politikos, I and Shpall, EJ and Scaradavou, A and Dehn, J}, title = {CD34+ cell content of 126 341 cord blood units in the US inventory: implications for transplantation and banking.}, journal = {Blood advances}, volume = {3}, number = {8}, pages = {1267-1271}, doi = {10.1182/bloodadvances.2018029157}, pmid = {30995984}, issn = {2473-9537}, abstract = {CD34+ cell dose is critical for cord blood (CB) engraftment. However, the CD34+ content of the CB inventory in the United States is unknown. We examined the CD34+ cell content of 126 341 red blood cell-depleted US units banked from January 2007 to September 2017 with a total nucleated cell (TNC) count of ≥90 × 107 and a cryovolume of 24-55 mL. Median pre-cryopreservation TNC content was 127 × 107 (interquartile range [IQR], 108-156 × 107); CD34+ cell content was 44 × 105 (IQR, 29 to 67 × 105). The median CD34+:TNC ratio was 0.34%. TNC and CD34+ cell content correlation was weak (r = 0.24). Of 7125 units with TNCs of ≥210 × 107, only 47% had CD34+ content of ≥100 × 105 However, some units had high CD34+ content for a given TNC count. Only 4% of CB units were acceptable as single-unit grafts (TNCs, ≥2.5 × 107/kg; CD34+ cells, ≥1.5 × 105/kg) for 70-kg patients; 22% of units were adequate for 70-kg patients using lower dose criteria (TNCs, ≥1.5 × 107/kg; CD34+ cells, ≥1.0 × 105/kg) suitable for a double-unit graft. These findings highlight that units with the highest TNC dose may not have the highest CD34+ dose, units with unexpectedly high CD34+ content (a ratio of >1.0%) should be verified, and the US CB inventory of adequately sized single units for larger patients is small. They also support the ongoing use of double-unit grafts, a focus on banking high-dose units, and development of expansion technologies.}, }
@article {pmid30994576, year = {2019}, author = {Mitchell, CM and Guthrie, KA and Larson, J and Diem, S and LaCroix, AZ and Caan, B and Shifren, JL and Woods, NF and Heiman, JR and Lindau, ST and Reed, SD}, title = {Sexual frequency and pain in a randomized clinical trial of vaginal estradiol tablets, moisturizer, and placebo in postmenopausal women.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/GME.0000000000001341}, pmid = {30994576}, issn = {1530-0374}, abstract = {OBJECTIVE: To evaluate the efficacy of two common interventions for bothersome postmenopausal vaginal symptoms on improving sexual frequency and pain.<br><br>METHODS: This is a post-hoc analysis of data from a 12-week double-blind placebo-controlled trial that randomized postmenopausal women (ages 45-70 years) with moderate-severe genitourinary discomfort to vaginal 10 μg estradiol tablet plus placebo gel (n = 102), placebo tablet plus vaginal moisturizer (n = 100), or dual placebo (n = 100). Outcomes were proportion of sexually active women at 12 weeks, frequency of sexual activity, and pain severity with sexual activity (0-3 scale). Consistent with the original study design, comparisons were made between each active arm and the dual placebo arm.<br><br>RESULTS: Most women enrolled in the trial, 294/302 (97%), had sufficient data to be included in this analysis. Mean age of participants was 61 years, most were white (88%), college educated (66%), and most reported sexual activity in the month before enrollment (81%). After 12 weeks of treatment, a similar proportion of women in the vaginal estrogen and dual placebo groups reported sexual activity in the past week (50% and 40%; P = 0.10) and the past month (78% and 84%, P = 0.52). Mean (standard deviation) pain with sexual activity scores at 12 weeks were similar between vaginal estrogen (1.0 [1.0]) and placebo (0.9 [0.9], P = 0.52] groups. The proportion sexually active at 12 weeks (35%) and mean (standard deviation) pain severity in the vaginal moisturizer group (1.1 [0.9]) did not differ from placebo (P = 0.36).<br><br>CONCLUSIONS: Compared to placebo, neither low-dose vaginal estradiol nor vaginal moisturizer treatment over 12 weeks resulted in significantly greater increases in the proportions of women reporting sexual activity or improvement in pain scores with sexual activity.<br><br>TRIAL REGISTRATION: Clinical trials.gov: NCT02516202.}, }
@article {pmid30994570, year = {2019}, author = {Otte, JL and Bakoyannis, G and Rand, KL and Ensrud, KE and Guthrie, KA and Joffe, H and McCurry, SM and Newton, KM and Carpenter, JS}, title = {Confirmatory factor analysis of the Insomnia Severity Index (ISI) and invariance across race: a pooled analysis of MsFLASH data.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/GME.0000000000001343}, pmid = {30994570}, issn = {1530-0374}, abstract = {OBJECTIVE: Women's sleep at menopause is widely reported to be problematic. The Insomnia Severity Index (ISI) is a commonly used tool for quantifying sleep problems in clinical and research settings, but psychometric properties in postmenopausal women have not been reported. Our study aim was to examine the factor structure of the ISI in a large and diverse sample of midlife women with hot flashes.<br><br>METHODS: Baseline data were from 899 women enrolled in one of the three clinical trials using similar entry criteria conducted by the Menopause Strategies Finding Lasting Answers to Symptoms and Health research network. We conducted confirmatory factor analyses for the total sample and within strata defined by race/ethnicity (black and white women).<br><br>RESULTS: The ISI had two factors in the total sample. The two-factor structure was consistent across black and white women, with the exception of one item &quot;difficulty falling asleep.&quot;<br><br>CONCLUSIONS: The ISI in midlife women with hot flashes is composed of two factors that capture dimensions of the insomnia severity and daytime impact. The instrument is a psychometrically sound scale appropriate for use in research and clinical practice to capture the severity and daytime impact of insomnia symptoms in diverse samples of midlife women with hot flashes. An abbreviated screening of two items could be considered to determine if further evaluation is needed of sleep complaints.}, }
@article {pmid30992266, year = {2019}, author = {Baker, KS and Leisenring, WM and Goodman, PJ and Ermoian, RP and Flowers, ME and Shoch, G and Storb, R and Sandmaier, BM and Deeg, HJ}, title = {Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2018874115}, pmid = {30992266}, issn = {1528-0020}, abstract = {We examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMN) in the era of reduced intensity and non-myeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4,905 one-year survivors of allogeneic HCT for hematologic malignancies (N=4,500) or non-malignant disorders (N=405) transplanted between 1969-2014 we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMN by 30 years after HCT was 22.0%. Compared to age, sex and calendar year matched SEER population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR 28.8), oral cavity (SIR 13.8), skin (SIR 7.3), central nervous system (SIR 6.0), and endocrine organs (SIR 4.9). The highest excess absolute risks (EAR) were seen with breast cancer (EAR 2.2) and cancers of the oral cavity (EAR 1.5) and skin (EAR 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1,00 cGy) or high dose fractionated (1,440-1,750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still 2-fold higher than in the general population. These data demonstrate a strong effect of TBI dose, and dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMN increases with follow-up time, thus HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs.}, }
@article {pmid30991417, year = {2019}, author = {Eickbush, MT and Young, JM and Zanders, SE}, title = {Killer meiotic drive and dynamic evolution of the wtf gene family.}, journal = {Molecular biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/molbev/msz052}, pmid = {30991417}, issn = {1537-1719}, abstract = {Natural selection works best when the two alleles in a diploid organism are transmitted to offspring at equal frequencies. Despite this, selfish loci known as meiotic drivers that bias their own transmission into gametes are found throughout eukaryotes. Drive is thought to be a powerful evolutionary force, but empirical evolutionary analyses of drive systems are limited by low numbers of identified meiotic drive genes. Here, we analyze the evolution of the wtf gene family of Schizosaccharomyces pombe that contains both killer meiotic drive genes and suppressors of drive. We completed assemblies of all wtf genes for two S. pombe isolates, as well as a subset of wtf genes from over 50 isolates. We find that wtf copy number can vary greatly between isolates, and that amino acid substitutions, expansions and contractions of DNA sequence repeats, and nonallelic gene conversion between family members all contribute to dynamic wtf gene evolution. This work demonstrates the power of meiotic drive to foster rapid evolution and identifies a recombination mechanism through which transposons can indirectly mobilize meiotic drivers.}, }
@article {pmid30990052, year = {2019}, author = {Dube, K and Simoni, J and Louella, M and Sylla, L and Mohamed, ZH and Patel, H and Luter, S and Collier, AC}, title = {Acceptability of Cell and Gene Therapy for Curing HIV Infection among People Living with HIV in the Northwestern United States: A Qualitative Study.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/AID.2019.0021}, pmid = {30990052}, issn = {1931-8405}, abstract = {Multiple strategies to cure HIV infection are under investigation, including cell and gene therapy approaches. Research, and ultimately treatment, with these novel strategies will require patients' willingness to participate. To elicit the perspectives of people living with HIV (PLWH) specific to these novel approaches, we conducted four focus group discussions with a diverse group of 19 English-speaking men and women living with HIV in care at a large academic HIV clinic in the northwestern U.S. Thematic analysis indicated participants expressed initial fear about cell and gene therapy research. They articulated specific concerns about risks, including analytical treatment interruptions, and thought only a person in desperate straits would participate. They voiced significant mistrust of research in general and believed there already was already a cure from HIV that was being withheld from the poor. Overall, they were satisfied with their health and quality of life on antiretroviral therapy. These findings suggest the importance of community engagement and educational efforts about cell and gene therapy for HIV cure to ensure optimal collaborative partnerships.}, }
@article {pmid30989580, year = {2019}, author = {Lorona, NC and Cook, LS and Tang, MC and Hill, DA and Wiggins, CL and Li, CI}, title = {Recent Use of Oral Contraceptives and Risk of Luminal B, Triple-Negative, and HER2-Overexpressing Breast Cancer.}, journal = {Hormones &amp; cancer}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12672-019-00362-5}, pmid = {30989580}, issn = {1868-8500}, support = {261201000029C//National Cancer Institute/ ; P50 CA148143//National Cancer Institute/ ; 261201000033C//National Cancer Institute/ ; P30 CA118100-11//National Cancer Institute/ ; HHSN261201800014I,Task Order HHSN26100001//National Cancer Institute/ ; P50 CA148143//National Cancer Institute/ ; P50 CA148143//National Cancer Institute/ ; P30 CA118100-11//National Cancer Institute/ ; P30 CA118100-11//National Cancer Institute/ ; BC112721//U.S. Department of Defense/ ; }, abstract = {Oral contraceptive use is a well-established risk factor for breast cancer and is common among reproductive-aged women in the USA. Its relationship with less common, more aggressive, molecular subtypes is less clear. A population-based case-case analysis was conducted comparing three less common molecular subtypes to luminal A breast cancer among 1701 premenopausal cases aged 21-49 diagnosed with a first primary invasive breast cancer between 2004 and 2015. Medical record reviews and structured interviewer-administered questionnaires were used to collect data on oral contraceptive use. Multinomial logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for recency of oral contraceptive use for each subtype of breast cancer. Current use of oral contraceptives and use within 5 years before diagnosis was associated with lower odds of H2E tumors compared with luminal A tumors [OR = 0.5, 95% CI: 0.3, 0.9 and OR = 0.5, 95% CI: 0.4, 0.8, respectively] with increasing duration associated with decreasing odds (p for trend < 0.05). Oral contraceptive use was not associated with risks of TN or luminal B breast cancer. Oral contraceptive use may be more strongly positively associated with risks of luminal A, luminal B, and TN breast cancer than with risk of H2E tumors. These findings contribute to the etiological understanding of different molecular subtypes of breast cancer.}, }
@article {pmid30982082, year = {2019}, author = {Selinger, C and Dimitrov, DT and Welkhoff, PA and Bershteyn, A}, title = {The future of a partially effective HIV vaccine: assessing limitations at the population level.}, journal = {International journal of public health}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00038-019-01234-z}, pmid = {30982082}, issn = {1661-8564}, support = {OPP1110049//Bill and Melinda Gates Foundation/ ; }, abstract = {OBJECTIVES: Mathematical models have unanimously predicted that a first-generation HIV vaccine would be useful and cost-effective to roll out, but that its overall impact would be insufficient to reverse the epidemic. Here, we explore what factors contribute most to limiting the impact of such a vaccine.<br><br>METHODS: Ranging from a theoretical ideal to a more realistic regimen, mirroring the one used in the currently ongoing trial in South Africa (HVTN 702), we model a nested hierarchy of vaccine attributes such as speed of scale-up, efficacy, durability, and return rates for booster doses.<br><br>RESULTS: The predominant reasons leading to a substantial loss of vaccine impact on the HIV epidemic are the time required to scale up mass vaccination, limited durability, and waning of efficacy.<br><br>CONCLUSIONS: A first-generation partially effective vaccine would primarily serve as an intermediate milestone, furnishing correlates of immunity and platforms that could serve to accelerate future development of a highly effective, durable, and scalable next-generation vaccine capable of reversing the HIV epidemic.}, }
@article {pmid30978619, year = {2019}, author = {Fisher, CE and Boeckh, M and Jerome, KR and Englund, J and Kuypers, J}, title = {Evaluating addition of self-collected throat swabs to nasal swabs for respiratory virus detection.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {115}, number = {}, pages = {43-46}, doi = {10.1016/j.jcv.2019.04.001}, pmid = {30978619}, issn = {1873-5967}, abstract = {BACKGROUND: Early and accurate detection of respiratory viruses (RV) is important for patient management. We have previously shown that self-collected nasal swabs (NS) are feasible and as sensitive as clinician-collected nasal washes for detection of RV, but the additive benefit of self-collected throat swabs is unknown.<br><br>OBJECTIVES: To evaluate the added yield of self-collected nasal to throat swabs for detection of RV by PCR in patients with upper respiratory tract infection (URTI) symptoms.<br><br>STUDY DESIGN: Patients with URTI symptoms self-collected paired polyurethane foam NS and nylon flocked throat swabs and completed a symptom survey. Swabs were tested for 12 RV by real-time reverse transcription (RT)-PCR. Descriptive, McNemar's, and Wilcoxon signed rank statistical tests were used.<br><br>RESULTS: 115 paired nasal and throat swabs were collected from 63 individuals, with 71/115 (62%) positive for a RV by at least one specimen, including 51 positive by both, 17 positive by NS only, and 3 positive by throat swab only. The sensitivity of NS was 96% (95%CI: 88-99) versus 76% (95% CI: 65-85) in throat swabs, p<0.001. The median PCR cycle threshold (Ct) in 51 concordant samples was lower (indicating higher viral concentration) in NS (25.1) versus throat swabs (32.0). The three samples positive only by throat swab had high Ct values (33.8, 36.2, and 38.8, all rhinovirus).<br><br>CONCLUSION: Self-collection of NS was significantly more sensitive than self collection of throat swabs for detection of RV by RT-PCR. The addition of throat sampling does not appear to increase the diagnostic load in the self-testing setting.}, }
@article {pmid30978304, year = {2019}, author = {Bien, SA and Wojcik, GL and Hodonsky, CJ and Gignoux, CR and Cheng, I and Matise, TC and Peters, U and Kenny, EE and North, KE}, title = {The Future of Genomic Studies Must Be Globally Representative: Perspectives from PAGE.}, journal = {Annual review of genomics and human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-genom-091416-035517}, pmid = {30978304}, issn = {1545-293X}, abstract = {The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinical domain for both rare-variant identification and genetic risk prediction. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, }
@article {pmid30977845, year = {2019}, author = {Stankiewicz Karita, HC and Hauge, K and Magaret, A and Mao, C and Schouten, J and Grieco, V and Xi, LF and Galloway, DA and Madeleine, MM and Wald, A}, title = {Effect of Human Papillomavirus Vaccine to Interrupt Recurrence of Vulvar and Anal Neoplasia (VIVA): A Trial Protocol.}, journal = {JAMA network open}, volume = {2}, number = {4}, pages = {e190819}, doi = {10.1001/jamanetworkopen.2019.0819}, pmid = {30977845}, issn = {2574-3805}, abstract = {Importance: Human papillomavirus (HPV), particularly HPV type 16, causes most anal and vulvar high-grade squamous intraepithelial lesions (HSIL), which are precursors to cancer. After initial treatment of HSIL, more than 30% of patients will have disease recurrence, with even higher recurrence among HIV-positive individuals and men who have sex with men. Recurrences can be debilitating and lead to significant morbidity and medical expense. Observational studies suggest a possible therapeutic benefit of the licensed HPV vaccines in reducing recurrent lesions in previously infected persons.<br><br>Objective: To test whether the licensed prophylactic HPV vaccine (Gardasil-9) can reduce the risk of HSIL recurrence by 50% in previously unvaccinated individuals recently treated for anal or vulvar HSIL.<br><br>This is a trial protocol for a randomized, double-blind, placebo-controlled, proof-of-concept clinical trial. Eligible participants are aged 27 to 69 at study start and have not received prior HPV vaccination, have had anal or vulvar HSIL diagnosed on or after January 1, 2014, and have no evidence of HSIL recurrence at screening. Persons infected with HIV are eligible for the study provided they are receiving antiretroviral therapy. Target enrollment is 345 individuals. The primary outcome is time to histopathologically confirmed recurrence of HSIL. Differences in the risk for recurrence of HSIL will be evaluated using Cox proportional hazard models. Additional analyses include (1) frequency of HSIL recurrence; (2) role of HPV antibodies in deterring recurrence; (3) role of HPV persistence in recurrence, as measured by HPV genotype or HPV-16 variant lineage determined using swab samples collected at months 0, 18, and 36; and (4) incidence of adverse events. The study will be conducted at the University of Washington Virology Research Clinic from 2017 through 2022. Participants will be followed up for up to 36 months in the clinic, and up to 42 months by telephone.<br><br>Discussion: Management of persistent or rapidly recurring anogenital HSIL remains challenging. Results from this study will provide evidence on whether incorporating the nonavalent HPV vaccine into routine care can decrease recurrence of anal and vulvar HSIL.<br><br>Trial Registration: ClinicalTrials.gov identifier: NCT03051516.}, }
@article {pmid30976958, year = {2019}, author = {Niu, X and Li, CI and Mueller, BA}, title = {Obstetrical and infant outcomes among women with neoplasms during pregnancy.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10552-019-01167-1}, pmid = {30976958}, issn = {1573-7225}, abstract = {PURPOSE: One in 1,000 pregnancies is complicated by malignancies. Prevalence is greater for benign neoplasms. Adverse outcomes among women with malignancies have been reported. Less is known of postpartum outcomes for infants, or outcomes among women with benign neoplasms.<br><br>METHODS: We conducted a population-based cohort study using Washington State-linked vital-hospital discharge records. Women with neoplasms (707 malignant; 13,156 benign) with deliveries in 1987-2012 were identified, and a randomly selected comparison cohort. Obstetrical/infant outcomes and rehospitalization < 2 years post-delivery were compared separately for each group by multivariable regressions to estimate risk ratios (RR) and 95% confidence intervals (CI).<br><br>RESULTS: Women with either condition had increased anemia, cesarean, and preterm delivery; their infants were more often < 2,500 g or jaundiced. Women with benign conditions had increased gestational diabetes (RR = 1.20; 95% CI 1.12-1.28) and preeclampsia (RR = 1.27; 95% CI 1.18-1.36); their infants had increased malformations (RR = 1.29; 95% CI 1.19-1.38). Women with neoplasms more often were hospitalized seven or more days or rehospitalized; their infants' hospitalizations were also longer.<br><br>CONCLUSION: Malignant and benign neoplasms were associated with several adverse outcomes. Reasons for relationships of benign neoplasms with gestational diabetes, preeclampsia, and congenital malformations merit further study.}, }
@article {pmid30976806, year = {2019}, author = {Basta, NE and Halloran, ME}, title = {Evaluating the Effectiveness of Vaccines Using a Regression Discontinuity Design.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwz043}, pmid = {30976806}, issn = {1476-6256}, abstract = {The regression discontinuity design (RDD), first proposed in the educational psychology literature and popularized in econometrics in the 1960s, has only recently been applied to epidemiologic research. A critical aim of infectious disease epidemiologists and global health researchers is to evaluate disease prevention and control strategies, including the impact of vaccines and vaccination programs. RDDs have very rarely been used in this context. This quasi-experimental approach using observational data is designed to quantify the effect of an intervention when eligibility for the intervention is based on a defined cutoff such as age or grade in school, making it ideally suited to estimating vaccine effects given that many vaccination programs and mass-vaccination campaigns define eligibility in this way. Here, we describe key features of RDDs in general, then specific scenarios, with examples, to illustrate that RDDs are an important tool for advancing our understanding of vaccine effects. We argue that epidemiologic researchers should consider RDDs when evaluating interventions designed to prevent and control diseases. This approach can address a wide range of research questions, especially those for which randomized clinical trials would present major challenges or be infeasible. Finally, we propose specific ways in which RDDs could advance future vaccine research.}, }
@article {pmid30975893, year = {2019}, author = {Hartweger, H and McGuire, AT and Horning, M and Taylor, JJ and Dosenovic, P and Yost, D and Gazumyan, A and Seaman, MS and Stamatatos, L and Jankovic, M and Nussenzweig, MC}, title = {HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells.}, journal = {The Journal of experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1084/jem.20190287}, pmid = {30975893}, issn = {1540-9538}, abstract = {A small number of HIV-1-infected individuals develop broadly neutralizing antibodies to the virus (bNAbs). These antibodies are protective against infection in animal models. However, they only emerge 1-3 yr after infection, and show a number of highly unusual features including exceedingly high levels of somatic mutations. It is therefore not surprising that elicitation of protective immunity to HIV-1 has not yet been possible. Here we show that mature, primary mouse and human B cells can be edited in vitro using CRISPR/Cas9 to express mature bNAbs from the endogenous Igh locus. Moreover, edited B cells retain the ability to participate in humoral immune responses. Immunization with cognate antigen in wild-type mouse recipients of edited B cells elicits bNAb titers that neutralize HIV-1 at levels associated with protection against infection. This approach enables humoral immune responses that may be difficult to elicit by traditional immunization.}, }
@article {pmid30912228, year = {2019}, author = {Chen, L and Chen, D and Jiang, Y and Zhang, J and Yu, J and DuFort, CC and Hingorani, SR and Zhang, X and Wu, C and Chiu, DT}, title = {A BODIPY-Based Donor/Donor-Acceptor System: Towards Highly Efficient Long-Wavelength-Excitable Near-IR Polymer Dots with Narrow and Strong Absorption Features.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {}, number = {}, pages = {}, doi = {10.1002/anie.201902077}, pmid = {30912228}, issn = {1521-3773}, support = {R01MH115767//Foundation for the National Institutes of Health/ ; 61335001//National Natural Science Foundation of China/ ; 81771930//National Natural Science Foundation of China/ ; 2018YFB04007200//National Key R&amp;D Plan of China/ ; JCYJ20170307110157501//Shenzhen Science and Technology Innovation Commission/ ; R01 MH115767/MH/NIMH NIH HHS/United States ; }, abstract = {Bright long-wavelength-excitable semiconducting polymer dots (LWE-Pdots) are highly desirable for in vivo imaging and multiplexed in vitro bioassays. LWE-Pdots have been obtained by incorporating a near-infrared (NIR) emitter into the backbone of a polymer host to develop a binary donor-acceptor (D-A) system. However, they usually suffer from severe concentration quenching and a trade-off between fluorescence quantum yield (Φf) and absorption cross-section (σ). Herein, we describe a ternary component (D1 /D2 -A) strategy to achieve ultrabright, green laser-excitable Pdots with narrow-band NIR emission by introducing a BODIPY-based assistant polymer donor as D1 . The D1 /D2 -A Pdots possess improved Φf and σ compared to corresponding binary D2 -A Pdots. Their Φf is as high as 40.2 %, one of the most efficient NIR Pdots reported. The D1 /D2 -A Pdots show ultrahigh single-particle brightness, 83-fold brighter than Qdot 705 when excited by a 532 nm laser. When injected into mice, higher contrast in vivo tumor imaging was achieved using the ternary Pdots versus the binary D-A Pdots.}, }
@article {pmid30973942, year = {2019}, author = {Hensley-McBain, T and Wu, MC and Manuzak, JA and Cheu, RK and Gustin, A and Driscoll, CB and Zevin, AS and Miller, CJ and Coronado, E and Smith, E and Chang, J and Gale, M and Somsouk, M and Burgener, AD and Hunt, PW and Hope, TJ and Collier, AC and Klatt, NR}, title = {Increased mucosal neutrophil survival is associated with altered microbiota in HIV infection.}, journal = {PLoS pathogens}, volume = {15}, number = {4}, pages = {e1007672}, doi = {10.1371/journal.ppat.1007672}, pmid = {30973942}, issn = {1553-7374}, abstract = {Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions.}, }
@article {pmid30973611, year = {2019}, author = {Adams, S and Gatti-Mays, ME and Kalinsky, K and Korde, LA and Sharon, E and Amiri-Kordestani, L and Bear, H and McArthur, HL and Frank, E and Perlmutter, J and Page, DB and Vincent, B and Hayes, JF and Gulley, JL and Litton, JK and Hortobagyi, GN and Chia, S and Krop, I and White, J and Sparano, J and Disis, ML and Mittendorf, EA}, title = {Current Landscape of Immunotherapy in Breast Cancer: A Review.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2018.7147}, pmid = {30973611}, issn = {2374-2445}, abstract = {Importance: There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease.<br><br>Observations: After searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established.<br><br>Conclusions and Relevance: It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.}, }
@article {pmid30972645, year = {2019}, author = {Zahnd, WE and Davis, MM and Rotter, JS and Vanderpool, RC and Perry, CK and Shannon, J and Ko, LK and Wheeler, SB and Odahowski, CL and Farris, PE and Eberth, JM}, title = {Rural-urban differences in financial burden among cancer survivors: an analysis of a nationally representative survey.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00520-019-04742-z}, pmid = {30972645}, issn = {1433-7339}, support = {N/A//National Cancer Institute/ ; N/A//Centers for Disease Control and Prevention/ ; }, abstract = {PURPOSE: Rural cancer survivors may disproportionately experience financial problems due to their cancer because of greater travel costs, higher uninsured/underinsured rates, and other factors compared to their urban counterparts. Our objective was to examine rural-urban differences in reported financial problems due to cancer using a nationally representative survey.<br><br>METHODS: We used data from three iterations of the National Cancer Institute's Health Information and National Trends Survey (2012, 2014, and 2017) to identify participants who had a previous or current cancer diagnosis. Our outcome of interest was self-reported financial problems associated with cancer diagnosis and treatment. Rural-urban status was defined using 2003 Rural-Urban Continuum Codes. We calculated weighted percentages and Wald chi-square statistics to assess rural-urban differences in demographic and cancer characteristics. In multivariable logistic regression models, we examined the association between rural-urban status and other factors and financial problems, reporting the corresponding adjusted predicted probabilities.<br><br>FINDINGS: Our sample included 1359 cancer survivors. Rural cancer survivors were more likely to be married, retired, and live in the Midwest or South. Over half (50.5%) of rural cancer survivors reported financial problems due to cancer compared to 38.8% of urban survivors (p = 0.02). This difference was attenuated in multivariable models, 49.3 and 38.7% in rural and urban survivors, respectively (p = 0.06).<br><br>CONCLUSIONS: A higher proportion of rural survivors reported financial problems associated with their cancer diagnosis and treatment compared to urban survivors. Future research should aim to elucidate these disparities and interventions should be tested to address the cancer-related financial problems experienced by rural survivors.}, }
@article {pmid30972617, year = {2019}, author = {Poston, JN and Gernsheimer, TB}, title = {Glucocorticoids promote response to thrombopoietin-receptor agonists in refractory ITP: a case series.}, journal = {International journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12185-019-02638-6}, pmid = {30972617}, issn = {1865-3774}, support = {T32 HL007093//National Heart, Lung, and Blood Institute/ ; }, abstract = {A proportion of patients with immune thrombocytopenic purpura are refractory to multiple therapies including thrombopoietin-receptor agonists (TPO-RA). We report 10 patients who did not respond to a TPO-RA until the addition of a glucocorticoid. These patients were previously treated with a median of 6 therapies. One patient elected to discontinue both medications despite persistent thrombocytopenia. The remaining 9 patients continued on the combination of prednisone (doses 5 mg every other day to 10 mg daily) and a TPO-RA. Combination therapy with low dose glucocorticoid and a TPO-RA may be an option for patients unresponsive to a TPO-RA alone.}, }
@article {pmid30970227, year = {2019}, author = {Shadman, M and Pergam, SA}, title = {Influenza in the Air.}, journal = {Journal of oncology practice}, volume = {15}, number = {4}, pages = {185-186}, doi = {10.1200/JOP.19.00144}, pmid = {30970227}, issn = {1935-469X}, }
@article {pmid30969277, year = {2019}, author = {Nash, SH and Peters, U and Redwood, D}, title = {Developing an Epidemiologic Study to Investigate Risk Factors for Colorectal Cancer Among Alaska Native People.}, journal = {Journal of public health management and practice : JPHMP}, volume = {}, number = {}, pages = {}, doi = {10.1097/PHH.0000000000000994}, pmid = {30969277}, issn = {1550-5022}, abstract = {Alaska Native (AN) people have among the highest rates of colorectal cancer (CRC) recorded globally. Preventing CRC is an important health priority of AN tribal health leaders and communities. Lifestyle and genetic risk and protective factors for CRC among AN people remain understudied. We have been working to establish a tribally led, community-based, comprehensive investigation of lifestyle and genetic risk and protective factors for CRC among AN people. We describe the process of initiating this research study, including conversations with key tribal health system staff. We discuss themes that arose during these conversations and literature review and describe how those themes were used during the study design and protocol development phase. This description is intended to provide guidance to other researchers working to establish community-based studies of cancer risk, particularly among tribal communities.}, }
@article {pmid30964816, year = {2019}, author = {Sangaramoorthy, M and Hines, LM and Torres-Mejía, G and Phipps, AI and Baumgartner, KB and Wu, AH and Koo, J and Ingles, SA and Slattery, ML and John, EM}, title = {A Pooled Analysis of Breastfeeding and Breast Cancer Risk by Hormone Receptor Status in Parous Hispanic Women.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {30}, number = {3}, pages = {449-457}, doi = {10.1097/EDE.0000000000000981}, pmid = {30964816}, issn = {1531-5487}, abstract = {BACKGROUND: Data on breastfeeding and breast cancer risk are sparse and inconsistent for Hispanic women.<br><br>METHODS: Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the United States and Mexico, we examined the association of breastfeeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, and the joint effects of breastfeeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.<br><br>RESULTS: Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER- and PR- breast cancer. Increasing duration of breastfeeding was associated with decreasing breast cancer risk (≥25 vs. 0 months: OR = 0.73; 95% CI = 0.60, 0.89; Ptrend = 0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breastfeeding further reduced HR+ breast cancer risk. Additionally, breastfeeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.<br><br>CONCLUSIONS: Our findings suggest that breastfeeding is associated with reduced risk of both HR+ and ER- and PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.}, }
@article {pmid30964732, year = {2019}, author = {Sugalski, JM and Kubal, T and Mulkerin, DL and Caires, RL and Moore, PJ and Fiorarancio Fahy, R and Gordon, JN and Augustyniak, CZ and Szymanski, GM and Olsen, M and Frantz, DK and Quinn, MA and Kidd, SK and Krause, DM and Carlson, RW and Stewart, FM}, title = {National Comprehensive Cancer Network Infusion Efficiency Workgroup Study: Optimizing Patient Flow in Infusion Centers.}, journal = {Journal of oncology practice}, volume = {}, number = {}, pages = {JOP1800563}, doi = {10.1200/JOP.18.00563}, pmid = {30964732}, issn = {1935-469X}, abstract = {PURPOSE: The National Comprehensive Cancer Network (NCCN) formed an Infusion Efficiency Workgroup to determine best practices for operating efficient and effective infusion centers.<br><br>METHODS: The Workgroup conducted three surveys that were distributed to NCCN member institutions regarding average patient wait time, chemotherapy premixing practices, infusion chair use, and premedication protocols. To assess chair use, the Workgroup identified and defined five components of chair time.<br><br>RESULTS: The average patient wait time in infusion centers ranged from 25 to 102 minutes (n = 23; mean, 58 minutes). Five of 26 cancer centers (19%) routinely mix chemotherapy drugs before patient arrival for patients meeting specified criteria. Total planned chair time for subsequent doses of the same drug regimens for the same diseases varied greatly among centers, as follows: Administration of doxorubicin and cyclophosphamide ranged from 85 to 240 minutes (n = 22); of FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplation) ranged from 270 to 420 minutes (n = 22); of rituximab ranged from 120 to 350 minutes (n = 21); of paclitaxel plus carboplatin ranged from 255 to 380 minutes (n = 21); and of zoledronic acid ranged from 30 to 150 minutes (n = 22) for planned total chair time. Cancer centers were found to use different premedication regimens with varying administration routes that ranged in administration times from zero to 60 minutes.<br><br>CONCLUSION: There is a high degree of variation among cancer centers in regard to planned chair time for the same chemotherapy regimens, providing opportunities for improved efficiency, increased revenue, and more standardization across centers. The NCCN Workgroup demonstrates potential revenue impact and provides recommendations for cancer centers to move toward more efficient and more standard practices.}, }
@article {pmid30964382, year = {2019}, author = {Wagner, E and Patrick, DL and Khandelwal, N and Brumback, L and Starks, H and Fausto, J and Dunlap, BS and Lober, W and Sibley, J and Loggers, ET and Curtis, JR and Engelberg, RA}, title = {The Influence of Multimorbidity on Health Care Utilization at the End of Life for Patients with Chronic Conditions.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/jpm.2018.0349}, pmid = {30964382}, issn = {1557-7740}, abstract = {OBJECTIVE: To evaluate the association between the number of chronic conditions and hospital utilization at the end of life.<br><br>BACKGROUND: An understanding of the association of multimorbidity with health care utilization at the end of life may inform interventions to improve quality of care for these patients.<br><br>METHODS: A mortality follow-back analysis using Washington State death records and electronic health records. Subject included patients in the UW Medicine system who had at least one chronic condition and died between 2010 and 2015. Utilization was measured by inpatient admissions, emergency department use, and intensive care unit (ICU) admissions in the last 30 days of life.<br><br>RESULTS: For all utilization types, patients with three or more chronic conditions (n = 5124) had significantly higher utilization (p < 0.001) in the last 30 days of life than those with two (n = 5775) or one condition (n = 11,169). Comparing 3 versus 2 versus 1 conditions, the following percentages of patients had each type of utilization: inpatient admissions (37% vs. 28% vs. 19%), ED admissions (5% vs. 4% vs. 2%), and ICU care (28% vs. 20% vs. 12%).<br><br>DISCUSSION: Multimorbidity was associated with greater health care utilization at the end of life among patients representing a range of ages and covered by diverse insurers.}, }
@article {pmid30962501, year = {2019}, author = {Salit, RB and Scott, BL and Stevens, EA and Baker, KK and Gooley, TA and Deeg, HJ}, title = {Pre-hematopoietic cell transplant Ruxolitinib in patients with primary and secondary myelofibrosis.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0523-3}, pmid = {30962501}, issn = {1476-5365}, support = {P30 CA015704//U.S. Department of Health &amp; Human Services | NIH | NIH Clinical Center (Clinical Center)/ ; }, abstract = {Ruxolitinib (Rux), a Jak1/2 inhibitor, results in reduced spleen size and improvement in constitutional symptoms in the majority of patients with myelofibrosis (MF). Therefore Rux, when given prior to hematopoietic cell transplantation (HCT) in patients with MF was hypothesized to improve engraftment, decrease incidence and severity of graft-versus-host disease, and lower non-relapse mortality (NRM). We conducted a phase II prospective trial to assess the effects of pre-HCT Rux on post-HCT outcomes in patients with MF. The primary endpoint was 2-year overall survival. To date, 28 patients (median age 56 years) have been transplanted. The median time on Rux pre-HCT was 7 months. Twenty-three patients received myeloablative and five reduced intensity conditioning. Donors included 14 HLA-matched siblings, 11 matched unrelated, 1 allele mismatched unrelated, and 3 umbilical cord blood. There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Two patients died from NRM and two patients relapsed. With a median follow-up of 13 months, overall survival is 93% (95% CI: 0.73, 0.98) at 1 year and 86% (95% CI: 0.61, 0.96) at 2 years post-HCT. This study demonstrates that pre-HCT Rux is well tolerated and suggests that pre-HCT Rux may improve post-HCT outcome.}, }
@article {pmid30961831, year = {2019}, author = {Schuster, SL and Hsieh, AC}, title = {The Untranslated Regions of mRNAs in Cancer.}, journal = {Trends in cancer}, volume = {5}, number = {4}, pages = {245-262}, doi = {10.1016/j.trecan.2019.02.011}, pmid = {30961831}, issn = {2405-8025}, support = {R01 CA230617/CA/NCI NIH HHS/United States ; }, abstract = {The 5' and 3' untranslated regions (UTRs) regulate crucial aspects of post-transcriptional gene regulation that are necessary for the maintenance of cellular homeostasis. When these processes go awry through mutation or misexpression of certain regulatory elements, the subsequent deregulation of oncogenic gene expression can drive or enhance cancer pathogenesis. Although the number of known cancer-related mutations in UTR regulatory elements has recently increased markedly as a result of advances in whole-genome sequencing, little is known about how the majority of these genetic aberrations contribute functionally to disease. In this review we explore the regulatory functions of UTRs, how they are co-opted in cancer, new technologies to interrogate cancerous UTRs, and potential therapeutic opportunities stemming from these regions.}, }
@article {pmid30959042, year = {2019}, author = {Geller, AC and Keske, RR and Haneuse, S and Davine, JA and Emmons, KM and Daniel, CL and Gibson, TM and Marghoob, A and Mertens, AC and McDonald, AJ and Robison, LL and Howell, RM and Whitton, JA and Coroiu, A and Leisenring, WM and Armstrong, GT}, title = {Skin cancer early detection practices among adult survivors of childhood cancer treated with radiation.}, journal = {The Journal of investigative dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jid.2019.02.033}, pmid = {30959042}, issn = {1523-1747}, abstract = {Because rates of skin cancer are greater among adult survivors of childhood cancer who received radiation therapy than the general population, the National Cancer Institute recommends skin self-examinations and annual physician examination. There has been no comprehensive assessment of survivor's adherence with skin cancer screening guidelines associated with skin self-examination (SSE) and physician whole-body skin examination (PSE). We conducted a cross-sectional survey of radiation-treated, adult five-year survivors of childhood cancer, diagnosed between 1970-1986, in the Childhood Cancer Survivor Study (CCSS) cohort. Multivariate multinomial logit regression investigated the association between demographic, cancer diagnosis, patient activation, cancer treatment characteristics, and skin cancer screening practice. Among 728 survivors, 13.1% reported having had performed SSE in the prior 2 months plus received PSE in the prior 12 months, while 16.4% and 11.0% reported having had only a SSE or a PSE, respectively; 59.5% of survivors reported having had neither. Participants at the highest patient activation score were most likely to report SSE+PSE compared with neither (aRRR 4.16, 95% CI 1.34-12.85). Most adult survivors of childhood cancer who underwent radiation therapy do not practice strategies that promote early detection of skin cancer. Interventions designed to activate survivors to increase screening are needed.}, }
@article {pmid30956756, year = {2019}, author = {Li, Y and Xiao, X and Bossé, Y and Gorlova, O and Gorlov, I and Han, Y and Byun, J and Leighl, N and Johansen, JS and Barnett, M and Chen, C and Goodman, G and Cox, A and Taylor, F and Woll, P and Wichmann, HE and Manz, J and Muley, T and Risch, A and Rosenberger, A and Han, J and Siminovitch, K and Arnold, SM and Haura, EB and Bolca, C and Holcatova, I and Janout, V and Kontic, M and Lissowska, J and Mukeria, A and Ognjanovic, S and Orlowski, TM and Scelo, G and Swiatkowska, B and Zaridze, D and Bakke, P and Skaug, V and Zienolddiny, S and Duell, EJ and Butler, LM and Houlston, R and Artigas, MS and Grankvist, K and Johansson, M and Shepherd, FA and Marcus, MW and Brunnström, H and Manjer, J and Melander, O and Muller, DC and Overvad, K and Trichopoulou, A and Tumino, R and Liu, G and Bojesen, SE and Wu, X and Le Marchand, L and Albanes, D and Bickeböller, H and Aldrich, MC and Bush, WS and Tardon, A and Rennert, G and Teare, MD and Field, JK and Kiemeney, LA and Lazarus, P and Haugen, A and Lam, S and Schabath, MB and Andrew, AS and Bertazzi, PA and Pesatori, AC and Christiani, DC and Caporaso, N and Johansson, M and McKay, JD and Brennan, P and Hung, RJ and Amos, CI}, title = {Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.}, journal = {Oncotarget}, volume = {10}, number = {19}, pages = {1760-1774}, doi = {10.18632/oncotarget.26678}, pmid = {30956756}, issn = {1949-2553}, abstract = {The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.}, }
@article {pmid30956755, year = {2019}, author = {Cimino, PJ and Holland, EC}, title = {The molecular landscape of adult diffuse gliomas and relevance to clinical trials.}, journal = {Oncotarget}, volume = {10}, number = {19}, pages = {1758-1759}, doi = {10.18632/oncotarget.26750}, pmid = {30956755}, issn = {1949-2553}, }
@article {pmid30954972, year = {2019}, author = {Tapsoba, JD and Chao, EC and Wang, CY}, title = {Simulation Extrapolation Method for Cox Regression Model with a Mixture of Berkson and Classical Errors in the Covariates using Calibration Data.}, journal = {The international journal of biostatistics}, volume = {}, number = {}, pages = {}, doi = {10.1515/ijb-2018-0028}, pmid = {30954972}, issn = {1557-4679}, abstract = {Many biomedical or epidemiological studies often aim to assess the association between the time to an event of interest and some covariates under the Cox proportional hazards model. However, a problem is that the covariate data routinely involve measurement error, which may be of classical type, Berkson type or a combination of both types. The issue of Cox regression with error-prone covariates has been well-discussed in the statistical literature, which has focused mainly on classical error so far. This paper considers Cox regression analysis when some covariates are possibly contaminated with a mixture of Berkson and classical errors. We propose a simulation extrapolation-based method to address this problem when two replicates of the mismeasured covariates are available along with calibration data for some subjects in a subsample only. The proposed method places no assumption on the mixture percentage. Its finite-sample performance is assessed through a simulation study. It is applied to the analysis of data from an AIDS clinical trial study.}, }
@article {pmid30954717, year = {2019}, author = {Spunt, SL and Francotte, N and De Salvo, GL and Chi, YY and Zanetti, I and Hayes-Jordan, A and Kao, SC and Orbach, D and Brennan, B and Weiss, AR and van Noesel, MM and Million, L and Alaggio, R and Parham, DM and Kelsey, A and Randall, RL and McCarville, MB and Bisogno, G and Hawkins, DS and Ferrari, A}, title = {Clinical features and outcomes of young patients with epithelioid sarcoma: an analysis from the Children's Oncology Group and the European paediatric soft tissue Sarcoma Study Group prospective clinical trials.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {112}, number = {}, pages = {98-106}, doi = {10.1016/j.ejca.2019.02.001}, pmid = {30954717}, issn = {1879-0852}, abstract = {BACKGROUND: Data on the clinical features, optimal treatment and outcomes of paediatric patients with epithelioid sarcoma (ES) are limited and mostly retrospective.<br><br>METHODS: A subset analysis of ES patients < 30 years of age enrolled on two international prospective clinical trials conducted between 7/2005 and 11/2015 was performed. Risk-adapted therapy was based on tumour diameter, histologic grade, extent of surgery and presence/absence of metastases and included surgery ± radiotherapy for all patients with the addition of ifosfamide/doxorubicin chemotherapy for intermediate-/high-risk patients. Response to therapy, event-free and overall survival and pattern and predictors of treatment failure were evaluated.<br><br>RESULTS: Sixty-three ES patients (median age 13.1 years, 52% male) were eligible. Clinical features included the following: 68% extremity, median tumour diameter 3.5 cm, 56% high histologic grade, 14% nodal metastases, 14% distant metastases. Thirty-four low-risk patients underwent surgery (n = 30) or surgery/radiotherapy (n = 4); 16 intermediate-risk and 13 high-risk patients received chemotherapy ± surgery ± radiotherapy. Partial response was observed in 11/22 (50%) patients receiving neoadjuvant therapy. Events were local recurrence (n = 10) and distant recurrence (n = 15); estimated 5-year survival was 86.4%, 63.5% and 0%, respectively, for low-, intermediate- and high-risk patients. Locoregional nodal involvement, invasive tumour, high grade and lesser extent of resection predicted event-free survival in patients without metastases.<br><br>CONCLUSIONS: Most low-risk ES patients who have undergone an adequate resection fare well without adjuvant therapy. Large tumour size, high histologic grade, tumour invasiveness, inadequate tumour resection and metastatic disease predict poorer outcomes in higher risk ES patients, for whom more effective therapies are needed.<br><br>CLINICAL TRIAL REGISTRATION: COG ARST0332: ClinicalTrials.gov Identifier NCT00346164, EpSSG NRSTS 2005: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.}, }
@article {pmid30953767, year = {2019}, author = {Hoogland, AI and Nelson, AM and Gonzalez, BD and Small, BJ and Breen, EC and Sutton, SK and Syrjala, KL and Bower, JE and Pidala, J and Booth-Jones, M and Jacobsen, PB and Jim, HSL}, title = {Worsening cognitive performance is associated with increases in systemic inflammation following hematopoietic cell transplantation.}, journal = {Brain, behavior, and immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbi.2019.04.008}, pmid = {30953767}, issn = {1090-2139}, abstract = {BACKGROUND: Cognitive decline is a frequently cited concern among patients receiving hematopoietic cell transplantation (HCT), and patients often experience neurocognitive deficits (i.e., stable or worsening neurocognitive performance) throughout the transplant course. Deficits can be most severe during the acute transplant period (i.e., 90 days after transplantation), when patients also typically experience elevated systemic levels of inflammation. Previous studies have identified inflammation as a likely mechanism underlying neurocognitive deficits, primarily in women with breast cancer; however, longitudinal studies have been limited. In this study, our aim was to evaluate the relationship between changes in systemic inflammation and changes in cognition from pre- to post-transplant in patients receiving allogeneic HCT.<br><br>METHODS: Patients scheduled for allogeneic HCT (n=85) were assessed prior to HCT and 90 days after HCT. Biomarkers of inflammation included IL-6, sTNF-RII, CRP, and IL-1ra, which have been previously associated with neurocognitive deficits in cancer patients. Patients completed neuropsychological testing and self-report questionnaires.<br><br>RESULTS: Mixed models demonstrated that from pre- to post-HCT, increases in IL-6 and sTNF-RII were associated with neurocognitive deficits, and decreases in CRP were associated with better neurocognitive performance. There were no significant associations between changes in inflammation and self-reported cognitive performance.<br><br>CONCLUSIONS: Our findings are the first to our knowledge to report a robust relationship between increasing inflammation and neurocognitive deficits from pre- to post-HCT. Additional studies are needed to confirm these findings in a larger sample.}, }
@article {pmid30952678, year = {2019}, author = {Keating, AK and Langenhorst, J and Wagner, JE and Page, KM and Veys, P and Wynn, RF and Stefanski, H and Elfeky, R and Giller, R and Mitchell, R and Milano, F and O'Brien, TA and Dahlberg, A and Delaney, C and Kurtzberg, J and Verneris, MR and Boelens, JJ}, title = {The influence of stem cell source on transplant outcomes for pediatric patients with acute myeloid leukemia.}, journal = {Blood advances}, volume = {3}, number = {7}, pages = {1118-1128}, doi = {10.1182/bloodadvances.2018025908}, pmid = {30952678}, issn = {2473-9537}, abstract = {When hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; P = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; P = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.}, }
@article {pmid30952632, year = {2019}, author = {Li, S and Fong, KW and Gritsina, G and Zhang, A and Zhao, JC and Kim, J and Sharp, A and Yuan, W and Aversa, C and Yang, XJ and Nelson, PS and Feng, FY and Chinnaiyan, AM and de Bono, JS and Morrissey, C and Rettig, MB and Yu, J}, title = {Activation of MAPK signaling by CXCR7 leads to enzalutamide resistance in prostate cancer.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-18-2812}, pmid = {30952632}, issn = {1538-7445}, abstract = {Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance.}, }
@article {pmid30950224, year = {2019}, author = {Jain, R and Menzin, J and Lachance, K and McBee, P and Phatak, H and Nghiem, PT}, title = {Travel burden associated with rare cancers: The example of Merkel cell carcinoma.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.2085}, pmid = {30950224}, issn = {2045-7634}, support = {//EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany/ ; }, abstract = {BACKGROUND: There are limited data on the travel burden for cancer patients with rare tumor types, such as Merkel cell carcinoma (MCC).<br><br>OBJECTIVE: The objective of this study was to understand the travel burden of MCC patients.<br><br>METHODS: This study used data from an MCC registry at the Seattle Cancer Care Alliance (SCCA). All MCC patients enrolled at SCCA with a valid 3-digit ZIP code were included. Patients were followed up from January 1, 2012 until their last follow-up, death, or end of data (January 1, 2017). Travel burden was measured by one-way travel distance to SCCA from each patient's 3-digit ZIP code. Patient demographics, tumor characteristics, and follow-up visit were evaluated and stratified by one-way driving distance of ≤300 and >300 miles.<br><br>RESULTS: A total of 391 MCC patients were included (68% men, mean age = 67 years [±SD = ±11 years], 67% residing in the West, and 70% white). At diagnosis, 53% of the patients had Stage III or IV MCC. Mean one-way distance traveled by patients was 1,137 (median: 813) miles, and 57% of patients traveled >300 miles. Compared to patients who traveled ≤300 miles, those who traveled >300 miles were more likely to be <70 years old (46% vs 65%; P < 0.001), were diagnosed with advanced stage (III or IV) MCC (46% vs 59%; P = 0.01), had shorter follow-up in the cancer registry (mean: 509 vs 212 days; P < 0.001), and had fewer visits during follow-up (mean: 5.2 vs 2.5; P < 0.001).<br><br>CONCLUSIONS: In this single cancer center study, the majority of MCC patients trav-eled long distances to receive expert care. Longer travel distances appeared to be associated with younger age, a more advanced stage of cancer at study entry and fewer in-clinic visits, suggesting that travel burden may impact timely and adequate patient care for this rare cancer.}, }
@article {pmid30948355, year = {2019}, author = {Neves, A and Eisenman, RN}, title = {Distinct gene-selective roles for a network of core promoter factors in Drosophila neural stem cell identity.}, journal = {Biology open}, volume = {8}, number = {4}, pages = {}, doi = {10.1242/bio.042168}, pmid = {30948355}, issn = {2046-6390}, abstract = {The transcriptional mechanisms that allow neural stem cells (NSC) to balance self-renewal with differentiation are not well understood. Employing an in vivo RNAi screen we identify here NSC-TAFs, a subset of nine TATA-binding protein associated factors (TAFs), as NSC identity genes in Drosophila We found that depletion of NSC-TAFs results in decreased NSC clone size, reduced proliferation, defective cell polarity and increased hypersensitivity to cell cycle perturbation, without affecting NSC survival. Integrated gene expression and genomic binding analyses revealed that NSC-TAFs function with both TBP and TRF2, and that NSC-TAF-TBP and NSC-TAF-TRF2 shared target genes encode different subsets of transcription factors and RNA-binding proteins with established or emerging roles in NSC identity and brain development. Taken together, our results demonstrate that core promoter factors are selectively required for NSC identity in vivo by promoting cell cycle progression and NSC cell polarity. Because pathogenic variants in a subset of TAFs have all been linked to human neurological disorders, this work may stimulate and inform future animal models of TAF-linked neurological disorders.}, }
@article {pmid30948330, year = {2019}, author = {Cooper, JP and Khajaviyan, S and Smith, SD and Maloney, DG and Shustov, AR and Warren, EH and Soma, LA and Lynch, RC and Ujjani, C and Till, B and Halpern, AB and Gopal, AK and Deeg, HJ and Scott, BL and Shadman, M}, title = {Outcomes of Patients With Therapy-Related MDS After Chemoimmunotherapy for Chronic Lymphocytic Leukemia Compared With Patients With De Novo MDS: A Single-Institution Experience.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2019.03.003}, pmid = {30948330}, issn = {2152-2669}, abstract = {BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy are at increased risk of developing therapy-related (t-) myelodysplastic syndrome (MDS). It is unclear whether antecedent CLL adds prognostic value to the revised International Prognostic Scoring System (IPSS-R) for MDS. We performed a retrospective analysis to evaluate the significance of a previous CLL diagnosis as an independent adverse prognostic factor.<br><br>PATIENTS AND METHODS: We identified 18 consecutive patients with t-MDS, previously treated for CLL (CLL-MDS) from 2002 to 2016. For each CLL-MDS patient, we identified 2 control patients with de novo MDS matched for age (≤ 65 or > 65 years), IPSS-R (≤ 3 or > 3), and year of MDS diagnosis (before or after 2008). Multivariable models were developed to test for independent predictors of progression to acute myeloid leukemia (AML) and overall survival (OS).<br><br>RESULTS: Median time from CLL to MDS diagnosis was 58.8 months (range, 12-280 months) and median number of treatment lines for CLL was 1 (range, 1-5), including alkylating agents in 15 patients (83%) and fludarabine, cyclophosphamide, rituximab in 12 patients (67%). Hypomethylating agents were administered in 13 (72%) of CLL-MDS patients and 33 (91%) of de novo MDS patients. After a median follow-up of 19.2 months, OS was not different between CLL-MDS and matched de novo MDS patients. CLL-MDS patients with IPSS-R score ≤ 3 had better OS compared with those with IPSS-R score > 3. In multivariate analysis, there was no significant independent association between history of CLL OS or progression to AML.<br><br>CONCLUSION: History of CLL did not independently affect OS in t-MDS patients beyond IPSS-R score.}, }
@article {pmid30947891, year = {2019}, author = {Liao, GJ and Lee, CI and Liao, JM}, title = {Right Pockets, Right Solutions: Aligning Investments to Address Breast Cancer Screening Disparities.}, journal = {Journal of the American College of Radiology : JACR}, volume = {16}, number = {4 Pt B}, pages = {586-589}, doi = {10.1016/j.jacr.2019.02.045}, pmid = {30947891}, issn = {1558-349X}, }
@article {pmid30947280, year = {2019}, author = {Castañeda, SF and Garcia, ML and Lopez-Gurrola, M and Stoutenberg, M and Emory, K and Daviglus, ML and Kaplan, R and Giachello, AL and Molina, KM and Perreira, KM and Youngblood, ME and Vidot, DC and Talavera, GA}, title = {Alcohol use, acculturation and socioeconomic status among Hispanic/Latino men and women: The Hispanic Community Health Study/Study of Latinos.}, journal = {PloS one}, volume = {14}, number = {4}, pages = {e0214906}, doi = {10.1371/journal.pone.0214906}, pmid = {30947280}, issn = {1932-6203}, abstract = {The objective of this study was to examine the prevalence and patterns of alcohol use among U.S. Hispanic/Latino adults of diverse backgrounds. The population-based Hispanic Community Health Study/ Study of Latinos (HCHS/SOL) enrolled a cohort of Hispanic/Latino adults (N = 16,415) ages 18-74 years at time of recruitment, from four US metropolitan areas between 2008-11. Drinking patterns and socio-demographics questionnaires were administered as part of the baseline examination. The relationship between age, sex, socio-demographics, acculturation, current alcohol use, and alcohol risk disorder, defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) [no risk (i.e., never drinker), low risk (i.e., women<7 drinks/week; men<14 drinks/week), and at-risk (i.e., women>7 drinks/week; men>14 drinks/week)] were assessed in unadjusted and adjusted multinomial logistic regression analyses. Men reported a higher prevalence than women of at-risk drinking. For women, increased odds of at-risk alcohol use was associated with: a younger age, greater education, full-time employment, and acculturation after adjustment. For men, having a lower income (vs. higher income) or a higher income (vs. not reported) and being employed fulltime (vs. retired) was associated with at-risk alcohol use. For both men and women, there were variations in odds of at-risk drinking across Hispanic/Latino heritage backgrounds, after adjustment. Exact values, odds ratios and p-values are reported within the text. Common factors across sex associated with at-risk drinking included being of Mexican background and being employed full-time. Intervention strategies should consider diversity within the Hispanic/Latino community when designing alcohol abuse prevention programs.}, }
@article {pmid30946158, year = {2019}, author = {Hua, S and Scott, JM and Hanna, DB and Haberlen, SA and Shah, SJ and Hodis, HN and Landay, AL and Lazar, JM and Kizer, JR and Yu, B and Post, WS and Anastos, K and Kaplan, RC and Clish, CB and Qi, Q}, title = {Plasma acylcarnitines and progression of carotid artery atherosclerosis in HIV infection.}, journal = {AIDS (London, England)}, volume = {33}, number = {6}, pages = {1043-1052}, doi = {10.1097/QAD.0000000000002142}, pmid = {30946158}, issn = {1473-5571}, support = {U01 AI035042/AI/NIAID NIH HHS/United States ; U01 AI103397/AI/NIAID NIH HHS/United States ; U01 AI031834/AI/NIAID NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; U01 AI035004/AI/NIAID NIH HHS/United States ; R01 HL095140/HL/NHLBI NIH HHS/United States ; U01 AI034989/AI/NIAID NIH HHS/United States ; R01 HL126543/HL/NHLBI NIH HHS/United States ; R01 HL083760/HL/NHLBI NIH HHS/United States ; R01 HL132794/HL/NHLBI NIH HHS/United States ; U01 AI035041/AI/NIAID NIH HHS/United States ; K01 HL129892/HL/NHLBI NIH HHS/United States ; UM1 AI035043/AI/NIAID NIH HHS/United States ; R01 HL095129/HL/NHLBI NIH HHS/United States ; U01 AI034994/AI/NIAID NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; U01 AI103401/AI/NIAID NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; U01 AI035040/AI/NIAID NIH HHS/United States ; U01 AI103390/AI/NIAID NIH HHS/United States ; U01 AI034993/AI/NIAID NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; U01 AI103408/AI/NIAID NIH HHS/United States ; U01 AI035039/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; K01 HL137557/HL/NHLBI NIH HHS/United States ; U01 HD032632/HD/NICHD NIH HHS/United States ; U01 AI042590/AI/NIAID NIH HHS/United States ; }, abstract = {OBJECTIVE: To evaluate plasma acylcarnitine profiles and their relationships with progression of carotid artery atherosclerosis among individuals with and without HIV infection.<br><br>DESIGN: Prospective cohort studies of 499 HIV-positive and 206 HIV-negative individuals from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study.<br><br>METHODS: Twenty-four acylcarnitine species were measured in plasma samples of participants at baseline. Carotid artery plaque was assessed using repeated B-mode carotid artery ultrasound imaging in 2004-2013. We examined the associations of individual and aggregate short-chain (C2-C7), medium-chain (C8-C14) and long-chain acylcarnitines (C16-C26) with incident carotid artery plaque over 7 years.<br><br>RESULTS: Among 24 acylcarnitine species, C8-carnitines and C20 : 4-carnitines showed significantly lower levels comparing HIV-positive to HIV-negative individuals (false discovery rate adjusted P < 0.05); and C20-carnitines and C26-carnitines showed significantly higher levels in HIV positive using antiretroviral therapy than those without antiretroviral therapy (false discovery rate adjusted P < 0.05). In the univariate analyses, higher aggregated short-chain and long-chain acylcarnitine scores were associated with increased risk of carotid artery plaque [risk ratios (RRs) = 1.22 (95% confidence interval 1.02-1.45) and 1.20 (1.02-1.41) per SD increment, respectively]. The association for the short-chain acylcarnitine score remained significant [RR = 1.23 (1.05-1.44)] after multivariate adjustment (including traditional cardiovascular disease risk factors). This association was more evident in HIV-positive individuals without persistent viral suppression [RR = 1.37 (1.11-1.69)] compared with those with persistent viral suppression during follow-up [RR = 1.03 (0.76-1.40)] or HIV-negative individuals [RR = 1.02 (0.69-1.52)].<br><br>CONCLUSION: In two HIV cohorts, plasma levels of most acylcarnitines were not significantly different between HIV-positive and HIV-negative individuals. However, higher levels of aggregated short-chain acylcarnitines were associated with progression of carotid artery atherosclerosis.}, }
@article {pmid30946041, year = {2019}, author = {McGuire, AT}, title = {Targeting broadly neutralizing antibody precursors: a naïve approach to vaccine design.}, journal = {Current opinion in HIV and AIDS}, volume = {}, number = {}, pages = {}, doi = {10.1097/COH.0000000000000548}, pmid = {30946041}, issn = {1746-6318}, abstract = {PURPOSE OF REVIEW: It is believed that broadly neutralizing antibodies (bNAbs) will be an important component of an effective HIV-1 vaccine. Several immunogens have been designed that can target specific precursor B cells as a first step in a vaccine strategy to elicit bNAbs.<br><br>RECENT FINDINGS: Germline-targeting immunogens have been developed that specifically engage precursors of reproducible classes of anti-HIV antibodies, such as VRC01-class and apex-directed bNAbs. However, these precursors represent only a small portion of the immune repertoire and any antigen will inherently present off-target epitopes to the immune system that may confound bNAb development. Novel animal models are being utilized to understand the competitive fitness of bNAb precursors in the context of immunization with germline-targeting immunogens. In parallel, immunogen design efforts are being pursued to favor the development of bNAb responses over off-target responses following immunization. New studies of bNAb precursor interactions with glycosylated Env variants can inform prime-boost regimens geared towards accelerating bNAb development.<br><br>SUMMARY: Germline-targeting immunogens hold promise as a first step in eliciting a bNAb response through vaccination. A better understating of how efficiently germline-targeting immunogens can specifically target rare bNAb precursors is emerging. In addition, a more comprehensive structure-based understanding of critical barriers to bNAb elicitation, as well as commonalities between bNAb classes can further inform vaccine design.}, }
@article {pmid30945968, year = {2019}, author = {Calo, WA and Shah, PD and Gilkey, MB and Vanderpool, RC and Barden, S and Doucette, WR and Brewer, NT}, title = {Implementing pharmacy-located HPV vaccination: Findings from pilot projects in five U.S. states.}, journal = {Human vaccines &amp; immunotherapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1080/21645515.2019.1602433}, pmid = {30945968}, issn = {2164-554X}, abstract = {Pharmacies are promising alternative settings for human papillomavirus (HPV) vaccination because of their population reach, convenience, and existing infrastructure for vaccine delivery. However, pharmacies in the US are rarely used for adolescent HPV vaccination. We sought to document challenges and opportunities of implementing pharmacy-located HPV vaccination services in five US states by mapping process evaluation results onto key implementation science constructs: service penetration, acceptability, appropriateness, feasibility, fidelity, adoption, and sustainability. Pilot projects were planned in North Carolina (k=2 pharmacies), Michigan (k=10), Iowa (k=2), Kentucky (k=1), and Oregon (no pharmacy recruited) with varying procedures and recruitment strategies. Sites had open enrollment for a combined 12 months. Despite substantial efforts in these states, only 13 HPV vaccine doses were administered to adolescents and three doses to age-eligible young adults. We identified two major reasons for these underperforming results. First, poor outcomes on service penetration and appropriateness pointed to engagement barriers: low parent demand and engagement among pharmacy staff. Second, poor outcomes on feasibility, adoption, and sustainability appeared to result from administrative hurdles: lacking third party reimbursement (i.e., billing commercial payers, participation in Vaccines for Children program) and limited integration into primary care systems. In summary, pilot projects in five states all struggled to administer HPV vaccines. Opportunities for making pharmacies a successful setting for adolescent HPV vaccination include expanding third party reimbursement to cover all vaccines administered by pharmacists, increasing public awareness of pharmacists' immunization training, and improving care coordination with primary care providers.}, }
@article {pmid30945247, year = {2019}, author = {Andrews, SS}, title = {Rule-Based Modeling Using Wildcards in the Smoldyn Simulator.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1945}, number = {}, pages = {179-202}, doi = {10.1007/978-1-4939-9102-0_8}, pmid = {30945247}, issn = {1940-6029}, abstract = {Many biological molecules exist in multiple variants, such as proteins with different posttranslational modifications, DNAs with different sequences, and phospholipids with different chain lengths. Representing these variants as distinct species, as most biochemical simulators do, leads to the problem that the number of species, and chemical reactions that interconvert them, typically increase combinatorially with the number of ways that the molecules can vary. This can be alleviated by &quot;rule-based modeling methods,&quot; in which software generates the chemical reaction network from relatively simple &quot;rules.&quot; This chapter presents a new approach to rule-based modeling. It is based on wildcards that match to species names, much as wildcards can match to file names in computer operating systems. It is much simpler to use than the formal rule-based modeling approaches developed previously but can lead to unintended consequences if not used carefully. This chapter demonstrates rule-based modeling with wildcards through examples for signaling systems, protein complexation, polymerization, nucleic acid sequence copying and mutation, the &quot;SMILES&quot; chemical notation, and others. The method is implemented in Smoldyn, a spatial and stochastic biochemical simulator, for both generate-first and on-the-fly expansion, meaning whether the reaction network is generated before or during the simulation.}, }
@article {pmid30944862, year = {2019}, author = {Cao, S and Slack, SD and Levy, CN and Hughes, SM and Jiang, Y and Yogodzinski, C and Roychoudhury, P and Jerome, KR and Schiffer, JT and Hladik, F and Woodrow, KA}, title = {Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4+ T cell activation and HIV-1 latency reversal.}, journal = {Science advances}, volume = {5}, number = {3}, pages = {eaav6322}, doi = {10.1126/sciadv.aav6322}, pmid = {30944862}, issn = {2375-2548}, abstract = {A proposed strategy to cure HIV uses latency-reversing agents (LRAs) to reactivate latent proviruses for purging HIV reservoirs. A variety of LRAs have been identified, but none has yet proven effective in reducing the reservoir size in vivo. Nanocarriers could address some major challenges by improving drug solubility and safety, providing sustained drug release, and simultaneously delivering multiple drugs to target tissues and cells. Here, we formulated hybrid nanocarriers that incorporate physicochemically diverse LRAs and target lymphatic CD4+ T cells. We identified one LRA combination that displayed synergistic latency reversal and low cytotoxicity in a cell model of HIV and in CD4+ T cells from virologically suppressed patients. Furthermore, our targeted nanocarriers selectively activated CD4+ T cells in nonhuman primate peripheral blood mononuclear cells as well as in murine lymph nodes, and substantially reduced local toxicity. This nanocarrier platform may enable new solutions for delivering anti-HIV agents for an HIV cure.}, }
@article {pmid30942680, year = {2019}, author = {Fulton, S and Gibson, DS and Orick, J and Clark, AM}, title = {Developing a Cancer-Focused Library Survey - Assessing the Current Environment and Planning for the Future.}, journal = {Medical reference services quarterly}, volume = {38}, number = {1}, pages = {87-96}, doi = {10.1080/02763869.2018.1553451}, pmid = {30942680}, issn = {1540-9597}, abstract = {The primary goal of this project is to understand how each National Cancer Institute-designated cancer center library, and all libraries that support cancer research, function within their institutions. Through an in-depth survey focused on three major areas (staff, content and tools procurement, and user services), the research team hopes to determine how a cancer-centric library can be successful in supporting quality patient care, research excellence, and education. Additionally, the survey will examine the necessary minimum staffing levels for librarians and information professionals based on organizational size and degree of research focus. The survey will seek out the new skills librarians will need to deliver optimal services. The survey will also explore how content libraries purchase reflects and maps to constituents' current medical and research activities. Libraries within a research intense environment have a responsibility to align with researchers and health care professionals to provide resources and services that support their workflows. Cancer libraries need to be attuned to their institutions' missions, whether that includes excellent patient care, research endeavors, or cutting-edge educational programs. The information gathered from the survey will provide data for this research team to define the vision and standards of excellence for a cancer specialized research library.}, }
@article {pmid30940846, year = {2019}, author = {Loeb, KR and Hughes, BT and Fissel, BM and Osteen, NJ and Knoblaugh, SE and Grim, JE and Drury, LJ and Sarver, A and Dupuy, AJ and Clurman, BE}, title = {Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {5488}, doi = {10.1038/s41598-019-41805-x}, pmid = {30940846}, issn = {2045-2322}, support = {P30 DK 56465//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; 125006-RSG-13-183-01-CSM//American Cancer Society (American Cancer Society, Inc.)/ ; (125006-RSG-13-183-01-CSM//American Cancer Society (American Cancer Society, Inc.)/ ; 1R21CA229922//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA193808//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1R21CA229922//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; t P30 CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Insertional mutagenesis is a powerful means of identifying cancer drivers in animal models. We used the Sleeping Beauty (SB) transposon/transposase system to identify activated oncogenes in hematologic cancers in wild-type mice and mice that express a stabilized cyclin E protein (termed cyclin ET74AT393A). Cyclin E governs cell division and is misregulated in human cancers. Cyclin ET74AT393A mice develop ineffective erythropoiesis that resembles early-stage human myelodysplastic syndrome, and we sought to identify oncogenes that might cooperate with cyclin E hyperactivity in leukemogenesis. SB activation in hematopoietic precursors caused T-cell leukemia/lymphomas (T-ALL) and pure red blood cell erythroleukemias (EL). Analysis of >12,000 SB integration sites revealed markedly different oncogene activations in EL and T-ALL: Notch1 and Ikaros were most common in T-ALL, whereas ETS transcription factors (Erg and Ets1) were targeted in most ELs. Cyclin E status did not impact leukemogenesis or oncogene activations. Whereas most SB insertions were lost during culture of EL cell lines, Erg insertions were retained, indicating Erg's key role in these neoplasms. Surprisingly, cyclin ET74AT393A conferred growth factor independence and altered Erg-dependent differentiation in EL cell lines. These studies provide new molecular insights into erythroid leukemia and suggest potential therapeutic targets for human leukemia.}, }
@article {pmid30940657, year = {2019}, author = {Seo, YD and Jiang, X and Sullivan, KM and Jalikis, FG and Smythe, KS and Abbasi, A and Vignali, M and Park, JO and Daniel, SK and Pollack, SM and Kim, TS and Yeung, R and Crispe, IN and Pierce, RH and Robins, H and Pillarisetty, VG}, title = {Mobilization of CD8+ T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-19-0081}, pmid = {30940657}, issn = {1078-0432}, abstract = {PURPOSE: Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+T cells. We hypothesized that tumor-infiltrating CD8+T cells harbor latent anti-tumor activity that can be reactivated using combination immunotherapy.<br><br>EXPERIMENTAL DESIGN: Preserved human PDA specimens were analyzed using multiplex immunohistochemistry (IHC) and T cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry and live fluorescent microscopy to assess tumor kill, in addition to T cell expansion and mobilization.<br><br>RESULTS: Multiplex IHC demonstrated fewer CD8+T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8+T cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis.<br><br>CONCLUSION: Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA.}, }
@article {pmid30940363, year = {2019}, author = {Li, A and Wu, Q and Davis, C and Kirtane, KS and Pham, PD and Sorror, ML and Lee, SJ and Gopal, AK and Dong, JF and Garcia, DA and Weiss, NS and R Hingorani, S}, title = {Transplant-Associated Thrombotic Microangiopathy Is a Multifactorial Disease Unresponsive to Immunosuppressant Withdrawal.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {25}, number = {3}, pages = {570-576}, doi = {10.1016/j.bbmt.2018.10.015}, pmid = {30940363}, issn = {1523-6536}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {Transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic cell transplantation (HCT) has not been well characterized in large population studies with clinically adjudicated cases. We performed a retrospective cohort study of adults who underwent allogeneic HCT between 2006 and 2015 to determine the incidence of and risk factors for TA-TMA and to describe its natural history and response to immunosuppressant withdrawal management. Among 2145 patients in this study, 192 developed TA-TMA with a cumulative incidence of 7.6% by 100days post-transplant. Independent pretransplant risk factors included the receipt of a second (or third) allogeneic HCT, HLA-mismatched donor, and myeloablative conditioning with or without total body irradiation; post-transplant risk factors included the antecedent development of acute graft-versus-host disease, diffuse alveolar hemorrhage, bacteremia, invasive aspergillosis, BK viremia, and higher sirolimus trough level. Among TA-TMA patients 27% achieved hematologic resolution and 57% remained alive as of 90days after diagnosis. Antecedent risk factors stratified patients into different survival groups, and immunosuppressant withdrawal alone did not improve patient outcomes. In conclusion, TA-TMA is a heterogenous disease that occurs after allogeneic transplantation. Management with immunosuppressant withdrawal does not impact patient outcomes. Until further evidence becomes available, the management of TA-TMA should focus on the treatment of underlying diseases.}, }
@article {pmid30939245, year = {2019}, author = {Hori, S and Hiramuki, Y and Nishimura, D and Sato, F and Sehara-Fujisawa, A}, title = {PDH-mediated metabolic flow is critical for skeletal muscle stem cell differentiation and myotube formation during regeneration in mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {}, number = {}, pages = {fj201802479R}, doi = {10.1096/fj.201802479R}, pmid = {30939245}, issn = {1530-6860}, abstract = {Skeletal muscle satellite cells (SMSCs), the major stem cells responsible for the regeneration of skeletal muscle, are normally cell cycle arrested but differentiate to generate myocytes upon muscle damage, forming new myofibers along with self-renewing stem cells in preparation for subsequent injury. In this study, we investigated which factors stimulate the proliferation and differentiation of SMSCs and found that pyruvate, the end product of glycolysis, stimulates their differentiation. Pyruvate antagonizes the effects of hypoxia on preferential self-renewal of SMSCs through dephosphorylation or activation of pyruvate dehydrogenase (PDH), which mediates opening of the gateway from glycolysis to the tricarboxylic acid (TCA) cycle by producing acetyl coenzyme A from pyruvate. PDH kinase 1, highly expressed under hypoxia, is down-regulated under normoxic conditions, leading to an increase in dephosphorylated PDH. Conditional deletion of PDH in SMSCs affects cell divisions generating myocytes and subsequent myotube formation, inefficient skeletal muscle regeneration upon injury, and aggravated pathogenesis of a dystrophin-deficient mouse model of Duchenne muscular dystrophy. Thus, the flow from glycolysis to the TCA cycle mediated by PDH plays a pivotal role in the differentiation of SMSCs, which is critical for the progression of skeletal muscle regeneration.-Hori, S., Hiramuki, Y., Nishimura, D., Sato, F., Sehara-Fujisawa, A. PDH-mediated metabolic flow is critical for skeletal muscle stem cell differentiation and myotube formation during regeneration in mice.}, }
@article {pmid30937889, year = {2019}, author = {Ribrag, V and Avigan, DE and Green, DJ and Wise-Draper, T and Posada, JG and Vij, R and Zhu, Y and Farooqui, MZH and Marinello, P and Siegel, DS}, title = {Phase 1b trial of pembrolizumab monotherapy for relapsed/refractory multiple myeloma: KEYNOTE-013.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.15888}, pmid = {30937889}, issn = {1365-2141}, support = {//Merck Sharp &amp; Dohme Corp./ ; }, }
@article {pmid30936866, year = {2019}, author = {Ohlin, M and Scheepers, C and Corcoran, M and Lees, WD and Busse, CE and Bagnara, D and Thörnqvist, L and Bürckert, JP and Jackson, KJL and Ralph, D and Schramm, CA and Marthandan, N and Breden, F and Scott, J and Matsen Iv, FA and Greiff, V and Yaari, G and Kleinstein, SH and Christley, S and Sherkow, JS and Kossida, S and Lefranc, MP and van Zelm, MC and Watson, CT and Collins, AM}, title = {Inferred Allelic Variants of Immunoglobulin Receptor Genes: A System for Their Evaluation, Documentation, and Naming.}, journal = {Frontiers in immunology}, volume = {10}, number = {}, pages = {435}, doi = {10.3389/fimmu.2019.00435}, pmid = {30936866}, issn = {1664-3224}, support = {R01 AI097403/AI/NIAID NIH HHS/United States ; R21 AI142590/AI/NIAID NIH HHS/United States ; R01 GM113246/GM/NIGMS NIH HHS/United States ; R24 AI138963/AI/NIAID NIH HHS/United States ; R01 AI104739/AI/NIAID NIH HHS/United States ; U19 AI117891/AI/NIAID NIH HHS/United States ; R01 AI120961/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI138709/AI/NIAID NIH HHS/United States ; }, abstract = {Immunoglobulins or antibodies are the main effector molecules of the B-cell lineage and are encoded by hundreds of variable (V), diversity (D), and joining (J) germline genes, which recombine to generate enormous IG diversity. Recently, high-throughput adaptive immune receptor repertoire sequencing (AIRR-seq) of recombined V-(D)-J genes has offered unprecedented insights into the dynamics of IG repertoires in health and disease. Faithful biological interpretation of AIRR-seq studies depends upon the annotation of raw AIRR-seq data, using reference germline gene databases to identify the germline genes within each rearrangement. Existing reference databases are incomplete, as shown by recent AIRR-seq studies that have inferred the existence of many previously unreported polymorphisms. Completing the documentation of genetic variation in germline gene databases is therefore of crucial importance. Lymphocyte receptor genes and alleles are currently assigned by the Immunoglobulins, T cell Receptors and Major Histocompatibility Nomenclature Subcommittee of the International Union of Immunological Societies (IUIS) and managed in IMGT®, the international ImMunoGeneTics information system® (IMGT). In 2017, the IMGT Group reached agreement with a group of AIRR-seq researchers on the principles of a streamlined process for identifying and naming inferred allelic sequences, for their incorporation into IMGT®. These researchers represented the AIRR Community, a network of over 300 researchers whose objective is to promote all aspects of immunoglobulin and T-cell receptor repertoire studies, including the standardization of experimental and computational aspects of AIRR-seq data generation and analysis. The Inferred Allele Review Committee (IARC) was established by the AIRR Community to devise policies, criteria, and procedures to perform this function. Formalized evaluations of novel inferred sequences have now begun and submissions are invited via a new dedicated portal (https://ogrdb.airr-community.org). Here, we summarize recommendations developed by the IARC-focusing, to begin with, on human IGHV genes-with the goal of facilitating the acceptance of inferred allelic variants of germline IGHV genes. We believe that this initiative will improve the quality of AIRR-seq studies by facilitating the description of human IG germline gene variation, and that in time, it will expand to the documentation of TR and IG genes in many vertebrate species.}, }
@article {pmid30935953, year = {2019}, author = {Morschhauser, F and Flinn, IW and Advani, R and Sehn, LH and Diefenbach, C and Kolibaba, K and Press, OW and Salles, G and Tilly, H and Chen, AI and Assouline, S and Cheson, BD and Dreyling, M and Hagenbeek, A and Zinzani, PL and Jones, S and Cheng, J and Lu, D and Penuel, E and Hirata, J and Wenger, M and Chu, YW and Sharman, J}, title = {Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS).}, journal = {The Lancet. Haematology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3026(19)30026-2}, pmid = {30935953}, issn = {2352-3026}, abstract = {BACKGROUND: Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma.<br><br>METHODS: In this phase 2 randomised study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomisation scheme, to receive R-pola or R-pina (375 mg/m2 rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumour response. The study is registered with ClinicalTrials.gov, number NCT01691898, and is closed to accrual.<br><br>FINDINGS: 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event).<br><br>INTERPRETATION: R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola.<br><br>FUNDING: F Hoffmann-La Roche.}, }
@article {pmid30935561, year = {2019}, author = {Kim, E and Andersen, MR and Standish, LJ}, title = {Receiving/declining adjuvant breast cancer treatments and involvement in treatment decision-making.}, journal = {Complementary therapies in medicine}, volume = {43}, number = {}, pages = {85-91}, doi = {10.1016/j.ctim.2019.01.012}, pmid = {30935561}, issn = {1873-6963}, abstract = {OBJECTIVES: This study compared women who received all recommended breast cancer treatments (Receivers) with those who did not (Decliners). We sought to understand women's integrative naturopathic oncology (INO) use in addition to usual conventional oncology (UCO) use, their involvement in treatment decision-making (TDM), and their satisfaction with healthcare providers.<br><br>METHODS: A secondary analysis was conducted using baseline data from the Breast Cancer Integrative Oncology Study that recruited 427 women from INO clinics (INO cohort) and comparison women from the Cancer Surveillance System Registry who received UCO care (UCO cohort) in Western Washington State. Self-reported data and Registry data were analyzed using descriptive statistics, t-tests, and X2 tests to compare Receivers and Decliners in demographic and disease characteristics, use of INO in addition to UCO care, involvement in TDM, and satisfaction with healthcare providers.<br><br>RESULTS: Significantly more Decliners were in INO cohort than UCO cohort. Decliners in INO cohort were less likely to receive radiotherapy. Women who used INO care, and Decliners, compared with Receivers, tended to be &quot;very involved&quot; in their TDM. No difference was found in participation congruence, correspondence between preferred and actual involvement in medical TDM, between groups. Decliners in INO cohort reported significantly less satisfaction with their conventional oncologist than Receivers in INO cohort.<br><br>CONCLUSIONS: Decliners of conventional adjuvant therapies were very involved in their TDM and those Decliners who seek INO care were less satisfied with their conventional oncologist; these women may need the most attention to assure they receive the care they need.}, }
@article {pmid30933973, year = {2019}, author = {Magaret, CA and Benkeser, DC and Williamson, BD and Borate, BR and Carpp, LN and Georgiev, IS and Setliff, I and Dingens, AS and Simon, N and Carone, M and Simpkins, C and Montefiori, D and Alter, G and Yu, WH and Juraska, M and Edlefsen, PT and Karuna, S and Mgodi, NM and Edugupanti, S and Gilbert, PB}, title = {Prediction of VRC01 neutralization sensitivity by HIV-1 gp160 sequence features.}, journal = {PLoS computational biology}, volume = {15}, number = {4}, pages = {e1006952}, doi = {10.1371/journal.pcbi.1006952}, pmid = {30933973}, issn = {1553-7358}, abstract = {The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons.}, }
@article {pmid30930336, year = {2019}, author = {Woo, J and Deeg, HJ}, title = {Asymmetric dimethylarginine - a prognostic marker for transplant outcome?.}, journal = {Haematologica}, volume = {104}, number = {4}, pages = {646-647}, doi = {10.3324/haematol.2018.212191}, pmid = {30930336}, issn = {1592-8721}, }
@article {pmid30930007, year = {2019}, author = {Oster, NV and Williams, EC and Unger, JM and Newcomb, PA and Jacobson, EN and deHart, MP and Englund, JA and Hofstetter, AM}, title = {Sociodemographic, clinical and birth hospitalization characteristics and infant Hepatitis B vaccination in Washington State.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2019.03.050}, pmid = {30930007}, issn = {1873-2518}, abstract = {OBJECTIVE: Hepatitis B (HepB) vaccine is recommended at birth; however, national coverage estimates fall far below target levels. Studies describing the factors associated with infant HepB vaccination are lacking. This study aimed to identify the sociodemographic, clinical and birth hospitalization factors associated with timely receipt of the first HepB vaccine dose.<br><br>STUDY DESIGN: This retrospective cohort study included Washington State infants born weighing ≥2000 g who received birth hospitalization care at an urban academic medical center between January 2008-December 2013. Multivariable logistic regression was used to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI) for associations between maternal and infant characteristics and HepB vaccine receipt during the birth hospitalization.<br><br>RESULTS: Of the 9080 study infants, 75.5% received HepB vaccine during the birth hospitalization. Infants had higher odds of being vaccinated during the birth hospitalization if they were Hispanic (AOR 2.08; CI: 1.63, 2.65), non-Hispanic black (AOR 2.34; CI: 1.93, 2.84) or Asian (AOR 2.70; CI: 2.22, 3.28) compared to non-Hispanic white. Infants with a Spanish- vs. English-speaking mother (AOR 1.97; CI: 1.46, 2.68), public vs. private insurance (AOR 2.01; CI: 1.78, 2.29), and those hospitalized ≥96 h vs. 24 to <48 h (AOR 1.67; CI: 1.34, 2.09) also had higher odds of vaccination.<br><br>CONCLUSIONS: Populations that are typically underserved (e.g., publicly insured, racial/ethnic minorities) had higher odds of receiving HepB vaccine during the birth hospitalization. These findings may aid in identifying high-risk infants who could benefit from targeted interventions to increase initial HepB vaccination.}, }
@article {pmid30926973, year = {2019}, author = {Bentley, AR and Sung, YJ and Brown, MR and Winkler, TW and Kraja, AT and Ntalla, I and Schwander, K and Chasman, DI and Lim, E and Deng, X and Guo, X and Liu, J and Lu, Y and Cheng, CY and Sim, X and Vojinovic, D and Huffman, JE and Musani, SK and Li, C and Feitosa, MF and Richard, MA and Noordam, R and Baker, J and Chen, G and Aschard, H and Bartz, TM and Ding, J and Dorajoo, R and Manning, AK and Rankinen, T and Smith, AV and Tajuddin, SM and Zhao, W and Graff, M and Alver, M and Boissel, M and Chai, JF and Chen, X and Divers, J and Evangelou, E and Gao, C and Goel, A and Hagemeijer, Y and Harris, SE and Hartwig, FP and He, M and Horimoto, ARVR and Hsu, FC and Hung, YJ and Jackson, AU and Kasturiratne, A and Komulainen, P and Kühnel, B and Leander, K and Lin, KH and Luan, J and Lyytikäinen, LP and Matoba, N and Nolte, IM and Pietzner, M and Prins, B and Riaz, M and Robino, A and Said, MA and Schupf, N and Scott, RA and Sofer, T and Stancáková, A and Takeuchi, F and Tayo, BO and van der Most, PJ and Varga, TV and Wang, TD and Wang, Y and Ware, EB and Wen, W and Xiang, YB and Yanek, LR and Zhang, W and Zhao, JH and Adeyemo, A and Afaq, S and Amin, N and Amini, M and Arking, DE and Arzumanyan, Z and Aung, T and Ballantyne, C and Barr, RG and Bielak, LF and Boerwinkle, E and Bottinger, EP and Broeckel, U and Brown, M and Cade, BE and Campbell, A and Canouil, M and Charumathi, S and Chen, YI and Christensen, K and ,  and Concas, MP and Connell, JM and de Las Fuentes, L and de Silva, HJ and de Vries, PS and Doumatey, A and Duan, Q and Eaton, CB and Eppinga, RN and Faul, JD and Floyd, JS and Forouhi, NG and Forrester, T and Friedlander, Y and Gandin, I and Gao, H and Ghanbari, M and Gharib, SA and Gigante, B and Giulianini, F and Grabe, HJ and Gu, CC and Harris, TB and Heikkinen, S and Heng, CK and Hirata, M and Hixson, JE and Ikram, MA and ,  and Jia, Y and Joehanes, R and Johnson, C and Jonas, JB and Justice, AE and Katsuya, T and Khor, CC and Kilpeläinen, TO and Koh, WP and Kolcic, I and Kooperberg, C and Krieger, JE and Kritchevsky, SB and Kubo, M and Kuusisto, J and Lakka, TA and Langefeld, CD and Langenberg, C and Launer, LJ and Lehne, B and Lewis, CE and Li, Y and Liang, J and Lin, S and Liu, CT and Liu, J and Liu, K and Loh, M and Lohman, KK and Louie, T and Luzzi, A and Mägi, R and Mahajan, A and Manichaikul, AW and McKenzie, CA and Meitinger, T and Metspalu, A and Milaneschi, Y and Milani, L and Mohlke, KL and Momozawa, Y and Morris, AP and Murray, AD and Nalls, MA and Nauck, M and Nelson, CP and North, KE and O'Connell, JR and Palmer, ND and Papanicolau, GJ and Pedersen, NL and Peters, A and Peyser, PA and Polasek, O and Poulter, N and Raitakari, OT and Reiner, AP and Renström, F and Rice, TK and Rich, SS and Robinson, JG and Rose, LM and Rosendaal, FR and Rudan, I and Schmidt, CO and Schreiner, PJ and Scott, WR and Sever, P and Shi, Y and Sidney, S and Sims, M and Smith, JA and Snieder, H and Starr, JM and Strauch, K and Stringham, HM and Tan, NYQ and Tang, H and Taylor, KD and Teo, YY and Tham, YC and Tiemeier, H and Turner, ST and Uitterlinden, AG and ,  and van Heemst, D and Waldenberger, M and Wang, H and Wang, L and Wang, L and Wei, WB and Williams, CA and Wilson, G and Wojczynski, MK and Yao, J and Young, K and Yu, C and Yuan, JM and Zhou, J and Zonderman, AB and Becker, DM and Boehnke, M and Bowden, DW and Chambers, JC and Cooper, RS and de Faire, U and Deary, IJ and Elliott, P and Esko, T and Farrall, M and Franks, PW and Freedman, BI and Froguel, P and Gasparini, P and Gieger, C and Horta, BL and Juang, JJ and Kamatani, Y and Kammerer, CM and Kato, N and Kooner, JS and Laakso, M and Laurie, CC and Lee, IT and Lehtimäki, T and ,  and Magnusson, PKE and Oldehinkel, AJ and Penninx, BWJH and Pereira, AC and Rauramaa, R and Redline, S and Samani, NJ and Scott, J and Shu, XO and van der Harst, P and Wagenknecht, LE and Wang, JS and Wang, YX and Wareham, NJ and Watkins, H and Weir, DR and Wickremasinghe, AR and Wu, T and Zeggini, E and Zheng, W and Bouchard, C and Evans, MK and Gudnason, V and Kardia, SLR and Liu, Y and Psaty, BM and Ridker, PM and van Dam, RM and Mook-Kanamori, DO and Fornage, M and Province, MA and Kelly, TN and Fox, ER and Hayward, C and van Duijn, CM and Tai, ES and Wong, TY and Loos, RJF and Franceschini, N and Rotter, JI and Zhu, X and Bierut, LJ and Gauderman, WJ and Rice, K and Munroe, PB and Morrison, AC and Rao, DC and Rotimi, CN and Cupples, LA}, title = {Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.}, journal = {Nature genetics}, volume = {51}, number = {4}, pages = {636-648}, doi = {10.1038/s41588-019-0378-y}, pmid = {30926973}, issn = {1546-1718}, abstract = {The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.}, }
@article {pmid30926971, year = {2019}, author = {Iacobucci, I and Wen, J and Meggendorfer, M and Choi, JK and Shi, L and Pounds, SB and Carmichael, CL and Masih, KE and Morris, SM and Lindsley, RC and Janke, LJ and Alexander, TB and Song, G and Qu, C and Li, Y and Payne-Turner, D and Tomizawa, D and Kiyokawa, N and Valentine, M and Valentine, V and Basso, G and Locatelli, F and Enemark, EJ and Kham, SKY and Yeoh, AEJ and Ma, X and Zhou, X and Sioson, E and Rusch, M and Ries, RE and Stieglitz, E and Hunger, SP and Wei, AH and To, LB and Lewis, ID and D'Andrea, RJ and Kile, BT and Brown, AL and Scott, HS and Hahn, CN and Marlton, P and Pei, D and Cheng, C and Loh, ML and Ebert, BL and Meshinchi, S and Haferlach, T and Mullighan, CG}, title = {Genomic subtyping and therapeutic targeting of acute erythroleukemia.}, journal = {Nature genetics}, volume = {51}, number = {4}, pages = {694-704}, doi = {10.1038/s41588-019-0375-1}, pmid = {30926971}, issn = {1546-1718}, abstract = {Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.}, }
@article {pmid30926931, year = {2019}, author = {Rudin, CM and Poirier, JT and Byers, LA and Dive, C and Dowlati, A and George, J and Heymach, JV and Johnson, JE and Lehman, JM and MacPherson, D and Massion, PP and Minna, JD and Oliver, TG and Quaranta, V and Sage, J and Thomas, RK and Vakoc, CR and Gazdar, AF}, title = {Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.}, journal = {Nature reviews. Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41568-019-0133-9}, pmid = {30926931}, issn = {1474-1768}, support = {R01 CA201513/CA/NCI NIH HHS/United States ; R01 CA206540/CA/NCI NIH HHS/United States ; U01 CA213273/CA/NCI NIH HHS/United States ; }, abstract = {Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.}, }
@article {pmid30926392, year = {2019}, author = {El Gammal, MM and Ebid, GT and Madney, YM and Abo-Elazm, OM and Kelany, AK and Torra, OS and Radich, JP}, title = {Clinical Effect of Combined Mutations in DNMT3A, FLT3-ITD, and NPM1 Among Egyptian Acute Myeloid Leukemia Patients.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2019.02.001}, pmid = {30926392}, issn = {2152-2669}, abstract = {BACKGROUND: Genotypic mutation of fms like tyrosine kinase 3 (FLT3), Nucleophosmin (NPM1), and DNA-methyltransferase 3A (DNMT3A) has been involved in the leukemogenesis of acute myeloid leukemia (AML), with the well known poor prognostic role of FLT3 and DNMT3A and favorable role for the NPM1 mutation.<br><br>PATIENTS AND METHODS: A total of 123 patients with AML treated at the National Cancer Institute, Cairo University were examined for mutations in DNMT3A, FLT3, and NPM1 using polymerase chain reaction (PCR) for detecting FLT3 internal tandem duplication (ITD) and allele-specific PCR to detect DNMT3A and NPM1A mutations. Two-way direct sequencing and Gene Mapper version 4.0 software (Fred Hutchinson Cancer Research Center) sequencing were used as confirmatory tests for DNMT3A and NPM1A mutations, respectively.<br><br>RESULTS: DNMT3A, FLT3-ITD, and NPM1A gene mutations were detected in 22 (17.9%), 22 (17.9%), and 24 (19.5%) patients, respectively. DNMT3A/FLT3, NPM1A/FLT3, and DNMT3A/NPM1A combined mutant genotypes were detected in 5 (4.1%), 9 (7.3%), and 3 (2.4%) patients, respectively. Two patients (1.6%) had triple mutant genotypes (DNMT3A/FLT3/NPM1A). FLT3 and DNMT3A mutations had a significant negative effect on complete response (CR) rates (P = .016). FLT3-ITD mutation was significantly associated with older age (P = .029), and lower overall survival (OS) rates (P = .046). DNMT3A/FLT3 combined mutant genotypes were significantly associated with a lower OS rate (P = .016). Mutant NPM1/wild type FLT3, wild type DNMT3A/FLT3, and mutant NPM1A/wild type DNMT3A combinations were significantly associated with higher CR rates (P = .006, P = .006, and P = .023, respectively).<br><br>CONCLUSION: DNMT3A, FLT3-ITD, and NPM1A are frequent mutations in Egyptian AML. FLT3-ITD mutations are frequent in older patients. DNMT3A and FLT3-ITD mutations were associated with an unfavorable prognosis, but the NPM1A mutation has tendency to indicate a good prognosis.}, }
@article {pmid30925030, year = {2019}, author = {Brennen, WN and Schweizer, MT and Wang, H and Bivalacqua, TJ and Partin, AW and Lim, SJ and Chapman, C and Abdallah, R and Levy, O and Bhowmick, NA and Karp, JM and De Marzo, A and Isaacs, JT and Denmeade, SR}, title = {In Reply to the Letter to the Editor from Raj et al.: Clinical Evidence Indicates Allogeneic Mesenchymal Stem Cells Do Not Pose a Significant Risk for Cancer Progression in the Context of Cell-Based Drug Delivery.}, journal = {Stem cells translational medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/sctm.19-0068}, pmid = {30925030}, issn = {2157-6580}, }
@article {pmid30924901, year = {2019}, author = {Yang, JJ and Yu, D and Wen, W and Shu, XO and Saito, E and Rahman, S and Gupta, PC and He, J and Tsugane, S and Xiang, YB and Gao, YT and Koh, WP and Tamakoshi, A and Irie, F and Sadakane, A and Tsuji, I and Kanemura, S and Matsuo, K and Nagata, C and Chen, CJ and Yuan, JM and Shin, MH and Park, SK and Pan, WH and Qiao, YL and Pednekar, MS and Gu, D and Sawada, N and Li, HL and Gao, J and Cai, H and Grant, E and Tomata, Y and Sugawara, Y and Ito, H and Wada, K and Shen, CY and Wang, R and Ahn, YO and You, SL and Yoo, KY and Ashan, H and Chia, KS and Boffetta, P and Inoue, M and Kang, D and Potter, JD and Zheng, W}, title = {Tobacco Smoking and Mortality in Asia: A Pooled Meta-analysis.}, journal = {JAMA network open}, volume = {2}, number = {3}, pages = {e191474}, doi = {10.1001/jamanetworkopen.2019.1474}, pmid = {30924901}, issn = {2574-3805}, abstract = {Importance: Understanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations.<br><br>Objectives: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations.<br><br>This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India.<br><br>Exposures: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking.<br><br>Main Outcomes and Measures: Country or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer.<br><br>Results: Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions.<br><br>Conclusions and Relevance: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.}, }
@article {pmid30920610, year = {2019}, author = {Disis, MLN and Ellis, LM}, title = {Scientific Integrity and Data Accuracy.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2019.0656}, pmid = {30920610}, issn = {2374-2445}, }
@article {pmid30919583, year = {2019}, author = {Dintwe, O and Rohith, S and Schwedhelm, KV and McElrath, MJ and Andersen-Nissen, E and De Rosa, SC}, title = {OMIP-056: Evaluation of Human Conventional T Cells, Donor-Unrestricted T Cells, and NK Cells Including Memory Phenotype by Intracellular Cytokine Staining.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {}, number = {}, pages = {}, doi = {10.1002/cyto.a.23753}, pmid = {30919583}, issn = {1552-4930}, support = {P30 AI027757//University of Washington/Fred Hutch Center for AIDS Research/ ; UM1 AI068618//National Institute of Allergy and Infectious Diseases/ ; OPP1088952//Bill and Melinda Gates Foundation/ ; OPP1099507//Bill and Melinda Gates Foundation/ ; OPP1066048//Bill and Melinda Gates Foundation/ ; UM1 AI068618/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; P30 AI027757//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {A 26-color staining panel was developed to profile human antigen-specific T cells in an intracellular cytokine staining (ICS) assay using peptide pools to various antigens of interest. In addition to multiple functional markers, the panel includes differentiation/activation markers and markers to assess γδ, mucosal-associated invariant T, and NK T cells as well as conventional NK cells. Panel optimization was performed using previously cryopreserved PBMC from healthy adults, and then, expression of key functional markers in the panel was cross-validated against a validated ICS assay used in the HIV Vaccine Trials Network (HVTN). The panel is currently being used to evaluate the responses to tuberculosis and malaria vaccine candidates in volunteers from different geographic areas. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.}, }
@article {pmid30918961, year = {2019}, author = {Cimino, PJ and Holland, EC}, title = {Targeted copy number analysis outperforms histological grading in predicting patient survival for WHO grade II/III IDH-mutant astrocytomas.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noz052}, pmid = {30918961}, issn = {1523-5866}, }
@article {pmid30915676, year = {2019}, author = {Fang, CY and Lee, M and Feng, Z and Tan, Y and Levine, F and Nguyen, C and Ma, GX}, title = {Community-Based Cervical Cancer Education: Changes in Knowledge and Beliefs Among Vietnamese American Women.}, journal = {Journal of community health}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10900-019-00645-6}, pmid = {30915676}, issn = {1573-3610}, support = {R01 CA111570/CA/NCI NIH HHS/United States ; U54 CA221705/CA/NCI NIH HHS/United States ; R01 CA111570//National Cancer Institute/ ; U54 CA221705//National Cancer Institute/ ; }, abstract = {Low cervical cancer screening rates among Vietnamese American women have been attributed, in part, to inadequate knowledge about cervical cancer and health beliefs that hinder screening. A community-based educational program was developed to improve knowledge and attitudes toward cervical cancer screening in this underserved population. It was hypothesized that the program would result in increases in knowledge, as well as enhanced health beliefs and self-efficacy toward obtaining cervical cancer screening. Using a group-randomized design, 1488 women from 30 Vietnamese community-based organizations were assigned to either the intervention (n = 816) or control (n = 672) conditions. The intervention group received cervical cancer education delivered by bilingual community health educators. Intervention content addressed individual beliefs and expectancies regarding cervical cancer screening (e.g., perceived risk of developing cervical cancer; perceived benefits and barriers to screening; social and cultural norms regarding screening). The control group received general health education, including information about cancer screening. Knowledge and health beliefs were assessed at baseline and post-intervention. Among women in the intervention group, overall knowledge about cervical cancer and screening guidelines increased from pre- to post-program (30% vs. 88%, p < 0.001), perceived benefits of screening increased (3.50 vs. 4.49, p < 0.001), and perceived barriers to screening decreased (3.13 vs. 2.25, p < 0.001). Changes in knowledge and health beliefs were not observed among women in the control group. A community-based educational program can help increase knowledge about cervical cancer and screening, promote positive changes in women's beliefs about the benefits of cervical cancer screening, and reduce perceived barriers to screening. Such programs may play an important role in addressing health disparities and informing underserved populations about recommended screening tests.}, }
@article {pmid30915444, year = {2019}, author = {Prentice, RL and Pettinger, M and Neuhouser, ML and Tinker, LF and Huang, Y and Zheng, C and Manson, JE and Mossavar-Rahmani, Y and Anderson, GL and Lampe, JW}, title = {Application of blood concentration biomarkers in nutritional epidemiology: example of carotenoid and tocopherol intake in relation to chronic disease risk.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqy360}, pmid = {30915444}, issn = {1938-3207}, abstract = {BACKGROUND: Biomarkers provide potential to objectively measure the intake of nutrients and foods, and thereby to strengthen nutritional epidemiology association studies. However, there are only a few established intake biomarkers, mostly based on recovery of nutrients or their metabolites in urine. Blood concentration measures provide a potential biomarker source for many additional nutritional variables, but their use in disease-association studies requires further development.<br><br>OBJECTIVE: The aim of this study was to apply recently proposed serum-based carotenoid and tocopherol intake biomarkers and to examine their association with the incidence of major cardiovascular diseases, cancers, and diabetes in a subset of Women's Health Initiative (WHI) cohorts.<br><br>METHODS: Serum concentrations of α- and β-carotene, lutein plus zeaxanthin (L + Z), and α-tocopherol were routinely measured at baseline in a subset of 5488 enrollees in WHI cohorts. Intake biomarkers for these 4 micronutrients, obtained by combining serum concentrations with participant characteristics, were recently proposed using a 153-woman feeding study within WHI. These biomarker equations are augmented here to include pertinent disease risk factors and are associated with subsequent chronic disease incidence in this WHI subset.<br><br>RESULTS: HRs for a doubling of micronutrient intake differed only moderately from the null for the outcomes considered. However, somewhat lower risks of specific cardiovascular outcomes, breast cancer, and diabetes were associated with a higher intake of α- and β-carotene, lower risk of diabetes was associated with higher L + Z intake, and elevated risks of certain cardiovascular outcomes were associated with a higher intake of α-tocopherol. These patterns remained following the exclusion of baseline users of dietary supplements.<br><br>CONCLUSIONS: Concentration biomarkers can be calculated from blood specimens obtained in large epidemiologic cohorts and applied directly in disease-association analyses, without relying on self-reported dietary data. Observed associations between carotenoid and tocopherol biomarkers and chronic disease risk could be usefully evaluated further using stored serum specimens on the entire WHI cohort. This study was registered at www.clinicaltrials.gov as NCT00000611.}, }
@article {pmid30912699, year = {2019}, author = {Berdeja, JG and Heinrich, MC and Dakhil, SR and Goldberg, SL and Wadleigh, M and Kuriakose, P and Cortes, J and Radich, J and Helton, B and Rizzieri, D and Paley, C and Dautaj, I and Mauro, MJ}, title = {Rates of deep molecular response by digital and conventional PCR with frontline nilotinib in newly diagnosed chronic myeloid leukemia: a landmark analysis.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10428194.2019.1590569}, pmid = {30912699}, issn = {1029-2403}, abstract = {ENESTnext (NCT01227577) was a single-arm, multicenter trial evaluating the rate of deep molecular response by 2 years in patients with newly diagnosed (within 6 months) chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib 300 mg twice daily. Among 128 enrolled patients, 94 (73%) achieved major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1IS]) and 34 (27%) achieved confirmed MR4.5 (BCR-ABL1IS ≤0.0032% detectable or undetectable; primary endpoint) by 2 years. Three-month BCR-ABL1 levels were predictive of later responses. In exploratory analyses, digital polymerase chain reaction (PCR) detected BCR-ABL1 in 39.4% of samples from patients with confirmed MR4.5 and identified further decreases in BCR-ABL1 with continued nilotinib. Safety results, including cardiovascular events, were consistent with those in other nilotinib trials. These results further substantiate the molecular response rates associated with frontline nilotinib therapy and demonstrate the feasibility of monitoring very low BCR-ABL1 transcript levels using digital PCR.}, }
@article {pmid30912462, year = {2019}, author = {Mamolo, CM and Cappelleri, JC and Hoang, CJ and Kim, R and Hadfield, A and Middleton, C and Rider, A and Walter, RB}, title = {A real-world, cross-sectional, community survey of symptoms and health-related quality of life of adults with acute myeloid leukemia.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.2217/fon-2018-0842}, pmid = {30912462}, issn = {1744-8301}, abstract = {AIM: We used Adelphi Real World Disease-Specific Programme data to characterize adults with newly diagnosed or relapsed/refractory de novo acute myeloid leukemia (AML).<br><br>MATERIALS &amp; METHODS: Community-practice hematologists/oncologists completed patient record forms for their regular AML patients. Patients were invited to complete patient self-completion forms including 3-Level EuroQol 5-Dimensions (EQ-5D-3L) and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaires.<br><br>RESULTS: Physicians provided patient record forms for 389 patients (339 newly diagnosed, 50 relapsed/refractory); 68 patients completed patient self-completion forms. Mean EQ-5D visual-analog scale and index and FACT-General scores were significantly lower than US population norms (p < 0.0001); health-related quality of life (HRQoL) scores were generally lower than 11 other cancers.<br><br>CONCLUSION: HRQoL impairment is grave in AML. Efforts are needed to improve HRQoL in affected patients.}, }
@article {pmid30910758, year = {2019}, author = {Sapkota, Y and Turcotte, LM and Ehrhardt, MJ and Howell, RM and Arnold, MA and Wilson, CL and Leisenring, W and Wang, Z and Sampson, J and Dagnall, CL and Karlins, E and Li, SA and Hicks, BD and Weathers, R and Smith, SA and Shelton, K and Liu, Q and Tucker, MA and Chanock, SJ and Zhang, J and Hudson, MM and Neglia, JP and Armstrong, GT and Robison, LL and Morton, LM and Bhatia, S and Yasui, Y}, title = {Genome-wide association study in irradiated childhood cancer survivors identifies HTR2A for subsequent basal cell carcinoma.}, journal = {The Journal of investigative dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jid.2019.02.029}, pmid = {30910758}, issn = {1523-1747}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA216354/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, }
@article {pmid30910604, year = {2019}, author = {Lee, DW and Mead, E and Santomasso, BD and Turtle, CJ and Grupp, SA and Neelapu, SS}, title = {Authors' Response to the Letter-to-the-Editor by Brown ART and Gutierrez C.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.03.019}, pmid = {30910604}, issn = {1523-6536}, }
@article {pmid30909389, year = {2019}, author = {Schountz, T and Campbell, C and Wagner, K and Rovnak, J and Martellaro, C and DeBuysscher, BL and Feldmann, H and Prescott, J}, title = {Differential Innate Immune Responses Elicited by Nipah Virus and Cedar Virus Correlate with Disparate In Vivo Pathogenesis in Hamsters.}, journal = {Viruses}, volume = {11}, number = {3}, pages = {}, doi = {10.3390/v11030291}, pmid = {30909389}, issn = {1999-4915}, abstract = {Syrian hamsters (Mesocricetus auratus) are a pathogenesis model for the Nipah virus (NiV), and we sought to determine if they are also susceptible to the Cedar virus (CedPV). Following intranasal inoculation with CedPV, virus replication occurred in the lungs and spleens of infected hamsters, a neutralizing antibody was produced in some hamsters within 8 days post-challenge, and no conspicuous signs of disease occurred. CedPV replicated to a similar magnitude as NiV-Bangladesh in type I IFN-deficient BHK-21 Syrian hamster fibroblasts but replicated 4 logs lower in type I IFN-competent primary Syrian hamster and human pulmonary endothelial cells, a principal target of henipaviruses. The coinfection of these cells with CedPV and NiV failed to rescue CedPV titers and did not diminish NiV titers, suggesting the replication machinery is virus-specific. Type I IFN response transcripts Ifna7, Ddx58, Stat1, Stat2, Ccl5, Cxcl10, Isg20, Irf7, and Iigp1 were all significantly elevated in CedPV-infected hamster endothelial cells, whereas Ifna7 and Iigp1 expression were significantly repressed during NiV infection. These results are consistent with the hypothesis that CedPV's inability to counter the host type I IFN response may, in part, contribute to its lack of pathogenicity. Because NiV causes a fatal disease in Syrian hamsters with similarities to human disease, this model will provide valuable information about the pathogenic mechanisms of henipaviruses.}, }
@article {pmid30908669, year = {2019}, author = {Wang, CY and Dai, J}, title = {Best linear inverse probability weighted estimation for two-phase designs and missing covariate regression.}, journal = {Statistics in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/sim.8141}, pmid = {30908669}, issn = {1097-0258}, support = {CA53996//US National Institutes of Health/ ; GM100573//US National Institutes of Health/ ; HL114901//US National Institutes of Health/ ; HL130483//US National Institutes of Health/ ; MH105857//US National Institutes of Health/ ; }, abstract = {The inverse probability weighted estimator is often applied to two-phase designs and regression with missing covariates. Inverse probability weighted estimators typically are less efficient than likelihood-based estimators but, in general, are more robust against model misspecification. In this paper, we propose a best linear inverse probability weighted estimator for two-phase designs and missing covariate regression. Our proposed estimator is the projection of the SIPW onto the orthogonal complement of the score space based on a working regression model of the observed covariate data. The efficiency gain is from the use of the association between the outcome variable and the available covariates, which is the working regression model. One advantage of the proposed estimator is that there is no need to calculate the augmented term of the augmented weighted estimator. The estimator can be applied to general missing data problems or two-phase design studies in which the second phase data are obtained in a subcohort. The method can also be applied to secondary trait case-control genetic association studies. The asymptotic distribution is derived, and the finite sample performance of the proposed estimator is examined via extensive simulation studies. The methods are applied to a bladder cancer case-control study.}, }
@article {pmid30905192, year = {2019}, author = {Sun, S and Lulla, A and Sioda, M and Winglee, K and Wu, MC and Jacobs, DR and Shikany, JM and Lloyd-Jones, DM and Launer, LJ and Fodor, AA and Meyer, KA}, title = {Gut Microbiota Composition and Blood Pressure.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {73}, number = {5}, pages = {998-1006}, doi = {10.1161/HYPERTENSIONAHA.118.12109}, pmid = {30905192}, issn = {1524-4563}, support = {K01 HL127159/HL/NHLBI NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; UL1 TR002489/TR/NCATS NIH HHS/United States ; }, abstract = {Animal models support a role for the gut microbiota in the development of hypertension. There has been a lack of epidemiological cohort studies to confirm these findings in human populations. We examined cross-sectional associations between measures of gut microbial diversity and taxonomic composition and blood pressure (BP) in 529 participants of the biracial (black and white) CARDIA study (Coronary Artery Risk Development in Young Adults). We sequenced V3-V4 regions of the 16S ribosomal RNA marker gene using DNA extracted from stool samples collected at CARDIA's Year 30 follow-up examination (2015-2016; aged 48-60 years). We quantified associations between BP (hypertension [defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or antihypertension medication use] and systolic BP) and within and between-person diversity measures. We conducted genera-specific multivariable-adjusted regression analysis, accounting for multiple comparisons using the false discovery rate. Hypertension and systolic BP were inversely associated with measures of α-diversity, including richness and the Shannon Diversity Index, and were distinguished with respect to principal coordinates based on a similarity matrix of genera abundance. Several specific genera were significantly associated with hypertension and systolic BP, though results were attenuated with adjustment for body mass index. Our findings support associations between within-person and between-person gut microbial community diversity and taxonomic composition and BP in a diverse population-based cohort of middle-aged adults. Future study is needed to define functional pathways that underlie observed associations and identify specific microbial targets for intervention.}, }
@article {pmid30905014, year = {2019}, author = {Minlikeeva, AN and Cannioto, R and Jensen, A and Kjaer, SK and Jordan, SJ and Diergaarde, B and Szender, JB and Odunsi, K and Almohanna, H and Mayor, P and Starbuck, K and Zsiros, E and Bandera, EV and Cramer, DW and Doherty, JA and DeFazio, A and ,  and Edwards, R and Goode, EL and Goodman, MT and Høgdall, E and Matsuo, K and Mizuno, M and Nagle, CM and Ness, RB and Paddock, LE and Pearce, CL and Risch, HA and Rossing, MA and Terry, KL and Wu, AH and Modugno, F and Webb, PM and Moysich, KB and , }, title = {Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10552-019-01157-3}, pmid = {30905014}, issn = {1573-7225}, support = {4R25CA113951//National Cancer Institute/ ; P50CA159981//National Cancer Institute/ ; 2R25CA113951//National Cancer Institute/ ; R01CA095023//National Cancer Institute/ ; R01CA126841//National Cancer Institute/ ; K07-CA080668//National Cancer Institute/ ; R01-CA95023//National Cancer Institute/ ; R01-CA61107//National Cancer Institute/ ; K07 CA095666//National Cancer Institute/ ; K22-CA138563//National Cancer Institute/ ; P30-CA072720//National Cancer Institute/ ; T32CA108456//National Institutes of Health/ ; R01-CA074850//National Institutes of Health/ ; R01-CA080742//National Institutes of Health/ ; R01-CA112523//National Institutes of Health/ ; R01-CA87538//National Institutes of Health/ ; R01-CA58598//National Institutes of Health/ ; N01-CN-55424//National Institutes of Health/ ; N01-PC-67001//National Institutes of Health/ ; R01-CA122443//National Institutes of Health/ ; P30-CA15083//National Institutes of Health/ ; P50-CA136393//National Institutes of Health/ ; R01-CA54419//National Institutes of Health/ ; P50-CA105009//National Institutes of Health/ ; P01CA17054//National Institutes of Health/ ; P30CA14089//National Institutes of Health/ ; R01CA61132//National Institutes of Health/ ; N01PC67010//National Institutes of Health/ ; R03CA113148//National Institutes of Health/ ; R03CA115195//National Institutes of Health/ ; N01CN025403//National Institutes of Health/ ; APP1061341//National Health and Medical Research of Australia/ ; APP1073898//National Health &amp; Medical Research Council of Australia/ ; APP1043134//National Health &amp; Medical Research Council of Australia/ ; DAMD17-01-1-0729//Medical Research and Materiel Command/ ; 199600//National Health and Medical Research Council/ ; 400281//National Health and Medical Research Council/ ; P30-CA072720//National Health and Medical Research Council/ ; APP1120431//National Health and Medical Research Council/ ; None//Cancer Foundation of Western Australia/ ; DAMD17-02-1-0669//U.S. Department of Defense/ ; W81XWH-10-1-02802//U.S. Department of Defense/ ; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control//Ministry of Health, Labour and Welfare/ ; 94 222 52//Danish Cancer Society/ ; 00-01389V-20170//California Cancer Research Program/ ; 2II0200//California Cancer Research Program/ ; }, abstract = {PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated.<br><br>METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors.<br><br>RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS.<br><br>CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.}, }
@article {pmid30901049, year = {2019}, author = {Caterino, JM and Adler, D and Durham, DD and Yeung, SJ and Hudson, MF and Bastani, A and Bernstein, SL and Baugh, CW and Coyne, CJ and Grudzen, CR and Henning, DJ and Klotz, A and Madsen, TE and Pallin, DJ and Reyes-Gibby, CC and Rico, JF and Ryan, RJ and Shapiro, NI and Swor, R and Venkat, A and Wilson, J and Thomas, CR and Bischof, JJ and Lyman, GH}, title = {Analysis of Diagnoses, Symptoms, Medications, and Admissions Among Patients With Cancer Presenting to Emergency Departments.}, journal = {JAMA network open}, volume = {2}, number = {3}, pages = {e190979}, doi = {10.1001/jamanetworkopen.2019.0979}, pmid = {30901049}, issn = {2574-3805}, abstract = {Importance: Better understanding of the emergency care needs of patients with cancer will inform outpatient and emergency department (ED) management.<br><br>Objective: To provide a benchmark description of patients who present to the ED with active cancer.<br><br>This multicenter prospective cohort study included 18 EDs affiliated with the Comprehensive Oncologic Emergencies Research Network (CONCERN). Of 1564 eligible patients, 1075 adults with active cancer were included from February 1, 2016, through January 30, 2017. Data were analyzed from February 1 through August 1, 2018.<br><br>Main Outcomes and Measures: The proportion of patients reporting symptoms (eg, pain, nausea) before and during the ED visit, ED and outpatient medications, most common diagnoses, and suspected infection as indicated by ED antibiotic administration. The proportions observed, admitted, and with a hospital length of stay (LOS) of no more than 2 days were identified.<br><br>Results: Of 1075 participants, mean (SD) age was 62 (14) years, and 51.8% were female. Seven hundred ninety-four participants (73.9%; 95% CI, 71.1%-76.5%) had undergone cancer treatment in the preceding 30 days; 674 (62.7%; 95% CI, 59.7%-65.6%) had advanced or metastatic cancer; and 505 (47.0%; 95% CI, 43.9%-50.0%) were 65 years or older. The 5 most common ED diagnoses were symptom related. Of all participants, 82 (7.6%; 95% CI, 6.1%-9.4%) were placed in observation and 615 (57.2%; 95% CI, 54.2%-60.2%) were admitted; 154 of 615 admissions (25.0%; 95% CI, 21.7%-28.7%) had an LOS of 2 days or less (median, 3 days; interquartile range, 2-6 days). Pain during the ED visit was present in 668 patients (62.1%; 95% CI, 59.2%-65.0%; mean [SD] pain score, 6.4 [2.6] of 10.0) and in 776 (72.2%) during the prior week. Opioids were administered in the ED to 228 of 386 patients (59.1%; 95% CI, 18.8%-23.8%) with moderate to severe ED pain. Outpatient opioids were prescribed to 368 patients (47.4%; 95% CI, 3.14%-37.2%) of those with pre-ED pain, including 244 of 428 (57.0%; 95% CI, 52.2%-61.8%) who reported quite a bit or very much pain. Nausea in the ED was present in 336 (31.3%; 95% CI, 28.5%-34.1%); of these, 160 (47.6%; 95% CI, 12.8%-17.1%) received antiemetics in the ED. Antibiotics were administered in the ED to 285 patients (26.5%; 95% CI, 23.9%-29.2%). Of these, 209 patients (73.3%; 95% CI, 17.1%-21.9%) were admitted compared with 427 of 790 (54.1%; 95% CI, 50.5%-57.6%) not receiving antibiotics.<br><br>Conclusions and Relevance: This initial prospective, multicenter study profiling patients with cancer who were treated in the ED identifies common characteristics in this patient population and suggests opportunities to optimize care before, during, and after the ED visit. Improvement requires collaboration between specialists and emergency physicians optimizing ED use, improving symptom control, avoiding unnecessary hospitalizations, and appropriately stratifying risk to ensure safe ED treatment and disposition of patients with cancer.}, }
@article {pmid30899120, year = {2019}, author = {Fong, Y and Huang, Y}, title = {Modified Wilcoxon-Mann-Whitney Test and Power against Strong Null.}, journal = {The American statistician}, volume = {73}, number = {1}, pages = {43-49}, doi = {10.1080/00031305.2017.1328375}, pmid = {30899120}, issn = {0003-1305}, support = {R01 AI122991/AI/NIAID NIH HHS/United States ; R01 GM106177/GM/NIGMS NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {The Wilcoxon-Mann-Whitney (WMW) test is a popular rank-based two-sample testing procedure for the strong null hypothesis that the two samples come from the same distribution. A modified WMW test, the Fligner-Policello (FP) test, has been proposed for comparing the medians of two populations. A fact that may be underappreciated among some practitioners is that the FP test can also be used to test the strong null like the WMW. In this paper we compare the power of the WMW and FP tests for testing the strong null. Our results show that neither test is uniformly better than the other and that there can be substantial differences in power between the two choices. We propose a new, modified WMW test that combines the WMW and FP tests. Monte Carlo studies show that the combined test has good power compared to either the WMW and FP test. We provide a fast implementation of the proposed test in an open-source software. Supplementary materials are available online.}, }
@article {pmid30898893, year = {2019}, author = {Shin, YJ and Sa, JK and Lee, Y and Kim, D and Chang, N and Cho, HJ and Son, M and Oh, MYT and Shin, K and Lee, JK and Park, J and Jo, YK and Kim, M and Paddison, PJ and Tergaonkar, V and Lee, J and Nam, DH}, title = {PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma.}, journal = {The Journal of experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1084/jem.20172170}, pmid = {30898893}, issn = {1540-9538}, abstract = {Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.}, }
@article {pmid30898265, year = {2019}, author = {Sarthy, JF and Henikoff, S and Ahmad, K}, title = {Chromatin Bottlenecks in Cancer.}, journal = {Trends in cancer}, volume = {5}, number = {3}, pages = {183-194}, doi = {10.1016/j.trecan.2019.01.003}, pmid = {30898265}, issn = {2405-8025}, abstract = {Cancer accounts for ∼9 million deaths per year worldwide, predominantly affecting adults. Adult malignancies are usually examined after extensive clonal evolution and carry many mutations, obscuring the individual contributions of these alterations to oncogenesis. By contrast, pediatric cancers often contain few mutations, many of which cause defects in chromatin-associated proteins. We explore here the roles that chromatin plays in oncogenesis. We highlight how the developmental regulation of cell proliferation genes and the degradation of chromosome ends are two major bottlenecks in the evolution of malignant cells, and point to a third bottleneck where epigenomic dysfunction triggers expression of tumor-suppressor genes, limiting the development of aggressive and metastatic features in tumors. We also identify opportunities for chromatin-based therapies.}, }
@article {pmid30898164, year = {2019}, author = {Ishengoma, DS and Mandara, CI and Francis, F and Talundzic, E and Lucchi, NW and Ngasala, B and Kabanywanyi, AM and Mahende, MK and Kamugisha, E and Kavishe, RA and Muro, F and Mohamed, A and Mandike, R and Mkude, S and Chacky, F and Paxton, L and Greer, G and Kitojo, CA and Njau, R and Martin, T and Venkatesan, M and Warsame, M and Halsey, ES and Udhayakumar, V}, title = {Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania.}, journal = {Malaria journal}, volume = {18}, number = {1}, pages = {88}, doi = {10.1186/s12936-019-2730-1}, pmid = {30898164}, issn = {1475-2875}, abstract = {BACKGROUND: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance.<br><br>METHODS: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively.<br><br>RESULTS: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene.<br><br>CONCLUSION: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies. Trial Registration ClinicalTrials.gov NCT03387631.}, }
@article {pmid30896747, year = {2019}, author = {Disis, MLN}, title = {JAMA Oncology-The Year in Review, 2018.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2019.0231}, pmid = {30896747}, issn = {2374-2445}, }
@article {pmid30892988, year = {2019}, author = {Wei, AH and Strickland, SA and Hou, JZ and Fiedler, W and Lin, TL and Walter, RB and Enjeti, A and Tiong, IS and Savona, M and Lee, S and Chyla, B and Popovic, R and Salem, AH and Agarwal, S and Xu, T and Fakouhi, KM and Humerickhouse, R and Hong, WJ and Hayslip, J and Roboz, GJ}, title = {Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO1801600}, doi = {10.1200/JCO.18.01600}, pmid = {30892988}, issn = {1527-7755}, abstract = {PURPOSE: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.<br><br>PATIENTS AND METHODS: Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).<br><br>RESULTS: Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).<br><br>CONCLUSION: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.}, }
@article {pmid30892118, year = {2019}, author = {Sridharan, V and Shoda, Y and Heffner, JL and Bricker, J}, title = {Addiction Mindsets and Psychological Processes of Quitting Smoking.}, journal = {Substance use &amp; misuse}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10826084.2018.1555259}, pmid = {30892118}, issn = {1532-2491}, support = {R01 CA166646/CA/NCI NIH HHS/United States ; R01 CA192849/CA/NCI NIH HHS/United States ; R01 DA038411/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: Lay belief systems about the malleability of human attributes have been shown to impact behavior change in multiple domains. Addiction mindset-i.e., beliefs about the permanence (vs. malleability) of addiction - may affect cigarette smokers' ability to quit, but this has never been examined.<br><br>OBJECTIVES: The aims of the present research were to develop a measure of addiction mindset (study 1) and examine its associations with various psychological aspects of quitting smoking (study 2).<br><br>METHODS: In Study 1, using factor analysis of current smokers' and nonsmokers' (n = 600) responses to 22 items designed to measure addiction mindset, we developed a reliable six-item Addiction Mindset Scale (AMS). In Study 2, adult smokers (n = 200) completed the AMS, and measures of a number of psychological processes related to smoking.<br><br>RESULTS: Higher scores on the AMS, indicative of the belief that addiction is malleable (referred to as a growth mindset), were positively and significantly associated with greater motivation to quit, greater commitment to quitting, greater self-efficacy to abstain, less attribution of failure to lack of ability to change addiction, and fewer self-reported barriers to cessation (all p's < .05).<br><br>CONCLUSIONS: The results of this study show a relationship between the beliefs about the permanence of addiction and psychological processes relevant to quitting smoking. The findings underscore the potential of future research exploring how addiction mindsets relate to successful smoking cessation as well as other types of addictive behavior and how they can be applied to change people's behavior.}, }
@article {pmid30892059, year = {2019}, author = {Brusniak, MY and Christianson, C and Witthuhn, E and Needham, S and Olson, JM}, title = {Simultaneous extraction and analysis of multiple cystine-dense peptides by μSPE and microflow-MS/MS from plasma.}, journal = {Bioanalysis}, volume = {}, number = {}, pages = {}, doi = {10.4155/bio-2018-0276}, pmid = {30892059}, issn = {1757-6199}, abstract = {AIM: Develop a universal extraction and liquid chromatography-mass spectrometer method to simultaneously analyze cystine-dense peptide (CDP) miniproteins from rat and human plasma. The results of the analysis will be used to assist selection of therapeutic drug candidates from the vast CDP library.<br><br>METHODS &amp; RESULTS: A micro-elution solid-phase extraction method was developed for the sample preparation of the CDP peptides in rat and human plasma followed by analysis by microflow liquid chromatography MS/MS. The methods developed for drug discovery were found to be accurate (±≤15.2% from nominal concentrations) and precise (≤13.4% CV), with a dynamic range of 1.00-500 ng/ml and extraction recoveries of 47.2-99.0%.<br><br>CONCLUSION: This bioanalytical method can be utilized to screen CDP proteins and other miniproteins for drug discovery, candidate selection and further drug development.}, }
@article {pmid30892052, year = {2019}, author = {Bull, M and McKernan, J and Styrchak, S and Kraft, K and Hitti, J and Cohn, SE and Tapia, K and Deng, W and Holte, S and Mullins, JI and Coombs, RW and Frenkel, L}, title = {Phylogenetic analyses comparing HIV sequences from plasma at virologic failure to cervix vs. blood sequences from antecedent antiretroviral therapy suppression.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/AID.2018.0211}, pmid = {30892052}, issn = {1931-8405}, abstract = {INTRODUCTION: Identifying tissue sources of HIV that rebound following &quot;failure&quot; of antiretroviral therapy (ART) is critical to evaluating cure strategies. To assess the role of the uterine cervix and peripheral blood mononuclear cells (PBMC) as viral reservoirs, nearest-neighbor phylogenetic analyses compared genetic relatedness of tissue sequences during ART-suppression to those detected in plasma at viral rebound.<br><br>METHODS: Blood and genital tract specimens from a natural history cohort of HIV-infected women were collected over five years. HIV DNA sequences extracted from PBMC and cervical biopsies during ART-suppression and plasma RNA from rebound (defined as HIV RNA >3 log10 copies/mL) were derived by single-genome-amplification. Phylogenetic and nearest-neighbor analyses of HIV env sequences and drug resistance in pol sequences were compared between tissues.<br><br>RESULTS: Nine instances of plasma viral rebound (median HIV RNA 3.6 log10 c/mL; IQR: 3.1-3.8) were detected in 7 of 57 women. Nearest-neighbor analyses found rebound plasma sequences were closer to uterine cervical sequences in 4/9 (44%), closer to PBMC in 3/9 (33%), and ambiguous in 2/9 (22%) cases. Rebound plasma clades (n=27) shared identical sequences in 7 instances with the cervix vs. 2 with PBMC. Novel drug resistance mutations were detected in 4/9 (44%) rebounds.<br><br>CONCLUSIONS: The observed tendency for greater sharing of identical HIV variants and greater nearest-neighbor association between rebounding plasma and uterine cervical vs. PBMC sequences suggests that the uterine cervix may be a relevant HIV reservoir. The cervix, a readily accessible tissue in women, that can be repeatedly sampled, could help assess the HIV reservoir when evaluating cure strategies.}, }
@article {pmid30890759, year = {2019}, author = {Alsinnawi, M and Zhang, A and Bianchi-Frias, D and Burns, J and Cho, E and Zhang, X and Sowalsky, A and Ye, H and Slee, AE and True, L and Porter, C and Taplin, ME and Balk, S and Nelson, PS and Montgomery, RB and Mostaghel, EA}, title = {Association of prostate cancer SLCO gene expression with Gleason grade and alterations following androgen deprivation therapy.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41391-019-0141-6}, pmid = {30890759}, issn = {1476-5608}, support = {P50 CA090381/CA/NCI NIH HHS/United States ; YIA//Prostate Cancer Foundation (PCF)/ ; W81XWH-16-1-0431//U.S. Department of Defense (United States Department of Defense)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; P50 CA090381//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 5P30 CA015704-40//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; W81XWH-13-1-0267//U.S. Department of Defense (United States Department of Defense)/ ; P01 CA163227//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; W81XWH-16-1-0432//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH-11-2-0154//U.S. Department of Defense (United States Department of Defense)/ ; P50 CA097186//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01 CA163227/CA/NCI NIH HHS/United States ; Challenge Award//Prostate Cancer Foundation (PCF)/ ; }, abstract = {BACKGROUND: SLCO-encoded transporters have been associated with progression to castration-resistant prostate cancer (CRPC) after initiation of androgen deprivation therapy (ADT). Although expressed at lower levels than in CRPC tissues, SLCO-encoded transporters may also play a role in response of primary prostate cancer (PCa) to ADT and biochemical recurrence.<br><br>METHODS: We systematically explored expression of the 11 human SLCO genes in a large sample of untreated and ADT-treated normal prostate (NP) and primary PCa tissues, including tumors treated with neoadjuvant abiraterone.<br><br>RESULTS: Transporters with the most recognized role in steroid uptake in PCa, including SLCO2B1 (DHEAS) and 1B3 (testosterone), were consistently detected in primary PCa. SLCO1B3 was nearly 5-fold higher in PCa vs NP with no difference in Gleason 3 vs 4 and no change with ADT. SLCO2B1 was detected at 3-fold lower levels in PCa than NP but was nearly 7-fold higher in Gleason 4 vs Gleason 3 and increased 3-fold following ADT (p < 0.05 for all).<br><br>CONCLUSIONS: We observed clear differences in SLCO expression in PCa vs NP samples, in Gleason 4 vs Gleason 3 tumors, and in ADT-treated vs untreated tissues. These findings are hypothesis generating due to small sample size, but suggest that baseline and ADT-induced changes in PCa OATP expression may influence steroid uptake and response to ADT, as well as uptake and response to drugs such as abiraterone and docetaxel which are also subject to OATP-mediated transport and are now being routinely combined with ADT in the metastatic castration sensitive setting.}, }
@article {pmid30890385, year = {2019}, author = {Selinger, C and Bershteyn, A and Dimitrov, DT and Adamson, BJS and Revill, P and Hallett, TB and Phillips, AN and Bekker, LG and Rees, H and Gray, G}, title = {Targeting and vaccine durability are key for population-level impact and cost-effectiveness of a pox-protein HIV vaccine regimen in South Africa.}, journal = {Vaccine}, volume = {37}, number = {16}, pages = {2258-2267}, doi = {10.1016/j.vaccine.2019.02.073}, pmid = {30890385}, issn = {1873-2518}, abstract = {BACKGROUND: RV144 is to date the only HIV vaccine trial to demonstrate efficacy, albeit rapidly waning over time. The HVTN 702 trial is currently evaluating in South Africa a similar vaccine formulation to that of RV144 for subtype C HIV with additional boosters (pox-protein regimen). Using a detailed stochastic individual-based network model of disease transmission calibrated to the HIV epidemic, we investigate population-level impact and maximum cost of an HIV vaccine to remain cost-effective.<br><br>METHODS: Consistent with the original pox-protein regimen, we model a primary series of five vaccinations meeting the goal of 50% cumulative efficacy 24 months after the first dose and include two-yearly boosters that maintain durable efficacy over 10 years. We simulate vaccination programs in South Africa starting in 2027 under various vaccine targeting and HIV treatment and prevention assumptions.<br><br>RESULTS: Our analysis shows that this partially effective vaccine could prevent, at catch-up vaccination with 60% coverage, up to 941,000 (15.6%) new infections between 2027 and 2047 assuming current trends of antiretroviral treatment. An impact of up to 697,000 (11.5%) infections prevented could be achieved by targeting age cohorts of highest incidence. Economic evaluation indicates that, if treatment scale-up was achieved, vaccination could be cost-effective at a total cost of less than $385 and $62 per 10-year series (cost-effectiveness thresholds of $5,691 and $750).<br><br>CONCLUSIONS: While a partially effective, rapidly waning vaccine could help to prevent HIV infections, it will not eliminate HIV as a public health priority in sub-Saharan Africa. Vaccination is expected to be most effective under targeted delivery to age groups of highest HIV incidence. Awaiting results of trial, the introduction of vaccination should go in parallel with continued innovation in HIV prevention, including studies to determine the costs of delivery and feasibility and further research into products with greater efficacy and durability.}, }
@article {pmid30889382, year = {2019}, author = {Srivastava, S and Salter, AI and Liggitt, D and Yechan-Gunja, S and Sarvothama, M and Cooper, K and Smythe, KS and Dudakov, JA and Pierce, RH and Rader, C and Riddell, SR}, title = {Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting.}, journal = {Cancer cell}, volume = {35}, number = {3}, pages = {489-503.e8}, doi = {10.1016/j.ccell.2019.02.003}, pmid = {30889382}, issn = {1878-3686}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA114536/CA/NCI NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; }, abstract = {Many potential targets for CAR-T cells in solid tumors are expressed in some normal tissues, raising concern for off-tumor toxicity. Following lymphodepletion, CAR-T cells targeting the tumor-associated antigen ROR1 lysed tumors in mice but induced lethal bone marrow failure due to recognition of ROR1+ stromal cells. To improve selectivity, we engineered T cells with synthetic Notch (synNotch) receptors specific for EpCAM or B7-H3, which are expressed on ROR1+ tumor cells but not ROR1+ stromal cells. SynNotch receptors induced ROR1 CAR expression selectively within the tumor, resulting in tumor regression without toxicity when tumor cells were segregated from, but not when co-localized with, normal ROR1+ cells. This strategy, thus, permits safe targeting of tumors that are sufficiently separated from normal cells.}, }
@article {pmid30887029, year = {2019}, author = {Ma, J and Karnovsky, A and Afshinnia, F and Wigginton, J and Rader, DJ and Natarajan, L and Sharma, K and Porter, AC and Rahman, M and He, J and Hamm, L and Shafi, T and Gipson, D and Gadegbeku, C and Feldman, H and Michailidis, G and Pennathur, S}, title = {Differential network enrichment analysis reveals novel lipid pathways in chronic kidney disease.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btz114}, pmid = {30887029}, issn = {1367-4811}, support = {K08 DK106523/DK/NIDDK NIH HHS/United States ; }, abstract = {MOTIVATION: Functional enrichment testing methods can reduce data comprising hundreds of altered biomolecules to smaller sets of altered biological 'concepts' that help generate testable hypotheses. This study leveraged differential network enrichment analysis methodology to identify and validate lipid subnetworks that potentially differentiate chronic kidney disease (CKD) by severity or progression.<br><br>RESULTS: We built a partial correlation interaction network, identified highly connected network components, applied network-based gene-set analysis to identify differentially enriched subnetworks, and compared the subnetworks in patients with early-stage versus late-stage CKD. We identified two subnetworks 'triacylglycerols' and 'cardiolipins-phosphatidylethanolamines (CL-PE)' characterized by lower connectivity, and a higher abundance of longer polyunsaturated triacylglycerols in patients with severe CKD (stage ≥4) from the Clinical Phenotyping Resource and Biobank Core. These finding were replicated in an independent cohort, the Chronic Renal Insufficiency Cohort. Using an innovative method for elucidating biological alterations in lipid networks, we demonstrated alterations in triacylglycerols and cardiolipins-phosphatidylethanolamines that precede the clinical outcome of end-stage kidney disease by several years.<br><br>A complete list of NetGSA results in HTML format can be found at http://metscape.ncibi.org/netgsa/12345-022118/cric_cprobe/022118/results_cric_cprobe/main.html. The DNEA is freely available at https://github.com/wiggie/DNEA. Java wrapper leveraging the cytoscape.js framework is available at http://js.cytoscape.org.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid30886357, year = {2019}, author = {Setoh, YX and Amarilla, AA and Peng, NYG and Griffiths, RE and Carrera, J and Freney, ME and Nakayama, E and Ogawa, S and Watterson, D and Modhiran, N and Nanyonga, FE and Torres, FJ and Slonchak, A and Periasamy, P and Prow, NA and Tang, B and Harrison, J and Hobson-Peters, J and Cuddihy, T and Cooper-White, J and Hall, RA and Young, PR and Mackenzie, JM and Wolvetang, E and Bloom, JD and Suhrbier, A and Khromykh, AA}, title = {Determinants of Zika virus host tropism uncovered by deep mutational scanning.}, journal = {Nature microbiology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41564-019-0399-4}, pmid = {30886357}, issn = {2058-5276}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; R01 AI140891/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, abstract = {Arboviruses cycle between, and replicate in, both invertebrate and vertebrate hosts, which for Zika virus (ZIKV) involves Aedes mosquitoes and primates1. The viral determinants required for replication in such obligate hosts are under strong purifying selection during natural virus evolution, making it challenging to resolve which determinants are optimal for viral fitness in each host. Herein we describe a deep mutational scanning (DMS) strategy2-5 whereby a viral cDNA library was constructed containing all codon substitutions in the C-terminal 204 amino acids of ZIKV envelope protein (E). The cDNA library was transfected into C6/36 (Aedes) and Vero (primate) cells, with subsequent deep sequencing and computational analyses of recovered viruses showing that substitutions K316Q and S461G, or Q350L and T397S, conferred substantial replicative advantages in mosquito and primate cells, respectively. A 316Q/461G virus was constructed and shown to be replication-defective in mammalian cells due to severely compromised virus particle formation and secretion. The 316Q/461G virus was also highly attenuated in human brain organoids, and illustrated utility as a vaccine in mice. This approach can thus imitate evolutionary selection in a matter of days and identify amino acids key to the regulation of virus replication in specific host environments.}, }
@article {pmid30886348, year = {2019}, author = {Talbert, PB and Meers, MP and Henikoff, S}, title = {Old cogs, new tricks: the evolution of gene expression in a chromatin context.}, journal = {Nature reviews. Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41576-019-0105-7}, pmid = {30886348}, issn = {1471-0064}, abstract = {Sophisticated gene-regulatory mechanisms probably evolved in prokaryotes billions of years before the emergence of modern eukaryotes, which inherited the same basic enzymatic machineries. However, the epigenomic landscapes of eukaryotes are dominated by nucleosomes, which have acquired roles in genome packaging, mitotic condensation and silencing parasitic genomic elements. Although the molecular mechanisms by which nucleosomes are displaced and modified have been described, just how transcription factors, histone variants and modifications and chromatin regulators act on nucleosomes to regulate transcription is the subject of considerable ongoing study. We explore the extent to which these transcriptional regulatory components function in the context of the evolutionarily ancient role of chromatin as a barrier to processes acting on DNA and how chromatin proteins have diversified to carry out evolutionarily recent functions that accompanied the emergence of differentiation and development in multicellular eukaryotes.}, }
@article {pmid30886145, year = {2019}, author = {Tsang, TK and Ghebremariam, SL and Gresh, L and Gordon, A and Halloran, ME and Katzelnick, LC and Rojas, DP and Kuan, G and Balmaseda, A and Sugimoto, J and Harris, E and Longini, IM and Yang, Y}, title = {Effects of infection history on dengue virus infection and pathogenicity.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {1246}, doi = {10.1038/s41467-019-09193-y}, pmid = {30886145}, issn = {2041-1723}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; P01 AI106695/AI/NIAID NIH HHS/United States ; U54-GM111274/NH/NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI099631/AI/NIAID NIH HHS/United States ; U54 GM111274/GM/NIGMS NIH HHS/United States ; R37-AI032042/NH/NIH HHS/United States ; }, mesh = {Adolescent ; Age Factors ; Antibodies, Viral/*blood/immunology ; Child ; Child, Preschool ; Cross Reactions/genetics/immunology ; Dengue/blood/epidemiology/*immunology/virology ; Dengue Virus/genetics/immunology/isolation &amp; purification/*pathogenicity ; Female ; Host Microbial Interactions/*immunology ; Humans ; Male ; Nicaragua/epidemiology ; Prospective Studies ; Risk Factors ; Serogroup ; Vaccination/*methods ; Virulence/genetics/immunology ; }, abstract = {The understanding of immunological interactions among the four dengue virus (DENV) serotypes and their epidemiological implications is often hampered by the lack of individual-level infection history. Using a statistical framework that infers full infection history, we analyze a prospective pediatric cohort in Nicaragua to characterize how infection history modulates the risks of DENV infection and subsequent clinical disease. After controlling for age, one prior infection is associated with 54% lower, while two or more are associated with 91% higher, risk of a new infection, compared to DENV-naive children. Children >8 years old have 55% and 120% higher risks of infection and subsequent disease, respectively, than their younger peers. Among children with ≥1 prior infection, intermediate antibody titers increase, whereas high titers lower, the risk of subsequent infection, compared with undetectable titers. Such complex dependency needs to be considered in the design of dengue vaccines and vaccination strategies.}, }
@article {pmid30884788, year = {2019}, author = {Schübel, R and Sookthai, D and Greimel, J and Johnson, TS and Grafetstätter, ME and Kirsten, R and Kratz, M and Ulrich, CM and Kaaks, R and Kühn, T}, title = {Key Genes of Lipid Metabolism and WNT-Signaling Are Downregulated in Subcutaneous Adipose Tissue with Moderate Weight Loss.}, journal = {Nutrients}, volume = {11}, number = {3}, pages = {}, doi = {10.3390/nu11030639}, pmid = {30884788}, issn = {2072-6643}, support = {Metabolic Dysfunction//Helmholtz Association/ ; }, abstract = {Smaller cross-sectional studies and bariatric surgery trials suggest that weight loss may change the expression of genes in adipose tissue that have been implicated in the development of metabolic diseases, but well-powered intervention trials are lacking. In post hoc analyses of data from a 12-week dietary intervention trial initially designed to compare metabolic effects of intermittent vs. continuous calorie restriction, we analyzed the effects of overall weight loss on the subcutaneous adipose tissue (SAT) transcriptome. Changes in the transcriptome were measured by microarray using SAT samples of 138 overweight or obese individuals (age range: 35⁻65 years, BMI range: 25⁻40, non-smokers, non-diabetics). Participants were grouped post hoc according to the degree of their weight loss by quartiles (average weight loss in quartiles 1 to 4: 0%, -3.2%, -5.9%, and -10.7%). Candidate genes showing differential expression with weight loss according to microarray analyses were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and fold changes (FCs) were calculated to quantify differences in gene expression. A comparison of individuals in the highest vs. the lowest weight loss quartile revealed 681 genes to be differentially expressed (corrected p < 0.05), with 40 showing FCs of at least 0.4. Out of these, expression changes in secreted frizzled-related protein 2 (SFRP2, FC = 0.65, p = 0.006), stearoyl-CoA desaturase (SCD, FC = -1.00, p < 0.001), and hypoxia inducible lipid droplet-associated (HILPDA, FC = -0.45, p = 0.001) with weight loss were confirmed by RT-qPCR. Dietary weight loss induces significant changes in the expression of genes implicated in lipid metabolism (SCD and HILPDA) and WNT-signaling (SFRP2) in SAT.}, }
@article {pmid30883261, year = {2019}, author = {Singhvi, A and Shaham, S}, title = {Glia-Neuron Interactions in Caenorhabditis elegans.}, journal = {Annual review of neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-neuro-070918-050314}, pmid = {30883261}, issn = {1545-4126}, abstract = {Glia are abundant components of animal nervous systems. Recognized 170 years ago, concerted attempts to understand these cells began only recently. From these investigations glia, once considered passive filler material in the brain, have emerged as active players in neuron development and activity. Glia are essential for nervous system function, and their disruption leads to disease. The nematode Caenorhabditis elegans possesses glial types similar to vertebrate glia, based on molecular, morphological, and functional criteria, and has become a powerful model in which to study glia and their neuronal interactions. Facile genetic and transgenic methods in this animal allow the discovery of genes required for glial functions, and effects of glia at single synapses can be monitored by tracking neuron shape, physiology, or animal behavior. Here, we review recent progress in understanding glia-neuron interactions in C. elegans. We highlight similarities with glia in other animals, and suggest conserved emerging principles of glial function. Expected final online publication date for the Annual Review of Neuroscience Volume 42 is July 8, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, }
@article {pmid30879508, year = {2019}, author = {Yuan, T and Fitzpatrick, T and Ko, NY and Cai, Y and Chen, Y and Zhao, J and Li, L and Xu, J and Gu, J and Li, J and Hao, C and Yang, Z and Cai, W and Cheng, CY and Luo, Z and Zhang, K and Wu, G and Meng, X and Grulich, AE and Hao, Y and Zou, H}, title = {Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global data.}, journal = {The Lancet. Global health}, volume = {7}, number = {4}, pages = {e436-e447}, doi = {10.1016/S2214-109X(18)30567-9}, pmid = {30879508}, issn = {2214-109X}, abstract = {BACKGROUND: Men who have sex with men (MSM) are disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide. Previous reviews investigating the role of circumcision in preventing HIV and other STIs among MSM were inconclusive. Many new studies have emerged in the past decade. To inform global prevention strategies for HIV and other STIs among MSM, we reviewed all available evidence on the associations between circumcision and HIV and other STIs among MSM.<br><br>METHODS: In this systematic review and meta-analysis, we searched PubMed, Web of Science, BioMed Central, Scopus, ResearchGate, Cochrane Library, Embase, PsycINFO, Google Scholar, and websites of international HIV and STI conferences for studies published before March 8, 2018. Interventional or observational studies containing original quantitative data describing associations between circumcision and incident or prevalent infection of HIV and other STIs among MSM were included. Studies were excluded if MSM could not be distinguished from men who have sex with women only. We calculated pooled odds ratios (ORs) and their 95% CIs using random-effect models. We assessed risk of bias using the Newcastle-Ottawa scale.<br><br>FINDINGS: We identified 62 observational studies including 119 248 MSM. Circumcision was associated with 23% reduced odds of HIV infection among MSM overall (OR 0·77, 95% CI 0·67-0·89; number of estimates [k]=45; heterogeneity I2=77%). Circumcision was protective against HIV infection among MSM in countries of low and middle income (0·58, 0·41-0·83; k=23; I2=77%) but not among MSM in high-income countries (0·99, 0·90-1·09; k=20; I2=40%). Circumcision was associated with reduced odds of herpes simplex virus (HSV) infection among MSM overall (0·84, 0·75-0·95; k=5; I2=0%) and penile human papillomavirus (HPV) infection among HIV-infected MSM (0·71, 0·51-0·99; k=3; I2=0%).<br><br>INTERPRETATION: We found evidence that circumcision is likely to protect MSM from HIV infection, particularly in countries of low and middle income. Circumcision might also protect MSM from HSV and penile HPV infection. MSM should be included in campaigns promoting circumcision among men in countries of low and middle income. In view of the substantial proportion of MSM in countries of low and middle income who also have sex with women, well designed longitudinal studies differentiating MSM only and bisexual men are needed to clarify the effect of circumcision on male-to-male transmission of HIV and other STIs.<br><br>FUNDING: National Natural Science Foundation of China, National Science and Technology Major Project of China, Australian National Health and Medical Research Council Early Career Fellowship, Sanming Project of Medicine in Shenzhen, National Institutes of Health, Mega Projects of National Science Research for the 13th Five-Year Plan, Doris Duke Charitable Foundation.}, }
@article {pmid30877760, year = {2019}, author = {Kaluza, J and Harris, HR and Linden, A and Wolk, A}, title = {Alcohol Consumption and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwz020}, pmid = {30877760}, issn = {1476-6256}, abstract = {Studies indicate an inverse association between moderate alcohol consumption and chronic inflammatory diseases; however, the association between alcohol consumption and chronic obstructive pulmonary disease (COPD) incidence has not been widely studied. We investigated the associations of total alcohol consumption and intake of specific alcoholic beverages with risk of COPD in a population-based prospective cohort study, the Cohort of Swedish Men (n = 44,254). Alcohol consumption was assessed with a self-administered questionnaire in 1997. During follow-up (1998-2014), 2,177 COPD cases were ascertained. Moderate alcohol consumption was associated with the lowest risk of COPD. A J-shaped association was observed for ethanol consumption (P for nonlinearity = 0.003) and beer consumption (P for nonlinearity < 0.001); for wine consumption, a U-shaped association was observed (P for nonlinearity < 0.001). Defining a &quot;standard drink&quot; as 12 g of ethanol, the multivariable-adjusted hazard ratios were 0.77 (95% confidence interval (CI): 0.66, 0.90) and 0.92 (95% CI: 0.81, 1.05) for beer consumption of 4.1-6.0 and >6.0 standard drinks/week (SDW) versus <1.0 SDW, respectively; 0.80 (95% CI: 0.69, 0.93) and 1.00 (95% CI: 0.83, 1.21) for wine consumption of 2.0-4.0 and >4.0 SDW versus <1.0 SDW, respectively; and 1.10 (95% CI: 0.98, 1.24) and 1.20 (95% CI: 0.99, 1.44) for liquor consumption of 2.0-4.0 and >4.0 SDW versus <1.0 SDW, respectively. In conclusion, our findings suggest that moderate beer and wine consumption, but not liquor consumption, may decrease risk of COPD. Additional studies are needed to confirm these associations.}, }
@article {pmid30877580, year = {2019}, author = {Bauermeister, JA and Golinkoff, JM and Carballo-Diéguez, A and Giguere, R and López, D and Hoesley, CJ and Chen, BA and Anderson, P and Dezzutti, CS and Strizki, J and Sprinkle, C and Heard, F and Hall, W and Jacobson, C and Berthiaume, J and Mayo, A and Richardson, BA and Piper, J and , }, title = {A Mixed-Methods Study Examining Adherence to and Acceptability of Intravaginal Rings for HIV Prevention: Behavioral Results of MTN-027.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10461-019-02457-0}, pmid = {30877580}, issn = {1573-3254}, support = {UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; U01 AI068633/AI/NIAID NIH HHS/United States ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Intravaginal rings (IVR) containing antiretroviral drugs are a promising method for HIV prevention. We triangulated quantitative and qualitative assessments to evaluate the acceptability of four IVRs used continuously for 28 days as part of a Phase I trial (N = 48 HIV-negative women; ages 18-45). Adherence was high throughout the trial, yet 30% of participants reported involuntary IVR expulsions followed by re-insertion. Most participants (93.6%) felt comfortable with the IVR being inside their body. Participants reported liking the IVR more (36.2%) or the same amount (55.3%) since starting the study. When given the option of choosing between the IVR and/or a male condom for HIV-prevention, most reported preferring the IVR (n = 29, 63.0%), and over a quarter of the sample reported liking them equally (n = 12, 26.1%). We observed no differences in IVR acceptability across the study arms. High adherence and acceptability underscores the promise of an IVR as a female-controlled, sustained mechanism for HIV prevention.}, }
@article {pmid30875235, year = {2019}, author = {Roy, R and Chatterjee, A and Das, D and Ray, A and Singh, R and Chattopadhyay, E and Sarkar, N and Eccles, M and Pal, M and Maitra, A and Roy, B}, title = {Genome-wide miRNA methylome analysis in oral cancer: possible biomarkers associated with patient survival.}, journal = {Epigenomics}, volume = {11}, number = {5}, pages = {473-487}, doi = {10.2217/epi-2018-0078}, pmid = {30875235}, issn = {1750-192X}, abstract = {AIM: The methylome associated with miRNA loci was investigated in oral cancer to explore tobacco specific methylation and potential biomarkers for patient survival.<br><br>METHODS: Methylome data was generated from 16 pairs of cancer-normal tissues by reduced representation bisulfite sequencing method. Differentially methylated regions were identified using the DMAP pipeline. In silico validation and Kaplan-Meier survival analyses were performed on The Cancer Genome Atlas data based on our miRNA methylome data.<br><br>RESULTS: A total of 4310 unique differentially methylated regions, mapping to 144 miRNA loci, were identified. Three distinct groups of miRNAs were differentially methylated in cancer tissues from smokers, chewers and mixed habitués. Hypermethylation of miR-503, miR-200a/b, miR-320b and miR-489 was associated with worse 5-year survival.<br><br>CONCLUSION: Differential methylation patterns in miRNA loci are associated with poor survival underscoring their potential as predictive and prognostic biomarkers in oral cancer.}, }
@article {pmid30874775, year = {2019}, author = {LaCroix, AZ and Bellettiere, J and Rillamas-Sun, E and Di, C and Evenson, KR and Lewis, CE and Buchner, DM and Stefanick, ML and Lee, IM and Rosenberg, DE and LaMonte, MJ and , }, title = {Association of Light Physical Activity Measured by Accelerometry and Incidence of Coronary Heart Disease and Cardiovascular Disease in Older Women.}, journal = {JAMA network open}, volume = {2}, number = {3}, pages = {e190419}, doi = {10.1001/jamanetworkopen.2019.0419}, pmid = {30874775}, issn = {2574-3805}, support = {T32 HL079891/HL/NHLBI NIH HHS/United States ; }, abstract = {Importance: To our knowledge, no studies have examined light physical activity (PA) measured by accelerometry and heart disease in older women.<br><br>Objective: To investigate whether higher levels of light PA were associated with reduced risks of coronary heart disease (CHD) or cardiovascular disease (CVD) in older women.<br><br>Prospective cohort study of older women from baseline (March 2012 to April 2014) through February 28, 2017, for up to 4.91 years. The setting was community-dwelling participants from the Women's Health Initiative. Participants were ambulatory women with no history of myocardial infarction or stroke.<br><br>Exposures: Data from accelerometers worn for a requested 7 days were used to measure light PA.<br><br>Main Outcomes and Measures: Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs for physician-adjudicated CHD and CVD events across light PA quartiles adjusting for possible confounders. Light PA was also analyzed as a continuous variable with and without adjustment for moderate to vigorous PA (MVPA).<br><br>Results: Among 5861 women (mean [SD] age, 78.5 [6.7] years), 143 CHD events and 570 CVD events were observed. The HRs for CHD in the highest vs lowest quartiles of light PA were 0.42 (95% CI, 0.25-0.70; P for trend <.001) adjusted for age and race/ethnicity and 0.58 (95% CI, 0.34-0.99; P for trend = .004) after additional adjustment for education, current smoking, alcohol consumption, physical functioning, comorbidity, and self-rated health. Corresponding HRs for CVD in the highest vs lowest quartiles of light PA were 0.63 (95% CI, 0.49-0.81; P for trend <.001) and 0.78 (95% CI, 0.60-1.00; P for trend = .004). The HRs for a 1-hour/day increment in light PA after additional adjustment for MVPA were 0.86 (95% CI, 0.73-1.00; P for trend = .05) for CHD and 0.92 (95% CI, 0.85-0.99; P for trend = .03) for CVD.<br><br>Conclusions and Relevance: The present findings support the conclusion that all movement counts for the prevention of CHD and CVD in older women. Large, pragmatic randomized trials are needed to test whether increasing light PA among older women reduces cardiovascular risk.}, }
@article {pmid30873591, year = {2019}, author = {Watts, EL and Perez-Cornago, A and Appleby, PN and Albanes, D and Ardanaz, E and Black, A and Bueno-de-Mesquita, HB and Chan, JM and Chen, C and Chubb, SAP and Cook, MB and Deschasaux, M and Donovan, JL and English, DR and Flicker, L and Freedman, ND and Galan, P and Giles, GG and Giovannucci, EL and Gunter, MJ and Habel, LA and Häggström, C and Haiman, C and Hamdy, FC and Hercberg, S and Holly, JM and Huang, J and Huang, WY and Johansson, M and Kaaks, R and Kubo, T and Lane, JA and Layne, TM and Le Marchand, L and Martin, RM and Metter, EJ and Mikami, K and Milne, RL and Morris, HA and Mucci, LA and Neal, DE and Neuhouser, ML and Oliver, SE and Overvad, K and Ozasa, K and Pala, V and Pernar, CH and Pollak, M and Rowlands, MA and Schaefer, CA and Schenk, JM and Stattin, P and Tamakoshi, A and Thysell, E and Touvier, M and Trichopoulou, A and Tsilidis, KK and Van Den Eeden, SK and Weinstein, SJ and Wilkens, L and Yeap, BB and Key, TJ and Allen, NE and Travis, RC}, title = {The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.32276}, pmid = {30873591}, issn = {1097-0215}, support = {C18281/A19169//Cancer Research UK/United Kingdom ; C8221/A19170//Cancer Research UK/United Kingdom ; C8221/A20986//Cancer Research UK/United Kingdom ; //Hellenic Health Foundation/ ; U01 CA 167552//National Cancer Institute/ ; //NIHR Bristol Biomedical Research Centre/ ; }, abstract = {Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.}, }
@article {pmid30872361, year = {2019}, author = {Freitas-Andrade, M and Wang, N and Bechberger, JF and De Bock, M and Lampe, PD and Leybaert, L and Naus, CC}, title = {Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke.}, journal = {The Journal of experimental medicine}, volume = {216}, number = {4}, pages = {916-935}, doi = {10.1084/jem.20171452}, pmid = {30872361}, issn = {1540-9538}, support = {R01 GM055632/GM/NIGMS NIH HHS/United States ; }, abstract = {Connexin43 (Cx43) function is influenced by kinases that phosphorylate specific serine sites located near its C-terminus. Stroke is a powerful inducer of kinase activity, but its effect on Cx43 is unknown. We investigated the impact of wild-type (WT) and knock-in Cx43 with serine to alanine mutations at the protein kinase C (PKC) site Cx43S368A, the casein kinase 1 (CK1) sites Cx43S325A/328Y/330A, and the mitogen-activated protein kinase (MAPK) sites Cx43S255/262/279/282A (MK4) on a permanent middle cerebral artery occlusion (pMCAO) stroke model. We demonstrate that MK4 transgenic animals exhibit a significant decrease in infarct volume that was associated with improvement in behavioral performance. An increase in astrocyte reactivity with a concomitant decrease in microglial reactivity was observed in MK4 mice. In contrast to WT, MK4 astrocytes displayed reduced Cx43 hemichannel activity. Pharmacological blockade of Cx43 hemichannels with TAT-Gap19 also significantly decreased infarct volume in WT animals. This study provides novel molecular insights and charts new avenues for therapeutic intervention associated with Cx43 function.}, }
@article {pmid30871976, year = {2019}, author = {McCune, JS and Wang, T and Bo-Subait, K and Aljurf, M and Beitinjaneh, A and Bubalo, J and Cahn, JY and Cerny, J and Chhabra, S and Cumpston, A and Dupuis, LL and Lazarus, HM and Marks, DI and Maziarz, RT and Norkin, M and Prestidge, T and Mineishi, S and Krem, MM and Pasquini, M and Martin, PJ}, title = {Association of Antiepileptic Medications with Outcomes after Allogeneic Hematopoietic Cell Transplantation with Busulfan/Cyclophosphamide Conditioning.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.03.001}, pmid = {30871976}, issn = {1523-6536}, abstract = {High-dose busulfan (BU) followed by high-dose cyclophosphamide (CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative antiepileptic medications (AEMs) prevents seizures caused by BU. Phenytoin induces enzymes that increase exposure to active CY metabolites in vivo, whereas alternative AEMs do not have this effect. Lower exposure to active CY metabolites with the use of alternative AEMs could decrease the risk of toxicity but might increase the risk of recurrent malignancy after HCT. Previous studies have not determined whether outcomes with alternative AEMs differ from those with phenytoin in patients treated with BU/CY before allogeneic HCT. We studied a cohort of 2155 patients, including 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT between 2004 and 2014. We found no differences suggesting decreased overall survival or relapse-free survival or increased risks of relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or regimen-related toxicity associated with the use of alternative AEMs compared with phenytoin. The risk of dialysis was lower in the alternative AEM group than in the phenytoin group. Alternative AEMs are safe for prevention of seizures after BU administration and can avoid the undesirable toxicities and drug interactions caused by phenytoin.}, }
@article {pmid30871856, year = {2019}, author = {Minot, SS}, title = {De novo Assembly Vastly Expands the Known Microbial Universe.}, journal = {Trends in microbiology}, volume = {27}, number = {5}, pages = {385-386}, doi = {10.1016/j.tim.2019.02.007}, pmid = {30871856}, issn = {1878-4380}, abstract = {The study of the human microbiome relies heavily on the genomes of bacterial isolates that can be grown in culture. A recent study (Pasolli et al. Cell 2019;176:649-662) of stool microbiome samples generated over 150 000 microbial genomes without any culture, vastly expanding our knowledge of the biases in existing reference databases.}, }
@article {pmid30870493, year = {2019}, author = {Rytlewski, J and Deng, S and Xie, T and Davis, C and Robins, H and Yusko, E and Bienkowska, J}, title = {Model to improve specificity for identification of clinically-relevant expanded T cells in peripheral blood.}, journal = {PloS one}, volume = {14}, number = {3}, pages = {e0213684}, doi = {10.1371/journal.pone.0213684}, pmid = {30870493}, issn = {1932-6203}, abstract = {Current methods to quantify T-cell clonal expansion only account for variance due to random sampling from a highly diverse repertoire space. We propose a beta-binomial model to incorporate time-dependent variance into the assessment of differentially abundant T-cell clones, identified by unique T Cell Receptor (TCR) β-chain rearrangements, and show that this model improves specificity for detecting clinically relevant clonal expansion. Using blood samples from ten healthy donors, we modeled the variance of T-cell clones within each subject over time and calibrated the dispersion parameters of the beta distribution to fit this variance. As a validation, we compared pre- versus post-treatment blood samples from urothelial cancer patients treated with atezolizumab, where clonal expansion (quantified by the earlier binomial model) was previously reported to correlate with benefit. The beta-binomial model significantly reduced the false-positive rate for detecting differentially abundant clones over time compared to the earlier binomial method. In the urothelial cancer cohort, the beta-binomial model enriched for tumor infiltrating lymphocytes among the clones detected as expanding in the peripheral blood in response to therapy compared to the binomial model and improved the overall correlation with clinical benefit. Incorporating time-dependent variance into the statistical framework for measuring differentially abundant T-cell clones improves the model's specificity for T-cells that correlate more strongly with the disease and treatment setting of-interest. Reducing background-level clonal expansion, therefore, improves the quality of clonal expansion as a biomarker for assessing the T cell immune response and correlations with clinical measures.}, }
@article {pmid30869200, year = {2019}, author = {Amico, KR and Ramirez, C and Caplan, MR and Montgomery, BE and Stewart, J and Hodder, S and Swaminathan, S and Wang, J and Darden-Tabb, NY and McCauley, M and Mayer, KH and Wilkin, T and Landovitz, RJ and Gulick, R and Adimora, AA and , }, title = {Perspectives of US women participating in a candidate PrEP study: adherence, acceptability and future use intentions.}, journal = {Journal of the International AIDS Society}, volume = {22}, number = {3}, pages = {e25247}, doi = {10.1002/jia2.25247}, pmid = {30869200}, issn = {1758-2652}, support = {//Division of AIDS/ ; UM1-AI068617//National Institutes of Health/ ; //Gilead Sciences/ ; U54 GM104942/GM/NIGMS NIH HHS/United States ; UM1-AI068619//National Institutes of Health/ ; //Division of AIDS, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068613//National Institutes of Health/ ; UM1-AI-068636//AIDS Clinical Trials Group/ ; }, abstract = {INTRODUCTION: Limited data exist on acceptability of candidate pre-exposure prophylaxis (PrEP) regimens among US women. We evaluated PrEP experiences, attitudes and future use intentions among sexually active women who completed the US-based HIV Prevention Trials Network 069/AIDS Clinical Trials Group 5305 study.<br><br>METHODS: Women participated in the study between March 2013 and November 2015. We analysed computer-assisted self-interview (CASI) surveys among 130 women and conducted in-depth interviews among a subset of 26 women from three sites. Interviews were conducted in mid/late-2015.<br><br>RESULTS: Most women (57%) reported very good/excellent PrEP adherence on CASI, although 21% acknowledged over-reporting adherence at least some of the time. Commitment to preventing HIV infection, a sense of ownership of the study, and keeping pills stored in a visible location facilitated adherence. Adherence barriers included &quot;simply forgetting&quot; and being away from home. Most women interviewed did not intend to use PrEP in the future because of lack of perceived need due to their own (as opposed to their partners') low-risk behaviour and concerns about affordability - but not because of side effects or other characteristics of the regimens.<br><br>DISCUSSION: Improving HIV prevention options for US women will require access to affordable PrEP as well as expanding women's understanding of relationship- and community-level factors that increase their risk of acquiring HIV.}, }
@article {pmid30868739, year = {2019}, author = {Mitchell, KM and Hoots, B and Dimitrov, D and German, D and Flynn, C and Farley, JE and Gelman, M and Hughes, JP and Donnell, D and Adeyeye, A and Remien, RH and Beyrer, C and Paz-Bailey, G and Boily, MC}, title = {Improvements in the HIV care continuum needed to meaningfully reduce HIV incidence among men who have sex with men in Baltimore, US: a modelling study for HPTN 078.}, journal = {Journal of the International AIDS Society}, volume = {22}, number = {3}, pages = {e25246}, doi = {10.1002/jia2.25246}, pmid = {30868739}, issn = {1758-2652}, support = {//Maryland Department of Health and the Centers for Disease Control and Prevention, and the infrastructure, resources, and services of the Johns Hopkins University Center for AIDS Research/ ; //HPTN Statistical and Data Management Center/ ; //National Institute of Allergy and Infectious Diseases/ ; P30 AI094189/AI/NIAID NIH HHS/United States ; UM1AI1068617//US National Institutes of Health/ ; P30AI094189//US National Institutes of Health/ ; K01DA041259//US National Institutes of Health/ ; //National Institute of Mental Health/ ; UM1AI068619//US National Institutes of Health/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; K01 DA041259/DA/NIDA NIH HHS/United States ; //National Institute on Drug Abuse/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: HIV prevalence is high among men who have sex with men (MSM) in Baltimore, Maryland, United States, and the levels of viral suppression among HIV-positive MSM are relatively low. The HIV Prevention Trials Network 078 trial seeks to increase the levels of viral suppression among US MSM by increasing the rates of diagnosis and linkage to care and treatment. We estimated the increases in viral suppression needed to reach different HIV incidence reduction targets, and the impact of meeting diagnosis and treatment targets.<br><br>METHODS: We used a mathematical model of HIV transmission among MSM from Baltimore, US, parameterised with behavioural data and fitted to HIV prevalence and care continuum data for Baltimore wherever possible, to project increases in viral suppression needed to reduce the HIV incidence rate among Baltimore MSM by 10, 20, 30 or 50% after 2, 5 and 10 years. We also projected HIV incidence reductions achieved if US national targets - 90% of people living with HIV (PLHIV) know their HIV serostatus, 90% of those diagnosed are retained in HIV medical care and 80% of those diagnosed are virally suppressed - or UNAIDS 90-90-90 targets (90% of PLHIV know their status, 90% of those diagnosed receive antiretroviral therapy (ART), 90% of those receiving ART are virally suppressed) are each met by 2020.<br><br>RESULTS: To reduce the HIV incidence rate by 20% and 50% after five years (compared with the base-case at the same time point), the proportion of all HIV-positive MSM who are virally suppressed must increase above 2015 levels by a median 13 percentage points (95% uncertainty interval 9 to 16 percentage points) from median 49% to 60%, and 27 percentage points (22 to 35) from 49% to 75% respectively. Meeting all three US or 90-90-90 UNAIDS targets results in a 48% (31% to 63%) and 51% (38% to 65%) HIV incidence rate reduction in 2020 respectively.<br><br>CONCLUSIONS: Substantial improvements in levels of viral suppression will be needed to achieve significant incidence reductions among MSM in Baltimore, and to meet 2020 US and UNAIDS targets. Future modelling studies should additionally consider the impact of pre-exposure prophylaxis for MSM.}, }
@article {pmid30867038, year = {2019}, author = {Galipeau, PC and Oman, KM and Paulson, TG and Sanchez, CA and Zhang, Q and Marty, JA and Delrow, JJ and Kuhner, MK and Vaughan, TL and Reid, BJ and Li, X}, title = {Correction to: NSAID use and somatic exomic mutations in Barrett's esophagus.}, journal = {Genome medicine}, volume = {11}, number = {1}, pages = {14}, doi = {10.1186/s13073-019-0625-y}, pmid = {30867038}, issn = {1756-994X}, abstract = {It was highlighted that in the original article [1] the Availability of data and materials section was incorrect.}, }
@article {pmid30866962, year = {2019}, author = {Díaz Santana, MV and Hankinson, SE and Bigelow, C and Sturgeon, SR and Zoeller, RT and Tinker, L and Manson, JAE and Calafat, AM and Meliker, JR and Reeves, KW}, title = {Urinary concentrations of phthalate biomarkers and weight change among postmenopausal women: a prospective cohort study.}, journal = {Environmental health : a global access science source}, volume = {18}, number = {1}, pages = {20}, doi = {10.1186/s12940-019-0458-6}, pmid = {30866962}, issn = {1476-069X}, support = {R01ES024731/ES/NIEHS NIH HHS/United States ; R01ES024731S1/ES/NIEHS NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 ES024731/ES/NIEHS NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women.<br><br>METHODS: We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women's Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants' weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models.<br><br>RESULTS: In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80-6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93-3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years.<br><br>CONCLUSIONS: Certain phthalates may contribute to short-term weight gain among postmenopausal women.}, }
@article {pmid30865311, year = {2019}, author = {Schweizer, MT and Gulati, R and Beightol, M and Konnick, EQ and Cheng, HH and Klemfuss, N and De Sarkar, N and Yu, EY and Montgomery, RB and Nelson, PS and Pritchard, CC}, title = {Clinical determinants for successful circulating tumor DNA analysis in prostate cancer.}, journal = {The Prostate}, volume = {}, number = {}, pages = {}, doi = {10.1002/pros.23778}, pmid = {30865311}, issn = {1097-0045}, support = {//UW/FHCRC Institute for Prostate Cancer Research (IPCR)/ ; //FHCRC Solid Tumor Translational Research Program/ ; P30 CA015704//National Cancer Institute grants/ ; R50 CA221836//National Cancer Institute grants/ ; R01 CA181605//National Cancer Institute grants/ ; CA097186//Pacific Northwest Prostate Cancer SPORE/ ; //Prostate Cancer Foundation Young Investigator Awards/ ; W81XWH-16-1-0484//CDMRP Awards/ ; PC170510//CDMRP Awards/ ; PC170503P2//CDMRP Awards/ ; W81XWH-17-1-0380//CDMRP Awards/ ; W81XWH-15-1-0430//CDMRP Awards/ ; }, abstract = {BACKGROUND: Plasma-based cell-free DNA is an attractive biospecimen for assessing somatic mutations due to minimally-invasive real-time sampling. However, next generation sequencing (NGS) of cell-free DNA (cfDNA) may not be appropriate for all patients with advanced prostate cancer (PC).<br><br>METHODS: Blood was obtained from advanced PC patients for plasma-based sequencing. UW-OncoPlex, a ∼2 Mb multi-gene NGS panel performed in the CLIA/CAP environment, was optimized for detecting cfDNA mutations. Tumor tissue and germline samples were sequenced for comparative analyses. Multivariate logistic regression was performed to determine the clinical characteristic associated with the successful detection of somatic cfDNA alterations (ie detection of at least one clearly somatic PC mutation).<br><br>RESULTS: Plasma for cfDNA sequencing was obtained from 93 PC patients along with tumor tissue (N = 67) and germline (N = 93) controls. We included data from 76 patients (72 prostate adenocarcinoma; 4 variant histology PC) in the analysis. Somatic DNA aberrations were detected in 34 cfDNA samples from patients with prostate adenocarcinoma. High PSA level, high tumor volume, and castration-resistance were significantly associated with successful detection of somatic cfDNA alterations. Among samples with somatic mutations detected, the cfDNA assay detected 93/102 (91%) alterations found in tumor tissue, yielding a clustering-corrected sensitivity of 92% (95% confidence interval 88-97%). All germline pathogenic variants present in lymphocyte DNA were also detected in cfDNA (N = 12). Somatic mutations from cfDNA were detected in 30/33 (93%) instances when PSA was >10 ng/mL.<br><br>CONCLUSIONS: Disease burden, including a PSA >10 ng/mL, is strongly associated with detecting somatic mutations from cfDNA specimens.}, }
@article {pmid30865051, year = {2019}, author = {Mannheimer, S and Hirsch-Moverman, Y and Franks, J and Loquere, A and Hughes, JP and Li, M and Amico, KR and Grant, RM}, title = {Factors Associated With Sex-Related Pre-exposure Prophylaxis Adherence Among Men Who Have Sex With Men in New York City in HPTN 067.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {80}, number = {5}, pages = {551-558}, doi = {10.1097/QAI.0000000000001965}, pmid = {30865051}, issn = {1944-7884}, support = {R01 AI118575/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: HPTN 067 assessed the feasibility of daily and non-daily dosing of open-label emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)-based pre-exposure prophylaxis (PrEP).<br><br>METHODS: Factors associated with sex-related PrEP adherence were assessed among men who have sex with men (MSM) randomized to one of 3 PrEP dosing arms in HPTN 067 in New York City. Sex-related PrEP adherence was defined per protocol as at least 1 PrEP tablet taken within 4 days pre-sex and at least 1 additional PrEP tablet taken within 24 hours post-sex, assessed via electronic drug monitoring and weekly interviews. Demographic data and behavioral measures were evaluated for association with sex-related PrEP adherence. Logistic regression for clustered data was used to estimate the unadjusted and adjusted odds ratios.<br><br>RESULTS: Of 176 randomized MSM participants, 59% were Black, 10% White, 25% Hispanic, and 6% other; median age was 31 years. In the multivariable analyses, higher sex-related PrEP adherence was significantly associated with daily dosing arm, older age, employment, and higher PrEP adherence behavioral skills. Lower sex-related PrEP adherence was significantly associated with identifying as Black or Hispanic (compared with White), opiate use, and reporting &quot;I forgot&quot; as an adherence barrier.<br><br>CONCLUSIONS: This analysis identified populations of MSM who might benefit from additional support to optimize PrEP adherence, including those who are younger, unemployed, or opiate users. MSM with lower PrEP behavioral skills may benefit from targeted interventions. Further study is needed to assess racial and ethnic disparities in PrEP adherence, which may reflect broader social and economic inequalities not captured in this study.}, }
@article {pmid30863868, year = {2019}, author = {Plantinga, AM and Chen, J and Jenq, RR and Wu, MC}, title = {pldist: ecological dissimilarities for paired and longitudinal microbiome association analysis.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btz120}, pmid = {30863868}, issn = {1367-4811}, support = {S10 OD020069/OD/NIH HHS/United States ; }, abstract = {MOTIVATION: The human microbiome is notoriously variable across individuals, with a wide range of 'healthy' microbiomes. Paired and longitudinal studies of the microbiome have become increasingly popular as a way to reduce unmeasured confounding and to increase statistical power by reducing large inter-subject variability. Statistical methods for analyzing such datasets are scarce.<br><br>RESULTS: We introduce a paired UniFrac dissimilarity that summarizes within-individual (or within-pair) shifts in microbiome composition and then compares these compositional shifts across individuals (or pairs). This dissimilarity depends on a novel transformation of relative abundances, which we then extend to more than two time points and incorporate into several phylogenetic and non-phylogenetic dissimilarities. The data transformation and resulting dissimilarities may be used in a wide variety of downstream analyses, including ordination analysis and distance-based hypothesis testing. Simulations demonstrate that tests based on these dissimilarities retain appropriate type 1 error and high power. We apply the method in two real datasets.<br><br>The R package pldist is available on GitHub at https://github.com/aplantin/pldist.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid30863552, year = {2019}, author = {Jariani, A and Warth, C and Deforche, K and Libin, P and Drummond, AJ and Rambaut, A and Matsen Iv, FA and Theys, K}, title = {SANTA-SIM: simulating viral sequence evolution dynamics under selection and recombination.}, journal = {Virus evolution}, volume = {5}, number = {1}, pages = {vez003}, doi = {10.1093/ve/vez003}, pmid = {30863552}, issn = {2057-1577}, abstract = {Simulations are widely used to provide expectations and predictive distributions under known conditions against which to compare empirical data. Such simulations are also invaluable for testing and comparing the behaviour and power of inference methods. We describe SANTA-SIM, a software package to simulate the evolution of a population of gene sequences forwards through time. It models the underlying biological processes as discrete components: replication, recombination, point mutations, insertion-deletions, and selection under various fitness models and population size dynamics. The software is designed to be intuitive to work with for a wide range of users and executable in a cross-platform manner.}, }
@article {pmid30861098, year = {2019}, author = {Henry, NL and Unger, JM and Till, C and Schott, AF and Crew, KD and Lew, DL and Fisch, MJ and Moinpour, CM and Wade, JL and Hershman, DL}, title = {Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.32024}, pmid = {30861098}, issn = {1097-0142}, support = {5UG1CA189974//National Cancer Institute of the National Institutes of Health/ ; CI-53-10//Lilly USA LLC/ ; //The Hope Foundation/ ; }, abstract = {BACKGROUND: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to duloxetine therapy differed by obesity status.<br><br>METHODS: In SWOG S1202, a total of 299 AI-treated postmenopausal women with stage I to III (AJCC 7th Edition) breast cancer who developed new or worsening average pain were enrolled, randomized to duloxetine or placebo, and treated for 12 weeks. Patient-reported outcomes were obtained at baseline and through 12 weeks. Patients were categorized into nonobese (body mass index [BMI] <30 kg/m2) or obese (BMI ≥30 kg/m2). The authors tested the interaction between intervention and obesity with respect to average pain at 12 weeks in the 289 eligible patients, using a P value of .05 to indicate statistical significance.<br><br>RESULTS: In approximately 54% of evaluable patients with a BMI ≥30 kg/m2 , the reduction in the mean average pain score between baseline and 12 weeks was statistically significantly greater for patients treated with duloxetine compared with those receiving placebo (-2.73 vs -1.64 points; P = .003). Conversely, in the nonobese patients, the reduction in the mean average pain score was similar in the 2 cohorts (-2.46 vs -2.34 points; P = .75). The P value for interaction was .02, thereby meeting the threshold criteria of the current study. Similar findings were evident for other pain-related patient-reported outcomes.<br><br>CONCLUSIONS: In this trial, obese patients with AIMSS obtained more analgesic benefit from duloxetine compared with nonobese patients. Additional studies are warranted to determine the biologic basis for these findings.}, }
@article {pmid30860946, year = {2019}, author = {Bates, JE and Howell, RM and Liu, Q and Yasui, Y and Mulrooney, DA and Dhakal, S and Smith, SA and Leisenring, WM and Indelicato, DJ and Gibson, TM and Armstrong, GT and Oeffinger, KC and Constine, LS}, title = {Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO1801764}, doi = {10.1200/JCO.18.01764}, pmid = {30860946}, issn = {1527-7755}, abstract = {PURPOSE: The impacts of radiotherapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk for late-onset cardiac disease in survivors of childhood cancer remain unresolved.<br><br>PATIENTS AND METHODS: We determined the rates of severe to fatal cardiac disease in 24,214 5-year survivors in the Childhood Cancer Survivor Study diagnosed between 1970 and 1999 at a median age of 7.0 years (range, 0 to 20.9 years), with a median attained age of 27.5 years (range, 5.6 to 58.9 years). Using piecewise exponential models, we evaluated the association between cardiac disease rates and demographic and treatment characteristics.<br><br>RESULTS: The cumulative incidence of cardiac disease 30 years from diagnosis was 4.8% (95% CI, 4.3 to 5.2). Low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (≥ 50% of heart) were associated with an increased rate of cardiac disease (relative rate, 1.6; 95% CI, 1.1 to 2.3) compared with survivors without cardiac radiotherapy exposure. Similarly, high doses (≥ 20 Gy) to small cardiac volumes (0.1% to 29.9%) were associated with an elevated rate (relative rate, 2.4; 95% CI, 1.4 to 4.2). A dose-response relationship was observed between anthracycline chemotherapy and heart failure with younger children (age ≤ 13 years) at the greatest risk for heart failure after comparable dosing.<br><br>CONCLUSION: These observations support advances in radiation field design and delivery technology to reduce cardiac dose/volume and should guide future treatment protocols. They also inform clinical practice guidelines for post-therapy surveillance and risk-reducing strategies.}, }
@article {pmid30857553, year = {2019}, author = {Shenoy, MK and Fadrosh, DW and Lin, DL and Worodria, W and Byanyima, P and Musisi, E and Kaswabuli, S and Zawedde, J and Sanyu, I and Chang, E and Fong, S and McCauley, K and Davis, JL and Huang, L and Lynch, SV}, title = {Gut microbiota in HIV-pneumonia patients is related to peripheral CD4 counts, lung microbiota, and in vitro macrophage dysfunction.}, journal = {Microbiome}, volume = {7}, number = {1}, pages = {37}, doi = {10.1186/s40168-019-0651-4}, pmid = {30857553}, issn = {2049-2618}, support = {K24 HL087713//National Heart, Lung, and Blood Institute/ ; U01 HL098964//National Heart, Lung, and Blood Institute/ ; U01 HL098964/HL/NHLBI NIH HHS/United States ; K24 HL087713/HL/NHLBI NIH HHS/United States ; R01 HL090335/HL/NHLBI NIH HHS/United States ; R01 HL090335//National Heart, Lung, and Blood Institute/ ; }, abstract = {Pneumonia is common and frequently fatal in HIV-infected patients, due to rampant, systemic inflammation and failure to control microbial infection. While airway microbiota composition is related to local inflammatory response, gut microbiota has been shown to correlate with the degree of peripheral immune activation (IL6 and IP10 expression) in HIV-infected patients. We thus hypothesized that both airway and gut microbiota are perturbed in HIV-infected pneumonia patients, that the gut microbiota is related to peripheral CD4+ cell counts, and that its associated products differentially program immune cell populations necessary for controlling microbial infection in CD4-high and CD4-low patients. To assess these relationships, paired bronchoalveolar lavage and stool microbiota (bacterial and fungal) from a large cohort of Ugandan, HIV-infected patients with pneumonia were examined, and in vitro tests of the effect of gut microbiome products on macrophage effector phenotypes performed. While lower airway microbiota stratified into three compositionally distinct microbiota as previously described, these were not related to peripheral CD4 cell count. In contrast, variation in gut microbiota composition significantly related to CD4 cell count, lung microbiota composition, and patient mortality. Compared with patients with high CD4+ cell counts, those with low counts possessed more compositionally similar airway and gut microbiota, evidence of microbial translocation, and their associated gut microbiome products reduced macrophage activation and IL-10 expression and increased IL-1β expression in vitro. These findings suggest that the gut microbiome is related to CD4 status and plays a key role in modulating macrophage function, critical to microbial control in HIV-infected patients with pneumonia.}, }
@article {pmid30856272, year = {2019}, author = {Unger, JM and Vaidya, R and Hershman, DL and Minasian, LM and Fleury, ME}, title = {Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation.}, journal = {Journal of the National Cancer Institute}, volume = {111}, number = {3}, pages = {245-255}, doi = {10.1093/jnci/djy221}, pmid = {30856272}, issn = {1460-2105}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Barriers to cancer clinical trial participation have been the subject of frequent study, but the rate of trial participation has not changed substantially over time. Studies often emphasize patient-related barriers, but other types of barriers may have greater impact on trial participation. Our goal was to examine the magnitude of different domains of trial barriers by synthesizing prior research.<br><br>METHODS: We conducted a systematic review and meta-analysis of studies that examined the trial decision-making pathway using a uniform framework to characterize and quantify structural (trial availability), clinical (eligibility), and patient/physician barrier domains. The systematic review utilized the PubMed, Google Scholar, Web of Science, and Ovid Medline search engines. We used random effects to estimate rates of different domains across studies, adjusting for academic vs community care settings.<br><br>RESULTS: We identified 13 studies (nine in academic and four in community settings) with 8883 patients. A trial was unavailable for patients at their institution 55.6% of the time (95% confidence interval [CI] = 43.7% to 67.3%). Further, 21.5% (95% CI = 10.9% to 34.6%) of patients were ineligible for an available trial, 14.8% (95% CI = 9.0% to 21.7%) did not enroll, and 8.1% (95% CI = 6.3% to 10.0%) enrolled. Rates of trial enrollment in academic (15.9% [95% CI = 13.8% to 18.2%]) vs community (7.0% [95% CI = 5.1% to 9.1%]) settings differed, but not rates of trial unavailability, ineligibility, or non-enrollment.<br><br>CONCLUSIONS: These findings emphasize the enormous need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.}, }
@article {pmid30856024, year = {2019}, author = {Buckley, SA and Mark, NM and Othus, M and Estey, EH and Patel, K and Walter, RB}, title = {Diagnostic utility of bronchoscopy in adults with acute myeloid leukemia and other high-grade myeloid neoplasms.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/10428194.2019.1581933}, pmid = {30856024}, issn = {1029-2403}, }
@article {pmid30849373, year = {2019}, author = {Marcandalli, J and Fiala, B and Ols, S and Perotti, M and de van der Schueren, W and Snijder, J and Hodge, E and Benhaim, M and Ravichandran, R and Carter, L and Sheffler, W and Brunner, L and Lawrenz, M and Dubois, P and Lanzavecchia, A and Sallusto, F and Lee, KK and Veesler, D and Correnti, CE and Stewart, LJ and Baker, D and Loré, K and Perez, L and King, NP}, title = {Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus.}, journal = {Cell}, volume = {176}, number = {6}, pages = {1420-1431.e17}, doi = {10.1016/j.cell.2019.01.046}, pmid = {30849373}, issn = {1097-4172}, support = {R01 GM120553/GM/NIGMS NIH HHS/United States ; }, abstract = {Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.}, }
@article {pmid30844995, year = {2019}, author = {van der Straten, A and Browne, EN and Shapley-Quinn, MK and Brown, ER and Reddy, K and Scheckter, R and Soto-Torres, L and Palanee-Phillips, T and Baeten, JM and Mensch, B and , }, title = {First Impressions Matter: How Initial Worries Influence Adherence to the Dapivirine Vaginal Ring.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000002028}, pmid = {30844995}, issn = {1944-7884}, support = {U01 AI068633/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: In MTN-020/ASPIRE, a dapivirine vaginal ring effectiveness trial in sub-Saharan Africa, we assessed whether worries about ring use changed over time and were associated with adherence.<br><br>METHODS: Participants (N=2585) were surveyed at baseline and follow-up about worries regarding daily ring use. First, they answered a question about general worries and then responded to 15 items covering specific worries. From a nested qualitative component (N=214), we extracted themes related to ring worries and adherence. Seven months into the trial, aggregate adherence data were shared with study sites as part of an intervention that included counseling and social support. Nonadherence was defined as dapivirine plasma levels of ≤95 pg/ml. Mixed-effect logistic regression models were used to assess changes in ring worries and nonadherence from baseline to month 3 and later.<br><br>RESULTS: Worry about wearing the ring decreased from 29% at baseline to 4% at month 3 (p<0.001), while having a specific worry decreased from 47% to 16% (p<0.001). Among those enrolled preintervention, 29% with baseline worries were nonadherent at month 3 (95% CI: 19%, 39%) compared to 14% without worries (95% CI: 9%, 19%; p=0.005); the difference persisted through month 6. There was no difference in nonadherence by baseline worry for those enrolled postintervention (p=0.40). In the qualitative subset, initial ring anxieties reportedly subsided with self-experimentation and practice and the beneficial influence of the intervention.<br><br>CONCLUSIONS: Although worries may be an initial deterrent to correct ring use, intervening early by leveraging social influences from peers and clinicians should facilitate successful adoption and correct ring use.}, }
@article {pmid30844424, year = {2019}, author = {Creary, LE and Guerra, SG and Chong, W and Brown, CJ and Turner, TR and Robinson, J and Bultitude, WP and Mayor, NP and Marsh, SGE and Saito, K and Lam, K and Duke, JL and Mosbruger, TL and Ferriola, D and Monos, D and Willis, A and Askar, M and Fischer, G and Loong Saw, C and Ragoussis, I and Petrek, M and Serra-Pagés, C and Juan Otero, M and Stavropoulos-Giokas, C and Dinou, A and Ameen, R and Al Shemmari, S and Spierings, E and Gendzekhadze, K and Morris, GP and Zhang, Q and Kashi, Z and Hsu, S and Gangavarapu, S and Mallempati, KC and Yamamoto, F and Osoegawa, K and Vayntrub, T and Chang, CJ and Hansen, JA and Fernández-Viňa, MA}, title = {Next-generation HLA typing of 382 International Histocompatibility Working Group reference B-Lymphoblastoid cell lines: report from the 17th International HLA and Immunogenetics Workshop.}, journal = {Human immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.humimm.2019.03.001}, pmid = {30844424}, issn = {1879-1166}, abstract = {Extended molecular characterization of HLA genes in the IHWG reference B-lymphoblastoid cell lines (B-LCLs) was one of the major goals for the 17th International HLA and Immunogenetics Workshop (IHIW). Although reference B-LCLs have been examined extensively in previous workshops complete high-resolution typing was not completed for all the classical class I and class II HLA genes. To address this, we conducted a single-blind study where select panels of B-LCL genomic DNA samples were distributed to multiple laboratories for HLA genotyping by next-generation sequencing methods. Identical cell panels comprised of 24 and 346 samples were distributed and typed by at least four laboratories in order to derive accurate consensus HLA genotypes. Overall concordance rates calculated at both 2- and 4-field allele-level resolutions ranged from 90.4% to 100%. Concordance for the class I genes ranged from 91.7 to 100%, whereas concordance for class II genes was variable; the lowest observed at HLA-DRB3 (84.2%). At the maximum allele-resolution 78 B-LCLs were defined as homozygous for all 11 loci. We identified 11 novel exon polymorphisms in the entire cell panel. A comparison of the B-LCLs NGS HLA genotypes with the HLA genotypes catalogued in the IPD-IMGT/HLA Database Cell Repository, revealed an overall allele match at 68.4%. Typing discrepancies between the two datasets were mostly due to the lower-resolution historical typing methods resulting in incomplete HLA genotypes for some samples listed in the IPD-IMGT/HLA Database Cell Repository. Our approach of multiple-laboratory NGS HLA typing of the B-LCLs has provided accurate genotyping data. The data generated by the tremendous collaborative efforts of the 17th IHIW participants is useful for updating the current cell and sequence databases and will be a valuable resource for future studies.}, }
@article {pmid30840360, year = {2019}, author = {Markey, KA and Gartlan, KH}, title = {Imaging Flow Cytometry to Assess Antigen-Presenting-Cell Function.}, journal = {Current protocols in immunology}, volume = {}, number = {}, pages = {e72}, doi = {10.1002/cpim.72}, pmid = {30840360}, issn = {1934-368X}, abstract = {This unit describes methods for quantifying phagocytosis and imaging the immunological synapse between T cells and antigen-presenting cells (APCs), with both techniques delivering valuable information about APC function. These aspects of APC biology have traditionally been challenging to quantify, and imaging flow cytometry, which harnesses the high-throughput nature of flow cytometry combined with the capacity of microscopy to deliver spatial localization, facilitates analysis of these APC functions in a fashion that was previously not possible. Imaging flow cytometry allows large numbers of events to be captured and large amounts of fluorescence data to be quantified at the physical location of markers of interest, both on the cell surface and in intracellular compartments, combining key features of traditional flow cytometry and fluorescence microscopy. © 2019 by John Wiley &amp; Sons, Inc.}, }
@article {pmid30840336, year = {2019}, author = {Baglia, ML and Lin, IH and Cartmel, B and Sanft, T and Ligibel, J and Hershman, DL and Harrigan, M and Ferrucci, LM and Li, FY and Irwin, ML}, title = {Endocrine-related quality of life in a randomized trial of exercise on aromatase inhibitor-induced arthralgias in breast cancer survivors.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.32051}, pmid = {30840336}, issn = {1097-0142}, support = {R01 CA132931/CA/NCI NIH HHS/United States ; P30 CA016359//Breast Cancer Research Fund/ ; R01 CA132931//National Cancer Institute/ ; UL1 TR000142//Clinical and Translational Science Award/ ; }, abstract = {BACKGROUND: The objective of this study was to evaluate the role of a 12-month exercise intervention on endocrine-related quality of life (QOL) and overall QOL among breast cancer survivors with aromatase inhibitor (AI)-induced arthralgia in the Hormones and Physical Exercise (HOPE) Study.<br><br>METHODS: This was a randomized controlled trial of 121 breast cancer survivors who were currently receiving AIs and experiencing at least mild arthralgia. QOL was assessed using the Functional Assessment of Cancer Therapy (FACT) questionnaires and the 36-Item Short Form Survey (SF-36) at baseline, 6 months, and 12 months. Participants were randomized to either a 1-year gym-based, supervised exercise intervention group (150 minutes of aerobic exercise and 2 strength-training sessions each week) or a usual care group. Effects of the intervention on QOL were assessed using mixed-model, repeated-measures analysis.<br><br>RESULTS: At 12 months, the exercise group had greater improvement in the overall QOL measures as well as the breast cancer-specific (scores, 2.2 vs 0.7; P = .02), endocrine-specific (scores, 5.6 vs 1.6; P < .001), and fatigue-specific (score, 5.8 vs 0.5; P < .001) subscales compared with the usual care group. The results indicated a stronger effect at 12 months versus 6 months after the intervention.<br><br>CONCLUSIONS: Combined aerobic and resistance exercise, such as treadmill walking and strength training, improved endocrine-related and overall QOL among breast cancer survivors who were experiencing adverse side effects from AIs. Because adverse side effects associated with AI use are quite common and this is the main reason for treatment discontinuation, this nonpharmacologic intervention could benefit many breast cancer survivors and increase successful adherence to AIs in breast cancer treatment.}, }
@article {pmid30840335, year = {2019}, author = {Chu, AT and Holt, SK and Wright, JL and Ramos, JD and Grivas, P and Yu, EY and Gore, JL}, title = {Delays in radical cystectomy for muscle-invasive bladder cancer.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.32048}, pmid = {30840335}, issn = {1097-0142}, abstract = {BACKGROUND: Delays from the diagnosis of muscle-invasive bladder cancer (MIBC) to radical cystectomy (RC) longer than 12 weeks result in higher mortality and shorter progression-free survival. This study sought to identify factors associated with RC delays and to determine whether delays in care in the current treatment paradigm, which includes neoadjuvant chemotherapy (NAC), affect survival.<br><br>METHODS: Subjects with American Joint Committee on Cancer stage II urothelial carcinoma of the bladder who underwent RC from 2004 to 2012 were identified from the linked Surveillance, Epidemiology, and End Results national cancer registry and the Medicare claims database and were stratified into RC groups with or without NAC. Cox multivariable proportional hazard models and multivariable logistic regression models assessed the significance of delays in RC for survival and identified independent characteristics associated with RC delays, respectively.<br><br>RESULTS: This study identified 1509 patients with MIBC who underwent RC during the study period. In comparison with timely surgery, delays in RC increased overall mortality, regardless of the use of NAC (hazard ratio [HR] without NAC, 1.34; 95% confidence interval [CI], 1.03-1.76; HR after NAC, 1.63; 95% CI, 1.06-2.52). Patients proceeding to RC without NAC had higher odds of delayed care if they lived in a high-poverty neighborhood (odds ratio [OR], 1.37; 95% CI, 1.01-2.08) or nonmetropolitan area (OR, 1.61; 95% CI, 1.01-2.55), were men (OR, 2.22; 95% CI, 1.25-4.00), or required a provider transfer for bladder cancer care (OR, 1.82; 95% CI, 1.10-3.03).<br><br>CONCLUSIONS: Delays in care from the time of either the initial diagnosis or the completion of NAC to RC are associated with worse overall survival among patients with MIBC. Timely surgery is fundamental in the treatment of MIBC, and this necessitates attention to disparities in access to complex surgical care and care coordination.}, }
@article {pmid30840316, year = {2019}, author = {Denburg, AE and Laher, N and Mutyaba, I and McGoldrick, S and Kambugu, J and Sessle, E and Orem, J and Casper, C}, title = {The cost effectiveness of treating Burkitt lymphoma in Uganda.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.32006}, pmid = {30840316}, issn = {1097-0142}, support = {//Burkitt Lymphoma Fund of Africa/ ; //Martin Fabert Foundation/ ; }, abstract = {BACKGROUND: Perceptions of high cost and resource intensity remain political barriers to the prioritization of childhood cancer treatment programs in many low- and middle-income countries (LMICs). Little knowledge exists of the actual cost and cost-effectiveness of such programs. To improve outcomes for children with Burkitt lymphoma (BL), the most common childhood cancer in Africa, the Uganda Cancer Institute implemented a comprehensive BL treatment program in 2012. We undertook an economic evaluation of the program to ascertain the cost-effectiveness of BL therapy in a specific LIC setting.<br><br>METHODS: We compared the treatment of BL to usual care in a cohort of 122 patients treated between 2012 and 2014. Costs included variable, fixed, and family costs. Our primary measure of effectiveness was overall survival (OS). Patient outcomes were determined through prospective capture and retrospective chart abstraction. The cost per disability-adjusted life-year (DALY) averted was calculated using the World Health Organization's Choosing Interventions That Are Cost-Effective (WHO-CHOICE) methodology.<br><br>RESULTS: The 2-year OS with treatment was 55% (95% CI, 45% to 64%). The cost per DALY averted in the treatment group was US$97 (Int$301). Cumulative estimate of national DALYs averted through treatment was 8607 years, and the total national annual cost of treatment was US$834,879 (Int$2,590,845). The cost of BL treatment fell well within WHO-CHOICE cost-effectiveness thresholds. The ratio of cost per DALY averted to per capita gross domestic product was 0.14, reflecting a very cost-effective intervention.<br><br>CONCLUSION: This study demonstrates that treating BL with locally tailored protocols is very cost-effective by international standards. Studies of this kind will furnish crucial evidence to help policymakers prioritize the allocation of LMIC health system resources among noncommunicable diseases, including childhood cancer.}, }
@article {pmid30839944, year = {2018}, author = {de Montigny, S and Boily, MC and Mâsse, BR and Mitchell, KM and Dimitrov, DT}, title = {Assessing the utility of the tipping point ratio to monitor HIV treatment programmes in the era of universal access to ART.}, journal = {Infectious Disease Modelling}, volume = {3}, number = {}, pages = {85-96}, doi = {10.1016/j.idm.2018.03.005}, pmid = {30839944}, issn = {2468-0427}, support = {UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {Background: The epidemiological tipping point ratio (TPR) has been suggested as a useful indicator to monitor the scale-up of antiretroviral treatment (ART) programmes and determine when scale-up is sufficient to control the epidemic. TPR has been defined as the ratio of yearly number of new HIV infections to the yearly number of new ART initiations or to the yearly net increase in the number of people on ART. It has been used to rank the progress of treatment programmes across countries, with the objective of reaching a TPR value under 1. Our study aims to assess if TPR alone can be used as an indicator of ART success across settings by comparing the expected changes in HIV incidence and ART coverage when TPR is maintained constant over time. In particular, we focus on the effect of ART initiation timing (emphasis on ART being initiated early or late during HIV progression) on the interpretation of the TPR.<br><br>Methods: We used a dynamic model of HIV transmission in South Africa representing ART rollout leading to universal treatment in 2017. The model is calibrated to HIV incidence, HIV prevalence and ART coverage in 2012 in South Africa, and 1000 simulations are selected for the base-case scenario. To measure the effect of TPR, we simulate TPR-preserving interventions, maintaining TPR (yearly number of new ART initiations denominator) at the value observed in 2019 (between 0.65 and 1.25) for 15 years. We compare ART coverage and HIV incidence across TPR values and across strategies in which ART access is prioritized differently. In a secondary analysis, we illustrate the sensitivity of new ART initiations to ART retention, and we compare both definitions of the TPR.<br><br>Results: Our analysis shows that HIV incidence reduction is weakly correlated to TPR: the same reduction in HIV incidence (15%) can be achieved by implementing the same strategy with a wide range of TPR maintained (0.65-1.12). Assuming high retention in ART, TPR-preserving strategies prioritizing early ART initiation yield greater reduction in HIV incidence than strategies where most individuals initiate ART late. High ART coverage is associated with low HIV incidence and it can be reached with a TPR below or equal to one with strategies favoring early ART initiation. Low ART retention over time results in higher HIV incidence even if TPR is maintained low. If ART retention is low, strategies prioritizing late ART initiation are associated with lower HIV incidence than strategies where ART is initiated early. Maintaining a fixed TPR value based on the net increase in people on ART gives higher HIV incidence reduction and requires fast ART scale-up.<br><br>Conclusion: Our analysis suggests that the TPR is not an adequate indicator of ART programme impact, without information on ART coverage and retention. Achieving early initiation and adherence to treatment to improve ART coverage might be as important as attaining a specific TPR target. Comparisons of TPR in different settings should account for differences in epidemic conditions.}, }
@article {pmid30835630, year = {2019}, author = {Winters, BR and Wen, L and Holt, SK and Dash, A and Gore, JL and Schade, GR and Wright, JL}, title = {Does the diagnosis of bladder cancer lead to higher rates of smoking cessation? Findings from the Medicare Health Outcomes Survey.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000000206}, doi = {10.1097/JU.0000000000000206}, pmid = {30835630}, issn = {1527-3792}, abstract = {PURPOSE: Smoking is the most common risk factor for bladder cancer (BC) and is associated with adverse clinical outcomes. The diagnosis of BC represents a 'teachable moment' for smoking cessation. We investigate the likelihood of smoking cessation after BC diagnosis in a population database.<br><br>MATERIALS AND METHODS: We evaluated SEER-MHOS (1998-2013) for all patients diagnosed with incident BC who had pre- and post-diagnosis survey data available. We compared these patients to propensity matched non-cancer controls (NCCs) and to a cohort of incident renal cell carcinoma (RCC) patients. Differences in smoking cessation were compared between groups and multivariate logistic regression performed to assess the likelihood of smoking cessation.<br><br>RESULTS: 394 newly diagnosed bladder cancer patients were propensity matched to 1,970 NCCs and compared with 169 incident RCC patients. Baseline smoking prevalence was more common in patients diagnosed with BC (16%) compared with RCC (11%) (NS). The smoking cessation rates in BC patients was 27% compared with 21% in NCCs (p=0.30) and 26% in RCC patients (p=0.90). There were no significant differences in the adjusted odds ratios of quitting smoking in BC and RCC patients compared with NCCs (1.3, 95%CI: 0.7 - 2.5; 1.2, 95%CI: 0.5 - 3.6). Independent predictors of smoking cessation in BC patients included age (p=0.03), African American race (p=0.03), and college education (p=0.01).<br><br>CONCLUSIONS: Smoking cessation was not significantly different following the diagnosis of BC compared to propensity-matched NCCs. The proportion of individuals quitting was low overall, suggesting improved efforts are needed to utilize this teachable moment in BC patients.}, }
@article {pmid30834353, year = {2019}, author = {Neuhouser, ML and Clowry, C and Beatty, SJ and Wang, CY and Drewnowski, A and Perrigue, MM}, title = {Rationale and design of the frequency of eating and Satiety Hormones (FRESH) study: A randomized cross-over clinical trial.}, journal = {Contemporary clinical trials communications}, volume = {14}, number = {}, pages = {100334}, doi = {10.1016/j.conctc.2019.100334}, pmid = {30834353}, issn = {2451-8654}, abstract = {Background: The goal of the Frequency of Eating and Satiety Hormones (FRESH) Study is to understand the relationship between eating frequency (EF) and biomarkers of appetite and disease risk. This report gives the study rationale and design.<br><br>Methods: The FRESH study was conducted in n = 50 overweight and obese, but otherwise healthy, male and female adults aged 18-50 years. The protocol included four in-person clinic visits for protocol instruction, blood draws, anthropometry, and meal testing; all other activities were done at home. Participants completed two 21-day phases in random order with a two-week washout between phases. One phase was high EF (6 eating occasions/day) and the other was low EF (3 eating occasions/day). Each phase specified time of day for each eating occasion. Participants prepared their own meals throughout the study using study-provided individualized, structured meal plans ensuring that calories, macronutrients and micronutrients were identical during both study phases. Fasting blood was collected before and after each phase to test intervention effects on the biomarkers. At the end of each phase participants also completed extended appetite testing with meals prepared by the study clinic.<br><br>Results: Participants were recruited using print, radio, and digital ads. 60 participants consented to enroll; 10 dropped out due to work or school scheduling conflicts and 50 (target sample size) completed the study. Compliance was assessed by completion of daily on-line meal plan checklists.<br><br>Conclusions: The FRESH study will provide data on whether higher vs. lower daily EF in the context of constant energy and nutrient intake may be harmful or beneficial based on intervention effects on biomarkers of health and disease risk.}, }
@article {pmid30830766, year = {2019}, author = {Huang, W and Hulverson, MA and Choi, R and Arnold, SLM and Zhang, Z and McCloskey, MC and Whitman, GR and Hackman, RC and Rivas, KL and Barrett, LK and Ojo, KK and Van Voorhis, WC and Fan, E}, title = {Development of 5-Aminopyrazole-4-carboxamide-based Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.}, journal = {Journal of medicinal chemistry}, volume = {62}, number = {6}, pages = {3135-3146}, doi = {10.1021/acs.jmedchem.9b00069}, pmid = {30830766}, issn = {1520-4804}, support = {R01 AI089441/AI/NIAID NIH HHS/United States ; R01 AI111341/AI/NIAID NIH HHS/United States ; R01 HD080670/HD/NICHD NIH HHS/United States ; }, abstract = {Cryptosporidium is a leading cause of pediatric diarrhea worldwide. Currently, there is neither a vaccine nor a consistently effective drug available for this disease. Selective 5-aminopyrazole-4-carboxamide-based bumped-kinase inhibitors (BKIs) are effective in both in vitro and in vivo models of Cryptosporidium parvum. Potential cardiotoxicity in some BKIs led to the continued exploration of the 5-aminopyrazole-4-carboxamide scaffold to find safe and effective drug candidates for Cryptosporidium. A series of newly designed BKIs were tested for efficacy against C. parvum using in vitro and in vivo (mouse infection model) assays and safety issues. Compound 6 (BKI 1708) was found to be efficacious at 8 mg/kg dosed once daily (QD) for 5 days with no observable signs of toxicity up to 200 mg/kg dosed QD for 7 days. Compound 15 (BKI 1770) was found to be efficacious at 30 mg/kg dosed twice daily (BID) for 5 days with no observable signs of toxicity up to 300 mg/kg dosed QD for 7 days. Compounds 6 and 15 are promising preclinical leads for cryptosporidiosis therapy with acceptable safety parameters and efficacy in the mouse model of cryptosporidiosis.}, }
@article {pmid30830494, year = {2019}, author = {Thompson, B and Barrington, WE and Briant, KJ and Kupay, E and Carosso, E and Gonzalez, NE and Gonzalez, VJ}, title = {Educating Latinas about cervical cancer and HPV: a pilot randomized study.}, journal = {Cancer causes &amp; control : CCC}, volume = {30}, number = {4}, pages = {375-384}, doi = {10.1007/s10552-019-01150-w}, pmid = {30830494}, issn = {1573-7225}, support = {UL1RR025014//National Center for Research Resources/ ; U54CA132381//National Cancer Institute/ ; U54 CA153502/CA/NCI NIH HHS/United States ; U53CA153502-05S1//National Cancer Institute/ ; U54CA153502//National Cancer Institute/ ; }, abstract = {INTRODUCTION: The purpose of this study was to assess effects of three different educational intervention arms on knowledge of and intention to receive Pap testing and HPV co-testing.<br><br>METHODS: Three active educational intervention arms were developed: a fotonovela, a radionovela, and a digital story. A pilot randomized controlled trial of 160 Latinas was conducted to assess the effectiveness of the intervention arms in increasing knowledge of cervical cancer and HPV and intention to be screened for cervical cancer compared to an attention control group (flu vaccination).<br><br>RESULTS: Women in all three treatment arms significantly increased knowledge about cervical cancer compared to control arm (p = 0.02). Knowledge about cervical cancer screening also increased in the active arms compared to control (p = 0.0003). Knowledge of HPV risk also increased relative to the control (p = 0.0001). There were no significant differences between the intervention arms in increased knowledge of cervical cancer or cervical cancer screening (p = 0.57 and 0.16, respectively).<br><br>DISCUSSION: This study supported the use of small media interventions in narrative education form as effective in increasing knowledge and intention to be screened for cervical cancer. The three culturally relevant interventions, built on qualitative data, were all successful in increasing knowledge.}, }
@article {pmid30829324, year = {2019}, author = {Radtke, S and Perez, AM and Venkataraman, R and Reddy, S and Haworth, KG and Humbert, O and Kiem, HP and Peterson, CW}, title = {Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {144}, pages = {}, doi = {10.3791/58933}, pmid = {30829324}, issn = {1940-087X}, abstract = {Hematopoietic stem and progenitor cell (HSPC) transplantation has been a cornerstone therapy for leukemia and other cancers for nearly half a century, underlies the only known cure of human immunodeficiency virus (HIV-1) infection, and shows immense promise in the treatment of genetic diseases such as beta thalassemia. Our group has developed a protocol to model HSPC gene therapy in nonhuman primates (NHPs), allowing scientists to optimize many of the same reagents and techniques that are applied in the clinic. Here, we describe methods for purifying CD34+ HSPCs and long-term persisting hematopoietic stem cell (HSC) subsets from primed bone marrow (BM). Identical techniques can be employed for the purification of other HSPC sources (e.g., mobilized peripheral blood stem cells [PBSCs]). Outlined is a 2 day protocol in which cells are purified, cultured, modified with lentivirus (LV), and prepared for infusion back into the autologous host. Key readouts of success include the purity of the CD34+ HSPC population, the ability of purified HSPCs to form morphologically distinct colonies in semisolid media, and, most importantly, gene modification efficiency. The key advantage to HSPC gene therapy is the ability to provide a source of long-lived cells that give rise to all hematopoietic cell types. As such, these methods have been used to model therapies for cancer, genetic diseases, and infectious diseases. In each case, therapeutic efficacy is established by enhancing the function of distinct HSPC progeny, including red blood cells, T cells, B cells, and/or myeloid subsets. The methods to isolate, modify, and prepare HSPC products are directly applicable and translatable to multiple diseases in human patients.}, }
@article {pmid30828695, year = {2018}, author = {Zheng, Y}, title = {Study Design Considerations for Cancer Biomarker Discoveries.}, journal = {The journal of applied laboratory medicine}, volume = {3}, number = {2}, pages = {282-289}, doi = {10.1373/jalm.2017.025809}, pmid = {30828695}, issn = {2475-7241}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM085047/GM/NIGMS NIH HHS/United States ; U01 CA086368/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {Background: Biomarker discovery studies have generated an array of omic data, however few novel biomarkers have reached clinical use. Guidelines for rigorous study designs are needed.<br><br>Content: Biases frequently occur in sample selection, outcome ascertainment, or unblinded sample handling and assaying process. The principles of a prospective-specimen collection and retrospective-blinded-evaluation (PRoBE) design can be adapted to mitigate various sources of biases in discovery. We recommend establishing quality biospecimen repositories using matched two-phase designs to minimize biases and maximize efficiency. We also highlight the importance of taking the clinical context into consideration in both sample selection and power calculation for discovery studies.<br><br>Summary: Biomarker discovery research should follow rigorous design principles in sample se- lection to avoid biases. Consideration of clinical application and the corresponding biomarker performance characteristics in study designs will lead to a more fruitful discovery study.<br><br>Impact: Appropriate study designs will improve the quality and clinical rigor of biomarker discovery studies.}, }
@article {pmid30828438, year = {2019}, author = {Gopaulakrishnan, S and Pollack, S and Stubbs, BJ and Pagès, H and Readey, J and Davis, S and Waldron, L and Morgan, M and Carey, V}, title = {restfulSE: A semantically rich interface for cloud-scale genomics with Bioconductor.}, journal = {F1000Research}, volume = {8}, number = {}, pages = {21}, doi = {10.12688/f1000research.17518.1}, pmid = {30828438}, issn = {2046-1402}, abstract = {Bioconductor's SummarizedExperiment class unites numerical assay quantifications with sample- and experiment-level metadata. SummarizedExperiment is the standard Bioconductor class for assays that produce matrix-like data, used by over 200 packages. We describe the restfulSE package, a deployment of this data model that supports remote storage. We illustrate use of SummarizedExperiment with remote HDF5 and Google BigQuery back ends, with two applications in cancer genomics. Our intent is to allow the use of familiar and semantically meaningful programmatic idioms to query genomic data, while abstracting the remote interface from end users and developers.}, }
@article {pmid30824040, year = {2019}, author = {Bolaños-Meade, J and Reshef, R and Fraser, R and Fei, M and Abhyankar, S and Al-Kadhimi, Z and Alousi, AM and Antin, JH and Arai, S and Bickett, K and Chen, YB and Damon, LE and Efebera, YA and Geller, NL and Giralt, SA and Hari, P and Holtan, SG and Horowitz, MM and Jacobsohn, DA and Jones, RJ and Liesveld, JL and Logan, BR and MacMillan, ML and Mielcarek, M and Noel, P and Pidala, J and Porter, DL and Pusic, I and Sobecks, R and Solomon, SR and Weisdorf, DJ and Wu, J and Pasquini, MC and Koreth, J}, title = {Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).}, journal = {The Lancet. Haematology}, volume = {6}, number = {3}, pages = {e132-e143}, doi = {10.1016/S2352-3026(18)30221-7}, pmid = {30824040}, issn = {2352-3026}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; UG1 HL108945/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Bortezomib/pharmacology ; Cyclophosphamide/pharmacology ; Drug Interactions ; Female ; Graft vs Host Disease/*etiology/*prevention &amp; control ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Male ; Maraviroc/pharmacology ; Methotrexate/pharmacology ; Middle Aged ; Mycophenolic Acid/pharmacology ; Tacrolimus/pharmacology ; *Transplantation Conditioning ; }, abstract = {BACKGROUND: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.<br><br>METHODS: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.<br><br>FINDINGS: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).<br><br>INTERPRETATION: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.<br><br>FUNDING: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.}, }
@article {pmid30820706, year = {2019}, author = {Bien, SA and Su, YR and Conti, DV and Harrison, TA and Qu, C and Guo, X and Lu, Y and Albanes, D and Auer, PL and Banbury, BL and Berndt, SI and Bézieau, S and Brenner, H and Buchanan, DD and Caan, BJ and Campbell, PT and Carlson, CS and Chan, AT and Chang-Claude, J and Chen, S and Connolly, CM and Easton, DF and Feskens, EJM and Gallinger, S and Giles, GG and Gunter, MJ and Hampe, J and Huyghe, JR and Hoffmeister, M and Hudson, TJ and Jacobs, EJ and Jenkins, MA and Kampman, E and Kang, HM and Kühn, T and Küry, S and Lejbkowicz, F and Le Marchand, L and Milne, RL and Li, L and Li, CI and Lindblom, A and Lindor, NM and Martín, V and McNeil, CE and Melas, M and Moreno, V and Newcomb, PA and Offit, K and Pharaoh, PDP and Potter, JD and Qu, C and Riboli, E and Rennert, G and Sala, N and Schafmayer, C and Scacheri, PC and Schmit, SL and Severi, G and Slattery, ML and Smith, JD and Trichopoulou, A and Tumino, R and Ulrich, CM and van Duijnhoven, FJB and Van Guelpen, B and Weinstein, SJ and White, E and Wolk, A and Woods, MO and Wu, AH and Abecasis, GR and Casey, G and Nickerson, DA and Gruber, SB and Hsu, L and Zheng, W and Peters, U}, title = {Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.}, journal = {Human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00439-019-01989-8}, pmid = {30820706}, issn = {1432-1203}, support = {U01 CA164930//National Cancer Institute/ ; R01 CA201407//National Cancer Institute/ ; }, abstract = {Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.}, }
@article {pmid30820047, year = {2019}, author = {Kunkle, BW and Grenier-Boley, B and Sims, R and Bis, JC and Damotte, V and Naj, AC and Boland, A and Vronskaya, M and van der Lee, SJ and Amlie-Wolf, A and Bellenguez, C and Frizatti, A and Chouraki, V and Martin, ER and Sleegers, K and Badarinarayan, N and Jakobsdottir, J and Hamilton-Nelson, KL and Moreno-Grau, S and Olaso, R and Raybould, R and Chen, Y and Kuzma, AB and Hiltunen, M and Morgan, T and Ahmad, S and Vardarajan, BN and Epelbaum, J and Hoffmann, P and Boada, M and Beecham, GW and Garnier, JG and Harold, D and Fitzpatrick, AL and Valladares, O and Moutet, ML and Gerrish, A and Smith, AV and Qu, L and Bacq, D and Denning, N and Jian, X and Zhao, Y and Del Zompo, M and Fox, NC and Choi, SH and Mateo, I and Hughes, JT and Adams, HH and Malamon, J and Sanchez-Garcia, F and Patel, Y and Brody, JA and Dombroski, BA and Naranjo, MCD and Daniilidou, M and Eiriksdottir, G and Mukherjee, S and Wallon, D and Uphill, J and Aspelund, T and Cantwell, LB and Garzia, F and Galimberti, D and Hofer, E and Butkiewicz, M and Fin, B and Scarpini, E and Sarnowski, C and Bush, WS and Meslage, S and Kornhuber, J and White, CC and Song, Y and Barber, RC and Engelborghs, S and Sordon, S and Voijnovic, D and Adams, PM and Vandenberghe, R and Mayhaus, M and Cupples, LA and Albert, MS and De Deyn, PP and Gu, W and Himali, JJ and Beekly, D and Squassina, A and Hartmann, AM and Orellana, A and Blacker, D and Rodriguez-Rodriguez, E and Lovestone, S and Garcia, ME and Doody, RS and Munoz-Fernadez, C and Sussams, R and Lin, H and Fairchild, TJ and Benito, YA and Holmes, C and Karamujić-Čomić, H and Frosch, MP and Thonberg, H and Maier, W and Roschupkin, G and Ghetti, B and Giedraitis, V and Kawalia, A and Li, S and Huebinger, RM and Kilander, L and Moebus, S and Hernández, I and Kamboh, MI and Brundin, R and Turton, J and Yang, Q and Katz, MJ and Concari, L and Lord, J and Beiser, AS and Keene, CD and Helisalmi, S and Kloszewska, I and Kukull, WA and Koivisto, AM and Lynch, A and Tarraga, L and Larson, EB and Haapasalo, A and Lawlor, B and Mosley, TH and Lipton, RB and Solfrizzi, V and Gill, M and Longstreth, WT and Montine, TJ and Frisardi, V and Diez-Fairen, M and Rivadeneira, F and Petersen, RC and Deramecourt, V and Alvarez, I and Salani, F and Ciaramella, A and Boerwinkle, E and Reiman, EM and Fievet, N and Rotter, JI and Reisch, JS and Hanon, O and Cupidi, C and Andre Uitterlinden, AG and Royall, DR and Dufouil, C and Maletta, RG and de Rojas, I and Sano, M and Brice, A and Cecchetti, R and George-Hyslop, PS and Ritchie, K and Tsolaki, M and Tsuang, DW and Dubois, B and Craig, D and Wu, CK and Soininen, H and Avramidou, D and Albin, RL and Fratiglioni, L and Germanou, A and Apostolova, LG and Keller, L and Koutroumani, M and Arnold, SE and Panza, F and Gkatzima, O and Asthana, S and Hannequin, D and Whitehead, P and Atwood, CS and Caffarra, P and Hampel, H and Quintela, I and Carracedo, Á and Lannfelt, L and Rubinsztein, DC and Barnes, LL and Pasquier, F and Frölich, L and Barral, S and McGuinness, B and Beach, TG and Johnston, JA and Becker, JT and Passmore, P and Bigio, EH and Schott, JM and Bird, TD and Warren, JD and Boeve, BF and Lupton, MK and Bowen, JD and Proitsi, P and Boxer, A and Powell, JF and Burke, JR and Kauwe, JSK and Burns, JM and Mancuso, M and Buxbaum, JD and Bonuccelli, U and Cairns, NJ and McQuillin, A and Cao, C and Livingston, G and Carlson, CS and Bass, NJ and Carlsson, CM and Hardy, J and Carney, RM and Bras, J and Carrasquillo, MM and Guerreiro, R and Allen, M and Chui, HC and Fisher, E and Masullo, C and Crocco, EA and DeCarli, C and Bisceglio, G and Dick, M and Ma, L and Duara, R and Graff-Radford, NR and Evans, DA and Hodges, A and Faber, KM and Scherer, M and Fallon, KB and Riemenschneider, M and Fardo, DW and Heun, R and Farlow, MR and Kölsch, H and Ferris, S and Leber, M and Foroud, TM and Heuser, I and Galasko, DR and Giegling, I and Gearing, M and Hüll, M and Geschwind, DH and Gilbert, JR and Morris, J and Green, RC and Mayo, K and Growdon, JH and Feulner, T and Hamilton, RL and Harrell, LE and Drichel, D and Honig, LS and Cushion, TD and Huentelman, MJ and Hollingworth, P and Hulette, CM and Hyman, BT and Marshall, R and Jarvik, GP and Meggy, A and Abner, E and Menzies, GE and Jin, LW and Leonenko, G and Real, LM and Jun, GR and Baldwin, CT and Grozeva, D and Karydas, A and Russo, G and Kaye, JA and Kim, R and Jessen, F and Kowall, NW and Vellas, B and Kramer, JH and Vardy, E and LaFerla, FM and Jöckel, KH and Lah, JJ and Dichgans, M and Leverenz, JB and Mann, D and Levey, AI and Pickering-Brown, S and Lieberman, AP and Klopp, N and Lunetta, KL and Wichmann, HE and Lyketsos, CG and Morgan, K and Marson, DC and Brown, K and Martiniuk, F and Medway, C and Mash, DC and Nöthen, MM and Masliah, E and Hooper, NM and McCormick, WC and Daniele, A and McCurry, SM and Bayer, A and McDavid, AN and Gallacher, J and McKee, AC and van den Bussche, H and Mesulam, M and Brayne, C and Miller, BL and Riedel-Heller, S and Miller, CA and Miller, JW and Al-Chalabi, A and Morris, JC and Shaw, CE and Myers, AJ and Wiltfang, J and O'Bryant, S and Olichney, JM and Alvarez, V and Parisi, JE and Singleton, AB and Paulson, HL and Collinge, J and Perry, WR and Mead, S and Peskind, E and Cribbs, DH and Rossor, M and Pierce, A and Ryan, NS and Poon, WW and Nacmias, B and Potter, H and Sorbi, S and Quinn, JF and Sacchinelli, E and Raj, A and Spalletta, G and Raskind, M and Caltagirone, C and Bossù, P and Orfei, MD and Reisberg, B and Clarke, R and Reitz, C and Smith, AD and Ringman, JM and Warden, D and Roberson, ED and Wilcock, G and Rogaeva, E and Bruni, AC and Rosen, HJ and Gallo, M and Rosenberg, RN and Ben-Shlomo, Y and Sager, MA and Mecocci, P and Saykin, AJ and Pastor, P and Cuccaro, ML and Vance, JM and Schneider, JA and Schneider, LS and Slifer, S and Seeley, WW and Smith, AG and Sonnen, JA and Spina, S and Stern, RA and Swerdlow, RH and Tang, M and Tanzi, RE and Trojanowski, JQ and Troncoso, JC and Van Deerlin, VM and Van Eldik, LJ and Vinters, HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Wilhelmsen, KC and Williamson, J and Wingo, TS and Woltjer, RL and Wright, CB and Yu, CE and Yu, L and Saba, Y and ,  and ,  and ,  and ,  and Pilotto, A and Bullido, MJ and Peters, O and Crane, PK and Bennett, D and Bosco, P and Coto, E and Boccardi, V and De Jager, PL and Lleo, A and Warner, N and Lopez, OL and Ingelsson, M and Deloukas, P and Cruchaga, C and Graff, C and Gwilliam, R and Fornage, M and Goate, AM and Sanchez-Juan, P and Kehoe, PG and Amin, N and Ertekin-Taner, N and Berr, C and Debette, S and Love, S and Launer, LJ and Younkin, SG and Dartigues, JF and Corcoran, C and Ikram, MA and Dickson, DW and Nicolas, G and Campion, D and Tschanz, J and Schmidt, H and Hakonarson, H and Clarimon, J and Munger, R and Schmidt, R and Farrer, LA and Van Broeckhoven, C and C O'Donovan, M and DeStefano, AL and Jones, L and Haines, JL and Deleuze, JF and Owen, MJ and Gudnason, V and Mayeux, R and Escott-Price, V and Psaty, BM and Ramirez, A and Wang, LS and Ruiz, A and van Duijn, CM and Holmans, PA and Seshadri, S and Williams, J and Amouyel, P and Schellenberg, GD and Lambert, JC and Pericak-Vance, MA}, title = {Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.}, journal = {Nature genetics}, volume = {51}, number = {3}, pages = {414-430}, doi = {10.1038/s41588-019-0358-2}, pmid = {30820047}, issn = {1546-1718}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG053760/AG/NIA NIH HHS/United States ; MR/K013041/1//Medical Research Council/United Kingdom ; G0900421//Medical Research Council/United Kingdom ; MC_U123160657//Medical Research Council/United Kingdom ; MR/L501529/1//Medical Research Council/United Kingdom ; G0300429//Medical Research Council/United Kingdom ; K25 AG055620/AG/NIA NIH HHS/United States ; G0902227//Medical Research Council/United Kingdom ; MR/L501517/1//Medical Research Council/United Kingdom ; MR/L021803/1//Medical Research Council/United Kingdom ; G0500289//Medical Research Council/United Kingdom ; P01 AG019724/AG/NIA NIH HHS/United States ; G0900688//Medical Research Council/United Kingdom ; G0801418//Medical Research Council/United Kingdom ; G0600237//Medical Research Council/United Kingdom ; G9810900//Medical Research Council/United Kingdom ; }, abstract = {Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.}, }
@article {pmid30819455, year = {2019}, author = {Carlos, RC and Sicks, JD and Chiles, C and Gansauer, L and Kamen, CS and Kazak, AE and Neuman, HB and Unger, JM and Weaver, KE}, title = {Lung Cancer Screening in the National Cancer Institute Community Oncology Research Program: Availability and Service Organization.}, journal = {Journal of the American College of Radiology : JACR}, volume = {16}, number = {4 Pt A}, pages = {427-434}, doi = {10.1016/j.jacr.2018.12.016}, pmid = {30819455}, issn = {1558-349X}, abstract = {PURPOSE: Annual low-dose CT (LDCT) for lung screening in high-risk individuals decreases both lung cancer-specific mortality and all-cause mortality. Community oncology practice networks constituting the National Cancer Institute Community Oncology Research Program (NCORP) conduct clinical trials across the cancer spectrum. The authors report access to and characteristics of LDCT screening for lung cancer in these community oncology practices.<br><br>METHODS: A landscape capacity assessment was conducted in 2017 across the NCORP network. The primary outcome was the proportion of adult oncology practice groups offering LDCT lung screening on site. The secondary outcomes were the proportion of those screening services (1) with radiologist participation in service management and (2) offered at ACR Designated Lung Cancer Screening Centers.<br><br>RESULTS: Fifty-two percent of components and subcomponents responded to at least some portion of the assessment, representing 217 practice groups. Analyzing the 211 adult oncology practice groups responding to the primary question, 73% offered lung screening services on site. Radiologists participated in managing 69% of these services. Forty-seven percent were offered in ACR Designated Lung Cancer Screening Centers. Minority and underserved practice groups were less likely to offer lung screening; however, this association dissipated when analyses focused on practices within the United States. Safety net and Critical Access Hospital designation increased the likelihood of screening availability.<br><br>CONCLUSIONS: The majority of community oncology practice groups within the NCORP offered lung screening on site, although radiologist participation in service management and ACR Lung Cancer Screening Center designation, markers of service quality, were more variable.}, }
@article {pmid30819038, year = {2019}, author = {Bansal, A and Sullivan, SD and Lin, VW and Purdum, AG and Navale, L and Cheng, P and Ramsey, SD}, title = {Estimating Long-Term Survival for Patients with Relapsed or Refractory Large B-cell Lymphoma Treated with Chimeric Antigen Receptor Therapy: A Comparison of Standard and Mixture Cure Models.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {}, number = {}, pages = {272989X18820535}, doi = {10.1177/0272989X18820535}, pmid = {30819038}, issn = {1552-681X}, abstract = {Patients treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have shown either sustained remission or rapid progression. Traditional survival modeling may underestimate outcomes in these situations, by assuming the same mortality rate for all patients. To illustrate this issue, we compare standard parametric models to mixture cure models for estimating long-term overall survival in patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Compared to standard models without cure proportions, mixture cure models have similar fit, but substantially different extrapolated survival. Standard models (Weibull and generalized gamma) estimate mean survival of 2.0 years (95% CI (1.5, 3.0)) and 3.0 years (95% CI (1.7, 5.6)), respectively, compared to 15.7 years (95% CI (9.3, 21.1)) and 17.5 yrs (12.0, 22.8) from mixture cure models (using Weibull and generalized gamme distributions). For cancer therapies where substantial fractions achieve long term remission, our results suggest that assumptions of the modeling approach should be considered. Given sufficient follow-up, mixture cure models may provide a more accurate estimate of long-term overall survival compared with standard models.}, }
@article {pmid30819011, year = {2019}, author = {Stoner, MCD and Rucinski, KB and Edwards, JK and Selin, A and Hughes, JP and Wang, J and Agyei, Y and Gomez-Olive, FX and MacPhail, C and Kahn, K and Pettifor, A}, title = {The Relationship Between School Dropout and Pregnancy Among Adolescent Girls and Young Women in South Africa: A HPTN 068 Analysis.}, journal = {Health education &amp; behavior : the official publication of the Society for Public Health Education}, volume = {}, number = {}, pages = {1090198119831755}, doi = {10.1177/1090198119831755}, pmid = {30819011}, issn = {1552-6127}, abstract = {BACKGROUND: Prevention of both school dropout and teen pregnancy represent clear public health priorities for South Africa, yet their complex and potentially cyclical relationship has not been fully explored.<br><br>OBJECTIVE: To further understand how this relationship operates, we analyzed data from a randomized trial of young women aged 13 to 20 years enrolled in school in rural South Africa to estimate the association between pregnancy and subsequent dropout and between dropout and subsequent pregnancy.<br><br>METHOD: We examined inverse probability (IP) of exposure-weighted survival curves for school dropout by pregnancy and for pregnancy by school dropout. We used weighted curves to calculate 1-, 2-, and 3-year risk differences and risk ratios. Additionally, we used an IP-weighted marginal structural cox model to estimate a hazard ratio (HR) for each relationship.<br><br>RESULTS: Dropout from school was associated with subsequent pregnancy (HR 3.58; 95% confidence interval [CI] [2.04, 6.28]) and pregnancy was associated with subsequent school dropout (HR 2.36; 95% CI [1.29, 4.31]). Young women who attended school but attended fewer days had a higher hazard of pregnancy than those who attended more school (HR 3.64; 95% CI [2.27, 5.84]).<br><br>CONCLUSION: Pregnancy is both a cause and a consequence of school dropout. Consideration of school attendance and academic performance could ultimately enhance pregnancy prevention efforts in this population. Programs should be tailored differently for (1) girls who have dropped out of school, (2) those who are in school and at risk for pregnancy, and (3) those who are in school and become pregnant.}, }
@article {pmid30818369, year = {2019}, author = {Khanal, S and Galloway, DA}, title = {High-risk human papillomavirus oncogenes disrupt the Fanconi anemia DNA repair pathway by impairing localization and de-ubiquitination of FancD2.}, journal = {PLoS pathogens}, volume = {15}, number = {2}, pages = {e1007442}, doi = {10.1371/journal.ppat.1007442}, pmid = {30818369}, issn = {1553-7374}, support = {R01 CA064795/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; }, mesh = {Alphapapillomavirus/*genetics/metabolism ; Cisplatin/pharmacology ; DNA Damage ; *DNA Repair ; Fanconi Anemia Complementation Group D2 Protein/*metabolism ; Fanconi Anemia Complementation Group N Protein/metabolism ; Fanconi Anemia Complementation Group Proteins/metabolism ; Genomic Instability ; HEK293 Cells ; Humans ; Oncogene Proteins, Viral/biosynthesis/genetics ; Oncogenes ; Papillomavirus E7 Proteins/biosynthesis/genetics ; Primary Cell Culture ; Repressor Proteins/biosynthesis/genetics ; Signal Transduction ; Ubiquitination ; }, abstract = {Persistent expression of high-risk HPV oncogenes is necessary for the development of anogenital and oropharyngeal cancers. Here, we show that E6/E7 expressing cells are hypersensitive to DNA crosslinking agent cisplatin and have defects in repairing DNA interstrand crosslinks (ICL). Importantly, we elucidate how E6/E7 attenuate the Fanconi anemia (FA) DNA crosslink repair pathway. Though E6/E7 activated the pathway by increasing FancD2 monoubiquitination and foci formation, they inhibited the completion of the repair by multiple mechanisms. E6/E7 impaired FancD2 colocalization with double-strand breaks (DSB), which subsequently hindered the recruitment of the downstream protein Rad51 to DSB in E6 cells. Further, E6 expression caused delayed FancD2 de-ubiquitination, an important process for effective ICL repair. Delayed FancD2 de-ubiquitination was associated with the increased chromatin retention of FancD2 hindering USP1 de-ubiquitinating activity, and persistently activated ATR/CHK-1/pS565 FancI signaling. E6 mediated p53 degradation did not hamper the cell cycle specific process of FancD2 modifications but abrogated repair by disrupting FancD2 de-ubiquitination. Further, E6 reduced the expression and foci formation of Palb2, which is a repair protein downstream of FancD2. These findings uncover unique mechanisms by which HPV oncogenes contribute to genomic instability and the response to cisplatin therapies.}, }
@article {pmid30817250, year = {2019}, author = {Ramanathan, RK and McDonough, SL and Philip, PA and Hingorani, SR and Lacy, J and Kortmansky, JS and Thumar, J and Chiorean, EG and Shields, AF and Behl, D and Mehan, PT and Gaur, R and Seery, T and Guthrie, KA and Hochster, HS}, title = {Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO1801295}, doi = {10.1200/JCO.18.01295}, pmid = {30817250}, issn = {1527-7755}, abstract = {PURPOSE: Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC).<br><br>MATERIALS AND METHODS: Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS).<br><br>RESULTS: PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm.<br><br>CONCLUSION: Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.}, }
@article {pmid30817058, year = {2019}, author = {Daniel, LC and Wang, M and Mulrooney, DA and Srivastava, DK and Schwartz, LA and Edelstein, K and Brinkman, TM and Zhou, ES and Howell, RM and Gibson, TM and Leisenring, W and Oeffinger, KC and Neglia, J and Robison, LL and Armstrong, GT and Krull, KR}, title = {Sleep, emotional distress, and physical health in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Psycho-oncology}, volume = {28}, number = {4}, pages = {903-912}, doi = {10.1002/pon.5040}, pmid = {30817058}, issn = {1099-1611}, support = {//American Lebanese-Syrian Associated Charities (ALSAC)/ ; CA21765//National Cancer Institute/ ; CA55727//National Cancer Institute/ ; }, abstract = {OBJECTIVE: Sleep disorders are associated with psychological and physical health, although reports in long-term survivors of childhood cancer are limited. We characterized the prevalence and risk factors for behaviors consistent with sleep disorders in survivors and examined longitudinal associations with emotional distress and physical health outcomes.<br><br>METHODS: Survivors (n = 1933; median [IQR] age = 35 [30, 41]) and siblings (n = 380; age = 33 [27, 40]) from the Childhood Cancer Survivor Study completed measures of sleep quality, fatigue, and sleepiness. Emotional distress and physical health outcomes were assessed approximately 5 years before and after the sleep survey. Multivariable logistic or modified Poisson regression models examined associations with cancer diagnosis, treatment exposures, and emotional and physical health outcomes.<br><br>RESULTS: Survivors were more likely to report poor sleep efficiency (30.8% vs 24.7%; prevalence ratio [PR] = 1.26; 95% confidence interval, 1.04-1.53), daytime sleepiness (18.7% vs 14.2%; PR = 1.31 [1.01-1.71]), and sleep supplement use (13.5% vs 8.3%; PR = 1.56 [1.09-2.22]) than siblings. Survivors who developed emotional distress were more likely to report poor sleep efficiency (PR = 1.70 [1.40-2.07]), restricted sleep time (PR = 1.35 [1.12-1.62]), fatigue (PR = 2.11 [1.92-2.32]), daytime sleepiness (PR = 2.19 [1.71-2.82]), snoring (PR = 1.85 [1.08-3.16]), and more sleep medication (PR = 2.86 [2.00-4.09]) and supplement use (PR = 1.89[1.33-2.69]). Survivors reporting symptoms of insomnia (PR = 1.46 [1.02-2.08]), fatigue (PR = 1.31 [1.01-1.72]), and using sleep medications (PR = 2.16 [1.13-4.12]) were more likely to develop migraines/headaches.<br><br>CONCLUSIONS: Survivors report more sleep difficulties and efforts to manage sleep than siblings. These sleep behaviors are related to worsening or persistently elevated emotional distress and may result in increased risk for migraines. Behavioral interventions targeting sleep may be important for improving health outcomes.}, }
@article {pmid30816957, year = {2019}, author = {Kanate, AS and Kumar, A and Dreger, P and Dreyling, M and Le Gouill, S and Corradini, P and Bredeson, C and Fenske, TS and Smith, SM and Sureda, A and Moskowitz, A and Friedberg, JW and Inwards, DJ and Herrera, AF and Kharfan-Dabaja, MA and Reddy, N and Montoto, S and Robinson, SP and Abutalib, SA and Gisselbre, C and Vose, J and Gopal, A and Shadman, M and Perales, MA and Carpenter, P and Savani, BN and Hamadani, M}, title = {Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2018.6278}, pmid = {30816957}, issn = {2374-2445}, abstract = {Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma.<br><br>Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naïve high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naïve FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice.<br><br>Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.}, }
@article {pmid30816931, year = {2019}, author = {Conant, EF and Barlow, WE and Herschorn, SD and Weaver, DL and Beaber, EF and Tosteson, ANA and Haas, JS and Lowry, KP and Stout, NK and Trentham-Dietz, A and diFlorio-Alexander, RM and Li, CI and Schnall, MD and Onega, T and Sprague, BL and , }, title = {Association of Digital Breast Tomosynthesis vs Digital Mammography With Cancer Detection and Recall Rates by Age and Breast Density.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2018.7078}, pmid = {30816931}, issn = {2374-2445}, abstract = {Importance: Breast cancer screening examinations using digital breast tomosynthesis (DBT) has been shown to be associated with decreased false-positive test results and increased breast cancer detection compared with digital mammography (DM). Little is known regarding the size and stage of breast cancer types detected and their association with age and breast density.<br><br>Objective: To determine whether screening examinations using DBT detect breast cancers that are associated with an improved prognosis and to compare the detection rates by patient age and breast density.<br><br>This retrospective analysis of prospective cohort data from 3 research centers in the Population-based Research Optimizing Screening Through Personalized Regimens (PROSPR) consortium included data of women aged 40 to 74 years who underwent screening examinations using DM and DBT from January 1, 2011, through September 30, 2014. Statistical analysis was performed from November 8, 2017, to August 14, 2018.<br><br>Exposures: Use of DBT as a supplement to DM at breast cancer screening examination.<br><br>Main Outcomes and Measures: Recall rate, cancer detection rate, positive predictive value, biopsy rate, and distribution of invasive cancer subtypes.<br><br>Results: Among 96 269 women (mean [SD] patient age for all examinations, 55.9 [9.0] years), patient age was 56.4 (9.0) years for DM and 54.6 (8.9) years for DBT. Of 180 340 breast cancer screening examinations, 129 369 examinations (71.7%) used DM and 50 971 examinations (28.3%) used DBT. Screening examination with DBT (73 of 99 women [73.7%]) was associated with the detection of smaller, more often node-negative, HER2-negative, invasive cancers compared with DM (276 of 422 women [65.4%]). Screening examination with DBT was also associated with lower recall (odds ratio, 0.64; 95% CI, 0.57-0.72; P < .001) and higher cancer detection (odds ratio, 1.41; 95% CI, 1.05-1.89; P = .02) compared with DM for all age groups even when stratified by breast density. The largest increase in cancer detection rate and the greatest shift toward smaller, node-negative invasive cancers detected with DBT was for women aged 40 to 49 years. For women aged 40 to 49 years with nondense breasts, the cancer detection rate for examinations using DBT was 1.70 per 1000 women higher compared with the rate using DM; for women with dense breasts, the cancer detection rate was 2.27 per 1000 women higher for DBT. For these younger women, screening with DBT was associated with only 7 of 28 breast cancers (25.0%) categorized as poor prognosis compared with 19 of 47 breast cancers (40.4%) when screening with DM.<br><br>Conclusions and Relevance: The findings suggest that screening with DBT is associated with increased specificity and an increased proportion of breast cancers detected with better prognosis compared with DM. In the subgroup of women aged 40 to 49 years, routine DBT screening may have a favorable risk-benefit ratio.}, }
@article {pmid30816632, year = {2019}, author = {Kiweewa, FM and Brown, E and Mishra, A and Nair, G and Palanee-Phillips, T and Mgodi, N and Nakabiito, C and Chakhtoura, N and Hillier, SL and Baeten, JM and , }, title = {Acquisition of Sexually Transmitted Infections among Women Using a Variety of Contraceptive Options: A prospective Study among High-risk African Women.}, journal = {Journal of the International AIDS Society}, volume = {22}, number = {2}, pages = {e25257}, doi = {10.1002/jia2.25257}, pmid = {30816632}, issn = {1758-2652}, support = {UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; //National Institute of Mental Health/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P30 AI027757/AI/NIAID NIH HHS/United States ; NCT01617096//National Institutes of Health/ ; }, abstract = {INTRODUCTION: In many African settings, women concurrently face substantial risk of human immunodeficiency virus type 1 (HIV-1) infection, sexually transmitted infections (STIs) and unintended pregnancies. Few studies have evaluated STI risk among users of hormonal implants and copper intrauterine devices (IUDs) although these long-acting reversible contraceptive methods are being promoted widely because of their benefits. Within a prospective study of women at risk for HIV-1, we compared the risk of acquisition of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women using different contraceptive methods.<br><br>METHODS: MTN-020/ASPIRE was a randomized trial of the dapivirine vaginal ring for HIV-1 prevention among 2629 women aged 18 to 45 years from Malawi, South Africa, Uganda and Zimbabwe, of whom 2264 used copper IUDs or progestin-based injectables or implants during follow-up. Screening for the above STIs occurred semi-annually.<br><br>RESULTS: Over 3440 person-years of follow-up, 408 cases of C. trachomatis (incidence 11.86/100 person-years), 196 of N. gonorrhoeae (5.70/100 person-years) and 213 cases of T. vaginalis (6.19/100 person-years) were detected. C. trachomatis and N. gonorrhoeae incidence were not significantly different across contraceptive methods. T. vaginalis incidence was significantly higher for copper IUD users compared to depot medroxyprogesterone acetate (DMPA), implant and norethisterone enanthate users.<br><br>CONCLUSION: Among African women at high HIV-1 risk, STIs were common. Risk of cervical infections did not differ across contraceptive methods. Significantly higher rates of T. vaginalis were observed among progestin-based methods compared to copper IUD users. Overall, these findings call for more intensive routine screening for STIs, and they support current World Health Organization guidance that women should have a wide range of contraceptive options.}, }
@article {pmid30814672, year = {2019}, author = {Maloney, DG}, title = {Anti-CD19 CAR T cell therapy for lymphoma - off to the races!.}, journal = {Nature reviews. Clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41571-019-0183-7}, pmid = {30814672}, issn = {1759-4782}, }
@article {pmid30814668, year = {2019}, author = {Li, AZ and Corey, L and Zhu, J}, title = {Random-Reaction-Seed Method for Automated Identification of Neurite Elongation and Branching.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {2908}, doi = {10.1038/s41598-019-39962-0}, pmid = {30814668}, issn = {2045-2322}, support = {R01 AI134878/AI/NIAID NIH HHS/United States ; R01 AI042528//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 AI111780//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; PO1 AI030731//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Conventional deterministic algorithms (i.e., skeletonization and edge-detection) lack robustness and sensitivity to reliably detect the neurite elongation and branching of low signal-to-noise-ratio microscopy images. Neurite outgrowth experiments produce an enormous number of images that require automated measurement; however, the tracking of neurites is easily lost in the automated process due to the intrinsic variability of neurites (either axon or dendrite) under stimuli. We have developed a stochastic random-reaction-seed (RRS) method to identify neurite elongation and branching accurately and automatically. The random-seeding algorithm of RRS is based on the hidden-Markov-model (HMM) to offer a robust enough way for tracing arbitrary neurite structures, while the reaction-seeding algorithm of RRS secures the efficiency of random seeding. It is noteworthy that RRS is capable of tracing a whole neurite branch by only one initial seed, so that RRS is proficient at quantifying extensive amounts of neurite outgrowth images with noisy background in microfluidic devices of biomedical engineering fields. The method also showed notable performance for reconstructing of net-like structures, and thus is expected to be proficient for biomedical feature extractions in a wide range of applications, such as retinal vessel segmentation and cell membrane profiling in spurious-edge-tissues.}, }
@article {pmid30814056, year = {2019}, author = {Varelias, A and Gartlan, KH and Wilkinson, AN and Olver, SD and Samson, LD and Tey, SK and MacDonald, KPA and Hill, GR}, title = {Expansion of IL-17A-secreting CD8+ mucosa-associated invariant T cells in peripheral blood following stem cell mobilization.}, journal = {Blood advances}, volume = {3}, number = {5}, pages = {718-723}, doi = {10.1182/bloodadvances.2018025601}, pmid = {30814056}, issn = {2473-9537}, }
@article {pmid30811478, year = {2019}, author = {Richardson, LA and Schmid, SL and Bhandoola, A and Harly, C and Hedenström, A and Laub, MT and Mace, GM and Sengupta, P and Stock, AM and Read, AF and Malik, HS and Estelle, M and Lowell, S and Kimmelman, J}, title = {The PLOS Biology XV Collection: 15 Years of Exceptional Science Highlighted across 12 Months.}, journal = {PLoS biology}, volume = {17}, number = {2}, pages = {e3000180}, doi = {10.1371/journal.pbio.3000180}, pmid = {30811478}, issn = {1545-7885}, }
@article {pmid30809032, year = {2019}, author = {Inamoto, Y and Petriček, I and Burns, L and Chhabra, S and DeFilipp, Z and Hematti, P and Rovó, A and Schears, R and Shah, A and Agrawal, V and Al-Khinji, A and Ahmed, I and Ali, A and Aljurf, M and Alkhateeb, H and Beitinjaneh, A and Bhatt, N and Buchbinder, D and Byrne, M and Callander, N and Fahnehjelm, K and Farhadfar, N and Gale, RP and Ganguly, S and Hildebrandt, GC and Horn, E and Jakubowski, A and Kamble, RT and Law, J and Lee, C and Nathan, S and Penack, O and Pingali, R and Prasad, P and Pulanic, D and Rotz, S and Shreenivas, A and Steinberg, A and Tabbara, K and Tichelli, A and Wirk, B and Yared, J and Basak, GW and Battiwalla, M and Duarte, R and Savani, BN and Flowers, MED and Shaw, BE and Valdés-Sanz, N}, title = {Correction: Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0472-x}, pmid = {30809032}, issn = {1476-5365}, abstract = {In the original version of this article, author 'Aisha Al-Khinji' was incorrectly listed as 'Aisha Ahmed'. This has now been corrected in both the PDF and HTML versions of the article to 'Aisha Al-Khinji'.}, }
@article {pmid30808685, year = {2019}, author = {Yeshurun, M and Weisdorf, D and Rowe, JM and Tallman, MS and Zhang, MJ and Wang, HL and Saber, W and de Lima, M and Sandmaier, BM and Uy, G and Kamble, RT and Cairo, MS and Cooper, BW and Cahn, JY and Ganguly, S and Camitta, B and Verdonck, LF and Dandoy, C and Diaz, MA and Savani, BN and George, B and Liesveld, J and McGuirk, J and Byrne, M and Grunwald, MR and Drobyski, WR and Pulsipher, MA and Abdel-Azim, H and Prestidge, T and Wieduwilt, MJ and Martino, R and Norkin, M and Beitinjaneh, A and Seo, S and Nishihori, T and Wirk, B and Frangoul, H and Bashey, A and Mori, S and Marks, DI and Bachanova, V}, title = {The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia.}, journal = {Blood advances}, volume = {3}, number = {4}, pages = {670-680}, doi = {10.1182/bloodadvances.2018027003}, pmid = {30808685}, issn = {2473-9537}, abstract = {Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.}, }
@article {pmid30808470, year = {2019}, author = {Marcum, ZA and Hohl, SD and Gray, SL and Barthold, D and Crane, PK and Larson, EB}, title = {Brain Health and Dementia Prevention: A Mixed-method Analysis.}, journal = {American journal of health behavior}, volume = {43}, number = {2}, pages = {300-310}, doi = {10.5993/AJHB.43.2.7}, pmid = {30808470}, issn = {1945-7359}, abstract = {Objective: In this study, we assessed patient knowledge, beliefs, and attitudes about brain health and strategies for Alzheimer's disease and related dementias (ADRD) prevention. Methods: We administered a Web-based survey consisting of 17 questions about brain health and strategies for ADRD prevention in a convenience sample of 1661 patients in an integrated healthcare delivery system in Washington state between February and March 2018. We calculated frequency distributions of the quantitative data and conducted inductive content analysis of qualitative data. Results: Most respondents were female (77%), 51-70 years of age (64%), and white (89%). Although most agreed it is possible to improve brain health and reduce personal ADRD risk, one- third lacked confidence that they could take action to reduce personal ADRD risk. Participants' responses to open-ended questions revealed 10 themes grouped into 3 organizing categories regarding their perceptions about how to prevent ADRD onset: (1) understand ADRD; (2) stay engaged; and (3) manage one's own health and healthcare. Conclusions: Survey respondents were engaged and aware of dementia prevention, but they lacked access to personally action- able evidence..}, }
@article {pmid30804564, year = {2019}, author = {Xue, KS and Bloom, JD}, title = {Reconciling disparate estimates of viral genetic diversity during human influenza infections.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41588-019-0349-3}, pmid = {30804564}, issn = {1546-1718}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; }, }
@article {pmid30804488, year = {2019}, author = {Godwin, CD and Fromm, JR and Othus, M and Sandmaier, BM and Mielcarek, MB and Wood, BL and Appelbaum, FR and Storb, R and Walter, RB}, title = {Pre-transplant bone marrow monocytic myeloid-derived suppressor cell frequency is not associated with outcome after allogeneic hematopoietic cell transplantation for acute myeloid leukemia in remission.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0481-9}, pmid = {30804488}, issn = {1476-5365}, support = {T32-HL007093//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; T32 HL007093/HL/NHLBI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30-CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA018029//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01-CA078902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P01 CA078902/CA/NCI NIH HHS/United States ; }, }
@article {pmid30802187, year = {2019}, author = {Mossavar-Rahmani, Y and Kamensky, V and Manson, JE and Silver, B and Rapp, SR and Haring, B and Beresford, SAA and Snetselaar, L and Wassertheil-Smoller, S}, title = {Artificially Sweetened Beverages and Stroke, Coronary Heart Disease, and All-Cause Mortality in the Women's Health Initiative.}, journal = {Stroke}, volume = {50}, number = {3}, pages = {555-562}, doi = {10.1161/STROKEAHA.118.023100}, pmid = {30802187}, issn = {1524-4628}, support = {HHSN268201600018C/HL/NHLBI NIH HHS/United States ; P30 AG049638/AG/NIA NIH HHS/United States ; R01 AG055527/AG/NIA NIH HHS/United States ; }, abstract = {Background and Purpose- We examine the association between self-reported consumption of artificially sweetened beverages (ASB) and stroke and its subtypes, coronary heart disease, and all-cause mortality in a cohort of postmenopausal US women. Methods- The analytic cohort included 81 714 women from the Women's Health Initiative Observational Study, a multicenter longitudinal study of the health of 93 676 postmenopausal women of ages 50 to 79 years at baseline who enrolled in 1993 to 1998. This prospective study had a mean follow-up time of 11.9 years (SD of 5.3 years.) Participants who completed a follow-up visit 3 years after baseline were included in the study. Results- Most participants (64.1%) were infrequent consumers (never or <1/week) of ASB, with only 5.1% consuming ≥2 ASBs/day. In multivariate analyses, those consuming the highest level of ASB compared to never or rarely (<1/wk) had significantly greater likelihood of all end points (except hemorrhagic stroke), after controlling for multiple covariates. Adjusted models indicated that hazard ratios and 95% confidence intervals were 1.23 (1.02-1.47) for all stroke; 1.31 (1.06-1.63) for ischemic stroke; 1.29 (1.11-1.51) for coronary heart disease; and 1.16 (1.07-1.26) for all-cause mortality. In women with no prior history of cardiovascular disease or diabetes mellitus, high consumption of ASB was associated with more than a 2-fold increased risk of small artery occlusion ischemic stroke hazard ratio =2.44 (95% confidence interval, 1.47-4.04.) High consumption of ASBs was associated with significantly increased risk of ischemic stroke in women with body mass index ≥30; hazard ratio =2.03 (95% confidence interval, 1.38-2.98). Conclusions- Higher intake of ASB was associated with increased risk of stroke, particularly small artery occlusion subtype, coronary heart disease, and all-cause mortality. Although requiring replication, these new findings add to the potentially harmful association of consuming high quantities of ASB with these health outcomes.}, }
@article {pmid30801179, year = {2019}, author = {Fei, Q and Wang, D and Jasbi, P and Zhang, P and Nagana Gowda, GA and Raftery, D and Gu, H}, title = {Combining NMR and MS with Chemical Derivatization for Absolute Quantification with Reduced Matrix Effects.}, journal = {Analytical chemistry}, volume = {91}, number = {6}, pages = {4055-4062}, doi = {10.1021/acs.analchem.8b05611}, pmid = {30801179}, issn = {1520-6882}, abstract = {Absolute quantitation is a major challenge in metabolomics. Previously, we [ Nagana Gowda et al. Anal. Chem. 2018 , 90 , 2001 - 2009 ] showed that nuclear magnetic resonance (NMR) spectroscopy can guide absolute quantitation using mass spectrometry (MS); however, this method does not account for the matrix effect in MS measurements. To surmount this challenge, we have developed a novel method, qNMR-MS, for the absolute quantitation of metabolites using MS by combining it with NMR and chemical derivatization. Metabolite concentrations are first obtained using NMR for a reference sample. Subsequently, both reference and study samples are chemically derivatized with isotope-labeled and unlabeled reagents, respectively. The derivatized reference sample is then mixed with study samples and measured using MS. Comparison of paired isotope unlabeled and labeled MS peaks enables absolute quantitation with virtually no matrix effects. As a proof of concept, we applied the qNMR-MS method for absolute quantitation of amino acids using propyl-chloroformate (PCF) derivatization. For standards, the observed coefficients of determination (R2) of most amino acids were greater than 0.99 across concentrations of 0.2 to 20 uM. For human serum, the results of the qNMR-MS method are comparable to the conventional isotope-labeled internal standard (iSTD) method (R2 ≥ 0.99), with an average median coefficient of variation (CV) of 5.45%. The qNMR-MS method is relatively simple, highly quantitative, has high cost-efficiency (no iSTD required), and offers new avenues for the routine quantitation of amino acids in blood samples; it can, in principle, be extended to a wide variety of metabolites in different biological samples.}, }
@article {pmid30799773, year = {2019}, author = {Zhao, W and Zheng, J and Chen, YQ and Hsu, L}, title = {Adjusted time-varying population attributable hazard in case-control studies.}, journal = {Statistical methods in medical research}, volume = {}, number = {}, pages = {962280219831725}, doi = {10.1177/0962280219831725}, pmid = {30799773}, issn = {1477-0334}, abstract = {Population attributable fraction is a widely used measure for quantifying the disease burden associated with a modifiable exposure of interest at the population level. It has been extended to a time-varying measure, population attributable hazard function, to provide additional information on when and how the exposure's impact varies over time. However, like the classic population attributable fraction, the population attributable hazard is generally biased if confounders are present. In this article, we provide a natural definition of adjusted population attributable hazard to take into account the effects of confounders, and its alternative that is identifiable from case-control studies under the rare disease assumption. We propose a novel estimator, which combines the odds ratio estimator from logistic regression model, and the conditional density function estimator of the exposure and confounding variables distribution given the failure times of cases or the current times of controls from a kernel smoother. We show that the proposed estimators are consistent and asymptotically normal with variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimators perform well in finite sample sizes. Finally, we illustrate the method by an analysis of a case-control study of colorectal cancer. Supplementary materials for this article are available online.}, }
@article {pmid30798855, year = {2019}, author = {McKean, M and Oba, J and Ma, J and Roth, KG and Wang, WL and Macedo, MP and Carapeto, FCL and Haydu, LE and Siroy, AE and Vo, P and Hong, DS and Eterovic, AK and Patel, KP and Bassett, RL and Grimm, EA and Lazar, AJ and Woodman, SE}, title = {Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma.}, journal = {The Journal of investigative dermatology}, volume = {139}, number = {3}, pages = {728-731}, doi = {10.1016/j.jid.2018.10.009}, pmid = {30798855}, issn = {1523-1747}, }
@article {pmid30797618, year = {2019}, author = {Marshall, CH and Sokolova, AO and McNatty, AL and Cheng, HH and Eisenberger, MA and Bryce, AH and Schweizer, MT and Antonarakis, ES}, title = {Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2019.02.002}, pmid = {30797618}, issn = {1873-7560}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.<br><br>OBJECTIVE: To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.<br><br>This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.<br><br>The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.<br><br>RESULTS AND LIMITATIONS: The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05-0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.<br><br>CONCLUSIONS: Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.<br><br>PATIENT SUMMARY: Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.}, }
@article {pmid30794931, year = {2019}, author = {Kilari, D and D'Souza, A and Fraser, R and Qayed, M and Davila, O and Agrawal, V and Diaz, MA and Chhabra, S and Cerny, J and Copelan, E and Farhadfar, N and Freytes, CO and Gale, RP and Ganguly, S and Hildebrandt, GC and Holmberg, L and Kamble, RT and Kapoor, P and Lazarus, H and Lee, C and Murthy, HS and Naik, S and Nishihori, T and Saad, A and Savani, BN and Seo, S and Warwick, A and Wirk, B and Yared, JA and Nieto, Y and Hari, P}, title = {Autologous Hematopoietic Cell Transplantation for Male Germ Cell Tumors: Improved Outcomes Over 3 Decades.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.02.015}, pmid = {30794931}, issn = {1523-6536}, abstract = {The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.}, }
@article {pmid30794930, year = {2019}, author = {Cohen, JA and Baldassari, LE and Atkins, HL and Bowen, JD and Bredeson, C and Carpenter, PA and Corboy, JR and Freedman, MS and Griffith, LM and Lowsky, R and Majhail, NS and Muraro, PA and Nash, RA and Pasquini, MC and Sarantopoulos, S and Savani, BN and Storek, J and Sullivan, KM and Georges, GE}, title = {Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.02.014}, pmid = {30794930}, issn = {1523-6536}, abstract = {Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a &quot;standard of care, clinical evidence available&quot; indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.}, }
@article {pmid30794764, year = {2019}, author = {Moon, AM and Weiss, NS and Beste, LA and Su, F and Ho, SB and Jin, GY and Lowy, E and Berry, K and Ioannou, GN}, title = {Reply.}, journal = {Gastroenterology}, volume = {156}, number = {4}, pages = {1218-1220}, doi = {10.1053/j.gastro.2019.02.024}, pmid = {30794764}, issn = {1528-0012}, mesh = {*Carcinoma, Hepatocellular ; Humans ; *Liver Cirrhosis ; *Liver Neoplasms ; }, }
@article {pmid30794725, year = {2019}, author = {Leeman, J and Askelson, N and Ko, LK and Rohweder, CL and Avelis, J and Best, A and Friedman, D and Glanz, K and Seegmiller, L and Stradtman, L and Vanderpool, RC}, title = {Understanding the processes that Federally Qualified Health Centers use to select and implement colorectal cancer screening interventions: a qualitative study.}, journal = {Translational behavioral medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/tbm/ibz023}, pmid = {30794725}, issn = {1613-9860}, abstract = {Colorectal cancer (CRC) screening is highly effective at reducing cancer-related morbidity and mortality, yet screening rates remain suboptimal. Evidence-based interventions can increase screening rates, particularly when they target multiple levels (e.g., patients, providers, health care systems). However, effective interventions remain underutilized. Thus, there is a pressing need to build capacity to select and implement multilevel CRC screening interventions. We report on formative research aimed at understanding how Federally Qualified Health Center (FQHC) staff select and implement CRC screening interventions, which will inform development of capacity-building strategies. We report the qualitative findings from a study that used a mixed methods design, starting with a quantitative survey followed by a qualitative study. In-depth interviews were conducted with 28 staff from 14 FQHCs in 8 states. The Consolidated Framework for Implementation Research (CFIR) guided interview questions and data analysis. Related to the CFIR process domain, few respondents described conducting formal assessments of factors contributing to low screening rates prior to planning their interventions. Many described engaging champions, implementation leaders, and external change agents. Few described a systematic approach to executing implementation plans beyond conducting plan-do-study-act cycles. Reflection and evaluation consisted primarily of reviewing Uniform Data System performance measures. Findings also include themes related to factors influencing these implementation processes. Although FQHCs are implementing CRC screening interventions, they are not actively targeting the multilevel factors influencing their CRC screening rates. Our findings on gaps in FQHCs' implementation processes will inform development of strategies to build capacity to select and implement multilevel CRC screening interventions.}, }
@article {pmid30794534, year = {2019}, author = {Hart, SFM and Mi, H and Green, R and Xie, L and Pineda, JMB and Momeni, B and Shou, W}, title = {Uncovering and resolving challenges of quantitative modeling in a simplified community of interacting cells.}, journal = {PLoS biology}, volume = {17}, number = {2}, pages = {e3000135}, doi = {10.1371/journal.pbio.3000135}, pmid = {30794534}, issn = {1545-7885}, abstract = {Quantitative modeling is useful for predicting behaviors of a system and for rationally constructing or modifying the system. The predictive power of a model relies on accurate quantification of model parameters. Here, we illustrate challenges in parameter quantification and offer means to overcome these challenges, using a case example in which we quantitatively predict the growth rate of a cooperative community. Specifically, the community consists of two Saccharomyces cerevisiae strains, each engineered to release a metabolite required and consumed by its partner. The initial model, employing parameters measured in batch monocultures with zero or excess metabolite, failed to quantitatively predict experimental results. To resolve the model-experiment discrepancy, we chemically identified the correct exchanged metabolites, but this did not improve model performance. We then remeasured strain phenotypes in chemostats mimicking the metabolite-limited community environments, while mitigating or incorporating effects of rapid evolution. Almost all phenotypes we measured, including death rate, metabolite release rate, and the amount of metabolite consumed per cell birth, varied significantly with the metabolite environment. Once we used parameters measured in a range of community-like chemostat environments, prediction quantitatively agreed with experimental results. In summary, using a simplified community, we uncovered and devised means to resolve modeling challenges that are likely general to living systems.}, }
@article {pmid30793950, year = {2019}, author = {Thill, M and Thatcher, N and Hanes, V and Lyman, GH}, title = {Biosimilars: what the oncologist should know.}, journal = {Future oncology (London, England)}, volume = {15}, number = {10}, pages = {1147-1165}, doi = {10.2217/fon-2018-0728}, pmid = {30793950}, issn = {1744-8301}, abstract = {As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex therapies with a goal of providing more affordable treatment options. Many of these molecules, known as biosimilars, are now approved worldwide and several more are expected to be introduced in the near future. As more biosimilars become available, it is important for clinicians to become familiar with this new category of products and understand how biosimilars are developed, how their development differs from that of originator biologics and how they differ from generics. This review aims to provide the practicing clinician with the knowledge needed to understand biosimilars, along with some guidance on their use in treating oncologic diseases.}, }
@article {pmid30793644, year = {2019}, author = {Acharya, UH and Dhawale, T and Yun, S and Jacobson, CA and Chavez, JC and Ramos, JD and Appelbaum, J and Maloney, DG}, title = {Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.}, journal = {Expert review of hematology}, volume = {12}, number = {3}, pages = {195-205}, doi = {10.1080/17474086.2019.1585238}, pmid = {30793644}, issn = {1747-4094}, abstract = {INTRODUCTION: Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren't fully elucidated, risk factors and mitigation strategies have been reported. Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity. Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRS/neurotoxicity management.}, }
@article {pmid30793095, year = {2019}, author = {Hemming, ML and Klega, KS and Rhoades, J and Ha, G and Acker, KE and Andersen, JL and Thai, E and Nag, A and Thorner, AR and Raut, CP and George, S and Crompton, BD}, title = {Detection of Circulating Tumor DNA in Patients With Leiomyosarcoma With Progressive Disease.}, journal = {JCO precision oncology}, volume = {2019}, number = {}, pages = {}, doi = {10.1200/PO.18.00235}, pmid = {30793095}, issn = {2473-4284}, support = {K08 CA188073/CA/NCI NIH HHS/United States ; }, abstract = {Purpose: Leiomyosarcoma (LMS) is a soft tissue sarcoma characterized by multiple copy number alterations (CNAs) and without common recurrent single nucleotide variants. We evaluated the feasibility of detecting circulating tumor DNA (ctDNA) with next-generation sequencing in a cohort of patients with LMS whose tumor burden ranged from no evidence of disease to metastatic progressive disease.<br><br>Patients and Methods: Cell-free DNA in plasma samples and paired genomic DNA from resected tumors were evaluated from patients with LMS by ultra-low passage whole genome sequencing (ULP-WGS). Sequencing reads were aligned to the human genome and CNAs identified in cell-free DNA and tumor DNA by ichorCNA software to determine the presence of ctDNA. Clinical data were reviewed to assess disease burden and clinicopathologic features.<br><br>Results: We identified LMS ctDNA in eleven of sixteen patients (69%) with disease progression and total tumor burden over 5 cm. Sixteen patients with stable disease or low disease burden at the time of blood draw were found to have no detectable ctDNA. Higher ctDNA fraction of total cell-free DNA was associated with increasing tumor size and disease progression. Conserved CNAs were found between primary tumors and ctDNA in each case, and recurrent CNAs were found across LMS samples. ctDNA levels declined following resection of progressive disease in one case and became detectable upon disease relapse in another individual patient.<br><br>Conclusion: These results suggest that ctDNA, assayed by a widely available sequencing approach, may be useful as a biomarker for a subset of uterine and extrauterine LMS. Higher levels of ctDNA correlate with tumor size and disease progression. Liquid biopsies may assist in guiding treatment decisions, monitoring response to systemic therapy, surveying for disease recurrence and differentiating benign and malignant smooth muscle tumors.}, }
@article {pmid30789451, year = {2019}, author = {Lin, J and Xue, X and Anastos, K and Cohen, MH and Gange, SJ and Lazar, JM and Liu, C and Mack, WJ and Tien, PC and Tilley, C and Hodis, HN and Landay, AL and Tracy, RP and Kaplan, RC and Hanna, DB}, title = {Elevated Microparticle Tissue Factor Activity Is Associated With Carotid Artery Plaque in HIV-Infected Women.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {81}, number = {1}, pages = {36-43}, doi = {10.1097/QAI.0000000000001988}, pmid = {30789451}, issn = {1944-7884}, support = {L30 AI107910/AI/NIAID NIH HHS/United States ; U01 AI103397/AI/NIAID NIH HHS/United States ; U01 AI031834/AI/NIAID NIH HHS/United States ; U01 AI035004/AI/NIAID NIH HHS/United States ; R01 HL095140/HL/NHLBI NIH HHS/United States ; R21 HL120394/HL/NHLBI NIH HHS/United States ; U01 AI034989/AI/NIAID NIH HHS/United States ; R01 HL126543/HL/NHLBI NIH HHS/United States ; R01 HL083760/HL/NHLBI NIH HHS/United States ; R01 HL132794/HL/NHLBI NIH HHS/United States ; U01 AI034994/AI/NIAID NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; U01 AI103401/AI/NIAID NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; U01 AI103390/AI/NIAID NIH HHS/United States ; U01 AI034993/AI/NIAID NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; U01 AI103408/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; K01 HL137557/HL/NHLBI NIH HHS/United States ; U01 HD032632/HD/NICHD NIH HHS/United States ; U01 AI042590/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women.<br><br>SETTING: In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques.<br><br>METHODS: Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP).<br><br>RESULTS: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation.<br><br>CONCLUSIONS: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.}, }
@article {pmid30789436, year = {2019}, author = {Sangaramoorthy, M and Hines, LM and Torres-Mejía, G and Phipps, AI and Baumgartner, KB and Wu, AH and Koo, J and Ingles, SA and Slattery, ML and John, EM}, title = {A pooled analysis of breast-feeding and breast cancer risk by hormone receptor status in parous Hispanic women.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/EDE.0000000000000981}, pmid = {30789436}, issn = {1531-5487}, support = {R03 CA199343/CA/NCI NIH HHS/United States ; R01 CA078682/CA/NCI NIH HHS/United States ; R01 CA140002/CA/NCI NIH HHS/United States ; R01 CA063446/CA/NCI NIH HHS/United States ; U01 CA164920/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Data on breast-feeding and breast cancer risk are sparse and inconsistent for Hispanic women.<br><br>METHODS: Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the U.S. and Mexico, we examined the association of breast-feeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, as well as the joint effects of breast-feeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.<br><br>RESULTS: Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER-PR- breast cancer. Increasing duration of breast-feeding was associated with decreasing breast cancer risk (≥25 vs. 0 months: OR=0.73, 95% CI=0.60-0.89, Ptrend =0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breast-feeding further reduced HR+ breast cancer risk. Additionally, breast-feeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.<br><br>CONCLUSIONS: Our findings suggest that breast-feeding is associated with reduced risk of both HR+ and ER-PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.}, }
@article {pmid30789432, year = {2019}, author = {VanderWeele, TJ and Luedtke, AR and van der Laan, MJ and Kessler, RC}, title = {Selecting Optimal Subgroups for Treatment Using Many Covariates.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {30}, number = {3}, pages = {334-341}, doi = {10.1097/EDE.0000000000000991}, pmid = {30789432}, issn = {1531-5487}, support = {R01 CA222147/CA/NCI NIH HHS/United States ; }, abstract = {We consider the problem of selecting the optimal subgroup to treat when data on covariates are available from a randomized trial or observational study. We distinguish between four different settings including: (1) treatment selection when resources are constrained; (2) treatment selection when resources are not constrained; (3) treatment selection in the presence of side effects and costs; and (4) treatment selection to maximize effect heterogeneity. We show that, in each of these cases, the optimal treatment selection rule involves treating those for whom the predicted mean difference in outcomes comparing those with versus without treatment, conditional on covariates, exceeds a certain threshold. The threshold varies across these four scenarios, but the form of the optimal treatment selection rule does not. The results suggest a move away from the traditional subgroup analysis for personalized medicine. New randomized trial designs are proposed so as to implement and make use of optimal treatment selection rules in healthcare practice.}, }
@article {pmid30787463, year = {2019}, author = {Escala-Garcia, M and Guo, Q and Dörk, T and Canisius, S and Keeman, R and Dennis, J and Beesley, J and Lecarpentier, J and Bolla, MK and Wang, Q and Abraham, J and Andrulis, IL and Anton-Culver, H and Arndt, V and Auer, PL and Beckmann, MW and Behrens, S and Benitez, J and Bermisheva, M and Bernstein, L and Blomqvist, C and Boeckx, B and Bojesen, SE and Bonanni, B and Børresen-Dale, AL and Brauch, H and Brenner, H and Brentnall, A and Brinton, L and Broberg, P and Brock, IW and Brucker, SY and Burwinkel, B and Caldas, C and Caldés, T and Campa, D and Canzian, F and Carracedo, A and Carter, BD and Castelao, JE and Chang-Claude, J and Chanock, SJ and Chenevix-Trench, G and Cheng, TD and Chin, SF and Clarke, CL and ,  and Cordina-Duverger, E and Couch, FJ and Cox, DG and Cox, A and Cross, SS and Czene, K and Daly, MB and Devilee, P and Dunn, JA and Dunning, AM and Durcan, L and Dwek, M and Earl, HM and Ekici, AB and Eliassen, AH and Ellberg, C and Engel, C and Eriksson, M and Evans, DG and Figueroa, J and Flesch-Janys, D and Flyger, H and Gabrielson, M and Gago-Dominguez, M and Galle, E and Gapstur, SM and García-Closas, M and García-Sáenz, JA and Gaudet, MM and George, A and Georgoulias, V and Giles, GG and Glendon, G and Goldgar, DE and González-Neira, A and Alnæs, GIG and Grip, M and Guénel, P and Haeberle, L and Hahnen, E and Haiman, CA and Håkansson, N and Hall, P and Hamann, U and Hankinson, S and Harkness, EF and Harrington, PA and Hart, SN and Hartikainen, JM and Hein, A and Hillemanns, P and Hiller, L and Holleczek, B and Hollestelle, A and Hooning, MJ and Hoover, RN and Hopper, JL and Howell, A and Huang, G and Humphreys, K and Hunter, DJ and Janni, W and John, EM and Jones, ME and Jukkola-Vuorinen, A and Jung, A and Kaaks, R and Kabisch, M and Kaczmarek, K and Kerin, MJ and Khan, S and Khusnutdinova, E and Kiiski, JI and Kitahara, CM and Knight, JA and Ko, YD and Koppert, LB and Kosma, VM and Kraft, P and Kristensen, VN and Krüger, U and Kühl, T and Lambrechts, D and Le Marchand, L and Lee, E and Lejbkowicz, F and Li, L and Lindblom, A and Lindström, S and Linet, M and Lissowska, J and Lo, WY and Loibl, S and Lubiński, J and Lux, MP and MacInnis, RJ and Maierthaler, M and Maishman, T and Makalic, E and Mannermaa, A and Manoochehri, M and Manoukian, S and Margolin, S and Martinez, ME and Mavroudis, D and McLean, C and Meindl, A and Middha, P and Miller, N and Milne, RL and Moreno, F and Mulligan, AM and Mulot, C and Nassir, R and Neuhausen, SL and Newman, WT and Nielsen, SF and Nordestgaard, BG and Norman, A and Olsson, H and Orr, N and Pankratz, VS and Park-Simon, TW and Perez, JIA and Pérez-Barrios, C and Peterlongo, P and Petridis, C and Pinchev, M and Prajzendanc, K and Prentice, R and Presneau, N and Prokofieva, D and Pylkäs, K and Rack, B and Radice, P and Ramachandran, D and Rennert, G and Rennert, HS and Rhenius, V and Romero, A and Roylance, R and Saloustros, E and Sawyer, EJ and Schmidt, DF and Schmutzler, RK and Schneeweiss, A and Schoemaker, MJ and Schumacher, F and Schwentner, L and Scott, RJ and Scott, C and Seynaeve, C and Shah, M and Simard, J and Smeets, A and Sohn, C and Southey, MC and Swerdlow, AJ and Talhouk, A and Tamimi, RM and Tapper, WJ and Teixeira, MR and Tengström, M and Terry, MB and Thöne, K and Tollenaar, RAEM and Tomlinson, I and Torres, D and Truong, T and Turman, C and Turnbull, C and Ulmer, HU and Untch, M and Vachon, C and van Asperen, CJ and van den Ouweland, AMW and van Veen, EM and Wendt, C and Whittemore, AS and Willett, W and Winqvist, R and Wolk, A and Yang, XR and Zhang, Y and Easton, DF and Fasching, PA and Nevanlinna, H and Eccles, DM and Pharoah, PDP and Schmidt, MK}, title = {Genome-wide association study of germline variants and breast cancer-specific mortality.}, journal = {British journal of cancer}, volume = {120}, number = {6}, pages = {647-657}, doi = {10.1038/s41416-019-0393-x}, pmid = {30787463}, issn = {1532-1827}, support = {RP-PG-0707-10031//Department of Health/United Kingdom ; 0000//Cancer Research UK (CRUK)/ ; 14-04-97088, 17-29-06014 and 17-44-020498//Russian Foundation for Basic Research (RFBR)/ ; C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956//Cancer Research UK (CRUK)/ ; 2007-3839, 2009 4363//KWF Kankerbestrijding (Dutch Cancer Society)/ ; C490/A10124, C490/A16561//Cancer Research UK (CRUK)/ ; DAMD17-01-1-0729//United States Department of Defense | United States Air Force | Air Force Materiel Command (AFMC)/ ; G0700491//Medical Research Council/United Kingdom ; C1287/A16563, C1287/A10118//Cancer Research UK (CRUK)/ ; 10119//Cancer Research UK/United Kingdom ; 0000//Breast Cancer Now (BCN)/ ; 10118//Cancer Research UK/United Kingdom ; 2010PR62, 2013PR044//Breast Cancer Campaign/United Kingdom ; 266528//Suomen Akatemia | Biotieteiden ja Ympäristön Tutkimuksen Toimikunta (Research Council for Biosciences and Environment)/ ; 10124//Cancer Research UK/United Kingdom ; }, abstract = {BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.<br><br>METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).<br><br>RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.<br><br>CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.}, }
@article {pmid30787294, year = {2019}, author = {Fourati, S and Ribeiro, SP and Blasco Tavares Pereira Lopes, F and Talla, A and Lefebvre, F and Cameron, M and Kaewkungwal, J and Pitisuttithum, P and Nitayaphan, S and Rerks-Ngarm, S and Kim, JH and Thomas, R and Gilbert, PB and Tomaras, GD and Koup, RA and Michael, NL and McElrath, MJ and Gottardo, R and Sékaly, RP}, title = {Integrated systems approach defines the antiviral pathways conferring protection by the RV144 HIV vaccine.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {863}, doi = {10.1038/s41467-019-08854-2}, pmid = {30787294}, issn = {2041-1723}, mesh = {AIDS Vaccines/*immunology ; Antigen Presentation/genetics/immunology ; HIV Antibodies/immunology ; HIV Infections/immunology/*prevention &amp; control ; HIV-1/*immunology ; Humans ; Immunization ; Immunoglobulin A/blood/immunology ; Immunoglobulin G/blood/immunology ; Interferon Regulatory Factor-7/*metabolism ; Interferon Type I/*immunology ; Interferon-gamma/*immunology ; Mechanistic Target of Rapamycin Complex 1/genetics/*metabolism ; NF-kappa B/metabolism ; Placebos/administration &amp; dosage ; env Gene Products, Human Immunodeficiency Virus/immunology ; }, abstract = {The RV144 vaccine trial showed reduced risk of HIV-1 acquisition by 31.2%, although mechanisms that led to protection remain poorly understood. Here we identify transcriptional correlates for reduced HIV-1 acquisition after vaccination. We assess the transcriptomic profile of blood collected from 223 participants and 40 placebo recipients. Pathway-level analysis of HIV-1 negative vaccinees reveals that type I interferons that activate the IRF7 antiviral program and type II interferon-stimulated genes implicated in antigen-presentation are both associated with a reduced risk of HIV-1 acquisition. In contrast, genes upstream and downstream of NF-κB, mTORC1 and host genes required for viral infection are associated with an increased risk of HIV-1 acquisition among vaccinees and placebo recipients, defining a vaccine independent association with HIV-1 acquisition. Our transcriptomic analysis of RV144 trial samples identifies IRF7 as a mediator of protection and the activation of mTORC1 as a correlate of the risk of HIV-1 acquisition.}, }
@article {pmid30786186, year = {2019}, author = {Khorana, AA and Soff, GA and Kakkar, AK and Vadhan-Raj, S and Riess, H and Wun, T and Streiff, MB and Garcia, DA and Liebman, HA and Belani, CP and O'Reilly, EM and Patel, JN and Yimer, HA and Wildgoose, P and Burton, P and Vijapurkar, U and Kaul, S and Eikelboom, J and McBane, R and Bauer, KA and Kuderer, NM and Lyman, GH and , }, title = {Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.}, journal = {The New England journal of medicine}, volume = {380}, number = {8}, pages = {720-728}, doi = {10.1056/NEJMoa1814630}, pmid = {30786186}, issn = {1533-4406}, support = {U01 HL143402/HL/NHLBI NIH HHS/United States ; R34 HL127156/HL/NHLBI NIH HHS/United States ; }, mesh = {Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Double-Blind Method ; Factor Xa Inhibitors/adverse effects/*therapeutic use ; Female ; Hemorrhage/chemically induced ; Humans ; Incidence ; Intention to Treat Analysis ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasms/complications/*drug therapy ; Risk Factors ; Rivaroxaban/adverse effects/*therapeutic use ; Treatment Outcome ; Venous Thromboembolism/etiology/*prevention &amp; control ; }, abstract = {BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.<br><br>METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.<br><br>RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).<br><br>CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).}, }
@article {pmid30785776, year = {2019}, author = {Todd, JL and Hill, JA and Cheng, GS}, title = {Herpesviruses: Silent Instigators of Lung Injury after Hematopoietic Cell Transplant.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1164/rccm.201901-0185ED}, pmid = {30785776}, issn = {1535-4970}, }
@article {pmid30785418, year = {2019}, author = {Beieler, A and Magaret, A and Zhou, Y and Schleyer, A and Wald, A and Dhanireddy, S}, title = {Outpatient Parenteral Antimicrobial Therapy in Vulnerable Populations-- People Who Inject Drugs and the Homeless.}, journal = {Journal of hospital medicine}, volume = {14}, number = {2}, pages = {105-109}, doi = {10.12788/jhm.3138}, pmid = {30785418}, issn = {1553-5606}, abstract = {Outpatient parenteral antimicrobial therapy (OPAT) programs can provide high-value care but may be challenging in people who inject drugs (PWID) and homeless individuals. We conducted a single-center, retrospective, cohort study of adults who received OPAT at an urban, public health hospital from January 1, 2015 to April 30, 2016, grouped by PWID and housing status. Outcomes included clinical cure, length of stay, secondary bacteremia, line-tampering, and readmission. A total of 596 patients (homeless PWID (9%), housed PWID (8%), homeless non-PWID (8%), and housed non-PWID (75%), received OPAT. Assuming that patients lost to follow-up failed therapy, homeless PWID were least likely to achieve cure compared with housed non-PWID, (odds ratio [OR] = 0.33, 95% CI 0.18-0.59; P < .001). Housed PWID were also less likely to achieve cure (OR = 0.37, 95% CI 0.20-0.67; P = .001). Cure rates did not differ in patients not lost to follow-up. OPAT can be effective in PWID and the homeless, but loss to follow-up is a significant barrier.}, }
@article {pmid30785094, year = {2019}, author = {Deng, N and Li, M and Shen, D and He, Q and Sun, W and Liu, M and Liu, Y and Zhou, Y and Zheng, J and Shen, F}, title = {LRP1 receptor-mediated immunosuppression of α-MMC on monocytes.}, journal = {International immunopharmacology}, volume = {70}, number = {}, pages = {80-87}, doi = {10.1016/j.intimp.2019.01.036}, pmid = {30785094}, issn = {1878-1705}, abstract = {Alpha-MMC is a type I ribosome-inactivating protein purified from bitter gourd that has strong anti-tumour and antiviral activity. Alpha-MMC also has immunosuppressive effects, but the mechanism of these immunosuppressive effects remains unclear. It is reported that the binding of α-MMC to its specific cell membrane LRP1 receptor is key to its biological effects. In this study, we investigated the effect of α-MMC on cytotoxicity and cytokine release regulation in three immune cells, human monocyte THP-1 cells, B-lymphocyte WIL2 cells and T-lymphocyte H9 cells, and explored the correlation between this effect and LRP1 receptor distribution on these three cell types. We demonstrate that α-MMC has a significant effect of apoptosis induction and cytokine release in THP-1 cells but has no effect on WIL2-S and H9 cells. Specifically, at a non-cytotoxic dose (80 μg/ml), α-MMC regulates THP-1 cells by inhibiting IL-1β, IL-2, IL-8, IL-9, IL-12, MIP-1α/β, MCP-1 and TNF-α expression and enhancing IL-1ra and RANTES expression, resulting in the inhibition of cellular immune function. Subsequent experiments showed that the cytokine expression regulated by α-MMC can be blocked by silencing the LRP1 receptor of α-MMC. Further research indicated that phosphorylation of 9 signalling proteins of the MAPK pathway was significantly regulated by α-MMC and was blocked by LRP1 silencing. We conclude that the regulation of cytokine expression induced by α-MMC in monocyte THP-1 cells is mediated by the LRP1 receptor, likely via the MAPK signalling pathway. Our results suggest that the inhibition effect on monocytes/macrophages mediates the immunosuppressive function of α-MMC. Due to the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes/macrophages, α-MMC may be used for killing Tumour-Associated Macrophages (M2 subtypes) or inhibiting their cytokine release in the tumour microenvironment.}, }
@article {pmid30784102, year = {2019}, author = {Hirayama, AV and Turtle, CJ}, title = {Toxicities of CD19 CAR-T cell immunotherapy.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.25445}, pmid = {30784102}, issn = {1096-8652}, support = {//Juno Therapeutics/ ; //Nektar Therapeutics/ ; }, abstract = {CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy has demonstrated impressive results in B-cell malignancies, and CAR-T cell therapies targeting other antigens are in development for other cancers. Cytokine release syndrome (CRS) and neurotoxicity can be life-threatening in a subset of patients. The severity of CRS and neurotoxicity can be impacted by the disease burden, lymphodepletion regimen, and CAR-T cell dose. Tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR-T cells to be administered without obvious compromise in efficacy. Consensus criteria for grading and managing toxicities will facilitate the widespread application of this treatment modality.}, }
@article {pmid30782611, year = {2019}, author = {Hirayama, AV and Gauthier, J and Hay, KA and Voutsinas, JM and Wu, Q and Gooley, T and Li, D and Cherian, S and Chen, X and Pender, BS and Hawkins, RM and Vakil, A and Steinmetz, RN and Acharya, UH and Cassaday, RD and Chapuis, AG and Dhawale, TM and Hendrie, PC and Kiem, HP and Lynch, RC and Ramos, J and Shadman, M and Till, BG and Riddell, SR and Maloney, DG and Turtle, CJ}, title = {The response to lymphodepletion impacts PFS in aggressive non-Hodgkin lymphoma patients treated with CD19 CAR-T cells.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood-2018-11-887067}, pmid = {30782611}, issn = {1528-0020}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; R01 CA136551/CA/NCI NIH HHS/United States ; }, abstract = {Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors impacting response and progression-free survival (PFS) in aggressive NHL patients treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2x106 CD19 CAR-T cells/kg. The best overall response rate (ORR) was 51%, with 40% of patients achieving complete remission (CR). The median PFS of aggressive NHL patients who achieved CR was 20.0 months (median follow-up 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR-T cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum LDH and a favorable cytokine profile, defined as serum day 0 MCP-1 and peak IL-7 concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion and higher intensity of Cy/Flu lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared to those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR-T cell immunotherapy for aggressive B-cell NHL.}, }
@article {pmid30779811, year = {2019}, author = {Williams, KL and Stumpf, M and Naiman, NE and Ding, S and Garrett, M and Gobillot, T and Vézina, D and Dusenbury, K and Ramadoss, NS and Basom, R and Kim, PS and Finzi, A and Overbaugh, J}, title = {Identification of HIV gp41-specific antibodies that mediate killing of infected cells.}, journal = {PLoS pathogens}, volume = {15}, number = {2}, pages = {e1007572}, doi = {10.1371/journal.ppat.1007572}, pmid = {30779811}, issn = {1553-7374}, support = {T32 GM007266/GM/NIGMS NIH HHS/United States ; 352417//CIHR/Canada ; R37 AI038518/AI/NIAID NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Antibody-Dependent Cell Cytotoxicity/immunology/physiology ; Enzyme-Linked Immunosorbent Assay/methods ; Epitopes/immunology ; HIV Antibodies/*immunology/physiology ; HIV Envelope Protein gp41/*immunology ; HIV Infections/immunology ; HIV-1/immunology ; Humans ; Neutralization Tests/methods ; }, abstract = {Antibodies that mediate killing of HIV-infected cells through antibody-dependent cellular cytotoxicity (ADCC) have been implicated in protection from HIV infection and disease progression. Despite these observations, these types of HIV antibodies are understudied compared to neutralizing antibodies. Here we describe four monoclonal antibodies (mAbs) obtained from one individual that target the HIV transmembrane protein, gp41, and mediate ADCC activity. These four mAbs arose from independent B cell lineages suggesting that in this individual, multiple B cell responses were induced by the gp41 antigen. Competition and phage peptide display mapping experiments suggested that two of the mAbs target epitopes in the cysteine loop that are highly conserved and a common target of HIV gp41-specific antibodies. The amino acid sequences that bind these mAbs are overlapping but distinct. The two other mAbs were competed by mAbs that target the C-terminal heptad repeat (CHR) and the fusion peptide proximal region (FPPR) and appear to both target a similar unique conformational epitope. These gp41-specific mAbs mediated killing of infected cells that express high levels of Env due to either pre-treatment with interferon or deletion of vpu to increase levels of BST-2/Tetherin. They also mediate killing of target cells coated with various forms of the gp41 protein, including full-length gp41, gp41 ectodomain or a mimetic of the gp41 stump. Unlike many ADCC mAbs that target HIV gp120, these gp41-mAbs are not dependent on Env structural changes associated with membrane-bound CD4 interaction. Overall, the characterization of these four new mAbs that target gp41 and mediate ADCC provides evidence for diverse gp41 B cell lineages with overlapping but distinct epitopes within an individual. Such antibodies that can target various forms of envelope protein could represent a common response to a relatively conserved HIV epitope for a vaccine.}, }
@article {pmid30779729, year = {2019}, author = {Marceau West, R and Lu, W and Rotroff, DM and Kuenemann, MA and Chang, SM and Wu, MC and Wagner, MJ and Buse, JB and Motsinger-Reif, AA and Fourches, D and Tzeng, JY}, title = {Identifying individual risk rare variants using protein structure guided local tests (POINT).}, journal = {PLoS computational biology}, volume = {15}, number = {2}, pages = {e1006722}, doi = {10.1371/journal.pcbi.1006722}, pmid = {30779729}, issn = {1553-7358}, support = {T32 GM081057/GM/NIGMS NIH HHS/United States ; P01 CA142538/CA/NCI NIH HHS/United States ; R01 HL110380/HL/NHLBI NIH HHS/United States ; }, mesh = {Angiopoietin-like 4 Protein/genetics ; Cholesterol Ester Transfer Proteins/genetics ; Computational Biology/*methods ; Computer Simulation ; Genetic Association Studies/*methods ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Humans ; Models, Genetic ; Proprotein Convertase 9/genetics ; Protein Structure, Tertiary ; Risk Factors ; Sequence Analysis, DNA/*methods ; }, abstract = {Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9, ANGPTL4 and CETP in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.}, }
@article {pmid30778402, year = {2018}, author = {Prentice, RL and Huang, Y}, title = {Nutritional Epidemiology Methods and Related Statistical Challenges and Opportunities.}, journal = {Statistical theory and related fields}, volume = {2}, number = {1}, pages = {2-10}, doi = {10.1080/24754269.2018.1466098}, pmid = {30778402}, issn = {2475-4277}, support = {R01 CA119171/CA/NCI NIH HHS/United States ; R01 CA210921/CA/NCI NIH HHS/United States ; R01 GM106177/GM/NIGMS NIH HHS/United States ; }, abstract = {The public health importance of nutritional epidemiology research is discussed, along with methodologic challenges to obtaining reliable information on dietary approaches to chronic disease prevention. Measurement issues in assessing dietary intake need to be addressed to obtain reliable disease association information. Selfreported dietary data typically incorporate major random and systematic biases. In-take biomarkers offer potential for more reliable analyses, but biomarkers have been established only for a few dietary variables, and these may be too expensive to apply to all participants in large epidemiologic cohorts. A possible way forward involves additional nutritional biomarker development using high-dimensional metabolomic profiling, using blood and urine specimens, in conjunction with further development of statistical approaches for accommodating measurement error with failure time response data. Statisticians have the opportunity to contribute greatly to worldwide public health through the development of statistical methods to address these nutritional epidemiology research challenges, as is elaborated in this contribution.}, }
@article {pmid30778226, year = {2019}, author = {Justice, AE and Karaderi, T and Highland, HM and Young, KL and Graff, M and Lu, Y and Turcot, V and Auer, PL and Fine, RS and Guo, X and Schurmann, C and Lempradl, A and Marouli, E and Mahajan, A and Winkler, TW and Locke, AE and Medina-Gomez, C and Esko, T and Vedantam, S and Giri, A and Lo, KS and Alfred, T and Mudgal, P and Ng, MCY and Heard-Costa, NL and Feitosa, MF and Manning, AK and Willems, SM and Sivapalaratnam, S and Abecasis, G and Alam, DS and Allison, M and Amouyel, P and Arzumanyan, Z and Balkau, B and Bastarache, L and Bergmann, S and Bielak, LF and Blüher, M and Boehnke, M and Boeing, H and Boerwinkle, E and Böger, CA and Bork-Jensen, J and Bottinger, EP and Bowden, DW and Brandslund, I and Broer, L and Burt, AA and Butterworth, AS and Caulfield, MJ and Cesana, G and Chambers, JC and Chasman, DI and Chen, YI and Chowdhury, R and Christensen, C and Chu, AY and Collins, FS and Cook, JP and Cox, AJ and Crosslin, DS and Danesh, J and de Bakker, PIW and Denus, S and Mutsert, R and Dedoussis, G and Demerath, EW and Dennis, JG and Denny, JC and Angelantonio, ED and Dörr, M and Drenos, F and Dubé, MP and Dunning, AM and Easton, DF and Elliott, P and Evangelou, E and Farmaki, AE and Feng, S and Ferrannini, E and Ferrieres, J and Florez, JC and Fornage, M and Fox, CS and Franks, PW and Friedrich, N and Gan, W and Gandin, I and Gasparini, P and Giedraitis, V and Girotto, G and Gorski, M and Grallert, H and Grarup, N and Grove, ML and Gustafsson, S and Haessler, J and Hansen, T and Hattersley, AT and Hayward, C and Heid, IM and Holmen, OL and Hovingh, GK and Howson, JMM and Hu, Y and Hung, YJ and Hveem, K and Ikram, MA and Ingelsson, E and Jackson, AU and Jarvik, GP and Jia, Y and Jørgensen, T and Jousilahti, P and Justesen, JM and Kahali, B and Karaleftheri, M and Kardia, SLR and Karpe, F and Kee, F and Kitajima, H and Komulainen, P and Kooner, JS and Kovacs, P and Krämer, BK and Kuulasmaa, K and Kuusisto, J and Laakso, M and Lakka, TA and Lamparter, D and Lange, LA and Langenberg, C and Larson, EB and Lee, NR and Lee, WJ and Lehtimäki, T and Lewis, CE and Li, H and Li, J and Li-Gao, R and Lin, LA and Lin, X and Lind, L and Lindström, J and Linneberg, A and Liu, CT and Liu, DJ and Luan, J and Lyytikäinen, LP and MacGregor, S and Mägi, R and Männistö, S and Marenne, G and Marten, J and Masca, NGD and McCarthy, MI and Meidtner, K and Mihailov, E and Moilanen, L and Moitry, M and Mook-Kanamori, DO and Morgan, A and Morris, AP and Müller-Nurasyid, M and Munroe, PB and Narisu, N and Nelson, CP and Neville, M and Ntalla, I and O'Connell, JR and Owen, KR and Pedersen, O and Peloso, GM and Pennell, CE and Perola, M and Perry, JA and Perry, JRB and Pers, TH and Ewing, A and Polasek, O and Raitakari, OT and Rasheed, A and Raulerson, CK and Rauramaa, R and Reilly, DF and Reiner, AP and Ridker, PM and Rivas, MA and Robertson, NR and Robino, A and Rudan, I and Ruth, KS and Saleheen, D and Salomaa, V and Samani, NJ and Schreiner, PJ and Schulze, MB and Scott, RA and Segura-Lepe, M and Sim, X and Slater, AJ and Small, KS and Smith, BH and Smith, JA and Southam, L and Spector, TD and Speliotes, EK and Stefansson, K and Steinthorsdottir, V and Stirrups, KE and Strauch, K and Stringham, HM and Stumvoll, M and Sun, L and Surendran, P and Swart, KMA and Tardif, JC and Taylor, KD and Teumer, A and Thompson, DJ and Thorleifsson, G and Thorsteinsdottir, U and Thuesen, BH and Tönjes, A and Torres, M and Tsafantakis, E and Tuomilehto, J and Uitterlinden, AG and Uusitupa, M and van Duijn, CM and Vanhala, M and Varma, R and Vermeulen, SH and Vestergaard, H and Vitart, V and Vogt, TF and Vuckovic, D and Wagenknecht, LE and Walker, M and Wallentin, L and Wang, F and Wang, CA and Wang, S and Wareham, NJ and Warren, HR and Waterworth, DM and Wessel, J and White, HD and Willer, CJ and Wilson, JG and Wood, AR and Wu, Y and Yaghootkar, H and Yao, J and Yerges-Armstrong, LM and Young, R and Zeggini, E and Zhan, X and Zhang, W and Zhao, JH and Zhao, W and Zheng, H and Zhou, W and Zillikens, MC and ,  and ,  and ,  and ,  and ,  and ,  and ,  and ,  and ,  and ,  and Rivadeneira, F and Borecki, IB and Pospisilik, JA and Deloukas, P and Frayling, TM and Lettre, G and Mohlke, KL and Rotter, JI and Kutalik, Z and Hirschhorn, JN and Cupples, LA and Loos, RJF and North, KE and Lindgren, CM}, title = {Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.}, journal = {Nature genetics}, volume = {51}, number = {3}, pages = {452-469}, doi = {10.1038/s41588-018-0334-2}, pmid = {30778226}, issn = {1546-1718}, support = {RG/14/5/30893//British Heart Foundation/United Kingdom ; T32 HL007055/HL/NHLBI NIH HHS/United States ; }, abstract = {Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.}, }
@article {pmid30777648, year = {2019}, author = {Triplette, M and Thayer, JH and Pipavath, SN and Crothers, K}, title = {Poor Uptake of Lung Cancer Screening: Opportunities for Improvement.}, journal = {Journal of the American College of Radiology : JACR}, volume = {16}, number = {4 Pt A}, pages = {446-450}, doi = {10.1016/j.jacr.2018.12.018}, pmid = {30777648}, issn = {1558-349X}, abstract = {Lung cancer screening with low-dose chest CT has been demonstrated to reduce lung cancer mortality among a subset of high-risk current and former smokers. Despite randomized trial evidence and widespread guideline recommendations, uptake of lung cancer screening among currently eligible individuals remains poor. Recent studies estimate that less than 5% of all eligible individuals have undergone screening. Moreover, inappropriate screening of ineligible individuals seems to be common, and among those who have been screened, follow-up may also be poor. In this review, the authors examine recent studies demonstrating the current state of suboptimal implementation of lung cancer screening. The authors also introduce both patient- and provider-facing evidence-based interventions that may improve implementation of screening. These include tailored navigation interventions to overcome patient barriers throughout the screening care continuum and interventions to improve the identification of eligible individuals for providers. Further evidence on best practices around the implementation of lung cancer screening is essential to ensure that recent evidence can be translated into practice to improve the early detection of lung cancer for high-risk individuals.}, }
@article {pmid30777131, year = {2019}, author = {Buchbinder, EI and Dutcher, JP and Daniels, GA and Curti, BD and Patel, SP and Holtan, SG and Miletello, GP and Fishman, MN and Gonzalez, R and Clark, JI and Richart, JM and Lao, CD and Tykodi, SS and Silk, AW and McDermott, DF}, title = {Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition.}, journal = {Journal for immunotherapy of cancer}, volume = {7}, number = {1}, pages = {49}, doi = {10.1186/s40425-019-0522-3}, pmid = {30777131}, issn = {2051-1426}, support = {Not applicable//Prometheus/ ; }, abstract = {BACKGROUND: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored.<br><br>METHODS: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIMSM database. Patient characteristics, toxicity and efficacy were analyzed.<br><br>RESULTS: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy.<br><br>CONCLUSION: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.}, }
@article {pmid30776582, year = {2019}, author = {Panagopoulou, P and Skalkidou, A and Marcotte, E and Erdmann, F and Ma, X and Heck, JE and Auvinen, A and Mueller, BA and Spector, LG and Roman, E and Metayer, C and Magnani, C and Pombo-de-Oliveira, MS and Scheurer, ME and Mora, AM and Dockerty, JD and Hansen, J and Kang, AY and Wang, R and Doody, DR and Kane, E and Schüz, J and Christodoulakis, C and Ntzani, E and Petridou, ET and ,  and , }, title = {Parental age and the risk of childhood acute myeloid leukemia: results from the Childhood Leukemia International Consortium.}, journal = {Cancer epidemiology}, volume = {59}, number = {}, pages = {158-165}, doi = {10.1016/j.canep.2019.01.022}, pmid = {30776582}, issn = {1877-783X}, support = {P01 ES018172/ES/NIEHS NIH HHS/United States ; R01 CA155461/CA/NCI NIH HHS/United States ; R01 ES009137/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent.<br><br>AIM: To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies.<br><br>MATERIAL/METHODS: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants <1 year-old vs. children 1-14 years-old) and by study design, using five-year parental age increments and controlling for sex, ethnicity, birthweight, prematurity, multiple gestation, birth order, maternal smoking and education, age at diagnosis (cases aged 1-14 years), and recruitment time period.<br><br>RESULTS: Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from RCC, but not from the QCC, studies showed a higher AML risk for infants of mothers ≥40-year-old (OR = 6.87; 95% CI: 2.12-22.25). There were no associations observed between any other maternal or paternal age group and AML risk for children older than one year.<br><br>CONCLUSIONS: An increased risk of infant AML with advanced maternal age was found using data from RCC, but not from QCC studies; no parental age-AML associations were observed for older children.}, }
@article {pmid30774780, year = {2019}, author = {Nishida-Aoki, N and Gujral, TS}, title = {Emerging approaches to study cell-cell interactions in tumor microenvironment.}, journal = {Oncotarget}, volume = {10}, number = {7}, pages = {785-797}, doi = {10.18632/oncotarget.26585}, pmid = {30774780}, issn = {1949-2553}, support = {K22 CA201229/CA/NCI NIH HHS/United States ; }, abstract = {Cell-cell interactions are of crucial importance for tissue formation, homeostasis, regeneration processes, and immune response. Recent studies underlined contribution of cell-cell interaction in tumor microenvironment (TME) for tumor progression and metastasis. Cancer cells modify the host cells to tumor-supportive traits, and the modified host cells contribute to tumor progression by interacting with cancer cells and further modifying other normal cells. However, the complex interaction networks of cancer cells and host cells remained largely unknown. Recent advances in high throughput microscopy and single cells-based molecular analyses have unlocked a new era for studying cell-cell interactions in the complex tissue microenvironment at the resolution of a single cell. Here, we review various model systems and emerging experimental approaches that are used to study cell-cell interactions focusing on the studies of TME. We discuss strengths and weaknesses of each model system and each experimental approach, and how upcoming approaches can solve current fundamental questions of cell-cell interactions in TME.}, }
@article {pmid30773341, year = {2019}, author = {Cato, L and de Tribolet-Hardy, J and Lee, I and Rottenberg, JT and Coleman, I and Melchers, D and Houtman, R and Xiao, T and Li, W and Uo, T and Sun, S and Kuznik, NC and Göppert, B and Ozgun, F and van Royen, ME and Houtsmuller, AB and Vadhi, R and Rao, PK and Li, L and Balk, SP and Den, RB and Trock, BJ and Karnes, RJ and Jenkins, RB and Klein, EA and Davicioni, E and Gruhl, FJ and Long, HW and Liu, XS and Cato, ACB and Lack, NA and Nelson, PS and Plymate, SR and Groner, AC and Brown, M}, title = {ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer.}, journal = {Cancer cell}, volume = {35}, number = {3}, pages = {401-413.e6}, doi = {10.1016/j.ccell.2019.01.008}, pmid = {30773341}, issn = {1878-3686}, support = {T32 DK007529/DK/NIDDK NIH HHS/United States ; }, abstract = {Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.}, }
@article {pmid30773276, year = {2019}, author = {Grinde, KE and Brown, LA and Reiner, AP and Thornton, TA and Browning, SR}, title = {Genome-wide Significance Thresholds for Admixture Mapping Studies.}, journal = {American journal of human genetics}, volume = {104}, number = {3}, pages = {454-465}, doi = {10.1016/j.ajhg.2019.01.008}, pmid = {30773276}, issn = {1537-6605}, support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; N02HL64278/HL/NHLBI NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; }, abstract = {Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10-5 and 4.5 × 10-6 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.}, }
@article {pmid30771496, year = {2019}, author = {Dahlberg, A and Milano, F}, title = {Improved Survival after Cord Blood Transplantation: Single-Center Experience in Pediatric Patients Over a 2-Decade Period.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {25}, number = {4}, pages = {e117-e118}, doi = {10.1016/j.bbmt.2019.02.010}, pmid = {30771496}, issn = {1523-6536}, }
@article {pmid30769174, year = {2019}, author = {Inskip, PD and Veiga, LHS and Brenner, AV and Sigurdson, AJ and Ostroumova, E and Chow, EJ and Stovall, M and Smith, SA and Leisenring, W and Robison, LL and Armstrong, GT and Sklar, CA and Lubin, JH}, title = {Hyperthyroidism Following Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2019.02.009}, pmid = {30769174}, issn = {1879-355X}, abstract = {BACKGROUND: The association of hyperthyroidism with exposure to ionizing radiation is poorly understood. This study addresses the risk of hyperthyroidism in relation to incidental therapeutic radiation dose to the thyroid and pituitary glands in a large cohort of survivors of childhood cancer.<br><br>METHODS: Utilizing the Childhood Cancer Survivor Study, a cohort of five-year survivors of childhood cancer diagnosed at hospitals in the United States and Canada between 1970 and 1986, the occurrence of hyperthyroidism through 2009 was ascertained among 12,183 survivors based on serial questionnaires. Radiation doses to the thyroid and pituitary glands were estimated from radiotherapy records, and chemotherapy exposures were abstracted from medical records. Binary outcome regression was used to estimate prevalence odds ratios (ORs) for hyperthyroidism at five years from diagnosis of childhood cancer and Poisson regression to estimate incidence rate ratios (RRs) after the first five years.<br><br>RESULTS: Survivors reported 179 cases of hyperthyroidism, of which 148 were diagnosed five or more years after their cancer diagnosis. The cumulative proportion of survivors diagnosed with hyperthyroidism by 30 years after the cancer diagnosis was 2.5% (95% CI: 2.0-2.9) among those who received radiotherapy. A linear relation adequately described the thyroid radiation dose-response for prevalence of self-reported hyperthyroidism five years after cancer diagnosis (excess OR/Gy=0.24; 95% CI: 0.06-0.95) and incidence rate thereafter (excess RR/Gy = 0.06; 95% CI: 0.03-0.14) over the dose range of 0-63 Gy. Neither radiation dose to the pituitary gland nor chemotherapy was associated significantly with hyperthyroidism. Radiation-associated risk remained elevated > 25 years after exposure.<br><br>CONCLUSIONS: Risk of hyperthyroidism following radiotherapy during childhood is positively associated with external radiation dose to the thyroid gland, with radiation-related excess risks persisting for > 25 years. Neither radiation dose to the pituitary gland nor chemotherapy exposures were associated with hyperthyroidism among childhood cancer survivors through early adulthood.}, }
@article {pmid30768776, year = {2019}, author = {Wheeler, DP and Fields, SD and Beauchamp, G and Chen, YQ and Emel, LM and Hightow-Weidman, L and Hucks-Ortiz, C and Kuo, I and Lucas, J and Magnus, M and Mayer, KH and Nelson, LE and Hendrix, CW and Piwowar-Manning, E and Shoptaw, S and Watkins, P and Watson, CC and Wilton, L}, title = {Pre-exposure prophylaxis initiation and adherence among Black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study.}, journal = {Journal of the International AIDS Society}, volume = {22}, number = {2}, pages = {e25223}, doi = {10.1002/jia2.25223}, pmid = {30768776}, issn = {1758-2652}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; U01 AI069423/AI/NIAID NIH HHS/United States ; UL1 TR001111/TR/NCATS NIH HHS/United States ; R21 AI069053/AI/NIAID NIH HHS/United States ; //Gilead Sciences, Inc/ ; //US Department of Health and Human Services/ ; //National Institutes of Health/ ; UM1AI068619//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; //National Institute of Mental Health/ ; P30 AI117970/AI/NIAID NIH HHS/United States ; UM1AI068617//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1AI068613//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; UM1 AI068613/AI/NIAID NIH HHS/United States ; //National Institute on Drug Abuse/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: Randomized clinical trials have demonstrated the efficacy of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV acquisition among men who have sex with men (MSM). However, limited research has examined initiation and adherence to PrEP among Black MSM (BMSM) in the United States (US) who are disproportionately represented among newly HIV infected and late to care individuals. This research reports on the HIV Prevention Trials Network 073 (HPTN 073) study aimed to examine PrEP initiation, utilization and adherence among Black MSM utilizing the theoretically principled, culturally informed and client-centered care coordination (C4) model.<br><br>METHODS: The HPTN 073 study enrolled and followed 226 HIV-uninfected Black MSM in three US cities (Los Angeles, CA; Washington DC; and Chapel Hill, NC) from February 2013 through September 2015. Study participants were offered once daily oral emtricitabine/tenofovir (FTC/TDF) PrEP combined with C4 and followed up for 52 weeks. Participants received HIV testing, risk reduction education and clinical monitoring.<br><br>RESULTS: Of the 226 men enrolled, 178 participants initiated PrEP (79%), and of these 64% demonstrated PrEP utilization at week 26 (mid-point of the study) based on pharmacokinetic testing. Condomless anal sex with an HIV-infected or unknown status casual male partner was statistically significantly associated with a greater likelihood of PrEP initiation (adjusted odds ratio (OR) 4.4, 95% confidence interval (CI) 1.7, 11.7). Greater age (≥25 vs. <25, OR 2.95, 95% CI 1.37 -6.37), perception of having enough money (OR 3.6, 95% CI 1.7 to 7.7) and knowledge of male partner taking PrEP before sex (OR 2.22, 95% CI 1.03 to 4.79) were statistically significantly associated with increased likelihood of PrEP adherence at week 26. Annualized HIV incidence was 2.9 (95% CI 1.2 to 7.9) among those who initiated PrEP, compared to 7.7 (95% CI 2.5 to 24.1) among those who did not initiate PrEP (p = 0.18).<br><br>CONCLUSIONS: Results suggest a high level of PrEP initiation among at-risk Black MSM, a group historically characterized as hard to reach. The data support the importance of addressing contextual factors that affect PrEP initiation and adherence, and of additional research on the ultimate benefit of PrEP in HIV prevention among Black MSM.}, }
@article {pmid30768157, year = {2019}, author = {Chow, EJ and Leger, KJ and Bhatt, NS and Mulrooney, DA and Ross, CJ and Aggarwal, S and Bansal, N and Ehrhardt, MJ and Armenian, SH and Scott, JM and Hong, B}, title = {Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment.}, journal = {Cardiovascular research}, volume = {115}, number = {5}, pages = {922-934}, doi = {10.1093/cvr/cvz031}, pmid = {30768157}, issn = {1755-3245}, abstract = {With 5-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidaemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to paediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g. echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in paediatric cancer patients and childhood cancer survivors.}, }
@article {pmid30764690, year = {2019}, author = {Zhang, X and Tu, W and Manson, JE and Tinker, L and Liu, S and Cauley, JA and Qi, L and Mouton, C and Martin, LW and Hou, L and Song, Y}, title = {Racial/Ethnic Differences in 25-Hydroxy Vitamin D and Parathyroid Hormone Levels and Cardiovascular Disease Risk Among Postmenopausal Women.}, journal = {Journal of the American Heart Association}, volume = {8}, number = {4}, pages = {e011021}, doi = {10.1161/JAHA.118.011021}, pmid = {30764690}, issn = {2047-9980}, abstract = {Background Recent evidence suggests that racial/ethnic differences in circulating levels of free or bioavailable 25-hydroxy vitamin D (25[ OH ]D) rather than total 25(OH)D may explain apparent racial disparities in cardiovascular disease (CVD). We prospectively examined black-white differences in the associations of total, free, and bioavailable 25(OH)D, vitamin D-binding protein, and parathyroid hormone levels at baseline with incident CVD (including nonfatal myocardial infarction, nonfatal stroke, and CVD death) in postmenopausal women. Methods and Results We conducted a case-cohort study among 79 705 postmenopausal women, aged 50 to 79 years, who were free of CVD at baseline in the WHI-OS (Women's Health Initiative Observational Study). A subcohort of 1300 black and 1500 white participants were randomly chosen as controls; a total of 550 black and 1500 white women who developed incident CVD during a mean follow-up of 11 years were chosen as cases. We directly measured total 25(OH)D, vitamin D-binding protein, albumin, parathyroid hormone, and calculated free and bioavailable 25(OH)D. Weighted Cox proportional hazards models were used to examine their associations with CVD risk. Although vitamin D-binding protein and total, free, and bioavailable 25(OH)D were not significantly associated with CVD risk in black or white women, a significant positive association between parathyroid hormone and CVD risk persisted in white women (hazard ratio comparing the highest quartile with the lowest, 1.37; 95% CI , 1.06-1.77) but not in black women (hazard ratio comparing the highest quartile with the lowest, 1.12; 95% CI, 0.79-1.58), independent of total, free, and bioavailable 25(OH)D or vitamin D-binding protein. Conclusions Circulating levels of vitamin D biomarkers are not related to CVD risk in either white or black women. Higher parathyroid hormone levels may be an independent risk factor for CVD in white women.}, }
@article {pmid30763406, year = {2019}, author = {Karlsson, A and Jauhiainen, A and Gulati, R and Eklund, M and Grönberg, H and Etzioni, R and Clements, M}, title = {A natural history model for planning prostate cancer testing: Calibration and validation using Swedish registry data.}, journal = {PloS one}, volume = {14}, number = {2}, pages = {e0211918}, doi = {10.1371/journal.pone.0211918}, pmid = {30763406}, issn = {1932-6203}, abstract = {Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history. An existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden. We re-implemented and re-calibrated the US model to Sweden. We extended the model to more finely describe the disease states, their time to biopsy-detectable cancer and prostate cancer survival. We first calibrated the model to the incidence rate ratio observed in the European Randomised Study of Screening for Prostate Cancer (ERSPC) together with age-specific cancer staging observed in the Stockholm PSA (prostate-specific antigen) and Biopsy Register; we then calibrated age-specific survival by disease states under contemporary testing and treatment using the Swedish National Prostate Cancer Register. After calibration, we were able to closely match observed prostate cancer incidence trends in Sweden. Assuming that patients detected at an earlier stage by screening receive a commensurate survival improvement, we find that the calibrated model replicates the observed mortality reduction in a simulation of ERSPC. Using the resulting model, we predicted incidence and mortality following the introduction of regular testing. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55-69 years was predicted to reduce prostate cancer incidence by 14% and increase prostate cancer mortality by 2%. The model is open source and suitable for planning for effective prostate cancer screening into the future.}, }
@article {pmid30763144, year = {2019}, author = {Low, DH and Phipps, W and Orem, J and Casper, C and Bender Ignacio, RA}, title = {Engagement in HIV Care and Access to Cancer Treatment Among Patients With HIV-Associated Malignancies in Uganda.}, journal = {Journal of global oncology}, volume = {5}, number = {}, pages = {1-8}, doi = {10.1200/JGO.18.00187}, pmid = {30763144}, issn = {2378-9506}, support = {UL1 TR002319/TR/NCATS NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; K23 AI129659/AI/NIAID NIH HHS/United States ; R25 TW009345/TW/FIC NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Health system constraints limit access to HIV and cancer treatment programs in sub-Saharan Africa. Limited access and continuity of care affect morbidity and mortality of patients with cancer and HIV. We assessed barriers in the care cascade of comorbid HIV and cancer.<br><br>PATIENTS AND METHODS: Structured interviews were conducted with 100 adult patients with HIV infection and new diagnoses of cancer at the Uganda Cancer Institute. Participants completed follow-up questionnaires after 1 year to assess ongoing engagement with and barriers to care.<br><br>RESULTS: The median time from new-onset cancer symptoms to initiation of cancer care at the Uganda Cancer Institute was 209 days (interquartile range, 113 to 384 days). Persons previously established in HIV care waited less overall to initiate cancer care (P = .04). Patients established in HIV care experienced shorter times from initial symptoms to seeking of cancer care (P = .02) and from seeking of care to cancer diagnosis (P = .048). Barriers to receiving care for HIV and cancer included difficulty traveling to multiple clinics/hospitals (46%), conflicts between HIV and cancer appointments (23%), prohibitive costs (21%), and difficulty adhering to medications (15%). Reporting of any barriers to care was associated with premature discontinuation of cancer treatment (P = .003).<br><br>CONCLUSION: Patients with HIV-associated malignancies reported multiple barriers to receiving care for both conditions, although knowledge of HIV status and engagement in HIV care before presentation with malignancy reduced subsequent time to the start of cancer treatment. This study provides evidence to support creation and evaluation of integrated HIV and cancer care models.}, }
@article {pmid30762215, year = {2019}, author = {Adamson, B and Lipira, L and Katz, AB}, title = {The Impact of ACA and Medicaid Expansion on Progress Toward UNAIDS 90-90-90 Goals.}, journal = {Current HIV/AIDS reports}, volume = {16}, number = {1}, pages = {105-112}, doi = {10.1007/s11904-019-00429-6}, pmid = {30762215}, issn = {1548-3576}, abstract = {PURPOSE OF REVIEW: Passage of the Affordable Care Act (ACA) in 2010 and subsequent Medicaid expansion has influenced access to HIV treatment and care in the USA. This review aims to evaluate whether the implementation of these policies has impacted progress toward UNAIDS 90-90-90 goals.<br><br>RECENT FINDINGS: Preliminary evidence has emerged suggesting that the ACA and Medicaid expansion has increased the likelihood of HIV testing and diagnosis, reduced the number of people unaware of HIV infection, and increased the number of people on antiretroviral therapy (ART) who are virally suppressed. While the ACA is associated with some progress toward 90-90-90 goals, more years of data after policy implementation are needed for robust analysis. Methods including difference-in-differences, instrumental variables, and propensity scores are recommended to minimize bias from unmeasured confounders and make causal inference about non-random Medicaid expansion among states.}, }
@article {pmid30761386, year = {2018}, author = {Carlo, MI and Giri, VN and Paller, CJ and Abida, W and Alumkal, JJ and Beer, TM and Beltran, H and George, DJ and Heath, EI and Higano, CS and McKay, RR and Morgans, AK and Patnaik, A and Ryan, CJ and Schaeffer, EM and Stadler, WM and Taplin, ME and Kauff, ND and Vinson, J and Antonarakis, ES and Cheng, HH}, title = {Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium.}, journal = {JCO precision oncology}, volume = {2018}, number = {}, pages = {}, doi = {10.1200/PO.18.00060}, pmid = {30761386}, issn = {2473-4284}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; }, abstract = {Purpose: Advances in germline genetics, and related therapeutic opportunities, present new opportunities and challenges in prostate cancer. The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group was established to address genetic testing for men with prostate cancer, especially those with advanced disease undergoing testing for treatment-related objectives and clinical trials.<br><br>Methods: The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group met monthly to discuss the current state of genetic testing of men with prostate cancer for therapeutic or clinical trial purposes. We assessed current institutional practices, developed a framework to address unique challenges in this population, and identified areas of future research.<br><br>Results: Genetic testing practices in men with prostate cancer vary across institutions; however, there were several areas of agreement. The group recognized the clinical benefits of expanding germline genetic testing, beyond cancer risk assessment, for the goal of treatment selection or clinical trial eligibility determination. Genetic testing for treatment selection should ensure patients receive appropriate pretest education and consent and occur under auspices of a research study whenever feasible. Providers offering genetic testing should be able to interpret results and recommend post-test genetic counseling for patients. When performing tumor (somatic) genomic profiling, providers should discuss the potential for uncovering germline mutations and recommend appropriate genetic counseling. In addition, family members may benefit from cascade testing and early cancer screening and prevention strategies.<br><br>Conclusion: As germline genetic testing is incorporated into practice, further development is needed in establishing prompt testing for time-sensitive treatment decisions, integrating cascade testing for family, ensuring equitable access to testing, and elucidating the role of less-characterized germline DNA damage repair genes, individual gene-level biologic consequences, and treatment response prediction in advanced disease.}, }
@article {pmid30760869, year = {2019}, author = {McNeer, NA and Philip, J and Geiger, H and Ries, RE and Lavallée, VP and Walsh, M and Shah, M and Arora, K and Emde, AK and Robine, N and Alonzo, TA and Kolb, EA and Gamis, AS and Smith, M and Gerhard, DS and Guidry-Auvil, J and Meshinchi, S and Kentsis, A}, title = {Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-019-0402-3}, pmid = {30760869}, issn = {1476-5551}, support = {U10 CA098413//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24 CA114766//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA204396//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA204396/CA/NCI NIH HHS/United States ; U10 CA180886//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24 CA114766/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U10 CA180899//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA98543//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; P30 CA008748//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.}, }
@article {pmid30759018, year = {2018}, author = {Houghton, AM}, title = {Common Mechanisms Linking Chronic Obstructive Pulmonary Disease and Lung Cancer.}, journal = {Annals of the American Thoracic Society}, volume = {15}, number = {Supplement_4}, pages = {S273-S277}, doi = {10.1513/AnnalsATS.201808-537MG}, pmid = {30759018}, issn = {2325-6621}, abstract = {Chronic obstructive pulmonary disease (COPD) and lung cancer are linked diseases, with both the incidence of and risk of death from non-small cell lung cancer being increased by the presence of COPD. Despite numerous well-performed epidemiological studies having described this link over the past 30 years, the operative mechanisms remain elusive. One of the major obstacles to advancement in the field has been the lack of patient cohorts that have been phenotyped for both COPD and lung cancer. This review discusses several studies performed over the past few years highlighting the impact of COPD on the outcomes of patients with non-small cell lung cancer with respect to lung cancer screening, immune-based therapies, and lung cancer chemoprevention.}, }
@article {pmid30756321, year = {2019}, author = {Rosen, DM and Kundel, V and Rueschman, M and Kaplan, R and Guo, N and Wilson, JG and Min, YI and Redline, S and Shah, N}, title = {Self-reported snoring and incident cardiovascular disease events: results from the Jackson Heart Study.}, journal = {Sleep &amp; breathing = Schlaf &amp; Atmung}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11325-018-01776-1}, pmid = {30756321}, issn = {1522-1709}, support = {L30 HL110272/HL/NHLBI NIH HHS/United States ; R01 HL143221/HL/NHLBI NIH HHS/United States ; 5K23HL125923-03//National Heart, Lung, and Blood Institute/ ; }, abstract = {PURPOSE: Evidence suggests that snoring is associated with increased risk for cardiovascular disease (CVD) events such as myocardial infarction and stroke. Limited data exists pertaining to this association among African Americans. We therefore examined the association between self-reported habitual snoring and incident CVD in the Jackson Heart Study (JHS), a population-based cohort study of African Americans.<br><br>METHODS: Self-reported data on snoring and risk factors for CVD were collected at baseline (2000-2004). Participants were followed prospectively for the development of incident CVD. Habitual snoring was defined as present if the participants reported it as &quot;often&quot; or &quot;almost always&quot; or absent if reported as &quot;sometimes,&quot; &quot;never,&quot; or &quot;seldom.&quot; A CVD event included stroke, myocardial infarction, coronary revascularization procedure, or fatal CHD event. Cox proportional hazards models assessed the independent association between self-reported habitual snoring and incident CVD event adjusting for multiple covariates, including age, sex, hypertension, body mass index, diabetes, hypercholesterolemia, and smoking status.<br><br>RESULTS: The snorer group consisted of 787 participants (mean age 52.1 years) and the nonsnorer group consisted of 3708 participants (mean age 54.9 years). Frequency of incident CVD events in the snorer group was not significantly different from the nonsnorer group. The fully adjusted hazard ratio for a CVD event in the snorer group was 1.01 (95% confidence interval [0.69, 1.47], p value of 0.96).<br><br>CONCLUSION: In conclusion, self-reported habitual snoring was not associated with incident CVD among this large African American cohort. Future studies providing objective data on snoring and sleep apnea may provide more information on the snoring-CVD association among African Americans.<br><br>TRIAL REGISTRATION: Identification Number: NCT00005485.}, }
@article {pmid30755520, year = {2019}, author = {Hughes, KJ and Rodriguez, A and Flatt, KM and Ray, S and Schuler, A and Rodemoyer, B and Veerappan, V and Cuciarone, K and Kullman, A and Lim, C and Gutta, N and Vemuri, S and Andriulis, V and Niswonger, D and Barickman, L and Stein, W and Singhvi, A and Schroeder, NE and Vidal-Gadea, AG}, title = {Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, number = {9}, pages = {3508-3517}, doi = {10.1073/pnas.1811379116}, pmid = {30755520}, issn = {1091-6490}, support = {T32 NS099578/NS/NINDS NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R15 AR068583/AR/NIAMS NIH HHS/United States ; S10 OD021490/OD/NIH HHS/United States ; R01 GM111566/GM/NIGMS NIH HHS/United States ; }, abstract = {Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of the protein dystrophin. In humans, DMD has early onset, causes developmental delays, muscle necrosis, loss of ambulation, and death. Current animal models have been challenged by their inability to model the early onset and severity of the disease. It remains unresolved whether increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscle's disrupted contractile machinery. This knowledge has important implications for patients, as potential physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones. Recently we showed how burrowing dystrophic (dys-1) C. elegans recapitulate many salient phenotypes of DMD, including loss of mobility and muscle necrosis. Here, we report that dys-1 worms display early pathogenesis, including dysregulated sarcoplasmic calcium and increased lethality. Sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes (e.g., mitochondrial, and contractile machinery damage) and can be mitigated by reducing calmodulin expression. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring high intensity or high frequency of muscle exertion during locomotion. We find that several muscular parameters (e.g., size) improve with increased activity. However, longevity in dystrophic animals was negatively associated with muscular exertion, regardless of effort duration. The high degree of phenotypic conservation between dystrophic worms and humans provides a unique opportunity to gain insight into the pathology of the disease as well as the initial assessment of potential treatment strategies.}, }
@article {pmid30753642, year = {2019}, author = {Marrazzo, JM and Rabe, L and Kelly, C and Richardson, B and Deal, C and Schwartz, JL and Chirenje, ZM and Piper, J and Morrow, RA and Hendrix, CW and Marzinke, MA and Hillier, SL and , }, title = {Tenofovir gel for prevention of herpes simplex virus type-2 acquisition: findings from the VOICE Trial.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz045}, pmid = {30753642}, issn = {1537-6613}, support = {UM1 AI068615/AI/NIAID NIH HHS/United States ; }, abstract = {Background: Genital infection with herpes simplex virus type-2 (HSV-2) is common, and increases risk of HIV transmission and acquisition. Pericoital use of tenofovir (TFV) gel provided protection from HSV-2 acquisition in the CAPRISA 004 Study.<br><br>Methods: We measured estimate of effect of vaginal TFV 1% gel in preventing HSV-2 acquisition among women in VOICE, randomized, double-blind, placebo-controlled trial assessing daily use of oral and vaginal TFV for HIV-1 pre-exposure prophylaxis. TFV measured in plasma (first quarterly visit) was used as a measure of gel use.<br><br>Results: Of 566 participants at risk for HSV-2, 532 (94%) had first quarter plasma TFV and end-of-study HSV-2 serology available. Over follow-up of 501 PY, 92 incident HSV-2 cases occurred: 77 in women with no plasma TFV detected and 15 with plasma TFV (incidence 20.6 (16.2-25.7) vs. 11.9 (6.6-19.6), respectively). Plasma TFV detection was associated with trend towards reduced risk of HSV-2 seroconversion (unadjusted HR 0.59 (0.34-1.02; P=0.060); HR adjusted for site, age, ≥ 2 sex partners, hormonal contraception, anal sex, and HIV status 0.60 (0.33-1.08; P=0.086)).<br><br>Conclusions: Detection of plasma TFV among TFV gel users was associated with trend towards reduced risk of HSV-2 acquisition after controlling for sexual behavior and HIV-1 acquisition.}, }
@article {pmid30753483, year = {2019}, author = {Paulson, KG and Lahman, M and Chapuis, AG and Brownell, I}, title = {Immunotherapy for skin cancer.}, journal = {International immunology}, volume = {}, number = {}, pages = {}, doi = {10.1093/intimm/dxz012}, pmid = {30753483}, issn = {1460-2377}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {Among all tumor types, skin cancers are profoundly sensitive to immunotherapy. Indeed, the recently reported response rates for anti-PD-1 (anti-programmed-death 1) therapy for cutaneous malignant melanomas (MM), Merkel cell carcinomas, basal cell carcinomas, cutaneous squamous cell carcinomas and Kaposi sarcomas are all above 40%. This unique immunogenicity renders skin cancers as a paradigm for tumor-immune interactions and is driven by high mutational burdens, overexpressed tumor antigens and/or viral antigens. However, despite the clear demonstration of immunologic cure of skin cancer in some patients, most tumors develop either early (primary) or late (adaptive) resistance to immunotherapy. Resistance mechanisms are complex, and include contributions of tumor cell-intrinsic, T cell and microenvironment factors that have been recently further elucidated with the advent of single-cell technologies. This review will focus on the exciting progress with immunotherapy for skin cancers to date, and also our current understanding of the mechanisms of resistance to immunotherapy.}, }
@article {pmid30753368, year = {2019}, author = {Schwartz, LM and Zaman, K and Yunus, M and Basunia, AH and Faruque, ASG and Ahmed, T and Rahman, M and Sugimoto, JD and Halloran, ME and Rowhani-Rahbar, A and Neuzil, KM and Victor, JC}, title = {Impact of rotavirus vaccine introduction in children less than 2 years of age presenting for medical care with diarrhea in rural Matlab, Bangladesh.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciz133}, pmid = {30753368}, issn = {1537-6591}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; }, abstract = {Background: Following the conclusion of a Rotarix vaccine (HRV) cluster-randomized controlled trial (CRT) in Matlab, Bangladesh, HRV was included in Matlab's routine immunization program. We describe the population-level impact of programmatic rotavirus vaccination in Bangladesh in children <2 years of age.<br><br>Methods: Interrupted time series were used to estimate the impact of HRVintroduction. Diarrheal surveillance collected between 2000 and 2014 within the two service delivery areas (icddr,b service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System administered by icddr,b was used. Age-group specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea of any severity presenting to the hospital. Two models were used to assess impact within each service area: Model 1 used the pre-vaccine time period in all villages (HRV- and control-only) and Model 2 combined the pre-vaccine time period and the CRT time period using outcomes from control-only villages.<br><br>Results: Both models demonstrated a downward trend in RV+ diarrheal incidence in the ISA villages during 3.5 years of routine HRV use, though only Model 2 was statistically significant. Significant impact of HRV on RV+ diarrhea incidence in GSA villages was not observed in either model. Differences in population-level impact between the two delivery areas may be due to varied rotavirus vaccine coverage and presentation rate to the hospital.<br><br>Conclusions: This study provides initial evidence of the population-level impact of rotavirus vaccines in children <2 years of age in Matlab, Bangladesh. Further studies of rotavirus vaccine impact after nationwide introduction in Bangladesh are needed.}, }
@article {pmid30753327, year = {2019}, author = {Hishida, A and Ugai, T and Fujii, R and Nakatochi, M and Wu, MC and Ito, H and Oze, I and Masahiro, T and Yasumasa, N and Nishiyama, T and Nakagawa-Senda, H and Suzuki, S and Koyama, T and Matsui, D and Watanabe, Y and Kawaguchi, T and Matsuda, F and Momozawa, Y and Kubo, M and Naito, M and Matsuo, K and Wakai, K}, title = {GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy.}, journal = {Carcinogenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/carcin/bgz016}, pmid = {30753327}, issn = {1460-2180}, abstract = {Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the J-MICC Study were used in the discovery phase (Stage I); two datasets from the HERPACC2 Study were used in the replication phases (Stages II and III), and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel (FDR = 0.011, 0.230, and 7.2×10-7, respectively). The single variant-based GWAS revealed that nine PSCA SNPs fulfilled the genome-wide significance level (P < 5×10-8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31×10-27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.}, }
@article {pmid30740005, year = {2019}, author = {Qiu, Z and Wan, ATK and Zhou, Y and Gilbert, PB}, title = {Smoothed Rank Regression for the Accelerated Failure Time Competing Risks Model with Missing Cause of Failure.}, journal = {Statistica Sinica}, volume = {29}, number = {1}, pages = {23-46}, doi = {10.5705/ss.202016.0231}, pmid = {30740005}, issn = {1017-0405}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {This paper examines the accelerated failure time competing risks model with missing cause of failure using the monotone class rank-based estimating equations approach. We handle the non-smoothness of the rank-based estimating equations using a kernel smoothed estimation method, and estimate the unknown selection probability and the conditional expectation by non-parametric techniques. Under this setup, we propose three methods for estimating the unknown regression parameters based on 1) inverse probability weighting, 2) estimating equations imputation and 3) augmented inverse probability weighting. We also obtain the associated asymptotic theories of the proposed estimators and investigate the estimators' small sample behaviour in a simulation study. A direct plug-in method is suggested for estimating the asymptotic variances of the proposed estimators. A real data application based on a HIV vaccine efficacy trial study is considered.}, }
@article {pmid30738780, year = {2019}, author = {Smith, M and Parker, C and Saad, F and Miller, K and Tombal, B and Ng, QS and Boegemann, M and Matveev, V and Piulats, JM and Zucca, LE and Karyakin, O and Kimura, G and Matsubara, N and Nahas, WC and Nolè, F and Rosenbaum, E and Heidenreich, A and Kakehi, Y and Zhang, A and Krissel, H and Teufel, M and Shen, J and Wagner, V and Higano, C}, title = {Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial.}, journal = {The Lancet. Oncology}, volume = {20}, number = {3}, pages = {408-419}, doi = {10.1016/S1470-2045(18)30860-X}, pmid = {30738780}, issn = {1474-5488}, abstract = {BACKGROUND: Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients.<br><br>METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing.<br><br>FINDINGS: Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia).<br><br>INTERPRETATION: The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination.<br><br>FUNDING: Bayer.}, }
@article {pmid30738112, year = {2019}, author = {Osoegawa, K and Vayntrub, TA and Wenda, S and De Santis, D and Barsakis, K and Ivanova, M and Hsu, S and Barone, J and Holdsworth, R and Diviney, M and Askar, M and Willis, A and Railton, D and Laflin, S and Gendzekhadze, K and Oki, A and Sacchi, N and Mazzocco, M and Andreani, M and Ameen, R and Stavropoulos-Giokas, C and Dinou, A and Torres, M and Dos Santos Francisco, R and Serra-Pages, C and Goodridge, D and Balladares, S and Bettinotti, MP and Iglehart, B and Kashi, Z and Martin, R and Saw, CL and Ragoussis, J and Downing, J and Navarrete, C and Chong, W and Saito, K and Petrek, M and Tokic, S and Padros, K and Beatriz Rodriguez, M and Zakharova, V and Shragina, O and Marino, SR and Brown, NK and Shiina, T and Suzuki, S and Spierings, E and Zhang, Q and Yin, Y and Morris, GP and Hernandez, A and Ruiz, P and Khor, SS and Tokunaga, K and Geretz, A and Thomas, R and Yamamoto, F and Mallempati, KC and Gangavarapu, S and Kanga, U and Tyagi, S and Marsh, SGE and Bultitude, WP and Liu, X and Cao, D and Penning, M and Hurley, CK and Cesbron, A and Mueller, C and Mytilineos, J and Weimer, ET and Bengtsson, M and Fischer, G and Hansen, JA and Chang, CJ and Mack, SJ and Creary, LE and Fernandez-Viña, MA}, title = {Quality control project of NGS HLA genotyping for the 17th International HLA and Immunogenetics Workshop.}, journal = {Human immunology}, volume = {80}, number = {4}, pages = {228-236}, doi = {10.1016/j.humimm.2019.01.009}, pmid = {30738112}, issn = {1879-1166}, support = {R01 AI128775/AI/NIAID NIH HHS/United States ; RP-PG-0310-1003//Department of Health/United Kingdom ; U19 NS095774/NS/NINDS NIH HHS/United States ; }, abstract = {The 17th International HLA and Immunogenetics Workshop (IHIW) organizers conducted a Pilot Study (PS) in which 13 laboratories (15 groups) participated to assess the performance of the various sequencing library preparation protocols, NGS platforms and software in use prior to the workshop. The organizers sent 50 cell lines to each of the 15 groups, scored the 15 independently generated sets of NGS HLA genotyping data, and generated &quot;consensus&quot; HLA genotypes for each of the 50 cell lines. Proficiency Testing (PT) was subsequently organized using four sets of 24 cell lines, selected from 48 of 50 PS cell lines, to validate the quality of NGS HLA typing data from the 34 participating IHIW laboratories. Completion of the PT program with a minimum score of 95% concordance at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci satisfied the requirements to submit NGS HLA typing data for the 17th IHIW projects. Together, these PS and PT efforts constituted the 17th IHIW Quality Control project. Overall PT concordance rates for HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB3, HLA-DRB4 and HLA-DRB5 were 98.1%, 97.0% and 98.1%, 99.0%, 98.6%, 98.8%, 97.6%, 96.0%, 99.1%, 90.0% and 91.7%, respectively. Across all loci, the majority of the discordance was due to allele dropout. The high cost of NGS HLA genotyping per experiment likely prevented the retyping of initially failed HLA loci. Despite the high HLA genotype concordance rates of the software, there remains room for improvement in the assembly of more accurate consensus DNA sequences by NGS HLA genotyping software.}, }
@article {pmid30737640, year = {2019}, author = {Bowen, DJ and Hyams, T and Laurino, M and Woolley, T and Cohen, S and Leppig, KA and Jarvik, G}, title = {Development of FamilyTalk: an Intervention to Support Communication and Educate Families About Colorectal Cancer Risk.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, doi = {10.1007/s13187-019-1484-3}, pmid = {30737640}, issn = {1543-0154}, support = {R01 CA107430/CA/NCI NIH HHS/United States ; U01 HG008657/HG/NHGRI NIH HHS/United States ; P50 HG 3374//National Cancer Institute/ ; }, abstract = {IFamily members of individuals with colorectal cancer (CRC) may be at increased risk of developing the disease. However, the majority of CRC can be prevented through colonoscopy screening and family members may not be aware if they are recommended to pursue earlier screening because of their family history of CRC. As such, tools must be developed to effectively communicate potential changes to the recommended age for colonoscopy screening and other important CRC-related information to family members. We modified and adapted a successful intervention for families with melanoma to be appropriate for families with CRC to increase communication and screening in family members. The multistep process included the following: (1) developing a paper version of the intervention, (2) piloting the paper version among families with CRC, (3) developing the web-based version, and (4) testing the intervention for usability. Qualitative data was collected and analyzed for pilot testing. Usability testing utilized both qualitative and quantitative data. Patients with CRC liked the paper version and had multiple suggestions, including adding a better introduction, sections on genetics and family history, and clearer communication assistance. The web-based tool was well received and improved upon the linear book format with links, better section instructions, and more proactive communication tools for families. These processes produced materials that satisfied individuals from various families with assistance and support for communicating about CRC. Evaluating the effects of the tools in rigorous research projects is the next step.}, }
@article {pmid30737562, year = {2019}, author = {Witlox, WJA and van Osch, FHM and Brinkman, M and Jochems, S and Goossens, ME and Weiderpass, E and White, E and van den Brandt, PA and Giles, GG and Milne, RL and Huybrechts, I and Adami, HO and Bueno-de-Mesquita, B and Wesselius, A and Zeegers, MP}, title = {An inverse association between the Mediterranean diet and bladder cancer risk: a pooled analysis of 13 cohort studies.}, journal = {European journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00394-019-01907-8}, pmid = {30737562}, issn = {1436-6215}, abstract = {PURPOSE: The role of diet in bladder carcinogenesis has yet to be established. To date most studies have investigated dietary components individually, rather than as dietary patterns, which may provide stronger evidence for any influence of diet on bladder carcinogenesis. The Mediterranean diet has been associated with many health benefits, but few studies have investigated its association with bladder cancer risk.<br><br>METHODS: We investigated the potential association between the Mediterranean diet score (MDS) and risk of developing bladder cancer by pooling 13 prospective cohort studies included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study and applying a Cox regression analysis.<br><br>RESULTS: Dietary data from 646,222 study participants, including 3639 incident bladder cancer cases, were analysed. We observed an inverse association between Mediterranean diet and bladder cancer risk (HRhigh 0.85 [95% CI 0.77, 0.93]). When stratifying the results on non-muscle-invasive or muscle-invasive disease or sex the association remained similar and the HR estimate was consistently below 1.00 both for medium and high adherence to the Mediterranean diet. A consistent association was observed when disregarding fat or alcohol intake.<br><br>CONCLUSION: We found evidence that adherence to the Mediterranean diet was associated with reduced risk of developing bladder cancer, suggesting a positive effect of the diet as a whole and not just one component.}, }
@article {pmid30737354, year = {2019}, author = {Cheng, Y and Zhu, YO and Becht, E and Aw, P and Chen, J and Poidinger, M and de Sessions, PF and Hibberd, ML and Bertoletti, A and Lim, SG and Newell, EW}, title = {Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection.}, journal = {Science immunology}, volume = {4}, number = {32}, pages = {}, doi = {10.1126/sciimmunol.aau6905}, pmid = {30737354}, issn = {2470-9468}, abstract = {Associations between chronic antigen stimulation, T cell dysfunction, and the expression of various inhibitory receptors are well characterized in several mouse and human systems. During chronic hepatitis B virus (HBV) infection (CHB), T cell responses are blunted with low frequencies of virus-specific T cells observed, making these parameters difficult to study. Here, using mass cytometry and a highly multiplexed combinatorial peptide-major histocompatibility complex (pMHC) tetramer strategy that allows for the detection of rare antigen-specific T cells, we simultaneously probed 484 unique HLA-A*1101-restricted epitopes spanning the entire HBV genome on T cells from patients at various stages of CHB. Numerous HBV-specific T cell populations were detected, validated, and profiled. T cells specific for two epitopes (HBVpol387 and HBVcore169) displayed differing and complex heterogeneities that were associated with the disease progression, and the expression of inhibitory receptors on these cells was not linearly related with their extent of T cell dysfunction. For HBVcore169-specific CD8+ T cells, we found cellular markers associated with long-term memory, polyfunctionality, and the presence of several previously unidentified public TCR clones that correlated with viral control. Using high-dimensional trajectory analysis of these cellular phenotypes, a pseudo-time metric was constructed that fit with the status of viral infection in corresponding patients. This was validated in a longitudinal cohort of patients undergoing antiviral therapy. Our study uncovers complex relationships of inhibitory receptors between the profiles of antigen-specific T cells and the status of CHB with implications for new strategies of therapeutic intervention.}, }
@article {pmid30737173, year = {2019}, author = {Symonds, L and Linden, H and Gadi, V and Korde, L and Rodler, E and Gralow, J and Redman, M and Baker, K and Wu, QV and Jenkins, I and Kurland, B and Garrison, M and Smith, J and Anderson, J and Van Haelst, C and ,  and Specht, J}, title = {Combined Targeted Therapies for First-line Treatment of Metastatic Triple Negative Breast Cancer-A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Targeted Therapy With Bevacizumab and Erlotinib.}, journal = {Clinical breast cancer}, volume = {19}, number = {2}, pages = {e283-e296}, doi = {10.1016/j.clbc.2018.12.008}, pmid = {30737173}, issn = {1938-0666}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC.<br><br>PATIENTS AND METHODS: We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC. During induction, the patients received nab-paclitaxel 100 mg/m2 intravenously (days 1, 8, and 15) and bevacizumab 10 mg/kg intravenously (days 1 and 15) every 28 days for 6 cycles. Patients free of progression at 24 weeks received maintenance therapy with bevacizumab 10 mg/kg intravenously every 2 weeks and oral erlotinib 150 mg/d until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were best overall response, overall survival (OS), and adverse events. We explored the measurement of circulating tumor cells as a prognostic marker.<br><br>RESULTS: A total of 55 evaluable patients were enrolled. The median PFS and OS for the cohort was 9.1 months (95% confidence interval, 7.2-11.1) and 18.1 months (95% confidence interval, 15.6-21.7), respectively. Of the 53 patients with measurable disease, 39 (74%) had experienced a partial response and 10 (19%) had stable disease using the Response Evaluation Criteria In Solid Tumors. The most common toxicities were uncomplicated neutropenia, fatigue, and neuropathy. Decreased circulating tumor cells from baseline to the first assessment correlated with longer PFS and OS.<br><br>CONCLUSION: Nab-paclitaxel and bevacizumab, followed by maintenance targeted therapy with bevacizumab and erlotinib, resulted in PFS similar to that of other trials. Most patients experienced a partial response (74%). Most patients received maintenance therapy (55%), providing a break from cytotoxic chemotherapy.}, }
@article {pmid30735000, year = {2019}, author = {Schweizer, MT and Wang, H and Bivalacqua, TJ and Partin, AW and Lim, SJ and Chapman, C and Abdallah, R and Levy, O and Bhowmick, NA and Karp, JM and De Marzo, A and Isaacs, JT and Brennen, WN and Denmeade, SR}, title = {A Phase I Study to Assess the Safety and Cancer-Homing Ability of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells in Men with Localized Prostate Cancer.}, journal = {Stem cells translational medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/sctm.18-0230}, pmid = {30735000}, issn = {2157-6564}, support = {W81XWH-13-1-0304//Department of Defense Prostate Cancer Research Program Synergy Award/ ; P50 CA058236//NIH-Prostate SPORE/ ; //Prostate Cancer Foundation Young Investigator Award/ ; //Prostate Cancer Foundation Challenge Award/ ; }, abstract = {Animal models show that systemically administered bone marrow-derived mesenchymal stem cells (MSCs) home to sites of primary and metastatic prostate cancer (PC)-making them candidates to selectively deliver cytotoxic agents. To further assess this potential as a cell-based therapeutic vehicle, a phase I study testing homing of systemically infused allogeneic MSCs preprostatectomy was conducted. The primary objective was to assess safety and feasibility and to determine if MSCs accumulate within primary PC tissue. MSCs were quantified using beads, emulsion, amplification, magnetics digital polymerase chain reaction (limit of detection: ≥0.01% MSCs) to measure allogeneic MSC DNA relative to recipient DNA. MSCs were harvested from healthy donors and expanded ex vivo using standard protocols by the Johns Hopkins Cell Therapy Laboratory. PC patients planning to undergo prostatectomy were eligible for MSC infusion. Enrolled subjects received a single intravenous infusion 4-6 days prior to prostatectomy. The first three subjects received 1 x 106 cells per kilogram (maximum 1 x 108 cells), and subsequent four patients received 2 x 106 cells per kilogram (maximum 2 x 108 cells). No dose-limiting toxicities were observed and all patients underwent prostatectomy without delay. Pathologic assessment of prostate cores revealed ≥70% tumor involvement in cores from four subjects, with benign tissue in the others. MSCs were undetectable in all subjects, and the study was stopped early for futility. MSC infusions appear safe in PC patients. Although intended for eventual use in metastatic PC patients, in this study, MSCs did not home primary tumors in sufficient levels to warrant further development as a cell-based therapeutic delivery strategy using standard ex vivo expansion protocols. Stem Cells Translational Medicine 2019;00:1-9.}, }
@article {pmid30734210, year = {2019}, author = {Rinehart, R and Rao, D and Amico, RK and Ruiz, E and Brandes, P and Correa, C and Pasalar, S and Lama, JR and Duerr, A and Molina, Y}, title = {Correction to: Experienced HIV-Related Stigma and Psychological Distress in Peruvian Sexual and Gender Minorities: A Longitudinal Study to Explore Mediating Roles of Internalized HIV-Related Stigma and Coping Styles.}, journal = {AIDS and behavior}, volume = {23}, number = {3}, pages = {675}, doi = {10.1007/s10461-019-02394-y}, pmid = {30734210}, issn = {1573-3254}, abstract = {Correction to: AIDS and Behavior (2018) 1-14 https://doi.org/10.1007/s10461-018-2348-2 . In the original publication of the article, the given name of the second author was not correct. The name has been corrected with this erratum.}, }
@article {pmid30733593, year = {2019}, author = {Aldape, K and Brindle, KM and Chesler, L and Chopra, R and Gajjar, A and Gilbert, MR and Gottardo, N and Gutmann, DH and Hargrave, D and Holland, EC and Jones, DTW and Joyce, JA and Kearns, P and Kieran, MW and Mellinghoff, IK and Merchant, M and Pfister, SM and Pollard, SM and Ramaswamy, V and Rich, JN and Robinson, GW and Rowitch, DH and Sampson, JH and Taylor, MD and Workman, P and Gilbertson, RJ}, title = {Challenges to curing primary brain tumours.}, journal = {Nature reviews. Clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41571-019-0177-5}, pmid = {30733593}, issn = {1759-4782}, support = {P01 CA096832/CA/NCI NIH HHS/United States ; }, abstract = {Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.}, }
@article {pmid30733432, year = {2019}, author = {Mathieu, J and Detraux, D and Kuppers, D and Wang, Y and Cavanaugh, C and Sidhu, S and Levy, S and Robitaille, AM and Ferreccio, A and Bottorff, T and McAlister, A and Somasundaram, L and Artoni, F and Battle, S and Hawkins, RD and Moon, RT and Ware, CB and Paddison, PJ and Ruohola-Baker, H}, title = {Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {632}, doi = {10.1038/s41467-018-08020-0}, pmid = {30733432}, issn = {2041-1723}, support = {U01 HL099997/HL/NHLBI NIH HHS/United States ; R01 GM097372/GM/NIGMS NIH HHS/United States ; R01 GM083867/GM/NIGMS NIH HHS/United States ; P01 GM081619/GM/NIGMS NIH HHS/United States ; U01 HL099993/HL/NHLBI NIH HHS/United States ; }, mesh = {Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism ; CRISPR-Cas Systems/genetics/physiology ; Cell Line ; Estrone/genetics/metabolism ; Humans ; Immunoprecipitation ; Mechanistic Target of Rapamycin Complex 1/genetics/*metabolism ; Mechanistic Target of Rapamycin Complex 2/genetics/*metabolism ; Proteomics ; Receptors, Estrogen/genetics/metabolism ; Wnt Signaling Pathway/genetics/*physiology ; }, abstract = {To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.}, }
@article {pmid30730781, year = {2019}, author = {Salloum, R and Chen, Y and Yasui, Y and Packer, R and Leisenring, W and Wells, E and King, A and Howell, R and Gibson, TM and Krull, KR and Robison, LL and Oeffinger, KC and Fouladi, M and Armstrong, GT}, title = {Late Morbidity and Mortality Among Medulloblastoma Survivors Diagnosed Across Three Decades: A Report From the Childhood Cancer Survivor Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {37}, number = {9}, pages = {731-740}, doi = {10.1200/JCO.18.00969}, pmid = {30730781}, issn = {1527-7755}, abstract = {PURPOSE: Treatment of medulloblastoma has evolved from surgery and radiotherapy to contemporary multimodal regimens. However, the impact on long-term health outcomes remains unknown.<br><br>METHODS: Cumulative incidence of late mortality (5 or more years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of medulloblastoma diagnosed between 1970 and 1999. Outcomes were evaluated by treatment exposure, including historical therapy (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), high risk (CSI ≥ 30 Gy + chemotherapy), standard risk (CSI < 30 Gy + chemotherapy), and by treatment decade (1970s, 1980s, 1990s). Rate ratios (RRs) and 95% CIs estimated long-term outcomes using multivariable piecewise exponential models.<br><br>RESULTS: Among 1,311 eligible survivors (median age, 29 years [range, 6 to 60 years]; median time from diagnosis, 21 years [range, 5 to 44 years]), the 15-year cumulative incidence rate of all-cause late mortality was 23.2% (diagnosed 1970s) versus 12.8% (1990s; P = .002), with a recurrence-related mortality rate of 17.7% versus 9.6% (P = .008). Lower late mortality rates as a result of other health-related causes were not observed. Among 997 survivors who completed a baseline survey, the 15-year cumulative incidence of SNs was higher among survivors with multimodal therapy (standard risk, 9.5%; historical, 2.8%; P = .03). Survivors treated in the 1990s had a higher cumulative incidence of severe, disabling, life-threatening, and fatal chronic health conditions (56.5% in 1990s v 39.9% in 1970s; P < .001) and were more likely to develop multiple conditions (RR, 2.89; 95% CI, 1.31 to 6.38). However, survivors of standard-risk therapy were less likely to use special education services than high-risk therapy survivors (RR, 0.84; 95% CI, 0.75 to 0.93).<br><br>CONCLUSION: Historical changes in medulloblastoma therapy that improved 5-year survival have increased the risk for SNs and debilitating health conditions for survivors yet reduced the need for special education services.}, }
@article {pmid30729746, year = {2019}, author = {Crane, DA and Doody, DR and Schiff, MA and Mueller, BA}, title = {Pregnancy outcomes in women with spinal cord injuries: a population-based study.}, journal = {PM &amp; R : the journal of injury, function, and rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1002/pmrj.12122}, pmid = {30729746}, issn = {1934-1563}, abstract = {BACKGROUND: Pregnant women with congenital or acquired spinal cord injury face challenges due to compromised neurological function and mobility; factors that may also affect fetal/infant health. Few studies have examined pregnancy course and longer-term outcomes in this population.<br><br>OBJECTIVE: To assess pregnancy outcomes among women with spinal cord injury, paralysis, or spina bifida using population-based data.<br><br>DESIGN: Retrospective cohort study SETTING: Washington State linked birth-hospital discharge records PARTICIPANTS: All women (N=529) with spinal cord injury (SCI), paralysis, or spina bifida (SB) with singleton live birth deliveries 1987-2012, and a comparison group of women without disabilities.<br><br>METHODS: Diagnosis codes were screened to identify cases and a 10:1 random sample of comparison women. Relative risks (RR) and 95% confidence intervals (CI) were calculated overall and separately for each condition using multivariable regression. Subsequent hospitalizations or death were identified via linkage to hospital discharge/death records for 2 years after delivery.<br><br>MAIN OUTCOME MEASUREMENTS: Pregnancy course (weight gain, gestational diabetes, preeclampsia, infection, venous thromboembolism), delivery/labor characteristics, infant (birthweight/size, gestational age), and longer-term outcomes (occurrence/reasons for maternal/infant rehospitalization, mortality).<br><br>RESULTS: Cases had increased adjusted risks of prenatal urinary tract infection/pyelonephritis (RR 26.43 (95% CI 13.97-49.99), venous thromboembolism (RR 9.16, 95% CI 2.17-38.60), preterm rupture of membranes (RR 2.15, 95% CI 1.18-3.90), and cesarean delivery (RR 1.88, 95% CI 1.70-2.09). They had longer hospitalizations and increased rehospitalization (RR 1.54, 95% CI 1.28-1.87), including for postpartum depression (RR 8.15, 4.29-15.48) or injury (RR 13.05, 95% CI 6.60-25.81). Their infants were more often small for gestational age (RR 1.65, 95% CI 1.33-2.06), but had no increased risk of rehospitalization or death.<br><br>CONCLUSIONS: We observed no increased long-term morbidity among infants of women with these conditions. Possible increased maternal morbidities during the first postpartum years indicate areas for intervention.<br><br>LEVEL OF EVIDENCE: III This article is protected by copyright. All rights reserved.}, }
@article {pmid30729531, year = {2019}, author = {Tuazon, SA and Li, A and Gooley, T and Eunson, TW and Maloney, DG and Turtle, CJ and Linenberger, ML and Connelly-Smith, LS}, title = {Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.15178}, pmid = {30729531}, issn = {1537-2995}, support = {//Juno Therapeutics/Celgene/ ; T32 HL007093/HL/NHLBI NIH HHS/United States ; P30 CA015704//Fred Hutch/University of Washington Cancer Consortium/ ; P30 CA015704/CA/NCI NIH HHS/United States ; //National Institutes of Health/ ; T32CA009515//National Cancer Institute/ ; T32 CA009515/CA/NCI NIH HHS/United States ; T32HL007093//National Heart, Lung and Blood Institute/ ; }, abstract = {BACKGROUND: The clinical and procedural parameters that affect the optimal collection of lymphocytes for the production of chimeric antigen receptor (CAR) T cells remain undefined but are increasingly important, as commercial products are now available. We evaluated determinants of low lymphocyte collection efficiency (CE) and the rate of successful CAR T-cell manufacture in middle-aged and older adults with advanced B-cell malignancies.<br><br>STUDY DESIGNS AND METHODS: Mononuclear cell collections using two apheresis platforms (COBE Spectra and Spectra Optia, Terumo BCT) from patients participating in a CD19-directed CAR T-cell therapy trial were reviewed. Patient- and disease-specific factors, peripheral blood counts, apheresis parameters, and product cell counts were analyzed to determine effects on lymphocyte CE.<br><br>RESULTS: Ninety-two apheresis events from patients with acute lymphocytic leukemia (ALL) (n = 28), chronic lymphocytic leukemia (n = 18), and non-Hodgkin lymphoma (n = 46) were available for analysis. Forty-one collections (45%) had a lymphocyte CE of <40%. On multivariable analysis, age (every 10-year increase, odds ratio [OR] = 1.51; p = 0.034), disease type (chronic lymphocytic leukemia vs. ALL, OR = 0.24; p = 0.052; non-Hodgkin lymphoma vs. ALL, OR = 0.20; p = 0.009) and precollection platelets (every 10 × 103 /μL increase, OR = 1.07; p = 0.005) were appreciably associated with a lymphocyte CE of <40%. No major apheresis complications occurred.<br><br>CONCLUSIONS: Lymphocyte collection at our center was well tolerated and 100% successful in manufacturing CD19-directed CAR T cells from adult patients with B-cell malignancies despite low CE in some patients. A diagnosis of ALL, advancing age, and higher preapheresis platelet counts were observed to be associated with low CE.}, }
@article {pmid30728140, year = {2019}, author = {Hay, KA and Gauthier, J and Hirayama, AV and Voutsinas, JM and Wu, Q and Li, D and Gooley, TA and Cherian, S and Chen, X and Pender, BS and Hawkins, RM and Vakil, A and Steinmetz, RN and Schoch, G and Chapuis, AG and Till, BG and Kiem, HP and Ramos, JD and Shadman, M and Cassaday, RD and Acharya, UH and Riddell, SR and Maloney, DG and Turtle, CJ}, title = {Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy.}, journal = {Blood}, volume = {133}, number = {15}, pages = {1652-1663}, doi = {10.1182/blood-2018-11-883710}, pmid = {30728140}, issn = {1528-0020}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; R01 CA136551/CA/NCI NIH HHS/United States ; }, abstract = {Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.}, }
@article {pmid30726999, year = {2019}, author = {Ma, KK and Preusse, CJ and Stevenson, PA and Winget, VL and McDougall, JA and Li, CI and Gadi, VK and Gammill, HS}, title = {Obstetric Outcomes in Young Women with Breast Cancer: Prior, Postpartum, and Subsequent Pregnancies.}, journal = {American journal of perinatology}, volume = {}, number = {}, pages = {}, doi = {10.1055/s-0039-1678603}, pmid = {30726999}, issn = {1098-8785}, abstract = {OBJECTIVE: To describe obstetric outcomes in a large cohort of young women with breast cancer, considering the chronological relationship of pregnancies with breast cancer diagnosis.<br><br>STUDY DESIGN: From a population-based cohort study of young women with breast cancer from 2004 to 2010, we conducted secondary interviews to obtain detailed obstetric histories. Pregnancies were categorized based on timing of breast cancer diagnosis: prior, postpartum, and subsequent pregnancies after breast cancer diagnosis. A generalized estimated equation model was used to account for correlated data.<br><br>RESULTS: In this cohort (n = 366), median age at breast cancer diagnosis was 40.1 years, and 84.7% were Caucasian. Tumor type was notable for 25.1% triple negative, and 56.1% had Stage I disease. There were 922 prior pregnancies, 21 with postpartum diagnosis of breast cancer, and 24 pregnancies subsequent to breast cancer diagnosis. Non-live birth outcomes occurred significantly more often in the postpartum group (p-value: 0.001) compared with the other groups, which had higher live birth rates, after adjustment for maternal age, parity, body mass index, and race.<br><br>CONCLUSION: Overall, pregnancy outcomes before and after breast cancer diagnosis are reassuring.}, }
@article {pmid30726290, year = {2019}, author = {Ddungu, H and Krantz, EM and Kajja, I and Naluzze, S and Nabbanja, H and Nalubwama, F and Phipps, W and Orem, J and Kiwanuka, N and Wald, A}, title = {How low can you go: What is the safe threshold for platelet transfusions in patients with hematologic malignancy in sub-Saharan Africa.}, journal = {PloS one}, volume = {14}, number = {2}, pages = {e0211648}, doi = {10.1371/journal.pone.0211648}, pmid = {30726290}, issn = {1932-6203}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Despite the importance of platelet transfusions in treatment of hematologic cancer patients, the optimal platelet count threshold for prophylactic transfusion is unknown in sub-Saharan Africa.<br><br>METHODS: We followed patients admitted to the Uganda Cancer Institute with a hematological malignancy in 3 sequential 4-month time-periods using incrementally lower thresholds for prophylactic platelet transfusion: platelet counts ≤ 30 x 109/L in period 1, ≤ 20 x 109/L in period 2, and ≤ 10 x 109/L in period 3. Clinically significant bleeding was defined as WHO grade ≥ 2 bleeding. We used generalized estimating equations (GEE) to compare the frequency of clinically significant bleeding and platelet transfusions by study period, adjusting for age, sex, cancer type, chemotherapy, baseline platelet count, and baseline hemoglobin.<br><br>RESULTS: Overall, 188 patients were enrolled. The median age was 22 years (range 1-80). Platelet transfusions were given to 42% of patients in period 1, 55% in period 2, and 45% in period 3. These transfusions occurred on 8% of days in period 1, 12% in period 2, and 8% in period 3. In adjusted models, period 3 had significantly fewer transfusions than period 1 (RR = 0.6, 95% CI 0.4-0.9; p = 0.01) and period 2 (RR = 0.5, 95% CI 0.4-0.7; p<0.001). Eighteen patients (30%) had clinically significant bleeding on at least one day in period 1, 23 (30%) in period 2, and 15 (23%) in period 3. Clinically significant bleeding occurred on 8% of patient-days in period 1, 9% in period 2, and 5% in period 3 (adjusted p = 0.41). Thirteen (21%) patients died in period 1, 15 (22%) in period 2, and 11 (19%) in period 3 (adjusted p = 0.96).<br><br>CONCLUSION: Lowering the threshold for platelet transfusion led to fewer transfusions and did not change the incidence of clinically significant bleeding or mortality, suggesting that a threshold of 10 x 109/L platelets, used in resource-rich countries, may be implemented as a safe level for transfusions in sub-Saharan Africa.}, }
@article {pmid30726175, year = {2019}, author = {Nghiem, P and Bhatia, S and Lipson, EJ and Sharfman, WH and Kudchadkar, RR and Brohl, AS and Friedlander, PA and Daud, A and Kluger, HM and Reddy, SA and Boulmay, BC and Riker, AI and Burgess, MA and Hanks, BA and Olencki, T and Margolin, K and Lundgren, LM and Soni, A and Ramchurren, N and Church, C and Park, SY and Shinohara, MM and Salim, B and Taube, JM and Bird, SR and Ibrahim, N and Fling, SP and Homet Moreno, B and Sharon, E and Cheever, MA and Topalian, SL}, title = {Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {37}, number = {9}, pages = {693-702}, doi = {10.1200/JCO.18.01896}, pmid = {30726175}, issn = {1527-7755}, abstract = {PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited.<br><br>PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.<br><br>RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death.<br><br>CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.}, }
@article {pmid30725527, year = {2019}, author = {Liao, JB and Fisher, CE and Madeleine, MM}, title = {Gynecologic cancers and solid organ transplantation.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1111/ajt.15292}, pmid = {30725527}, issn = {1600-6143}, abstract = {Solid organ transplant (SOT) recipients have an approximately 2-fold greater risk of developing and dying from a malignancy compared to the general population. Among the gynecologic cancers, including uterine, cervical, vaginal, vulvar, and ovarian, the HPV-related cancers are known to increase among women posttransplant compared to women in the general population, but less is known about the risk of uterine and ovarian cancers. This review provides an overview of the epidemiology of gynecologic cancers after solid organ transplantation, as well as the pathophysiology, management, and specific risk factors associated with these cancers. Closer surveillance for cervical cancers is warranted and larger studies are needed to assess whether and how uterine and ovarian cancers are associated with excess incidence and mortality. Such studies may lead to improvements in screening, prevention, and treatment before and after transplantation.}, }
@article {pmid30725397, year = {2019}, author = {Tsuyuki, K and Shoptaw, SJ and Ransome, Y and Chau, G and Rodriguez-Diaz, CE and Friedman, RK and Srithanaviboonchai, K and Li, S and Mimiaga, MJ and Mayer, KH and Safren, SA}, title = {The Longitudinal Effects of Non-injection Substance Use on Sustained HIV Viral Load Undetectability Among MSM and Heterosexual Men in Brazil and Thailand: The Role of ART Adherence and Depressive Symptoms (HPTN 063).}, journal = {AIDS and behavior}, volume = {23}, number = {3}, pages = {649-660}, doi = {10.1007/s10461-019-02415-w}, pmid = {30725397}, issn = {1573-3254}, support = {K01 AA025009/AA/NIAAA NIH HHS/United States ; K01 MH111374/MH/NIMH NIH HHS/United States ; P30 MH058107//National Institute of Mental Health/ ; R01 HD077891-04S1//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; K01MH111374//National Institute of Mental Health/ ; L60 MD011184/MD/NIMHD NIH HHS/United States ; R01 HD077891/HD/NICHD NIH HHS/United States ; P30 MH058107/MH/NIMH NIH HHS/United States ; R25 MH083617/MH/NIMH NIH HHS/United States ; UM1 AI068619//National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, National Institute of Mental Health/ ; T32 DA023356//National Institute on Drug Abuse/ ; K24 DA040489/DA/NIDA NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; 9K24DA040489//National Institute on Drug Abuse/ ; T32 DA023356/DA/NIDA NIH HHS/United States ; K01AA025009//National Institute on Alcohol Abuse and Alcoholism/ ; L60MD011184//National Institute on Minority Health and Health Disparities/ ; }, abstract = {The effect of non-injection substance use on HIV viral load (VL) is understudied in international settings. Data are from HPTN063, a longitudinal observational study of HIV-infected individuals in Brazil, Thailand, and Zambia, with focus on men with VL data (Brazil = 146; Thailand = 159). Generalized linear mixed models (GLMM) assessed whether non-injection substance use (stimulants, cannabis, alcohol, polysubstance) was associated with VL undetectability. ART adherence and depressive symptoms were examined as mediators of the association. In Thailand, substance use was not significantly associated with VL undetectability or ART adherence, but alcohol misuse among MSM was associated with increased odds of depression (AOR = 2.75; 95% CI 1.20, 6.32, p = 0.02). In Brazil, alcohol misuse by MSM was associated with decreased odds of undetectable VL (AOR = 0.34; 95% CI 0.13, 0.92, p = 0.03). Polysubstance use by heterosexual men in Brazil was associated with decreased odds of ART adherence (AOR = 0.25; 95% CI 0.08, 0.78, p = 0.02). VL suppression appears attainable among non-injection substance users. Substance use interventions among HIV-positive men should address depression, adherence, and VL undetectability.}, }
@article {pmid30723176, year = {2019}, author = {Jiao, L and Maity, S and Coarfa, C and Rajapakshe, K and Chen, L and Jin, F and Putluri, V and Tinker, LF and Mo, Q and Chen, F and Sen, S and Sangi-Hyghpeykar, H and El-Serag, HB and Putluri, N}, title = {A Prospective Targeted Serum Metabolomics Study of Pancreatic Cancer in Postmenopausal Women.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {12}, number = {4}, pages = {237-246}, doi = {10.1158/1940-6207.CAPR-18-0201}, pmid = {30723176}, issn = {1940-6215}, support = {I50 HX001236/HX/HSRD VA/United States ; R01 CA172880/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; R01 CA220297/CA/NCI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; }, abstract = {To examine the association between metabolic deregulation and pancreatic cancer, we conducted a two-stage case-control targeted metabolomics study using prediagnostic sera collected one year before diagnosis in the Women's Health Initiative study. We used the LC/MS to quantitate 470 metabolites in 30 matched case/control pairs. From 180 detectable metabolites, we selected 14 metabolites to be validated in additional 18 matched case/control pairs. We used the paired t test to compare the concentrations of each metabolite between cases and controls and used the log fold change (FC) to indicate the magnitude of difference. FDR adjusted q-value < 0.25 was indicated statistically significant. Logistic regression model and ROC curve analysis were used to evaluate the clinical utility of the metabolites. Among 30 case/control pairs, 1-methyl-l-tryptophan (L-1MT) was significantly lower in the cases than in the controls (log2 FC = -0.35; q-value = 0.03). The area under the ROC curve was 0.83 in the discrimination analysis based on the levels of L-1MT, acadesine, and aspartic acid. None of the metabolites was validated in additional independent 18 case/control pairs. No significant association was found between the examined metabolites and undiagnosed pancreatic cancer.}, }
@article {pmid30723171, year = {2019}, author = {Augert, A and Eastwood, E and Ibrahim, AH and Wu, N and Grunblatt, E and Basom, R and Liggitt, D and Eaton, KD and Martins, R and Poirier, JT and Rudin, CM and Milletti, F and Cheng, WY and Mack, F and MacPherson, D}, title = {Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition.}, journal = {Science signaling}, volume = {12}, number = {567}, pages = {}, doi = {10.1126/scisignal.aau2922}, pmid = {30723171}, issn = {1937-9145}, support = {T32 GM007266/GM/NIGMS NIH HHS/United States ; }, abstract = {Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the NOTCH1 locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001-induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.}, }
@article {pmid30723117, year = {2019}, author = {Zhao, Y and Ding, L and Wang, D and Ye, Z and He, Y and Ma, L and Zhu, R and Pan, Y and Wu, Q and Pang, K and Hou, X and Weroha, SJ and Han, C and Coleman, R and Coleman, I and Karnes, RJ and Zhang, J and Nelson, PS and Wang, L and Huang, H}, title = {EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis.}, journal = {The EMBO journal}, volume = {38}, number = {5}, pages = {}, doi = {10.15252/embj.201899599}, pmid = {30723117}, issn = {1460-2075}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA203849/CA/NCI NIH HHS/United States ; R01 CA193239/CA/NCI NIH HHS/United States ; R01 CA130908/CA/NCI NIH HHS/United States ; R01 CA134514/CA/NCI NIH HHS/United States ; }, abstract = {In light of the increasing number of identified cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target several mutants, rather than developing strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation-sequencing (RIP-seq), we identified the Polycomb-group histone methyltransferase EZH2 as a p53 mRNA-binding protein. EZH2 bound to an internal ribosome entry site (IRES) in the 5'UTR of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing protein levels of mutant p53. EZH2 overexpression was associated with worsened outcome selectively in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.}, }
@article {pmid30723114, year = {2019}, author = {Yan, Y and Sun, N and Wang, H and Kobayashi, M and Ladd, JJ and Long, JP and Lo, KC and Patel, J and Sullivan, E and Albert, T and Goodman, GE and Do, KA and Hanash, SM}, title = {Whole Genome-Derived Tiled Peptide Arrays Detect Prediagnostic Autoantibody Signatures in Non-Small-Cell Lung Cancer.}, journal = {Cancer research}, volume = {79}, number = {7}, pages = {1549-1557}, doi = {10.1158/0008-5472.CAN-18-1536}, pmid = {30723114}, issn = {1538-7445}, support = {U01 CA063673/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; }, abstract = {The majority of non-small-cell lung cancer (NSCLC) cases are diagnosed at advanced stages, primarily because earlier stages of the disease are either asymptomatic or may be attributed to other causes such as infection or long-term effects from smoking. Therefore, early detection of NSCLC would likely increase response and survival rates due to timely intervention. Here, we utilize a novel approach based on whole genome-derived tiled peptide arrays to identify epitopes associated with autoantibody reactivity in NSCLC as a potential means for early detection. Arrays consisted of 2,781,902 tiled peptides representing 20,193 proteins encoded in the human genome. Analysis of 86 prediagnostic samples and 86 matched normal controls from a high-risk cohort revealed 48 proteins with three or more reactive epitopes in NSCLC samples relative to controls. Independent mass spectrometry analysis identified 40 of the 48 proteins in prediagnostic sera from NSCLC samples, of which, 21 occurred in the immunoglobulin-bound fraction. In addition, 63 and 34 proteins encompassed three or more epitopes that were distinct for squamous cell lung cancer and lung adenocarcinoma, respectively. Collectively, these data show that tiled peptide arrays provide a means to delineate epitopes encoded across the genome that trigger an autoantibody response associated with tumor development. SIGNIFICANCE: This study provides a modality for early diagnosis of NSCLC for precision oncology that can be applied to other cancer types.}, }
@article {pmid30723110, year = {2019}, author = {Dreger, P and Sureda, A and Ahn, KW and Eapen, M and Litovich, C and Finel, H and Boumendil, A and Gopal, A and Herrera, AF and Schmid, C and Diez-Martin, JL and Fuchs, E and Bolaños-Meade, J and Gooptu, M and Al Malki, MM and Castagna, L and Ciurea, SO and Dominietto, A and Blaise, D and Ciceri, F and Tischer, J and Corradini, P and Montoto, S and Robinson, S and Gülbas, Z and Hamadani, M}, title = {PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL.}, journal = {Blood advances}, volume = {3}, number = {3}, pages = {360-369}, doi = {10.1182/bloodadvances.2018027748}, pmid = {30723110}, issn = {2473-9537}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.}, }
@article {pmid30721924, year = {2019}, author = {Gunter, MJ and Alhomoud, S and Arnold, M and Brenner, H and Burn, J and Casey, G and Chan, AT and Cross, AJ and Giovannucci, E and Hoover, R and Houlston, R and Jenkins, M and Laurent-Puig, P and Peters, U and Ransohoff, D and Riboli, E and Sinha, R and Stadler, ZK and Brennan, P and Chanock, SJ}, title = {Meeting Report from the joint IARC-NCI international cancer seminar series: a focus on colorectal cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/annonc/mdz044}, pmid = {30721924}, issn = {1569-8041}, support = {09/22/192//Department of Health/United Kingdom ; }, abstract = {Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low and middle income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute (NCI) and the International Agency for Research on Cancer (IARC) which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.}, }
@article {pmid30721663, year = {2019}, author = {Whittle, MC and Hingorani, SR}, title = {Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2018.12.044}, pmid = {30721663}, issn = {1528-0012}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA161112/CA/NCI NIH HHS/United States ; R50 CA211425/CA/NCI NIH HHS/United States ; U01 CA224193/CA/NCI NIH HHS/United States ; }, abstract = {The desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets. More recently, however, it has also become apparent that diverse subpopulations of fibroblasts with distinct phenotypes and secretomes inhabit the stroma, and that targeted depletion of particular fibroblast subsets could either provide substantial therapeutic benefit or accelerate disease progression. An improved characterization of these fibroblast subtypes, along with their potential relationships to tumor subtypes and mutational repertoires, is needed in order to make anti-fibroblast therapies clinically viable.}, }
@article {pmid30719659, year = {2019}, author = {Loggers, ET and Kirtane, K and Palacios, R and Lewis, F}, title = {Leaving footprints, not scars: a qualitative pilot study of Hispanic mothers' willingness to communicate with dependent children about an advanced cancer diagnosis.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {27}, number = {4}, pages = {1573-1578}, doi = {10.1007/s00520-018-4576-4}, pmid = {30719659}, issn = {1433-7339}, support = {CA132381//National Cancer Institute/ ; CA132383//National Cancer Institute/ ; }, abstract = {PURPOSE: US Hispanics are more likely to be diagnosed with advanced cancer as parents than their non-Hispanic white counterparts but little is known about Hispanic parents' willingness to discuss a terminal cancer diagnosis with dependent children, potentially resulting in suboptimal child coping. Therefore, we investigated Hispanic mothers' willingness to communicate with dependent children about her actual or hypothetical advanced cancer diagnosis.<br><br>METHODS: Two focus groups (n = 6 participants) and three one-on-one interviews (n = 3) were conducted in either Spanish or English among adult, Mexican-American mothers with a current cancer diagnosis of any stage residing in US-Mexico border communities. Participants reported their perceived concerns, parenting challenges, and openness to discussing an incurable cancer diagnosis with a dependent child. Audio files were transcribed into English and qualitatively coded using content analysis.<br><br>RESULTS: Participants, most with breast cancer, ranged in age from 25 to 47. Five had considered the possibility of their own death from advanced cancer and three had previously discussed this with their children. While many expected their children would carry on well without them, seven expressed concern for the emotional/spiritual well-being of their children. Mothers anticipated physical and time-based parenting challenges but wanted the opportunity to focus on themselves and their children in advance of death. All but one would be willing to discuss an advance cancer diagnosis with dependent children; four expressed the value of doing so or the potential harm of abdicating this responsibility.<br><br>CONCLUSIONS: If faced with an advanced cancer diagnosis, Mexican-American mothers are open to communicating with dependent children.}, }
@article {pmid30716477, year = {2019}, author = {Dong, J and Gharahkhani, P and Chow, WH and Gammon, MD and Liu, G and Caldas, C and Wu, AH and Ye, W and Onstad, L and Anderson, LA and Bernstein, L and Pharoah, PD and Risch, HA and Corley, DA and Fitzgerald, RC and ,  and Iyer, PG and Reid, BJ and Lagergren, J and Shaheen, NJ and Vaughan, TL and MacGregor, S and Love, S and Palles, C and Tomlinson, I and Gockel, I and May, A and Gerges, C and Anders, M and Böhmer, AC and Becker, J and Kreuser, N and Thieme, R and Noder, T and Venerito, M and Veits, L and Schmidt, T and Schmidt, C and Izbicki, JR and Hölscher, AH and Lang, H and Lorenz, D and Schumacher, B and Mayershofer, R and Vashist, Y and Ott, K and Vieth, M and Weismüller, J and Nöthen, MM and Moebus, S and Knapp, M and Peters, WHM and Neuhaus, H and Rösch, T and Ell, C and Jankowski, J and Schumacher, J and Neale, RE and Whiteman, DC and Thrift, AP}, title = {No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cgh.2019.01.041}, pmid = {30716477}, issn = {1542-7714}, support = {K05 CA124911/CA/NCI NIH HHS/United States ; P01 CA091955/CA/NCI NIH HHS/United States ; R01 CA136725/CA/NCI NIH HHS/United States ; 10119//Cancer Research UK/United Kingdom ; 10124//Cancer Research UK/United Kingdom ; }, abstract = {BACKGROUND &amp; AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE).<br><br>METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC.<br><br>RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18).<br><br>CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.}, }
@article {pmid30715403, year = {2019}, author = {Cohen, MS and Donnell, D}, title = {Novel approaches for development of HIV pre-exposure prophylaxis (PrEP) agents.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz041}, pmid = {30715403}, issn = {1537-6613}, support = {UM1 AI068617/AI/NIAID NIH HHS/United States ; }, }
@article {pmid30714090, year = {2019}, author = {Zhou, J and Han, J and Nutescu, EA and Galanter, WL and Walton, SM and Gordeuk, VR and Saraf, SL and Calip, GS}, title = {Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S. population: a six-year population-based cohort analysis.}, journal = {British journal of haematology}, volume = {185}, number = {1}, pages = {116-127}, doi = {10.1111/bjh.15773}, pmid = {30714090}, issn = {1365-2141}, support = {//National Center for Advancing Translational Sciences/ ; KL2TR002002//National Institutes of Health/ ; UL1TR002003//National Institutes of Health/ ; }, abstract = {Conflicting evidence exists on the epidemiology of type 2 diabetes mellitus (T2DM) among patients with sickle cell disease (SCD). This study measured the prevalence, incidence and clinical outcomes associated with T2DM in a large US population of commercially-insured adults aged ≥20 years with SCD between 2009 and 2014. Among 7070 patients with SCD, the mean age (median) was 39 (37) years and 60·8% were female. The standardized prevalence of T2DM among patients with SCD showed a modest increase, from 15·7% to 16·5% (P trend = 0·026), and was comparable to African-American respondents to the National Health and Nutrition Examination Survey (18·2%). Over 17 024 person-years, the crude incidence rate for T2DM was 25·4 per 1000 person-years. Incident T2DM was associated with comorbid hypertension (hazard ratio [HR] = 1·45, 95% confidence interval [CI] 1·14-1·83), and dyslipidaemia (HR = 1·43, 95%CI 1·04-1·96). Compared to SCD patients without T2DM, more SCD patients with T2DM had diagnoses of nephropathy (28·0% vs. 9·5%; P < 0·001), neuropathy (17·7% vs. 5·2%; P < 0·001) and stroke (24·1% vs. 9·2%; P < 0·001). Prevalence of T2DM in SCD patients is similar to the general African American population with an increasing trend in recent years. These trends support routine screening for T2DM in aging patients with SCD, especially those with comorbid hypertension and/or dyslipidaemia.}, }
@article {pmid30713414, year = {2019}, author = {Duggan, C and Molina, Y and Carosso, E and Ibarra, G and Thompson, B}, title = {County of Residence and Screening Practices among Latinas and Non-Latina Whites in Two Rural Communities.}, journal = {Ethnicity &amp; disease}, volume = {29}, number = {1}, pages = {31-38}, doi = {10.18865/ed.29.1.31}, pmid = {30713414}, issn = {1049-510X}, abstract = {Objectives: Latinas are less likely than non-Latina Whites (NLW) to utilize mammographic screening and are more likely to be diagnosed with late-stage breast cancer. Here, we examine the effects of county-level factors on guideline-concordant breast-cancer screening behaviors in Latinas and NLWs.<br><br>Design: Latinas (N=108) and NLW women (N=132) aged >40 years, residing in two adjacent rural, medically underserved counties in eastern Washington State, completed a baseline questionnaire on mammography utilization and demographics.<br><br>Main Outcome Measures: Differences in socioeconomic variables and knowledge of screening practices were examined by ethnicity and county of residence. Predictors of having had a mammogram within the past two years were analyzed using multivariate logistic regression.<br><br>Results: Ethnicity was not associated with having a guideline-concordant mammogram; however, age (odds ratio [OR]=1.04, 95%CI:1.01-1.08); having >12 years of education (OR=2.09, 95%CI:1.16-3.79); having a regular clinic for health care (OR=2.22, 95%CI:1.05-4.70); having had a prior clinical breast exam (OR=5.07, 95%CI:1.71-15.02), and county of residence (OR=2.27, 95%CI:1.18-4.37) were all associated with having had a guideline-concordant mammogram.<br><br>Conclusions: County of residence and having had a prior CBE were strong predictors of screening utilization. Community-level factors in medically underserved areas may influence screening patterns.}, }
@article {pmid30712663, year = {2019}, author = {Larsen, TG and Hackmon, R and Geraghty, DE and Hviid, TVF}, title = {Fetal human leukocyte antigen-C and maternal killer-cell immunoglobulin-like receptors in cases of severe preeclampsia.}, journal = {Placenta}, volume = {75}, number = {}, pages = {27-33}, doi = {10.1016/j.placenta.2018.11.008}, pmid = {30712663}, issn = {1532-3102}, abstract = {INTRODUCTION: The pathogenesis of preeclampsia may involve inadequate trophoblast invasion caused by excessive inhibition of uterine natural killer cells (uNK) by extravillous trophoblast cells (EVT). This may be the result of a combination of maternal killer-cell immunoglobin-like receptor (KIR) AA genotype and fetal human leukocyte antigen-C2 (HLA-C2) genotype. A few studies have reported a significantly increased frequency of the maternal KIR AA/fetal HLA-C2 combination in cases of preeclampsia compared to controls.<br><br>METHODS: Study subjects were 259 cases of severe preeclampsia/eclampsia and 259 matched pregnant women without preeclampsia or eclampsia. All pregnancies were singleton pregnancies, and mothers were preferentially primigravidae. Blood samples from women and their newborns were obtained from the Danish National Birth Cohort (DNBC) and the Danish Neonatal Screening Biobank. Significant differences in the frequencies of KIR AA and HLA-C2 between cases and controls were investigated.<br><br>RESULTS: No significant difference was observed between cases and controls in the frequency of maternal KIR AA (OR = 0.86, 95%CI = 0.60-1.23, P = 0.41), neither when the fetus carried an HLA-C2 allele (OR = 0.85, 95%CI = 0.52-1.38, P = 0.51), nor when the fetus carried an HLA-C2 allele more than its mother (OR = 0.75, 95%CI = 0.34-1.64, P = 0.47).<br><br>CONCLUSION: The Results show no influence of HLA-C/KIR genetic variation on the risk of severe preeclampsia, contrary to what some previous studies have observed. An explanation could be that severe preeclampsia represents a separate pathological entity compared to mild preeclampsia.}, }
@article {pmid30711779, year = {2019}, author = {Cooper, JP and Farah, RJ and Stevenson, PA and Gooley, TA and Storb, R and Scott, BL}, title = {Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.01.033}, pmid = {30711779}, issn = {1523-6536}, abstract = {Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by the destruction of hematopoietic cells through activation of the complement system with manifestations that can be life-threatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the sole cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement-mediated hemolysis in patients with PNH since its approval by the Food and Drug Administration in 2007. We examined outcomes of HCT in patients with PNH to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre-HCT or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least 1 HCT, with 4 patients requiring a second HCT for graft failure. The median age at the time of first HCT was 30.0 years (range, 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH, and the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of the patients, myeloid malignancy (myelodysplastic syndrome, myeloproliferative neoplasm, or acute myelogenous leukemia) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of the 55 first HCTs, 26 were performed with myeloablative conditioning, 27 were performed with reduced-intensity conditioning, and 2 sets of identical twins underwent HCT without any conditioning. Donor types included HLA-matched related in 38.2%, HLA-matched unrelated in 34.5%, single HLA-allele mismatched unrelated in 16.4%, umbilical cord blood in 5.5%, syngeneic in 3.6%, and HLA-haploidentical in 1.8%. The median duration of follow-up in surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. The median time to neutrophil and platelet engraftment was 17 days and 19 days, respectively; all but 2 patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH subtype affected survival. Nineteen patients died during follow-up, including 12 patients before day +365. Six patients received treatment with eculizumab before HCT, and 2 were treated after HCT. All patients treated with eculizumab were alive at a median follow-up of 2.3 years (range, .2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (aGVHD), with grade I skin aGVHD in 1 patient and no aGVHD in the other patient, and no chronic GVHD at 2.1 and 4.1 years post-HCT, respectively. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in 2 patients who received eculizumab after HCT.}, }
@article {pmid30711778, year = {2019}, author = {Stohs, E and Chow, VA and Liu, C and Bourassa, L and Miles-Jay, A and Knight, J and Sweet, A and Storer, BE and Mielcarek, M and Pergam, SA}, title = {Limited Utility of Outpatient Surveillance Blood Cultures in Hematopoietic Cell Transplant Recipients on High-Dose Steroids for Treatment of Acute Graft-versus-Host-Disease.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.01.031}, pmid = {30711778}, issn = {1523-6536}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {Steroids used to treat acute graft-versus-host-disease (GVHD) are believed to blunt clinical symptoms of infection. We aimed to assess the value of weekly surveillance blood cultures (SBCs) drawn in an outpatient setting from hematopoietic cell transplant (HCT) patients receiving high-dose steroids. We hypothesized that most positive outpatient surveillance cultures would be low-pathogenicity, gram-positive organisms and would lead to excess vancomycin therapy. We conducted a retrospective review of blood cultures collected from a cohort of adult HCT patients enrolled in a clinical trial of acute GVHD therapy with high-dose steroids (prednisone-equivalent doses ≥ .5 mg/kg/day) between April 2009 and May 2013. SBCs were defined as those collected weekly from central venous catheters in the outpatient setting while patients were receiving high-dose steroids. Cultures obtained as part of a symptom workup or as follow-up for documented bacteremia were excluded. Clinical data were collected using center databases supplemented by medical record review. One hundred twenty-seven HCT recipients were eligible for inclusion in the study. A total of 1015 SBCs were obtained, with a median of 8 cultures (interquartile range, 5 to 10) per patient. Forty-two organisms were isolated from 36 of 1015 cultures (3.5%) in 30 unique patients, or 1 positive culture per 28 blood cultures drawn. The most frequently detected organisms were coagulase-negative Staphylococci (25/1015 [2.5%]). Gram-negative organisms were rare (4/1015 [.4%]. Antibiotics were administered to most patients with positive surveillance cultures (33/36 [92%]). Six were admitted to the hospital for treatment; none needed intensive care or died from their bacteremia. Vancomycin was the most frequently administered antibiotic, comprising 256 of 376 total days (68%) of antibiotic received by the cohort with a median duration of 10days ((interquartile range, 7 to 14). Weekly outpatient SBCs obtained from asymptomatic patients on high-dose glucocorticoids for treatment of acute GVHD after allogeneic HCT were infrequently positive, and most organisms were low-pathogenicity organisms. SBCs also led to excess antibiotic exposure and costs, suggesting benefits of such ambulatory screening may be of limited value in this setting.}, }
@article {pmid30711064, year = {2019}, author = {Adamson, B and El-Sadr, W and Dimitrov, D and Gamble, T and Beauchamp, G and Carlson, JJ and Garrison, L and Donnell, D}, title = {The Cost-Effectiveness of Financial Incentives for Viral Suppression: HPTN 065 Study.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {22}, number = {2}, pages = {194-202}, doi = {10.1016/j.jval.2018.09.001}, pmid = {30711064}, issn = {1524-4733}, support = {T32 HS013853/HS/AHRQ HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Anti-HIV Agents/*economics/therapeutic use ; Anti-Retroviral Agents/economics/therapeutic use ; Clinical Trials as Topic/economics/methods ; Cost-Benefit Analysis/*methods ; Female ; HIV Infections/drug therapy/*economics/epidemiology ; Humans ; Male ; Middle Aged ; *Models, Theoretical ; United States/epidemiology ; }, abstract = {OBJECTIVE: To evaluate the cost-effectiveness of financial incentives for human immunodeficiency virus (HIV) viral suppression compared to standard of care.<br><br>STUDY DESIGN: Mathematical model of 2-year intervention offering financial incentives ($70 quarterly) for viral suppression (<400 copies/ml3) based on the HPTN 065 clinical trial with HIV patients in the Bronx, NY and Washington, D.C.<br><br>METHODS: A disease progression model with HIV transmission risk equations was developed following guidelines from the Second Panel on Cost-Effectiveness in Health and Medicine. We used health care sector and societal perspectives, 3% discount rate, and lifetime horizon. Data sources included trial data (baseline N = 16,208 patients), CDC HIV Surveillance data, and published literature. Outcomes were costs (2017 USD), quality-adjusted life years (QALYs), HIV infections prevented, and incremental cost-effectiveness ratio (ICER).<br><br>RESULTS: Financial incentives for viral suppression were estimated to be cost-saving from a societal perspective and cost-effective ($49,877/QALY) from a health care sector perspective. Compared to the standard of care, financial incentives gain 0.06 QALYs and lower discounted lifetime costs by $4210 per patient. The model estimates that incentivized patients transmit 9% fewer infections than the standard-of-care patients. In the sensitivity analysis, ICER 95% credible intervals ranged from cost-saving to $501,610/QALY with 72% of simulations being cost-effective using a $150,000/QALY threshold. Modeling results are limited by uncertainty in efficacy from the clinical trial.<br><br>CONCLUSIONS: Financial incentives, as used in HTPN 065, are estimated to improve quality and length of life, reduce HIV transmissions, and save money from a societal perspective. Financial incentives offer a promising option for enhancing the benefits of medication in the United States.}, }
@article {pmid30710518, year = {2019}, author = {Verdial, F and Madtes, D and Hwang, B and Mulligan, M and Odem-Davis, K and Waworuntu, R and Wood, D and Farjah, F}, title = {A Prediction Model for Nodal Disease among Patients with Non-Small Cell Lung Cancer.}, journal = {The Annals of thoracic surgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.athoracsur.2018.12.041}, pmid = {30710518}, issn = {1552-6259}, support = {T32 DK070555/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: We characterized the performance characteristics of guideline-recommended invasive mediastinal staging for lung cancer and developed a prediction model for nodal disease as a potential alternative approach to staging.<br><br>METHODS: We conducted a prospective cohort study of adults with suspected/ confirmed non-small cell lung cancer without evidence of distant metastatic disease (by computed tomography/positron emission tomography) who underwent nodal evaluation by invasive mediastinal staging and/or at the time of resection. The true-positive rate (TPR) was the proportion of patients with true nodal disease selected to undergo invasive mediastinal staging based on guideline recommendations, and the false-positive rate (FPR) was the proportion of patients without true nodal disease selected to undergo invasive mediastinal staging. Logistic regression was used to predict nodal disease using radiographic predictors.<br><br>RESULTS: Among 123 eligible subjects, 31 (25%) had pathologically confirmed nodal disease. A guideline-recommended invasive staging strategy had a TPR and FPR of 100% and 65%, respectively. The prediction model fit the data well (goodness-of-fit test p=0.55) and had excellent discrimination (optimism corrected c-statistic 0.78, 95% confidence interval 0.72-0.89). Exploratory analysis revealed that use of the prediction model could achieve a FPR of 44% at a TPR of 97%.<br><br>CONCLUSIONS: A guideline-recommended strategy for invasive mediastinal staging selects all patients with true nodal disease and a majority of patients without nodal disease for invasive mediastinal staging. Our prediction model appears to maintain (within a margin of error) the sensitivity of a guideline-recommended invasive staging strategy and has the potential to reduce the use of invasive procedures.}, }
@article {pmid30709839, year = {2019}, author = {Chang, H and Yao, S and Tritchler, D and Hullar, MA and Lampe, JW and Thompson, LU and McCann, SE}, title = {Genetic Variation in Steroid and Xenobiotic Metabolizing Pathways and Enterolactone Excretion Before and After Flaxseed Intervention in African American and European American Women.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {28}, number = {2}, pages = {265-274}, doi = {10.1158/1055-9965.EPI-18-0826}, pmid = {30709839}, issn = {1538-7755}, support = {U01 CA161809/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Metabolism and excretion of the phytoestrogen enterolactone (ENL), which has been associated with breast cancer risk, may be affected by variation in steroid hormone and xenobiotic-metabolizing genes.<br><br>METHODS: We conducted a randomized, crossover flaxseed intervention study in 252 healthy, postmenopausal women [137 European ancestry (EA) and 115 African ancestry (AA)] from western New York. Participants were randomly assigned to maintain usual diet or consume 10 g/day ground flaxseed for 6 weeks. After a 2-month washout period, participants crossed over to the other diet condition for an additional 6 weeks. Urinary ENL excretion was measured by gas chromatography-mass spectrometry and 70 polymorphisms in 29 genes related to steroid hormone and xenobiotic metabolism were genotyped. Mixed additive genetic models were constructed to examine association of genetic variation with urinary ENL excretion at baseline and after the flaxseed intervention.<br><br>RESULTS: SNPs in several genes were nominally (P < 0.05) associated with ENL excretion at baseline and/or after intervention: ESR1, CYP1B1, COMT, CYP3A5, ARPC1A, BCL2L11, SHBG, SLCO1B1, and ZKSCAN5. A greater number of SNPs were associated among AA women than among EA women, and no SNPs were associated in both races. No SNP-ENL associations were statistically significant after correction for multiple comparisons.<br><br>CONCLUSIONS: Variation in several genes related to steroid hormone metabolism was associated with lignan excretion at baseline and/or after flaxseed intervention among postmenopausal women.<br><br>IMPACT: These findings may contribute to our understanding of the differences observed in urinary ENL excretion among AA and EA women and thus hormone-related breast cancer risk.}, }
@article {pmid30709739, year = {2019}, author = {Dingens, AS and Arenz, D and Weight, H and Overbaugh, J and Bloom, JD}, title = {An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes.}, journal = {Immunity}, volume = {50}, number = {2}, pages = {520-532.e3}, doi = {10.1016/j.immuni.2018.12.017}, pmid = {30709739}, issn = {1097-4180}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; DP1 DA039543/DA/NIDA NIH HHS/United States ; R01 AI127893/AI/NIAID NIH HHS/United States ; R01 AI120961/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, abstract = {Anti-HIV broadly neutralizing antibodies (bnAbs) have revealed vaccine targets on the virus's envelope (Env) protein and are themselves promising immunotherapies. The efficacy of bnAb-based therapies and vaccines depends in part on how readily the virus can escape neutralization. Although structural studies can define contacts between bnAbs and Env, only functional studies can define mutations that confer escape. Here, we mapped how all possible single amino acid mutations in Env affect neutralization of HIV by nine bnAbs targeting five epitopes. For most bnAbs, mutations at only a small fraction of structurally defined contact sites mediated escape, and most escape occurred at sites near, but not in direct contact with, the antibody. The Env mutations selected by two pooled bnAbs were similar to those expected from the combination of the bnAbs's independent action. Overall, our mutation-level antigenic atlas provides a comprehensive dataset for understanding viral immune escape and refining therapies and vaccines.}, }
@article {pmid30707763, year = {2019}, author = {Ketterl, TG and Syrjala, KL and Casillas, J and Jacobs, LA and Palmer, SC and McCabe, MS and Ganz, PA and Overholser, L and Partridge, A and Rajotte, EJ and Rosenberg, AR and Risendal, B and Rosenstein, DL and Baker, KS}, title = {Lasting effects of cancer and its treatment on employment and finances in adolescent and young adult cancer survivors.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31985}, pmid = {30707763}, issn = {1097-0142}, support = {T32 CA009351/CA/NCI NIH HHS/United States ; CA215134//National Cancer Institute/ ; P30 CA015704/CA/NCI NIH HHS/United States ; T32CA009351//Ruth L. Kirschstein National Research Service Award/ ; CA201179//National Cancer Institute/ ; 5P30 CA015704//National Cancer Institute/ ; R01 CA215134/CA/NCI NIH HHS/United States ; CA204378//National Cancer Institute/ ; //Livestrong Foundation/ ; }, abstract = {BACKGROUND: The impact of cancer and its treatment on employment and financial burden in adolescents/young adults (AYAs) is not fully known.<br><br>METHODS: Eligibility for this cross-sectional study of AYA cancer survivors included the diagnosis of a malignancy between ages 18 and 39 years and survey completion within 1 to 5 years from diagnosis and ≥1 year after therapy completion. Participants were selected randomly from the tumor registries of 7 participating sites and completed an online patient-reported outcomes survey to assess employment and financial concerns. Treatment data were abstracted from medical records. Data were analyzed across diagnoses and by tumor site using logistic regression and Wald-based 95% confidence intervals adjusting for age (categorized), sex, insurance status, education (categorized), and treatment exposures.<br><br>RESULTS: Participants included 872 survivors (breast cancer, n = 241; thyroid cancer, n = 126; leukemia/lymphoma, n = 163; other malignancies, n = 342). Exposure to chemotherapy in breast cancer survivors was associated with an increase in self-reported mental impairment in work tasks (odds ratio [OR], 2.66) and taking unpaid time off (OR, 2.62); survivors of &quot;other&quot; malignancies reported an increase in mental impairment of work tasks (OR, 3.67) and borrowing >$10,000 (OR, 3.43). Radiation exposure was associated with an increase of mental impairment in work tasks (OR, 2.05) in breast cancer survivors, taking extended paid time off work in thyroid cancer survivors (OR, 5.05), and physical impairment in work tasks in survivors of &quot;other&quot; malignancies (OR, 3.11). Finally, in survivors of &quot;other&quot; malignancies, having undergone surgery was associated with an increase in physical (OR, 3.11) and mental impairment (OR, 2.31) of work tasks.<br><br>CONCLUSIONS: Cancer treatment has a significant impact on AYA survivors' physical and mental work capacity and time off from work.}, }
@article {pmid30705922, year = {2019}, author = {Lux, CT and Pattabhi, S and Berger, M and Nourigat, C and Flowers, DA and Negre, O and Humbert, O and Yang, JG and Lee, C and Jacoby, K and Bernstein, I and Kiem, HP and Scharenberg, A and Rawlings, DJ}, title = {TALEN-Mediated Gene Editing of HBG in Human Hematopoietic Stem Cells Leads to Therapeutic Fetal Hemoglobin Induction.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {12}, number = {}, pages = {175-183}, doi = {10.1016/j.omtm.2018.12.008}, pmid = {30705922}, issn = {2329-0501}, support = {K12 HL087165/HL/NHLBI NIH HHS/United States ; R01 HL136135/HL/NHLBI NIH HHS/United States ; T32 CA009351/CA/NCI NIH HHS/United States ; }, abstract = {Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia.}, }
@article {pmid30705421, year = {2019}, author = {Bolouri, H and Farrar, JE and Triche, T and Ries, RE and Lim, EL and Alonzo, TA and Ma, Y and Moore, R and Mungall, AJ and Marra, MA and Zhang, J and Ma, X and Liu, Y and Liu, Y and Auvil, JMG and Davidsen, TM and Gesuwan, P and Hermida, LC and Salhia, B and Capone, S and Ramsingh, G and Zwaan, CM and Noort, S and Piccolo, SR and Kolb, EA and Gamis, AS and Smith, MA and Gerhard, DS and Meshinchi, S}, title = {Publisher Correction: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.}, journal = {Nature medicine}, volume = {25}, number = {3}, pages = {530}, doi = {10.1038/s41591-019-0369-7}, pmid = {30705421}, issn = {1546-170X}, abstract = {In the version of this article originally published, the color key in Fig. 1a was wrong. In the Cytogenetics key, the box over t(8;21) originally was green. It should have been red, matching the color of the sections of the pie graphs below the key that were labeled with 15% and 19%.}, }
@article {pmid30703192, year = {2019}, author = {Feijen, EAM and Leisenring, WM and Stratton, KL and Ness, KK and van der Pal, HJH and van Dalen, EC and Armstrong, GT and Aune, GJ and Green, DM and Hudson, MM and Loonen, J and Oeffinger, KC and Robison, LL and Yasui, Y and Kremer, LCM and Chow, EJ}, title = {Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2018.6634}, pmid = {30703192}, issn = {2374-2445}, abstract = {Importance: Anthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children's Oncology Group substitution rules consider daunorubicin and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin.<br><br>Objective: To determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone.<br><br>This multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005.<br><br>Exposures: Cumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records.<br><br>Main Outcomes and Measures: Cardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin) was estimated for each dose category as a ratio of the hazard ratios, and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories.<br><br>Results: Of 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model.<br><br>Conclusions and Relevance: In a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.}, }
@article {pmid30700828, year = {2019}, author = {Cao, J and Zhu, Z and Wang, H and Nichols, TC and Lui, GYL and Deng, S and Rejto, PA and VanArsdale, T and Hardwick, JS and Weinrich, SL and Wei, P}, title = {Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer.}, journal = {Oncogene}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41388-019-0708-7}, pmid = {30700828}, issn = {1476-5594}, abstract = {The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care.}, }
@article {pmid30700568, year = {2019}, author = {Rivkin, SE and Moon, J and Iriarte, DS and Bailey, E and Sloan, HL and Goodman, GE and BonDurant, AE and Velijovich, D and Wahl, T and Jiang, P and Shah, CA and Drescher, C and Fer, MF and Kaplan, HG and Ellis, ED}, title = {Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.}, journal = {International journal of gynecological cancer : official journal of the International Gynecological Cancer Society}, volume = {}, number = {}, pages = {}, doi = {10.1136/ijgc-2018-000035}, pmid = {30700568}, issn = {1525-1438}, abstract = {OBJECTIVE: Our goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose.<br><br>METHODS: In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis.<br><br>RESULTS: The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 BRCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3-4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1-2 non-hematologic toxicities.<br><br>CONCLUSIONS: Olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt.<br><br>TRIAL REGISTRATION NUMBER: NCT01650376.}, }
@article {pmid30700444, year = {2019}, author = {Zhu, Y and Wei, Y and Zhang, R and Dong, X and Shen, S and Zhao, Y and Bai, J and Albanes, D and Caporaso, NE and Landi, MT and Zhu, B and Chanock, SJ and Gu, F and Lam, S and Tsao, MS and Shepherd, FA and Tardon, A and Fernández-Somoano, A and Fernandez-Tardon, G and Chen, C and Barnett, MJ and Doherty, J and Bojesen, SE and Johansson, M and Brennan, P and McKay, JD and Carreras-Torres, R and Muley, T and Risch, A and Wichmann, HE and Bickeboeller, H and Rosenberger, A and Rennert, G and Saliba, W and Arnold, SM and Field, JK and Davies, MPA and Marcus, MW and Wu, X and Ye, Y and Le Marchand, L and Wilkens, LR and Melander, O and Manjer, J and Brunnström, H and Hung, RJ and Liu, G and Brhane, Y and Kachuri, L and Andrew, AS and Duell, EJ and Kiemeney, LA and van der Heijden, EHFM and Haugen, A and Zienolddiny, S and Skaug, V and Grankvist, K and Johansson, M and Woll, PJ and Cox, A and Taylor, F and Teare, DM and Lazarus, P and Schabath, MB and Aldrich, MC and Houlston, RS and McLaughlin, J and Stevens, VL and Shen, H and Hu, Z and Dai, J and Amos, CI and Han, Y and Zhu, D and Goodman, GE and Chen, F and Christiani, DC}, title = {Elevated platelet count appears to be causally associated with increased risk of lung cancer: A Mendelian randomization analysis.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-18-0356}, pmid = {30700444}, issn = {1538-7755}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; P50 CA119997/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear.<br><br>METHODS: We performed single and combined multiple instrumental variable Mendelian Randomization(MR) analysis by an inverse-weighted (IVW) method, in addition to a series of sensitivity analyses. Summary data for associations between single nucleotide polymorphisms (SNPs) and platelet count is from a recent publication including 48,666 Caucasian Europeans and International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls analyze associations between candidate single nucleotide polymorphisms and lung cancer risk.<br><br>RESULTS: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall NSCLC (OR, 1.62; 95%CI, 1.15-2.27; P = 0.005) and 200% increased risk for small cell lung cancer (OR, 3.00; 95%CI, 1.27-7.06; P = 0.01), respectively. Results showed only a trending association with NSCLC histological subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings.<br><br>CONCLUSIONS: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible anti-platelet interventions for lung cancer prevention.<br><br>IMPACT: Our findings suggest a causal relationship of increased platelet count and risk of lung cancer, which also provide a better understanding of lung cancer etiology and potential evidence for anti-platelet interventions for lung cancer prevention.}, }
@article {pmid30700041, year = {2019}, author = {Makhsous, S and Mohammad, HM and Schenk, JM and Mamishev, AV and Kristal, AR}, title = {A Novel Mobile Structured Light System in Food 3D Reconstruction and Volume Estimation.}, journal = {Sensors (Basel, Switzerland)}, volume = {19}, number = {3}, pages = {}, doi = {10.3390/s19030564}, pmid = {30700041}, issn = {1424-8220}, support = {5U01CA135133-04//Foundation for the National Institutes of Health/ ; }, abstract = {. Over the past ten years, diabetes has rapidly become more prevalent in all age demographics and especially in children. Improved dietary assessment techniques are necessary for epidemiological studies that investigate the relationship between diet and disease. Current nutritional research is hindered by the low accuracy of traditional dietary intake estimation methods used for portion size assessment. This paper presents the development and validation of a novel instrumentation system for measuring accurate dietary intake for diabetic patients. This instrument uses a mobile Structured Light System (SLS), which measures the food volume and portion size of a patient's diet in daily living conditions. The SLS allows for the accurate determination of the volume and portion size of a scanned food item. Once the volume of a food item is calculated, the nutritional content of the item can be estimated using existing nutritional databases. The system design includes a volume estimation algorithm and a hardware add-on that consists of a laser module and a diffraction lens. The experimental results demonstrate an improvement of around 40% in the accuracy of the volume or portion size measurement when compared to manual calculation. The limitations and shortcomings of the system are discussed in this manuscript.}, }
@article {pmid30699000, year = {2019}, author = {Bradley, P and Thomas, PG}, title = {Using T Cell Receptor Repertoires to Understand the Principles of Adaptive Immune Recognition.}, journal = {Annual review of immunology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-immunol-042718-041757}, pmid = {30699000}, issn = {1545-3278}, abstract = {Adaptive immune recognition is mediated by antigen receptors on B and T cells generated by somatic recombination during lineage development. The high level of diversity resulting from this process posed technical limitations that previously limited the comprehensive analysis of adaptive immune recognition. Advances over the last ten years have produced data and approaches allowing insights into how T cells develop, evolutionary signatures of recombination and selection, and the features of T cell receptors that mediate epitope-specific binding and T cell activation. The size and complexity of these data have necessitated the generation of novel computational and analytical approaches, which are transforming how T cell immunology is conducted. Here we review the development and application of novel biological, theoretical, and computational methods for understanding T cell recognition and discuss the potential for improved models of receptor:antigen interactions. Expected final online publication date for the Annual Review of Immunology Volume 37 is April 26, 2019 Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, }
@article {pmid30698728, year = {2019}, author = {Cheung, KJ and Davidson, NE}, title = {Double Trouble: Contralateral Breast Cancer Risk Management in the Modern Era.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djy203}, pmid = {30698728}, issn = {1460-2105}, }
@article {pmid30698716, year = {2019}, author = {de Vries, PS and Brown, MR and Bentley, AR and Sung, YJ and Winkler, TW and Ntalla, I and Schwander, K and Kraja, AT and Guo, X and Franceschini, N and Cheng, CY and Sim, X and Vojinovic, D and Huffman, JE and Musani, SK and Li, C and Feitosa, MF and Richard, MA and Noordam, R and Aschard, H and Bartz, TM and Bielak, LF and Deng, X and Dorajoo, R and Lohman, KK and Manning, AK and Rankinen, T and Smith, AV and Tajuddin, SM and Evangelou, E and Graff, M and Alver, M and Boissel, M and Chai, JF and Chen, X and Divers, J and Gandin, I and Gao, C and Goel, A and Hagemeijer, Y and Harris, SE and Hartwig, FP and He, M and Horimoto, ARVR and Hsu, FC and Jackson, AU and Kasturiratne, A and Komulainen, P and Kühnel, B and Laguzzi, F and Lee, JH and Luan, J and Lyytikäinen, LP and Matoba, N and Nolte, IM and Pietzner, M and Riaz, M and Said, MA and Scott, RA and Sofer, T and Stancáková, A and Takeuchi, F and Tayo, BO and van der Most, PJ and Varga, TV and Wang, Y and Ware, EB and Wen, W and Yanek, LR and Zhang, W and Zhao, JH and Afaq, S and Amin, N and Amini, M and Arking, DE and Aung, T and Ballantyne, C and Boerwinkle, E and Broeckel, U and Campbell, A and Canouil, M and Charumathi, S and Chen, YI and Connell, JM and de Faire, U and de Las Fuentes, L and de Mutsert, R and de Silva, HJ and Ding, J and Dominiczak, AF and Duan, Q and Eaton, CB and Eppinga, RN and Faul, JD and Fisher, V and Forrester, T and Franco, OH and Friedlander, Y and Ghanbari, M and Giulianini, F and Grabe, HJ and Grove, ML and Gu, CC and Harris, TB and Heikkinen, S and Heng, CK and Hirata, M and Hixson, JE and Howard, BV and Ikram, MA and ,  and Jacobs, DR and Johnson, C and Jonas, JB and Kammerer, CM and Katsuya, T and Khor, CC and Kilpeläinen, TO and Koh, WP and Koistinen, HA and Kolcic, I and Kooperberg, C and Krieger, JE and Kritchevsky, SB and Kubo, M and Kuusisto, J and Lakka, TA and Langefeld, CD and Langenberg, C and Launer, LJ and Lehne, B and Lemaitre, RN and Li, Y and Liang, J and Liu, J and Liu, K and Loh, M and Louie, T and Mägi, R and Manichaikul, AW and McKenzie, CA and Meitinger, T and Metspalu, A and Milaneschi, Y and Milani, L and Mohlke, KL and Mosley, TH and Mukamal, KJ and Nalls, MA and Nauck, M and Nelson, CP and Sotoodehnia, N and O'Connell, JR and Palmer, ND and Pazoki, R and Pedersen, NL and Peters, A and Peyser, PA and Polasek, O and Poulter, N and Raffel, LJ and Raitakari, OT and Reiner, AP and Rice, TK and Rich, SS and Robino, A and Robinson, JG and Rose, LM and Rudan, I and Schmidt, CO and Schreiner, PJ and Scott, WR and Sever, P and Shi, Y and Sidney, S and Sims, M and Smith, BH and Smith, JA and Snieder, H and Starr, JM and Strauch, K and Tan, N and Taylor, KD and Teo, YY and Tham, YC and Uitterlinden, AG and van Heemst, D and Vuckovic, D and Waldenberger, M and Wang, L and Wang, Y and Wang, Z and Wei, WB and Williams, C and Wilson, G and Wojczynski, MK and Yao, J and Yu, B and Yu, C and Yuan, JM and Zhao, W and Zonderman, AB and Becker, DM and Boehnke, M and Bowden, DW and Chambers, JC and Deary, IJ and Esko, T and Farrall, M and Franks, PW and Freedman, BI and Froguel, P and Gasparini, P and Gieger, C and Horta, BL and Kamatani, Y and Kato, N and Kooner, JS and Laakso, M and Leander, K and Lehtimäki, T and ,  and Magnusson, PKE and Penninx, B and Pereira, AC and Rauramaa, R and Samani, NJ and Scott, J and Shu, XO and van der Harst, P and Wagenknecht, LE and Wang, YX and Wareham, NJ and Watkins, H and Weir, DR and Wickremasinghe, AR and Zheng, W and Elliott, P and North, KE and Bouchard, C and Evans, MK and Gudnason, V and Liu, CT and Liu, Y and Psaty, BM and Ridker, PM and van Dam, RM and Kardia, SLR and Zhu, X and Rotimi, CN and Mook-Kanamori, DO and Fornage, M and Kelly, TN and Fox, ER and Hayward, C and van Duijn, CM and Tai, ES and Wong, TY and Liu, J and Rotter, JI and Gauderman, WJ and Province, MA and Munroe, PB and Rice, K and Chasman, DI and Cupples, LA and Rao, DC and Morrison, AC}, title = {Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwz005}, pmid = {30698716}, issn = {1476-6256}, support = {MR/K002414/1//Medical Research Council/United Kingdom ; G0700931//Medical Research Council/United Kingdom ; MR/L01632X/1//Medical Research Council/United Kingdom ; R01 HL142302/HL/NHLBI NIH HHS/United States ; MR/L01341X/1//Medical Research Council/United Kingdom ; G0601966//Medical Research Council/United Kingdom ; MC_UU_12015/1//Medical Research Council/United Kingdom ; R01 AG055406/AG/NIA NIH HHS/United States ; RG/12/16/29939//British Heart Foundation/United Kingdom ; }, abstract = {An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.}, }
@article {pmid30698666, year = {2019}, author = {Zuo, H and Ueland, PM and Midttun, Ø and Tell, GS and Fanidi, A and Zheng, W and Shu, X and Xiang, Y and Wu, J and Prentice, R and Pettinger, M and Thomson, CA and Giles, GG and Hodge, A and Cai, Q and Blot, WJ and Johansson, M and Hultdin, J and Grankvist, K and Stevens, VL and McCullough, ML and Weinstein, SJ and Albanes, D and Ziegler, RG and Freedman, ND and Caporaso, NE and Langhammer, A and Hveem, K and Næss, M and Buring, JE and Lee, I and Gaziano, JM and Severi, G and Zhang, X and Stampfer, MJ and Han, J and Zeleniuch-Jacquotte, A and Marchand, LL and Yuan, J and Wang, R and Koh, W and Gao, Y and Ericson, U and Visvanathan, K and Jones, MR and Relton, C and Brennan, P and Johansson, M and Ulvik, A}, title = {Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {30}, number = {3}, pages = {478-485}, doi = {10.1093/annonc/mdz002}, pmid = {30698666}, issn = {1569-8041}, support = {P01 CA087969/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; U01 CA155340/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known.<br><br>MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models.<br><br>RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23).<br><br>CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.}, }
@article {pmid30698482, year = {2019}, author = {Jones, SMW and Nguyen, T and Chennupati, S}, title = {Association of Financial Burden With Self-Rated and Mental Health in Older Adults With Cancer.}, journal = {Journal of aging and health}, volume = {}, number = {}, pages = {898264319826428}, doi = {10.1177/0898264319826428}, pmid = {30698482}, issn = {1552-6887}, abstract = {OBJECTIVE: Financial problems in cancer survivors are associated with distress and reduced quality of life. Most studies have been cross-sectional, and a longitudinal study is needed to guide clinical interventions.<br><br>METHOD: We used data from two surveys of the National Health and Aging Trends Study (NHATS). Participants (n = 307) reported whether they experienced six indicators of financial burden. The Patient Health Questionnaire 4 assessed depressive symptoms and general anxiety. Cross-lagged panel analyses assessed whether financial burden predicted distress and health or vice versa.<br><br>RESULTS: In the total sample, financial burden at the first survey predicted depressive symptoms (p < .01), general anxiety (p < .01), and self-rated health (p < .01) at the second survey. Depressive symptoms, general anxiety, and self-rated health at the first survey did not predict later financial burden (ps > .05).<br><br>DISCUSSION: Results suggest financial problems predict later distress and poor health. This study highlights the need to address financial burden in cancer survivors.}, }
@article {pmid30698046, year = {2019}, author = {Zager, RA and Johnson, ACM}, title = {Acute kidney injury induces dramatic p21 upregulation via a novel, glucocorticoid-activated, pathway.}, journal = {American journal of physiology. Renal physiology}, volume = {316}, number = {4}, pages = {F674-F681}, doi = {10.1152/ajprenal.00571.2018}, pmid = {30698046}, issn = {1522-1466}, support = {R01 DK038432/DK/NIDDK NIH HHS/United States ; }, abstract = {The cyclin kinase inhibitor p21 is acutely upregulated during acute kidney injury (AKI) and exerts cytoprotective effects. A proposed mechanism is oxidant stress-induced activation of p53, the dominant p21 transcription factor. Glycerol-induced rhabdomyolysis induces profound renal oxidant stress. Hence, we studied this AKI model to determine whether p53 activation corresponds with p21 gene induction and/or whether alternative mechanism(s) might be involved. CD-1 mice were subjected to glycerol-induced AKI. After 4 or 18 h, plasma, urinary, and renal cortical p21 protein and mRNA levels were assessed. Renal p53 activation was gauged by measurement of both total and activated (Ser15-phosphorylated) p53 and p53 mRNA levels. Glycerol evoked acute, progressive increases in renal cortical p21 mRNA and protein levels. Corresponding plasma (~25-fold) and urinary (~75-fold) p21 elevations were also observed. Renal cortical ratio of total to phosphorylated (Ser15) p53 rose three- to fourfold. However, the p53 inhibitor pifithrin-α failed to block glycerol-induced p21 gene induction, suggesting that an alternative p21 activator might also be at play. To this end, it was established that glycerol-induced AKI 1) dramatically increased plasma (~5-fold) and urinary (~75-fold) cortisol levels, 2) the glucocorticoid receptor antagonist mifepristone blocked glycerol-induced p21 mRNA and protein accumulation, and 3) dexamethasone or cortisol injections markedly increased p21 protein and mRNA in both normal and glycerol-treated mice, although no discernible p53 protein or mRNA increases were observed. We conclude that AKI-induced &quot;systemic stress&quot; markedly increases plasma and urinary cortisol, which can then activate renal p21 gene expression, at least in part, via a glucocorticoid receptor-dependent signaling pathway. Discernible renal cortical p53 increases are not required for this dexamethasone-mediated p21 response.}, }
@article {pmid30696998, year = {2019}, author = {Hong, S and Rybicki, L and Corrigan, D and Dabney, J and Hamilton, BK and Kalaycio, M and Lawrence, C and McLellan, L and Sobecks, R and Lee, SJ and Majhail, NS}, title = {Psychosocial Assessment of Candidates for Transplant (PACT) as a tool for psychological and social evaluation of allogeneic hematopoietic cell transplantation recipients.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0455-y}, pmid = {30696998}, issn = {1476-5365}, support = {R01-CA215134//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Psychosocial Assessment of Candidates for Transplant (PACT) is a tool originally developed to address psychosocial risks in solid organ transplant recipients and has the potential for application to hematopoietic cell transplantation (HCT) recipients. In a retrospective cohort study, we reviewed 404 adult allogeneic HCT cases from 2003 to 2014 to identify predictors of adverse psychosocial status as determined by PACT. Final PACT rating was poor/borderline (score 0-1) in 5%, acceptable (score 2) in 22%, good (score 3) in 44%, and excellent (score 4) in 29% recipients. In multivariable regression, higher PACT score was associated with White race (odds ratio [OR] 2.95, P < 0.001), having a related donor (OR 1.61, P = 0.015), and a higher quality of life score (OR 1.22/ 10-point increase in FACT-BMT total score, P < 0.001). PACT score correlated with all quality of life subscales. The final PACT score was associated with non-relapse mortality (HR 0.82/ 1-point increase, p = 0.03) in multivariable analysis that considered patient and disease factors, but not in models that also included transplant-related factors and performance status. PACT score was not associated with overall survival. PACT can be considered as part of a comprehensive psychosocial assessment for identifying patients who may require additional resources around allogeneic HCT.}, }
@article {pmid30696997, year = {2019}, author = {Abidi, MZ and Hari, P and Chen, M and Kim, S and Battiwala, M and Dahi, PB and Diaz, MA and Gale, RP and Ganguly, S and Gergis, U and Green, J and Hildebrandt, G and Hill, JA and Komanduri, K and Lazarus, H and Marks, D and Nishihori, T and Olsson, R and Seo, S and Ustun, C and Yared, J and Yin, D and Wingard, J and Wirk, BM and Auletta, J and Lindemans, C and Riches, M}, title = {Virus detection in the cerebrospinal fluid of hematopoietic stem cell transplant recipients is associated with poor patient outcomes: a CIBMTR contemporary longitudinal study.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0457-9}, pmid = {30696997}, issn = {1476-5365}, support = {U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Limited data exist on characteristics of central nervous system viruses (CNS-V) in allogeneic hematopoietic stem cell transplant (HCT) recipients. Between 2007 and 2015, the Center for International Blood and Marrow Transplant Research (CIBMTR) received information on 27,532 patients undergoing HCT. Of these, centers reported 165 HCT recipients with CNS-V detected in cerebrospinal fluid within 6 months after HCT. CNS viruses predominantly included human herpes virus 6 (HHV-6) (73%), followed by Epstein-Barr Virus (10%), cytomegalovirus (3%), varicella zoster virus (3%), herpes simplex virus (3%) and Adenovirus (3%). Median time of viral detection in CNS was 31 days after HCT; and viral detection was earlier in patients with CNS HHV-6. Concurrent viremia occurred in 52% of patients. Cord blood transplant recipients (CBT) accounted for the majority (53%) of patients with CNS-V. Myeloablative conditioning (65%), use of fludarabine (63%), or use of anti-thymocyte globulin (61%) were also predominant. Overall survival from the time of detection of CNS-V was 50% at 6 months and 30% at 5 years. Infections were the leading cause of death (32%). In summary, CBT recipients predominated in the population with CNS-V. Outcomes after CNS-V were poor with significant mortality seen in the first 6 months.}, }
@article {pmid30696834, year = {2019}, author = {Hidalgo, BA and Sofer, T and Qi, Q and Schneiderman, N and Chen, YI and Kaplan, RC and Avilés-Santa, ML and North, KE and Arnett, DK and Szpiro, A and Cai, J and Yu, B and Boerwinkle, E and Papanicolaou, G and Laurie, CC and Rotter, JI and Stilp, AM}, title = {Associations between SLC16A11 variants and diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {843}, doi = {10.1038/s41598-018-35707-7}, pmid = {30696834}, issn = {2045-2322}, support = {HHSN268201300005C/HL/NHLBI NIH HHS/United States ; HHSN268201300001//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201300001C/HL/NHLBI NIH HHS/United States ; R25 HL126146/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; P30 DK079626/DK/NIDDK NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; K01 HL129892/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; R01 DK101855/DK/NIDDK NIH HHS/United States ; K01 HL130609-02//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01HC65237/HL/NHLBI NIH HHS/United States ; U54 TR000123/TR/NCATS NIH HHS/United States ; R25HL126146//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; K01 HL130609/HL/NHLBI NIH HHS/United States ; }, abstract = {Five sequence variants in SLC16A11 (rs117767867, rs13342692, rs13342232, rs75418188, and rs75493593), which occur in two non-reference haplotypes, were recently shown to be associated with diabetes in Mexicans from the SIGMA consortium. We aimed to determine whether these previous findings would replicate in the HCHS/SOL Mexican origin group and whether genotypic effects were similar in other HCHS/SOL groups. We analyzed these five variants in 2492 diabetes cases and 5236 controls from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes U.S. participants from six diverse background groups (Mainland groups: Mexican, Central American, and South American; and Caribbean groups: Puerto Rican, Cuban, and Dominican). We estimated the SNP-diabetes association in the six groups and in the combined sample. We found that the risk alleles occur in two non-reference haplotypes in HCHS/SOL, as in the SIGMA Mexicans. The haplotype frequencies were very similar between SIGMA Mexicans and the HCHS/SOL Mainland groups, but different in the Caribbean groups. The SLC16A11 sequence variants were significantly associated with risk for diabetes in the Mexican origin group (P = 0.025), replicating the SIGMA findings. However, these variants were not significantly associated with diabetes in a combined analysis of all groups, although the power to detect such effects was 85% (assuming homogeneity of effects among the groups). Additional analyses performed separately in each of the five non-Mexican origin groups were not significant. We also analyzed (1) exclusion of young controls and, (2) SNP by BMI interactions, but neither was significant in the HCHS/SOL data. The previously reported effects of SLC16A11 variants on diabetes in Mexican samples was replicated in a large Mexican-American sample, but these effects were not significant in five non-Mexican Hispanic/Latino groups sampled from U.S. populations. Lack of replication in the HCHS/SOL non-Mexicans, and in the entire HCHS/SOL sample combined may represent underlying genetic heterogeneity. These results indicate a need for future genetic research to consider heterogeneity of the Hispanic/Latino population in the assessment of disease risk, but add to the evidence suggesting SLC16A11 as a potential therapeutic target for type 2 diabetes.}, }
@article {pmid30696752, year = {2019}, author = {Lokken, EM and Manguro, GO and Abdallah, A and Ngacha, C and Shafi, J and Kiarie, J and Jaoko, W and Srinivasan, S and Fiedler, TL and Munch, MM and Fredricks, DN and McClelland, RS and Balkus, JE}, title = {Association between vaginal washing and detection of Lactobacillus by culture and quantitative PCR in HIV-seronegative Kenyan women: a cross-sectional analysis.}, journal = {Sexually transmitted infections}, volume = {}, number = {}, pages = {}, doi = {10.1136/sextrans-2018-053769}, pmid = {30696752}, issn = {1472-3263}, abstract = {OBJECTIVES: Vaginal washing has been associated with reductions in cultivable Lactobacillus and an increased risk of both bacterial vaginosis (BV) and HIV infection. The effect of vaginal washing on the quantity of individual Lactobacillus species is not well characterised. This analysis tested the hypothesis that vaginal washing would be associated with a lower likelihood of Lactobacillus spp. detected by both culture and quantitative PCR (qPCR).<br><br>METHODS: We conducted a cross-sectional study of 272 HIV-seronegative women enrolled in an open-cohort study in Mombasa, Kenya. Vaginal washing and sexual risk behaviours were assessed using face-to-face interviews. Vaginal Lactobacillus spp. were detected using cultivation and PCR methods, with L. crispatus, L. jensenii and L. iners concentrations measured using qPCR assays targeting the 16S rRNA gene. Poisson regression with robust SEs was used to assess associations between vaginal washing and Lactobacillus detection by culture and qPCR.<br><br>RESULTS: Eighty percent (n=217) of participants reported vaginal washing in the prior week. One-fifth (n=58) of participants had BV by Nugent score. In unadjusted analysis, vaginal washing was associated with a 45% decreased likelihood of Lactobacillus spp. detection by culture (prevalence ratio (PR): 0.55, 95% CI 0.37 to 0.82). Adjusting for age and condomless sex in the prior week did not change the magnitude of the association (adjusted PR (aPR): 0.56, 95% CI (0.37 to 0.85). Vaginal washing was associated with approximately a 40% reduction in L. crispatus detection (aPR: 0.57, 95% CI 0.36 to 0.92), but was not significantly associated with L. jensenii (aPR: 0.68, 95% CI 0.42 to 1.09) or L. iners detection (aPR: 1.03, 95% CI 0.92 to 1.15).<br><br>CONCLUSIONS: Vaginal washing in the prior week was associated with a significantly reduced likelihood of detecting cultivable Lactobacillus and L. crispatus by qPCR. Given associations between Lactobacillus detection and improved reproductive health outcomes, these results provide motivation for additional study of vaginal washing cessation interventions to improve vaginal health.}, }
@article {pmid30696625, year = {2019}, author = {Sippel, TR and Radtke, S and Olsen, TM and Kiem, HP and Rongvaux, A}, title = {Human hematopoietic stem cell maintenance and myeloid cell development in next-generation humanized mouse models.}, journal = {Blood advances}, volume = {3}, number = {3}, pages = {268-274}, doi = {10.1182/bloodadvances.2018023887}, pmid = {30696625}, issn = {2473-9537}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 HL115128/HL/NHLBI NIH HHS/United States ; U19 AI096111/AI/NIAID NIH HHS/United States ; R01 HL098489/HL/NHLBI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, }
@article {pmid30693552, year = {2019}, author = {Chew, J and Carpenter, J and Haase, AM}, title = {Living with epilepsy in adolescence-A qualitative study of young people's experiences in Singapore: Peer socialization, autonomy, and self-esteem.}, journal = {Child: care, health and development}, volume = {45}, number = {2}, pages = {241-250}, doi = {10.1111/cch.12648}, pmid = {30693552}, issn = {1365-2214}, support = {NA//SingHealth Talent Development Fund/ ; }, abstract = {BACKGROUND: Systematic reviews of quantitative research on the effects of childhood epilepsy have established its association with higher levels of psychiatric diagnosis, externalizing and internalizing problems, lower health-related quality of life, social competence, and poorer academic achievements, compared with their peers. However, much less is known about young people's experiences of living with epilepsy and its impact on their development from their own perspectives.<br><br>METHODS: Semistructured interviews were conducted with 15 young people aged between 13 and 16 years. Participants were recruited as part of a larger mixed methods study examining individual and family influences on outcomes for young people with epilepsy. These young people attended an epilepsy clinic in KK Women's and Children's Hospital, Singapore. The framework approach to data management and analyses involved both inductive and deductive generation of themes.<br><br>RESULTS: Findings from young people's interviews provided in-depth descriptions of stressful circumstances encountered. Interconnectedness between severity of the impairment and its impact on key developmental tasks, such as independence, autonomy, and social development, were emphasized. Seizures and illness-related demands disrupted their day-to-day functioning and challenged their abilities to meet these tasks. In addition to these impairment effects, young people's experiences of social exclusion were also affected by social and environmental factors, which act as systemic barriers to participation. In turn, this has an effect on their self-esteem. Nevertheless, young people reported positive experiences, such as support from both family and friends, which served as protective factors against the stress of living with a chronic medical condition.<br><br>CONCLUSION: The demands of epilepsy affect various domains of young people's lives. In order to obtain a holistic understanding of young people's inclusion or exclusion to participation, it is necessary to consider impairment effects, barriers to doing, and barriers to being.}, }
@article {pmid30692054, year = {2019}, author = {Mueller, BA and Crane, D and Doody, DR and Stuart, SN and Schiff, MA}, title = {Pregnancy course, infant outcomes, rehospitalization, and mortality among women with intellectual disability.}, journal = {Disability and health journal}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.dhjo.2019.01.004}, pmid = {30692054}, issn = {1876-7583}, abstract = {BACKGROUND: Pregnant women with intellectual disability (ID) may have greater levels of comorbidity and decreased care access, social support, or ability to monitor their status and communicate needs, but few studies have examined their pregnancy course and outcome, and little is known about their longer-term maternal and infant health.<br><br>OBJECTIVE: We compared pre-pregnancy characteristics, pregnancy outcomes, and rehospitalization <2 years after delivery among women with and without ID.<br><br>METHOD: We identified all women with ID and randomly selected a 10:1 comparison group of women without ID with singleton live birth deliveries in Washington State population-based linked birth-hospital discharge data 1987-2012. Multivariable regressions estimated adjusted odds ratios comparing pre-pregnancy characteristics. In cohort analyses, we estimated relative risks (RR) and 95% confidence intervals (CI) for outcomes.<br><br>RESULTS: Women with ID (N = 103) more often had gestational diabetes (RR 3.39, 95% CI 1.81-6.37), preeclampsia (RR 1.88, 95% CI 1.03-3.42), and inadequate prenatal care (RR 2.48, 95% CI 1.67-3.70). Their infants more often were small for gestational age (RR 1.78, 95% CI 1.10-2.89). Need for rehospitalization postpartum was not increased among women with ID or their infants.<br><br>CONCLUSION: Reasons for increased preeclampsia and gestational diabetes among pregnant women with ID are unclear. Barriers to inadequate prenatal care are multifactorial and warrant further study, with consideration that wellness during pregnancy and other times involves social, familial and clinical support systems responsive to each woman's needs.}, }
@article {pmid30691120, year = {2019}, author = {Yimam, M and Horm, T and Wright, L and Jiao, P and Hong, M and Brownell, L and Jia, Q}, title = {UP1306: A Composition Containing Standardized Extracts of Acacia catechu and Morus alba for Arthritis Management.}, journal = {Nutrients}, volume = {11}, number = {2}, pages = {}, doi = {10.3390/nu11020272}, pmid = {30691120}, issn = {2072-6643}, mesh = {Acacia/*chemistry ; Animals ; Arthritis, Experimental/*drug therapy/pathology ; Cytokines/metabolism ; Male ; Morus/*chemistry ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Severity of Illness Index ; Tarsal Joints/chemistry/drug effects/pathology ; }, abstract = {Osteoarthritis (OA) is characterized by progressive articular cartilage degradation. Although there have been significant advances in OA management, to date, there are no effective treatment options to modify progression of the disease. We believe these unmet needs could be bridged by nutrients from natural products. Collagen induced arthritis in rats was developed and utilized to evaluate anti-inflammatory and cartilage protection activity of orally administered botanical composition, UP1306 (50 mg/kg) and Methotrexate (75 µg/kg) daily for three weeks. Objective arthritis severity markers, urine, synovial lavage, and serum were collected. At necropsy, the hock joint from each rat was collected for histopathology analysis. Urinary cartilage degradation marker (CTX-II), pro-inflammatory cytokines (tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6), and proteases (Matrix Metallopeptidase 3 (MMP3) and 13) were measured. Rats treated with UP1306 showed statistically significant improvements in arthritis severity markers, including uCTX-II (91.4% vs. collagen-induced arthritis (CIA)), serum IL-1β, TNF-α, and IL-6 levels as well as synovial MMP-13. The histopathology data were also well aligned with the severity score of arthritis for both UP1306 and Methotrexate. UP1306, a botanical composition that contains a standardized blend of extracts from the heartwood of Acacia catechu and the root bark of Morus alba, could potentially be considered as a dietary supplement product for the management of arthritis.}, }
@article {pmid30689757, year = {2019}, author = {Diallo, A and Diop, OM and Diop, D and Niang, MN and Sugimoto, JD and Ortiz, JR and Faye, EHA and Diarra, B and Goudiaby, D and Lewis, KDC and Emery, SL and Zangeneh, SZ and Lafond, KE and Sokhna, C and Halloran, ME and Widdowson, MA and Neuzil, KM and Victor, JC}, title = {Effectiveness of seasonal influenza vaccination of children in Senegal during a year of vaccine mismatch: a cluster-randomized trial.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciz066}, pmid = {30689757}, issn = {1537-6591}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; }, abstract = {Background: Population effects of influenza vaccination of children have not been extensively studied, especially in tropical developing countries. In rural Senegal, we assessed the total (primary objective) and indirect effectiveness of inactivated influenza vaccine, trivalent (IIV3).<br><br>Methods: In this double-blind, cluster-randomized trial, villages were randomly allocated (1:1) for high-coverage vaccination of children aged 6 months through 10 years with 2008-09 northern hemisphere IIV3 or inactivated polio vaccine (IPV). Vaccinees were monitored for serious adverse events. All village residents, vaccinated and unvaccinated, were monitored for signs and symptoms of influenza illness using weekly home visits and surveillance in designated clinics. The primary outcome was all laboratory-confirmed symptomatic influenza.<br><br>Results: Between May 23 and July 11, 2009, 20 villages were randomized, and 66.5% of age-eligible children were enrolled (3918 in IIV3 villages and 3848 in IPV villages). Follow-up continued until May 28, 2010. Four unrelated serious adverse events were identified. Among vaccinees, total effectiveness against illness caused by seasonal influenza virus (presumed all drifted A/H3N2 based on antigenic characterization data) circulating at high rates among children was 43.6% (95% CI, 18.6% to 60.9%). Indirect effectiveness against seasonal A/H3N2 was 15.4% (95% CI, -22.0% to 41.3%). Total effectiveness against illness caused by pandemic influenza virus (A/H1N1pdm09) was -52.1% (95% CI, -177.2% to 16.6%).<br><br>Conclusions: IIV3 provided statistically significant, moderate protection to children in Senegal against circulating pre-2010 seasonal influenza strains but not against A/H1N1pdm09 not included in the vaccine. No indirect effects were measured. Further study in low resource populations is warranted.}, }
@article {pmid30689736, year = {2019}, author = {Stein, JE and Soni, A and Danilova, L and Cottrell, TR and Gajewski, TF and Hodi, FS and Bhatia, S and Urba, WJ and Sharfman, WH and Wind-Rotolo, M and Edwards, R and Lipson, EJ and Taube, JM}, title = {Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/annonc/mdz019}, pmid = {30689736}, issn = {1569-8041}, abstract = {Background: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.<br><br>Materials and Methods: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&amp;E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score (from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)). This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively-collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).<br><br>Results: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to non-responders, (p ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (p = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, p = 0.015). Neither tumoral necrosis nor pre-treatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.<br><br>Conclusions: Features of immune-mediated tumor regression on routine H&amp;E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely-available.}, }
@article {pmid30689667, year = {2019}, author = {Dye, KN and Welcker, M and Clurman, BE and Roman, A and Galloway, DA}, title = {Merkel cell polyomavirus Tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and β-TrCP.}, journal = {PLoS pathogens}, volume = {15}, number = {1}, pages = {e1007543}, doi = {10.1371/journal.ppat.1007543}, pmid = {30689667}, issn = {1553-7374}, support = {R01 CA193808/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA183435/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, mesh = {Antigens, Neoplasm/metabolism ; Antigens, Polyomavirus Transforming/*metabolism ; Antigens, Viral, Tumor/metabolism ; Carcinoma, Merkel Cell/metabolism ; F-Box-WD Repeat-Containing Protein 7/*metabolism ; HEK293 Cells ; Humans ; Ligases/metabolism ; Merkel Cells ; Merkel cell polyomavirus/immunology/*metabolism/pathogenicity ; Oncogene Proteins/metabolism ; Polyomavirus Infections/metabolism ; Protein Domains ; Tumor Virus Infections/virology ; Ubiquitin/metabolism ; Virus Replication ; beta-Transducin Repeat-Containing Proteins/metabolism ; }, abstract = {Merkel cell polyomavirus (MCPyV) accounts for 80% of all Merkel cell carcinoma (MCC) cases through expression of two viral oncoproteins: the truncated large T antigen (LT-t) and small T antigen (ST). MCPyV ST is thought to be the main driver of cellular transformation and has also been shown to increase LT protein levels through the activity of its Large-T Stabilization Domain (LSD). The ST LSD was reported to bind and sequester several ubiquitin ligases, including Fbw7 and β-TrCP, and thereby stabilize LT-t and several other Fbw7 targets including c-Myc and cyclin E. Therefore, the ST LSD is thought to contribute to transformation by promoting the accumulation of these oncoproteins. Targets of Fbw7 and β-TrCP contain well-defined, conserved, phospho-degrons. However, as neither MCPyV LT, LT-t nor ST contain the canonical Fbw7 phospho-degron, we sought to further investigate the proposed model of ST stabilization of LT-t and transformation. In this study, we provide several lines of evidence that fail to support a specific interaction between MCPyV T antigens and Fbw7 or β-TrCP by co-immunoprecipitation or functional consequence. Although MCPyV ST does indeed increase LT protein levels through its Large-T Stabilization domain (LSD), this is accomplished independently of Fbw7. Therefore, our study indicates a need for further investigation into the role and mechanism(s) of MCPyV T antigens in viral replication, latency, transformation, and tumorigenesis.}, }
@article {pmid30686360, year = {2018}, author = {Gauthier, J}, title = {.}, journal = {Bulletin du cancer}, volume = {105 Suppl 2}, number = {}, pages = {S214-S217}, doi = {10.1016/S0007-4551(19)30052-9}, pmid = {30686360}, issn = {1769-6917}, mesh = {Antigens, CD19/*therapeutic use ; Drug Approval ; Humans ; Immunotherapy, Adoptive/adverse effects/*methods ; Lymphoma, Large B-Cell, Diffuse/therapy ; Lymphoma, Non-Hodgkin/therapy ; Receptors, Antigen, T-Cell/immunology/*therapeutic use ; *Receptors, Chimeric Antigen ; T-Lymphocytes/*immunology ; United States ; }, abstract = {CAR-T THERAPY: CURRENT USE IN THE UNITED STATES IN 2018: Treatment with T-cells engineered with chimeric antigen receptors (CAR T-cell therapy) has been a field of intense research in the United States since the 1980s. The recent approval in August 2017 of Kymriah (tisagenlecleucel) opened the door to broader access to CAR T-cell therapy outside of clinical trials. Here, we aim to give the reader a practical summary of the current practices in the US when considering a patient for CAR T-cell therapy. Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene.}, }
@article {pmid30685677, year = {2019}, author = {Boursiquot, BC and Larson, JC and Shalash, OA and Vitolins, MZ and Soliman, EZ and Perez, MV}, title = {Vitamin D with calcium supplementation and risk of atrial fibrillation in postmenopausal women.}, journal = {American heart journal}, volume = {209}, number = {}, pages = {68-78}, doi = {10.1016/j.ahj.2018.12.006}, pmid = {30685677}, issn = {1097-6744}, abstract = {BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in adults. Although vitamin D deficiency is associated with AF risk factors, retrospective studies of association with AF have shown mixed results. We sought to determine the efficacy of calcium and vitamin D (CaD) supplementation for AF prevention in a randomized trial.<br><br>METHODS: We performed a secondary analysis of the Women's Health Initiative trial on CaD supplementation versus placebo. We linked participants to their Medicare claims to ascertain incident AF.<br><br>RESULTS: Among 16,801 included participants, there were 1,453 (8.6%) cases of incident AF over an average of 4.5 years, at an average rate of 19.9 events per 1,000 person-years. We found no significant difference in incident AF rates between the CaD and placebo arms (hazard ratio 1.02 for CaD vs placebo, 95% CI 0.92-1.13). After multivariate adjustment, there was no significant association between baseline 25-hydroxyvitamin D serum levels and incident AF (hazard ratio 0.92 for lowest subgroup vs highest subgroup, 95% CI 0.66-1.28).<br><br>CONCLUSIONS: We present the first analysis of a large randomized trial of daily vitamin D supplementation for AF prevention. We found that CaD had no effect on incidence of AF in Women's Health Initiative CaD trial participants. We also found that baseline serum 25-hydroxyvitamin D level was not predictive of long-term incident AF risk.}, }
@article {pmid30684389, year = {2019}, author = {Trabert, B and Michels, KA and Anderson, GL and Brinton, LA and Falk, RT and Geczik, AM and Harris, HR and Pan, K and Pfeiffer, RM and Qi, L and Rohan, T and Wentzensen, N and Xu, X}, title = {Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.32157}, pmid = {30684389}, issn = {1097-0215}, support = {HHSN268201100001C//National Heart, Lung, and Blood Institute/ ; HHSN268201100002C//National Heart, Lung, and Blood Institute/ ; HHSN268201100003C//National Heart, Lung, and Blood Institute/ ; HHSN268201100004C//National Heart, Lung, and Blood Institute/ ; HHSN268201100046C//National Heart, Lung, and Blood Institute/ ; HHSN271201100004C//National Heart, Lung, and Blood Institute/ ; K22 CA193860//National Cancer Institute/ ; //The Intramural Research Program of the National Cancer Institute/ ; }, abstract = {Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC-MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68-11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47-8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer.}, }
@article {pmid30683880, year = {2019}, author = {Jiang, X and Finucane, HK and Schumacher, FR and Schmit, SL and Tyrer, JP and Han, Y and Michailidou, K and Lesseur, C and Kuchenbaecker, KB and Dennis, J and Conti, DV and Casey, G and Gaudet, MM and Huyghe, JR and Albanes, D and Aldrich, MC and Andrew, AS and Andrulis, IL and Anton-Culver, H and Antoniou, AC and Antonenkova, NN and Arnold, SM and Aronson, KJ and Arun, BK and Bandera, EV and Barkardottir, RB and Barnes, DR and Batra, J and Beckmann, MW and Benitez, J and Benlloch, S and Berchuck, A and Berndt, SI and Bickeböller, H and Bien, SA and Blomqvist, C and Boccia, S and Bogdanova, NV and Bojesen, SE and Bolla, MK and Brauch, H and Brenner, H and Brenton, JD and Brook, MN and Brunet, J and Brunnström, H and Buchanan, DD and Burwinkel, B and Butzow, R and Cadoni, G and Caldés, T and Caligo, MA and Campbell, I and Campbell, PT and Cancel-Tassin, G and Cannon-Albright, L and Campa, D and Caporaso, N and Carvalho, AL and Chan, AT and Chang-Claude, J and Chanock, SJ and Chen, C and Christiani, DC and Claes, KBM and Claessens, F and Clements, J and Collée, JM and Correa, MC and Couch, FJ and Cox, A and Cunningham, JM and Cybulski, C and Czene, K and Daly, MB and deFazio, A and Devilee, P and Diez, O and Gago-Dominguez, M and Donovan, JL and Dörk, T and Duell, EJ and Dunning, AM and Dwek, M and Eccles, DM and Edlund, CK and Edwards, DRV and Ellberg, C and Evans, DG and Fasching, PA and Ferris, RL and Liloglou, T and Figueiredo, JC and Fletcher, O and Fortner, RT and Fostira, F and Franceschi, S and Friedman, E and Gallinger, SJ and Ganz, PA and Garber, J and García-Sáenz, JA and Gayther, SA and Giles, GG and Godwin, AK and Goldberg, MS and Goldgar, DE and Goode, EL and Goodman, MT and Goodman, G and Grankvist, K and Greene, MH and Gronberg, H and Gronwald, J and Guénel, P and Håkansson, N and Hall, P and Hamann, U and Hamdy, FC and Hamilton, RJ and Hampe, J and Haugen, A and Heitz, F and Herrero, R and Hillemanns, P and Hoffmeister, M and Høgdall, E and Hong, YC and Hopper, JL and Houlston, R and Hulick, PJ and Hunter, DJ and Huntsman, DG and Idos, G and Imyanitov, EN and Ingles, SA and Isaacs, C and Jakubowska, A and James, P and Jenkins, MA and Johansson, M and Johansson, M and John, EM and Joshi, AD and Kaneva, R and Karlan, BY and Kelemen, LE and Kühl, T and Khaw, KT and Khusnutdinova, E and Kibel, AS and Kiemeney, LA and Kim, J and Kjaer, SK and Knight, JA and Kogevinas, M and Kote-Jarai, Z and Koutros, S and Kristensen, VN and Kupryjanczyk, J and Lacko, M and Lam, S and Lambrechts, D and Landi, MT and Lazarus, P and Le, ND and Lee, E and Lejbkowicz, F and Lenz, HJ and Leslie, G and Lessel, D and Lester, J and Levine, DA and Li, L and Li, CI and Lindblom, A and Lindor, NM and Liu, G and Loupakis, F and Lubiński, J and Maehle, L and Maier, C and Mannermaa, A and Marchand, LL and Margolin, S and May, T and McGuffog, L and Meindl, A and Middha, P and Miller, A and Milne, RL and MacInnis, RJ and Modugno, F and Montagna, M and Moreno, V and Moysich, KB and Mucci, L and Muir, K and Mulligan, AM and Nathanson, KL and Neal, DE and Ness, AR and Neuhausen, SL and Nevanlinna, H and Newcomb, PA and Newcomb, LF and Nielsen, FC and Nikitina-Zake, L and Nordestgaard, BG and Nussbaum, RL and Offit, K and Olah, E and Olama, AAA and Olopade, OI and Olshan, AF and Olsson, H and Osorio, A and Pandha, H and Park, JY and Pashayan, N and Parsons, MT and Pejovic, T and Penney, KL and Peters, WHM and Phelan, CM and Phipps, AI and Plaseska-Karanfilska, D and Pring, M and Prokofyeva, D and Radice, P and Stefansson, K and Ramus, SJ and Raskin, L and Rennert, G and Rennert, HS and van Rensburg, EJ and Riggan, MJ and Risch, HA and Risch, A and Roobol, MJ and Rosenstein, BS and Rossing, MA and De Ruyck, K and Saloustros, E and Sandler, DP and Sawyer, EJ and Schabath, MB and Schleutker, J and Schmidt, MK and Setiawan, VW and Shen, H and Siegel, EM and Sieh, W and Singer, CF and Slattery, ML and Sorensen, KD and Southey, MC and Spurdle, AB and Stanford, JL and Stevens, VL and Stintzing, S and Stone, J and Sundfeldt, K and Sutphen, R and Swerdlow, AJ and Tajara, EH and Tangen, CM and Tardon, A and Taylor, JA and Teare, MD and Teixeira, MR and Terry, MB and Terry, KL and Thibodeau, SN and Thomassen, M and Bjørge, L and Tischkowitz, M and Toland, AE and Torres, D and Townsend, PA and Travis, RC and Tung, N and Tworoger, SS and Ulrich, CM and Usmani, N and Vachon, CM and Van Nieuwenhuysen, E and Vega, A and Aguado-Barrera, ME and Wang, Q and Webb, PM and Weinberg, CR and Weinstein, S and Weissler, MC and Weitzel, JN and West, CML and White, E and Whittemore, AS and Wichmann, HE and Wiklund, F and Winqvist, R and Wolk, A and Woll, P and Woods, M and Wu, AH and Wu, X and Yannoukakos, D and Zheng, W and Zienolddiny, S and Ziogas, A and Zorn, KK and Lane, JM and Saxena, R and Thomas, D and Hung, RJ and Diergaarde, B and McKay, J and Peters, U and Hsu, L and García-Closas, M and Eeles, RA and Chenevix-Trench, G and Brennan, PJ and Haiman, CA and Simard, J and Easton, DF and Gruber, SB and Pharoah, PDP and Price, AL and Pasaniuc, B and Amos, CI and Kraft, P and Lindström, S}, title = {Shared heritability and functional enrichment across six solid cancers.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {431}, doi = {10.1038/s41467-018-08054-4}, pmid = {30683880}, issn = {2041-1723}, support = {U01 CA199277/CA/NCI NIH HHS/United States ; U01 CA179715/CA/NCI NIH HHS/United States ; UL1 TR000117/TR/NCATS NIH HHS/United States ; U01 CA069417/CA/NCI NIH HHS/United States ; R01 CA092039/CA/NCI NIH HHS/United States ; RP-PG-0707-10031//Department of Health/United Kingdom ; P20 CA090578/CA/NCI NIH HHS/United States ; UM1 CA164917/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R01 CA128931/CA/NCI NIH HHS/United States ; HHSN268201100001I/HL/NHLBI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; U54 CA156733/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; P20 GM103534/GM/NIGMS NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R01 CA092824/CA/NCI NIH HHS/United States ; P30 ES010126/ES/NIEHS NIH HHS/United States ; UM1 CA164973/CA/NCI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; R01 CA176785/CA/NCI NIH HHS/United States ; N01 PC067010/PC/NCI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P50 CA159981/CA/NCI NIH HHS/United States ; R01 CA089085/CA/NCI NIH HHS/United States ; RC4 CA153828/CA/NCI NIH HHS/United States ; U01 CA074799/CA/NCI NIH HHS/United States ; R01 DA017932/DA/NIDA NIH HHS/United States ; P30 CA016056/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; Z01 CP010200/CP/NCI NIH HHS/United States ; P50 CA125183/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; UM1 CA164920/CA/NCI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; HHSN261201000035C/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; R01 CA106414/CA/NCI NIH HHS/United States ; HHSN261201000006C/CP/NCI NIH HHS/United States ; U01 CA194393/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; P30 CA072720/CA/NCI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; R01 CA097396/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; N01 CN067009/CN/NCI NIH HHS/United States ; Z01 ES049033/ES/NIEHS NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; R03 CA113148/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; R01 CA092447/CA/NCI NIH HHS/United States ; K22 CA138563/CA/NCI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; U01 CA188392/CA/NCI NIH HHS/United States ; R01 CA058860/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; P20 RR018787/RR/NCRR NIH HHS/United States ; U01 CA181770/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; R01 CA080742/CA/NCI NIH HHS/United States ; S10 RR025141/RR/NCRR NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA074386/CA/NCI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; G1000143//Medical Research Council/United Kingdom ; R01 CA074850/CA/NCI NIH HHS/United States ; R01 CA176568/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; K07 CA172294/CA/NCI NIH HHS/United States ; R01 CA063678/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; N01PC35137/CA/NCI NIH HHS/United States ; K07 CA092044/CA/NCI NIH HHS/United States ; P50 CA119997/CA/NCI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; U24 CA074806/CA/NCI NIH HHS/United States ; P50 CA058223/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA100374/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; U01 CA098216/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U24 CA097735/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; U01 CA116167/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; Z01 ES044005/ES/NIEHS NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA128978/CA/NCI NIH HHS/United States ; R01 CA090731/CA/NCI NIH HHS/United States ; HHSN261201300011C/RC/CCR NIH HHS/United States ; HHSN261201300012I/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA064277/CA/NCI NIH HHS/United States ; R01 CA047147/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; 14136//Cancer Research UK/United Kingdom ; U19 CA148537/CA/NCI NIH HHS/United States ; D43 TW009112/TW/FIC NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; R01 CA116167/CA/NCI NIH HHS/United States ; R01 CA148667/CA/NCI NIH HHS/United States ; R01 CA177150/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; Z01 ES049030/ES/NIEHS NIH HHS/United States ; P50 CA116201/CA/NCI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; N01PC35142/CA/NCI NIH HHS/United States ; G0401527//Medical Research Council/United Kingdom ; HHSN271201100004C/AG/NIA NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; R03 CA115195/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; P30 CA177558/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; P50 CA097190/CA/NCI NIH HHS/United States ; P50 CA090578/CA/NCI NIH HHS/United States ; HHSN261201300021C/CA/NCI NIH HHS/United States ; R01 CA122443/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN261201000035I/CA/NCI NIH HHS/United States ; R01 CA144040/CA/NCI NIH HHS/United States ; U01 CA098233/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; R01 CA076016/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; U01 CA063464/CA/NCI NIH HHS/United States ; R01 CA132839/CA/NCI NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; R01 CA160669/CA/NCI NIH HHS/United States ; U01 CA058860/CA/NCI NIH HHS/United States ; U01 CA097735/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; U19 CA148112/CA/NCI NIH HHS/United States ; U01 CA196386/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; Z01 CP010119/CP/NCI NIH HHS/United States ; R01 CA149429/CA/NCI NIH HHS/United States ; UM1 CA167551/CA/NCI NIH HHS/United States ; N01RC37004/RC/CCR NIH HHS/United States ; U01 CA098758/CA/NCI NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; N01 CN025403/CA/NCI NIH HHS/United States ; R01 MH107649/MH/NIMH NIH HHS/United States ; R01 CA142081/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; 10119//Cancer Research UK/United Kingdom ; R01 CA069664/CA/NCI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; U01 HG004798/HG/NHGRI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R01 CA063682/CA/NCI NIH HHS/United States ; R01 CA151989/CA/NCI NIH HHS/United States ; N01 CN045165/CN/NCI NIH HHS/United States ; U24 CA074799/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; U01 CA074806/CA/NCI NIH HHS/United States ; U24 CA074800/CA/NCI NIH HHS/United States ; K07 CA095666/CA/NCI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; 10118//Cancer Research UK/United Kingdom ; R01 CA192393/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; R01 DA035825/DA/NIDA NIH HHS/United States ; HHSN261201000121C/CP/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R01 CA140286/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; U01 CA074800/CA/NCI NIH HHS/United States ; R01 CA120120/CA/NCI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; K24 CA169004/CA/NCI NIH HHS/United States ; R01 CA126841/CA/NCI NIH HHS/United States ; R01 CA047305/CA/NCI NIH HHS/United States ; R01 CA111703/CA/NCI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; U01 CA098710/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; 10124//Cancer Research UK/United Kingdom ; UM1 CA182876/CA/NCI NIH HHS/United States ; }, mesh = {Breast Neoplasms/diagnosis/ethnology/*genetics/pathology ; Case-Control Studies ; Colorectal Neoplasms/diagnosis/ethnology/*genetics/pathology ; European Continental Ancestry Group ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Head and Neck Neoplasms/diagnosis/ethnology/*genetics/pathology ; Humans ; *Inheritance Patterns ; Lung Neoplasms/diagnosis/ethnology/*genetics/pathology ; Male ; Mental Disorders/ethnology/genetics/physiopathology ; Neoplasm Proteins/genetics ; Ovarian Neoplasms/diagnosis/ethnology/*genetics/pathology ; Phenotype ; Polymorphism, Single Nucleotide ; Prostatic Neoplasms/diagnosis/ethnology/*genetics/pathology ; Smoking/ethnology/genetics/physiopathology ; }, abstract = {Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.}, }
@article {pmid30679201, year = {2019}, author = {Diab, A and Kao, M and Kehrli, K and Kim, HY and Sidorova, J and Mendez, E}, title = {Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition.}, journal = {Molecular cancer research : MCR}, volume = {}, number = {}, pages = {}, doi = {10.1158/1541-7786.MCR-18-0860}, pmid = {30679201}, issn = {1557-3125}, support = {R01 CA215647/CA/NCI NIH HHS/United States ; }, abstract = {The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, γH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despite evidence of unresolved damage. A faulty G1-S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug.Implications: The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma.}, }
@article {pmid30679032, year = {2018}, author = {Brazel, DM and Jiang, Y and Hughey, JM and Turcot, V and Zhan, X and Gong, J and Batini, C and Weissenkampen, JD and Liu, M and ,  and ,  and Barnes, DR and Bertelsen, S and Chou, YL and Erzurumluoglu, AM and Faul, JD and Haessler, J and Hammerschlag, AR and Hsu, C and Kapoor, M and Lai, D and Le, N and de Leeuw, CA and Loukola, A and Mangino, M and Melbourne, CA and Pistis, G and Qaiser, B and Rohde, R and Shao, Y and Stringham, H and Wetherill, L and Zhao, W and Agrawal, A and Bierut, L and Chen, C and Eaton, CB and Goate, A and Haiman, C and Heath, A and Iacono, WG and Martin, NG and Polderman, TJ and Reiner, A and Rice, J and Schlessinger, D and Scholte, HS and Smith, JA and Tardif, JC and Tindle, HA and van der Leij, AR and Boehnke, M and Chang-Claude, J and Cucca, F and David, SP and Foroud, T and Howson, JMM and Kardia, SLR and Kooperberg, C and Laakso, M and Lettre, G and Madden, P and McGue, M and North, K and Posthuma, D and Spector, T and Stram, D and Tobin, MD and Weir, DR and Kaprio, J and Abecasis, GR and Liu, DJ and Vrieze, S}, title = {Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.}, journal = {Biological psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.biopsych.2018.11.024}, pmid = {30679032}, issn = {1873-2402}, support = {RG/13/13/30194//British Heart Foundation/United Kingdom ; MC_QA137853//Medical Research Council/United Kingdom ; R01 GM126479/GM/NIGMS NIH HHS/United States ; R21 DA040177/DA/NIDA NIH HHS/United States ; MR/L003120/1//Medical Research Council/United Kingdom ; MC_UU_12015/1//Medical Research Council/United Kingdom ; R01 HG008983/HG/NHGRI NIH HHS/United States ; R01 DA042755/DA/NIDA NIH HHS/United States ; U01 DK062370/DK/NIDDK NIH HHS/United States ; R01 DA037904/DA/NIDA NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; }, abstract = {BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.<br><br>METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.<br><br>RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.<br><br>CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.}, }
@article {pmid30677510, year = {2019}, author = {Meier, JA and Haque, M and Fawaz, M and Abdeen, H and Coffey, D and Towlerton, A and Abdeen, A and Toor, A and Warren, E and Reed, J and Kanakry, CG and Keating, A and Luznik, L and Toor, AA}, title = {T Cell Repertoire Evolution after Allogeneic Bone Marrow Transplantation: An Organizational Perspective.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2019.01.021}, pmid = {30677510}, issn = {1523-6536}, abstract = {High-throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire, which makes it difficult to correlate T cell reconstitution with clinical outcomes. The associations identified thus far are of a broadly statistical nature, precluding precise modeling of outcomes based on T cell repertoire development following bone marrow transplantation (BMT). Previous work has demonstrated an inherent, mathematically definable order observed in the T cells from a diverse group of donors, which is perturbed in recipients following BMT. In this study, T cell receptor (TCR)-β sequences from HLA-matched related donor and recipient pairs are analyzed to further develop this methodology. TCR-β sequencing from unsorted and sorted T cell subsets isolated from the peripheral blood samples of BMT donors and recipients show conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR-β VJ segment translational symmetry is preserved post-transplantation and even in cases of acute graft-versus-host disease (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antigens. The complexity of the repertoire is significantly diminished after BMT, and the T cell clonal hierarchy is altered post-transplantation. Low-frequency donor clones tended to take on a higher rank in the recipients following BMT, especially in patients with aGVHD. Over time, the repertoire evolves to a more donor-like state in the recipients who did not develop GVHD as opposed to those who did. The results presented here support new methods of quantifying and characterizing post-transplantation T cell repertoire reconstitution.}, }
@article {pmid30677427, year = {2019}, author = {Chemaly, RF and Hill, JA and Voigt, S and Peggs, KS}, title = {In vitro comparison of currently available and investigational antiviral agents against pathogenic human double-stranded DNA viruses: A systematic literature review.}, journal = {Antiviral research}, volume = {163}, number = {}, pages = {50-58}, doi = {10.1016/j.antiviral.2019.01.008}, pmid = {30677427}, issn = {1872-9096}, abstract = {BACKGROUND: Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA viruses.<br><br>METHODS: A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA viruses; 3) in vitro activity. We summarized data from 210 publications.<br><br>RESULTS: Activity against ≤3 viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all viruses except papillomaviruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus.<br><br>CONCLUSION: Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC50 values. These findings could assist clinical practice and developmental research.}, }
@article {pmid30677048, year = {2019}, author = {Sabo, MC and Balkus, JE and Richardson, BA and Srinivasan, S and Kimani, J and Anzala, O and Schwebke, J and Feidler, TL and Fredricks, DN and McClelland, RS}, title = {Association between vaginal washing and vaginal bacterial concentrations.}, journal = {PloS one}, volume = {14}, number = {1}, pages = {e0210825}, doi = {10.1371/journal.pone.0210825}, pmid = {30677048}, issn = {1932-6203}, support = {T32 AI007044/AI/NIAID NIH HHS/United States ; }, abstract = {Vaginal washing is a common practice associated with adverse outcomes including bacterial vaginosis (BV) and HIV infection. Prior studies have not examined the associations between vaginal washing and individual vaginal bacteria, or whether these associations are independent of the effect of vaginal washing on BV. The purpose of this study was to characterize the association between vaginal washing and the presence and concentrations of vaginal bacteria associated with optimal and sub-optimal vaginal states. The analysis utilized data from participants in the placebo arm of the Preventing Vaginal Infections trial, which enrolled HIV-uninfected women from the United States and Kenya. Detection of bacterial taxa associated with BV was compared between visits with versus without reported vaginal washing. The effect of vaginal washing on a number of vaginal bacteria differed substantially (p<0.05) between the US and Kenya, so results were stratified by country. In US women, vaginal washing was associated with a significantly higher likelihood of detection of BV associated bacterium 1 (BVAB1) (relative risk [RR] 1.55, 95% confidence interval [CI] 1.15-2.09, p = 0.004), BVAB2 (RR 1.99, 95%CI 1.46-2.71, p<0.001), Mageeibacillus indolicus (RR 2.08, 95%CI 1.46-2.96, p<0.001), Atopobium vaginae (RR 1.34, 95%CI 1.13-1.59, p = 0.001), Leptotrichia/Sneathia species (RR 1.66, 95% CI 1.33-2.09, p<0.001), Megasphaera species (RR 1.78, 95%CI 1.34-2.37, p<0.001) and Gardnerella vaginalis (RR 1.08, 95%CI 1.01-1.16, p = 0.02). No significant association between vaginal washing and bacterial detection was found in Kenyan women. Adjustment for bacterial vaginosis diagnosed by Gram stain did not alter these results. This study provides evidence that the association between vaginal washing and detection of individual bacterial taxa can vary regionally. For some vaginal bacteria, the association with vaginal washing may be independent of the effect on Gram stain detection of BV. Larger prospective studies in diverse geographic settings should explore whether eliminating vaginal washing impacts the presence and concentrations of key vaginal bacteria.}, }
@article {pmid30676523, year = {2019}, author = {Zheng, HB and Yeung, C and Summers, C and Lee, D and Wahbeh, G and Braly, K and Suskind, D}, title = {Dietary Therapy in Conjunction with Immunosuppression to Treat Gastrointestinal Graft-Versus-Host Disease (GVHD).}, journal = {Journal of pediatric gastroenterology and nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPG.0000000000002288}, pmid = {30676523}, issn = {1536-4801}, }
@article {pmid30674418, year = {2019}, author = {Khan, AS and Bodem, J and Buseyne, F and Gessain, A and Johnson, W and Kuhn, JH and Kuzmak, J and Lindemann, D and Linial, ML and Löchelt, M and Materniak-Kornas, M and Soares, MA and Switzer, WM}, title = {Corrigendum to &quot;Spumaretroviruses: Updated taxonomy and nomenclature&quot; [Virology 516 (2018) 158-164].}, journal = {Virology}, volume = {528}, number = {}, pages = {}, doi = {10.1016/j.virol.2018.12.018}, pmid = {30674418}, issn = {1096-0341}, }
@article {pmid30674273, year = {2019}, author = {Shean, RC and Makhsous, N and Stoddard, GD and Lin, MJ and Greninger, AL}, title = {VAPiD: a lightweight cross-platform viral annotation pipeline and identification tool to facilitate virus genome submissions to NCBI GenBank.}, journal = {BMC bioinformatics}, volume = {20}, number = {1}, pages = {48}, doi = {10.1186/s12859-019-2606-y}, pmid = {30674273}, issn = {1471-2105}, mesh = {Databases, Nucleic Acid/*standards ; Genome, Viral/*genetics ; Genomics/*methods ; Humans ; }, abstract = {BACKGROUND: With sequencing technologies becoming cheaper and easier to use, more groups are able to obtain whole genome sequences of viruses of public health and scientific importance. Submission of genomic data to NCBI GenBank is a requirement prior to publication and plays a critical role in making scientific data publicly available. GenBank currently has automatic prokaryotic and eukaryotic genome annotation pipelines but has no viral annotation pipeline beyond influenza virus. Annotation and submission of viral genome sequence is a non-trivial task, especially for groups that do not routinely interact with GenBank for data submissions.<br><br>RESULTS: We present Viral Annotation Pipeline and iDentification (VAPiD), a portable and lightweight command-line tool for annotation and GenBank deposition of viral genomes. VAPiD supports annotation of nearly all unsegmented viral genomes. The pipeline has been validated on human immunodeficiency virus, human parainfluenza virus 1-4, human metapneumovirus, human coronaviruses (229E/OC43/NL63/HKU1/SARS/MERS), human enteroviruses/rhinoviruses, measles virus, mumps virus, Hepatitis A-E Virus, Chikungunya virus, dengue virus, and West Nile virus, as well the human polyomaviruses BK/JC/MCV, human adenoviruses, and human papillomaviruses. The program can handle individual or batch submissions of different viruses to GenBank and correctly annotates multiple viruses, including those that contain ribosomal slippage or RNA editing without prior knowledge of the virus to be annotated. VAPiD is programmed in Python and is compatible with Windows, Linux, and Mac OS systems.<br><br>CONCLUSIONS: We have created a portable, lightweight, user-friendly, internet-enabled, open-source, command-line genome annotation and submission package to facilitate virus genome submissions to NCBI GenBank. Instructions for downloading and installing VAPiD can be found at https://github.com/rcs333/VAPiD .}, }
@article {pmid30673779, year = {2019}, author = {Machkovech, HM and Bloom, JD and Subramaniam, AR}, title = {Comprehensive profiling of translation initiation in influenza virus infected cells.}, journal = {PLoS pathogens}, volume = {15}, number = {1}, pages = {e1007518}, doi = {10.1371/journal.ppat.1007518}, pmid = {30673779}, issn = {1553-7374}, support = {T32 AI083203/AI/NIAID NIH HHS/United States ; R35 GM119835/GM/NIGMS NIH HHS/United States ; R01 AI127893/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Birds/genetics ; Codon/genetics ; Codon, Initiator/genetics/metabolism ; Humans ; Influenza A Virus, H5N1 Subtype/genetics ; Influenza in Birds/genetics ; Influenza, Human/genetics ; Orthomyxoviridae/*genetics/pathogenicity ; Orthomyxoviridae Infections/*genetics/metabolism ; Peptide Chain Initiation, Translational/*genetics ; Protein Biosynthesis ; Protein Processing, Post-Translational/genetics ; Proteins/metabolism ; Proteomics/methods ; RNA, Messenger/metabolism ; Ribosomes/metabolism ; Sequence Homology, Amino Acid ; Swine/virology ; Transcriptome/genetics ; }, abstract = {Translation can initiate at alternate, non-canonical start codons in response to stressful stimuli in mammalian cells. Recent studies suggest that viral infection and anti-viral responses alter sites of translation initiation, and in some cases, lead to production of novel immune epitopes. Here we systematically investigate the extent and impact of alternate translation initiation in cells infected with influenza virus. We perform evolutionary analyses that suggest selection against non-canonical initiation at CUG codons in influenza virus lineages that have adapted to mammalian hosts. We then use ribosome profiling with the initiation inhibitor lactimidomycin to experimentally delineate translation initiation sites in a human lung epithelial cell line infected with influenza virus. We identify several candidate sites of alternate initiation in influenza mRNAs, all of which occur at AUG codons that are downstream of canonical initiation codons. One of these candidate downstream start sites truncates 14 amino acids from the N-terminus of the N1 neuraminidase protein, resulting in loss of its cytoplasmic tail and a portion of the transmembrane domain. This truncated neuraminidase protein is expressed on the cell surface during influenza virus infection, is enzymatically active, and is conserved in most N1 viral lineages. We do not detect globally higher levels of alternate translation initiation on host transcripts upon influenza infection or during the anti-viral response, but the subset of host transcripts induced by the anti-viral response is enriched for alternate initiation sites. Together, our results systematically map the landscape of translation initiation during influenza virus infection, and shed light on the evolutionary forces shaping this landscape.}, }
@article {pmid30673723, year = {2019}, author = {Hansen, SG and Womack, J and Scholz, I and Renner, A and Edgel, KA and Xu, G and Ford, JC and Grey, M and St Laurent, B and Turner, JM and Planer, S and Legasse, AW and Richie, TL and Aguiar, JC and Axthelm, MK and Villasante, ED and Weiss, W and Edlefsen, PT and Picker, LJ and Früh, K}, title = {Cytomegalovirus vectors expressing Plasmodium knowlesi antigens induce immune responses that delay parasitemia upon sporozoite challenge.}, journal = {PloS one}, volume = {14}, number = {1}, pages = {e0210252}, doi = {10.1371/journal.pone.0210252}, pmid = {30673723}, issn = {1932-6203}, abstract = {The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While sporozoite vaccines targeting the pre-erythrocytic stage show great promise, it has not been possible to maintain efficacy long-term, likely due to an inability of these vaccines to maintain effector memory T cell responses in the liver. Vaccines based on human cytomegalovirus (HCMV) might overcome this limitation since vectors based on rhesus CMV (RhCMV), the homologous virus in rhesus macaques (RM), elicit and indefinitely maintain high frequency, non-exhausted effector memory T cells in extralymphoid tissues, including the liver. Moreover, RhCMV strain 68-1 elicits CD8+ T cells broadly recognizing unconventional epitopes exclusively restricted by MHC-II and MHC-E. To evaluate the potential of these unique immune responses to protect against malaria, we expressed four Plasmodium knowlesi (Pk) antigens (CSP, AMA1, SSP2/TRAP, MSP1c) in RhCMV 68-1 or in Rh189-deleted 68-1, which additionally elicits canonical MHC-Ia-restricted CD8+ T cells. Upon inoculation of RM with either of these Pk Ag expressing RhCMV vaccines, we obtained T cell responses to each of the four Pk antigens. Upon challenge with Pk sporozoites we observed a delayed appearance of blood stage parasites in vaccinated RM consistent with a 75-80% reduction of parasite release from the liver. Moreover, the Rh189-deleted RhCMV/Pk vectors elicited sterile protection in one RM. Once in the blood, parasite growth was not affected. In contrast to T cell responses induced by Pk infection, RhCMV vectors maintained sustained T cell responses to all four malaria antigens in the liver post-challenge. The delayed appearance of blood stage parasites is thus likely due to a T cell-mediated inhibition of liver stage parasite development. As such, this vaccine approach can be used to efficiently test new T cell antigens, improve current vaccines targeting the liver stage and complement vaccines targeting erythrocytic antigens.}, }
@article {pmid30673620, year = {2019}, author = {Medeiros, BC and Othus, M and Tallman, MS and Sun, Z and Fernandez, HF and Rowe, JM and Lazarus, HM and Appelbaum, FR and Luger, SM and Litzow, MR and Erba, HP}, title = {The relationship between clinical trial accrual volume and outcomes in acute myeloid leukemia: A SWOG/ECOG-ACRIN study (S0106 and E1900).}, journal = {Leukemia research}, volume = {78}, number = {}, pages = {29-33}, doi = {10.1016/j.leukres.2019.01.007}, pmid = {30673620}, issn = {1873-5835}, abstract = {PURPOSE: To study whether institutional clinical trial accrual volume affects clinical outcomes of younger (age less than 61 years) patients with acute myeloid leukemia.<br><br>PATIENTS AND METHODS: We investigated the impact of clinical trial accrual on response rates, early mortality and survival in patients with AML enrolled between 2002 and 2009 into two parallel cooperative group clinical trials SWOG S0106/ECOG-ACRIN E1900. Institutions were classified as low- (LAIs) (≤ 9 enrolled patients) or high-accruing institutions (HAIs) (≥10 enrolled patients). Fisher's exact text and logistic regression analysis were used to analyze the response and early mortality rates. The effect of accrual volume on survival was analyzed by log-rank tests and Cox regression models.<br><br>RESULTS: A total of 1252 patients from 152 institutions were included in the final analyses. The median clinical trial registrations in HAIs was 19 patients (range, 10 to 92) versus 3 (range, 1 to 9) patients in LAIs. In multivariate analyses, HAIs, as a quantitative covariate, was associated with improved complete remission rates (odds ratio (OR) 1.08, p = 0.0051), but no improvement median overall survival (HR 0.97, p = 0.065) or median event-free (hazard ratio (HR) 0.97, p = 0.05). Early mortality rates were similar between cohorts and academic affiliation had no impact on response rates or survival.<br><br>CONCLUSION: Clinical trial accrual volume, had an independent, albeit modest, impact on complete remission rates, but not on overall survival and event-free in younger patients with AML.}, }
@article {pmid30673548, year = {2019}, author = {Goodman, PJ and Tangen, CM and Darke, AK and Lucia, MS and Ford, LG and Minasian, LM and Parnes, HL and LeBlanc, ML and Thompson, IM}, title = {Long-Term Effects of Finasteride on Prostate Cancer Mortality.}, journal = {The New England journal of medicine}, volume = {380}, number = {4}, pages = {393-394}, doi = {10.1056/NEJMc1809961}, pmid = {30673548}, issn = {1533-4406}, mesh = {5-alpha Reductase Inhibitors/adverse effects/therapeutic use ; Early Detection of Cancer ; Finasteride/adverse effects/*therapeutic use ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/chemically induced/*mortality/prevention &amp; control ; }, }
@article {pmid30671673, year = {2019}, author = {He, KY and Li, X and Kelly, TN and Liang, J and Cade, BE and Assimes, TL and Becker, LC and Beitelshees, AL and Bress, AP and Chang, YC and Chen, YI and de Vries, PS and Fox, ER and Franceschini, N and Furniss, A and Gao, Y and Guo, X and Haessler, J and Hwang, SJ and Irvin, MR and Kalyani, RR and Liu, CT and Liu, C and Martin, LW and Montasser, ME and Muntner, PM and Mwasongwe, S and Palmas, W and Reiner, AP and Shimbo, D and Smith, JA and Snively, BM and Yanek, LR and Boerwinkle, E and Correa, A and Cupples, LA and He, J and Kardia, SLR and Kooperberg, C and Mathias, RA and Mitchell, BD and Psaty, BM and Vasan, RS and Rao, DC and Rich, SS and Rotter, JI and Wilson, JG and ,  and Chakravarti, A and Morrison, AC and Levy, D and Arnett, DK and Redline, S and Zhu, X}, title = {Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.}, journal = {Human genetics}, volume = {138}, number = {2}, pages = {199-210}, doi = {10.1007/s00439-019-01975-0}, pmid = {30671673}, issn = {1432-1203}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; R01 HL071025/HL/NHLBI NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; K01 HL133468/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; R01 HG003054/HG/NHGRI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL087698/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 HL121007/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; HG003054//National Human Genome Research Institute/ ; R01 HL087660/HL/NHLBI NIH HHS/United States ; U10 HL054464/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; R01 HL086694/HL/NHLBI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; U01 HL054464/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; HL086694//National Heart, Lung, and Blood Institute/ ; U10 HL054457/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R01 HL098433/HL/NHLBI NIH HHS/United States ; U10 HL054481/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; P30 DK072488/DK/NIDDK NIH HHS/United States ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; U01 HL054457/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; HL113338//National Heart, Lung, and Blood Institute/ ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; M01 RR000052/RR/NCRR NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 HL049762/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; U01 HL072515/HL/NHLBI NIH HHS/United States ; U01 HL072518/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; R01 HL087263/HL/NHLBI NIH HHS/United States ; T32 HL007567//National Heart, Lung, and Blood Institute/ ; U01 HL072507/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; U01 HL054481/HL/NHLBI NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; T32 HL007567/HL/NHLBI NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; P20 GM121334/GM/NIGMS NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; R01 HL090682/HL/NHLBI NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; R01 AG018728/AG/NIA NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; K01 HL135405/HL/NHLBI NIH HHS/United States ; R01 HL088119/HL/NHLBI NIH HHS/United States ; }, mesh = {Alternative Splicing/genetics ; Blood Pressure/*genetics ; Chromosomes, Human, Pair 16/*genetics ; *Exome ; Female ; Follow-Up Studies ; *Genetic Linkage ; *Genetic Variation ; *Genome, Human ; Genome-Wide Association Study ; *High-Throughput Nucleotide Sequencing ; Humans ; Male ; RNA Splicing Factors/genetics ; Recombinases/genetics ; }, abstract = {In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.}, }
@article {pmid30670822, year = {2019}, author = {Dahlberg, A and Leisenring, W and Bleakley, M and Meshinchi, S and Baker, KS and Summers, C and Hadland, B and Delaney, C and Mallhi, K and Burroughs, L and Carpenter, P and Woolfrey, A}, title = {Prognosis of relapse after hematopoietic cell transplant (HCT) for treatment of leukemia or myelodysplastic syndrome (MDS) in children.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-019-0438-z}, pmid = {30670822}, issn = {1476-5365}, support = {P01 HL122173/HL/NHLBI NIH HHS/United States ; K23 HL077446/HL/NHLBI NIH HHS/United States ; Ro1 HL121568-04//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL121568/HL/NHLBI NIH HHS/United States ; RC2 HL101844/HL/NHLBI NIH HHS/United States ; P01 HL036444/HL/NHLBI NIH HHS/United States ; }, abstract = {We studied 232 consecutive children transplanted between 1990 and 2011 with relapse after first hematopoietic cell transplant (HCT). Kaplan-Meier survival and hazard ratios for mortality were calculated for factors known at time of relapse using Cox proportional hazards models. The median (range) age at time of first HCT was 10.9 (0.5-20.9) years, time to relapse was 6.1 (0.2-89.5) months after HCT, and age at relapse was 11.7 (0.7-23.6) years. The 3-year overall survival (OS) after relapse was 13% (95% confidence interval (CI): 9%, 18%).The median (range) follow-up for the 18 surviving patients was 7.2 (3.0-24.4) years after relapse. The remaining 214 died after a median of 3 months (0.02-190.4). OS was not significantly different for patients with ALL as compared to AML. Fifty-one patients proceeded to second transplant of whom nine survive. Factors associated with improved survival included late relapse (>12 months), ALL in first CR at the time of first transplant and chemotherapy-based first conditioning regimens. These results can be used to counsel patients at the time of relapse after first transplant and as a baseline for comparison as to the effectiveness of newer therapies which are greatly needed for treatment of post-transplant relapse.}, }
@article {pmid30670784, year = {2019}, author = {Estey, E and Othus, M and Gale, RP}, title = {New study-designs to address the clinical complexity of acute myeloid leukemia.}, journal = {Leukemia}, volume = {33}, number = {3}, pages = {567-569}, doi = {10.1038/s41375-018-0363-y}, pmid = {30670784}, issn = {1476-5551}, }
@article {pmid30670697, year = {2019}, author = {Kilpeläinen, TO and Bentley, AR and Noordam, R and Sung, YJ and Schwander, K and Winkler, TW and Jakupović, H and Chasman, DI and Manning, A and Ntalla, I and Aschard, H and Brown, MR and de Las Fuentes, L and Franceschini, N and Guo, X and Vojinovic, D and Aslibekyan, S and Feitosa, MF and Kho, M and Musani, SK and Richard, M and Wang, H and Wang, Z and Bartz, TM and Bielak, LF and Campbell, A and Dorajoo, R and Fisher, V and Hartwig, FP and Horimoto, ARVR and Li, C and Lohman, KK and Marten, J and Sim, X and Smith, AV and Tajuddin, SM and Alver, M and Amini, M and Boissel, M and Chai, JF and Chen, X and Divers, J and Evangelou, E and Gao, C and Graff, M and Harris, SE and He, M and Hsu, FC and Jackson, AU and Zhao, JH and Kraja, AT and Kühnel, B and Laguzzi, F and Lyytikäinen, LP and Nolte, IM and Rauramaa, R and Riaz, M and Robino, A and Rueedi, R and Stringham, HM and Takeuchi, F and van der Most, PJ and Varga, TV and Verweij, N and Ware, EB and Wen, W and Li, X and Yanek, LR and Amin, N and Arnett, DK and Boerwinkle, E and Brumat, M and Cade, B and Canouil, M and Chen, YI and Concas, MP and Connell, J and de Mutsert, R and de Silva, HJ and de Vries, PS and Demirkan, A and Ding, J and Eaton, CB and Faul, JD and Friedlander, Y and Gabriel, KP and Ghanbari, M and Giulianini, F and Gu, CC and Gu, D and Harris, TB and He, J and Heikkinen, S and Heng, CK and Hunt, SC and Ikram, MA and Jonas, JB and Koh, WP and Komulainen, P and Krieger, JE and Kritchevsky, SB and Kutalik, Z and Kuusisto, J and Langefeld, CD and Langenberg, C and Launer, LJ and Leander, K and Lemaitre, RN and Lewis, CE and Liang, J and ,  and Liu, J and Mägi, R and Manichaikul, A and Meitinger, T and Metspalu, A and Milaneschi, Y and Mohlke, KL and Mosley, TH and Murray, AD and Nalls, MA and Nang, EK and Nelson, CP and Nona, S and Norris, JM and Nwuba, CV and O'Connell, J and Palmer, ND and Papanicolau, GJ and Pazoki, R and Pedersen, NL and Peters, A and Peyser, PA and Polasek, O and Porteous, DJ and Poveda, A and Raitakari, OT and Rich, SS and Risch, N and Robinson, JG and Rose, LM and Rudan, I and Schreiner, PJ and Scott, RA and Sidney, SS and Sims, M and Smith, JA and Snieder, H and Sofer, T and Starr, JM and Sternfeld, B and Strauch, K and Tang, H and Taylor, KD and Tsai, MY and Tuomilehto, J and Uitterlinden, AG and van der Ende, MY and van Heemst, D and Voortman, T and Waldenberger, M and Wennberg, P and Wilson, G and Xiang, YB and Yao, J and Yu, C and Yuan, JM and Zhao, W and Zonderman, AB and Becker, DM and Boehnke, M and Bowden, DW and de Faire, U and Deary, IJ and Elliott, P and Esko, T and Freedman, BI and Froguel, P and Gasparini, P and Gieger, C and Kato, N and Laakso, M and Lakka, TA and Lehtimäki, T and Magnusson, PKE and Oldehinkel, AJ and Penninx, BWJH and Samani, NJ and Shu, XO and van der Harst, P and Van Vliet-Ostaptchouk, JV and Vollenweider, P and Wagenknecht, LE and Wang, YX and Wareham, NJ and Weir, DR and Wu, T and Zheng, W and Zhu, X and Evans, MK and Franks, PW and Gudnason, V and Hayward, C and Horta, BL and Kelly, TN and Liu, Y and North, KE and Pereira, AC and Ridker, PM and Tai, ES and van Dam, RM and Fox, ER and Kardia, SLR and Liu, CT and Mook-Kanamori, DO and Province, MA and Redline, S and van Duijn, CM and Rotter, JI and Kooperberg, CB and Gauderman, WJ and Psaty, BM and Rice, K and Munroe, PB and Fornage, M and Cupples, LA and Rotimi, CN and Morrison, AC and Rao, DC and Loos, RJF}, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {376}, doi = {10.1038/s41467-018-08008-w}, pmid = {30670697}, issn = {2041-1723}, support = {K01 HL136700/HL/NHLBI NIH HHS/United States ; MR/L01632X/1//Medical Research Council/United Kingdom ; R01 HL142302/HL/NHLBI NIH HHS/United States ; P30 DK079626/DK/NIDDK NIH HHS/United States ; MR/L01341X/1//Medical Research Council/United Kingdom ; MR/K026992/1//Medical Research Council/United Kingdom ; R01 HL118305/HL/NHLBI NIH HHS/United States ; R01 AG055406/AG/NIA NIH HHS/United States ; BB/F019394/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Adolescent ; Adult ; African Continental Ancestry Group/genetics ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/genetics ; Brazil ; Calcium-Binding Proteins/genetics ; Cholesterol/blood ; Cholesterol, HDL/blood/genetics ; Cholesterol, LDL/blood/genetics ; European Continental Ancestry Group/genetics ; *Exercise ; Female ; Genetic Loci/*genetics ; Genome-Wide Association Study ; Genotype ; Hispanic Americans/genetics ; Humans ; LIM-Homeodomain Proteins/genetics ; Lipid Metabolism/genetics ; Lipids/*blood/*genetics ; Male ; Membrane Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Middle Aged ; Muscle Proteins/genetics ; Nerve Tissue Proteins/genetics ; Transcription Factors/genetics ; Triglycerides/blood/genetics ; Young Adult ; }, abstract = {Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.}, }
@article {pmid30670584, year = {2019}, author = {Shah, PD and Calo, WA and Gilkey, MB and Boynton, MH and Alton Dailey, S and Todd, KG and Robichaud, MO and Margolis, MA and Brewer, NT}, title = {Questions and Concerns About HPV Vaccine: A Communication Experiment.}, journal = {Pediatrics}, volume = {143}, number = {2}, pages = {}, doi = {10.1542/peds.2018-1872}, pmid = {30670584}, issn = {1098-4275}, support = {T32 HS000032/HS/AHRQ HHS/United States ; U48 DP005017/DP/NCCDPHP CDC HHS/United States ; U48DP005017//ACL HHS/United States ; }, abstract = {: media-1vid110.1542/5972295740001PEDS-VA_2018-1872Video Abstract OBJECTIVES: We sought to identify effective responses to parents' questions and concerns about human papillomavirus (HPV) vaccine.<br><br>METHODS: In 2017-2018, we surveyed a national sample of 1196 US parents of children aged 9 to 17 years. We recorded brief videos of a pediatrician providing messages that addressed 7 HPV vaccination topics that commonly elicit questions or concerns (eg, recommended age). We randomly assigned parents to 1 of the message topics; parents then viewed 4 videos on that topic in random order and evaluated the messages.<br><br>RESULTS: Parents were more confident in HPV vaccine when they were exposed to messages that addressed lack of knowledge about HPV vaccine (b = 0.13; P = .01), messages that included information about cancer prevention (b = 0.11; P < .001), messages that required a higher reading level (b = 0.02; P = .01), and messages that were longer (b = 0.03; P < .001). Parents were less confident in HPV vaccine when exposed to messages in which urgency was expressed (b = -0.06; P = .005). Analyses conducted by using HPV vaccine motivation as an outcome revealed the same pattern of findings.<br><br>CONCLUSIONS: We provide research-tested messages that providers can use to address parents' HPV vaccination questions and concerns about 7 common topics. Important principles for increasing message effectiveness are to include information on the benefits of vaccination (including cancer prevention) and avoid expressing urgency to vaccinate when addressing parents' questions or concerns. Additionally, providers may need to be prepared to have longer conversations with parents who express concerns about HPV vaccine, especially regarding safety and side effects.}, }
@article {pmid30669119, year = {2019}, author = {Lu, AT and Quach, A and Wilson, JG and Reiner, AP and Aviv, A and Raj, K and Hou, L and Baccarelli, AA and Li, Y and Stewart, JD and Whitsel, EA and Assimes, TL and Ferrucci, L and Horvath, S}, title = {DNA methylation GrimAge strongly predicts lifespan and healthspan.}, journal = {Aging}, volume = {11}, number = {2}, pages = {303-327}, doi = {10.18632/aging.101684}, pmid = {30669119}, issn = {1945-4589}, support = {U01 AG060908/AG/NIA NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 ES020836/ES/NIEHS NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201300048C/HL/NHLBI NIH HHS/United States ; HHSN268201300049C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 AG029451/AG/NIA NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; HHSN268201300047C/HL/NHLBI NIH HHS/United States ; HHSN268201300050C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201300046C/HL/NHLBI NIH HHS/United States ; U54 GM115428/GM/NIGMS NIH HHS/United States ; }, abstract = {It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration, AgeAccelGrim.Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.}, }
@article {pmid30668198, year = {2019}, author = {Gyurkocza, B and Storb, R and Chauncey, TR and Maloney, DG and Storer, BE and Sandmaier, BM}, title = {Second allogeneic hematopoietic cell transplantation for relapse after first allografts.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/10428194.2018.1542149}, pmid = {30668198}, issn = {1029-2403}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 HL036444/HL/NHLBI NIH HHS/United States ; P01 HL122173/HL/NHLBI NIH HHS/United States ; }, abstract = {We analyzed outcomes of 126 patients with hematologic malignancies, who relapsed after first allogeneic hematopoietic cell transplantation (HCT) and received subsequent allografts. In 17 cases, the original donors were utilized, while in 109 cases different donors were identified. The 2-year overall survival (OS), relapse, and non-relapse mortality (NRM) rates were 33%, 42%, and 33%, respectively. Patients with early relapse after first allogeneic HCT (within 100 days vs. 100 days to 12 months vs. >12 months) had higher relapse rates (50% vs. 47% vs. 34%, respectively; p = .01) and worse OS (15% vs. 25% vs. 45%, respectively, p = .005) at 2 years after second allogeneic HCT. In conclusion, second allogeneic HCT should be considered in patients who relapse after first allografts, especially in those who relapse after more than a year. Utilizing a different donor for the second allotransplant including umbilical cord blood or HLA-haploidentical, related donors did not adversely impact outcomes.}, }
@article {pmid30667142, year = {2019}, author = {Ramos, JD and Holt, SK and Schade, GR and Galsky, MD and Wright, JL and Gore, JL and Yu, EY}, title = {Chemotherapy regimen is associated with venous thromboembolism risk in patients with urothelial tract cancer.}, journal = {BJU international}, volume = {}, number = {}, pages = {}, doi = {10.1111/bju.14685}, pmid = {30667142}, issn = {1464-410X}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: To assess the association of venous thromboembolism (VTE) with different chemotherapy regimens in patients with urothelial tract cancer.<br><br>PATIENTS AND METHODS: We identified patients aged ≥66 years, diagnosed with urothelial tract cancer in the period 1998 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database. The chemotherapy regimens analysed were gemcitabine/cisplatin (GC), methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), or gemcitabine/carboplatin (CarboG). Propensity scores for treatment regimen based on comorbidities, tumour characteristics, age, and year of diagnosis were calculated. VTE rates within 120 days of chemotherapy initiation were calculated. VTE risk stratified by chemotherapy regimen was modelled using multivariable logistic regression, adjusting for treatment propensity scores and additional demographic characteristics. Overall survival stratified by VTE and chemotherapy regimen was estimated using Kaplan-Meier methods and the log-rank test.<br><br>RESULTS: Of 5594 identified patients, a VTE occurred in 13.0%. The VTE rates within 120 days of chemotherapy initiation were 15.3% for GC, 8.7% for MVAC, and 12.0% for CarboG. On multivariable analysis, MVAC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.94) and CarboG (OR 0.71, 95% CI: 0.59-0.85) were associated with lower VTE risk compared with GC. VTE was associated with worse overall survival (P < 0.001).<br><br>CONCLUSIONS: Compared with GC, MVAC and CarboG were associated with a lower rate of VTE. This finding suggests that gemcitabine may add to the increased thrombosis risk from cisplatin. Additionally, patients with a VTE had worse survival outcomes than those without a VTE. Analysis of the risk of blood clots with different chemotherapy regimens in patients with urothelial tract cancer showed that GC was associated with the highest rate. We also found that blood clots were associated with worse patient outcomes.}, }
@article {pmid30666629, year = {2019}, author = {Zhabotynsky, V and Inoue, K and Magnuson, T and Mauro Calabrese, J and Sun, W}, title = {A statistical method for joint estimation of cis-eQTLs and parent-of-origin effects under family trio design.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13026}, pmid = {30666629}, issn = {1541-0420}, support = {R01 GM105785/GM/NIGMS NIH HHS/United States ; }, abstract = {RNA sequencing allows one to study allelic imbalance of gene expression, which may be due to genetic factors or genomic imprinting (i.e., higher expression of maternal or paternal allele). It is desirable to model both genetic and parent-of-origin effects simultaneously to avoid confounding and to improve the power to detect either effect. In studies of genetically tractable model organisms, separation of genetic and parent-of-origin effects can be achieved by studying reciprocal cross of two inbred strains. In contrast, this task is much more challenging in outbred populations such as humans. To address this challenge, we propose a new framework to combine experimental strategies and novel statistical methods. Specifically, we propose to study genetic and imprinting effects in family trios with RNA-seq data from the children and genotype data from both parents and children, and quantify genetic effects by cis-eQTLs. Towards this end, we have extended our method that studies the eQTLs of RNA-seq data (Sun, Biometrics 2012, 68(1): 1-11) to model both cis-eQTL and parent-of-origin effects, and evaluated its performance using extensive simulations. Since sample size may be limited in family trios, we have developed a data analysis pipeline that borrows information from external data of unrelated individuals for cis-eQTL mapping. We have also collected RNA-seq data from the children of 30 family trios, applied our method to analyze this dataset, and identified some previously reported imprinted genes as well as some new candidates of imprinted genes.}, }
@article {pmid30665727, year = {2019}, author = {Hanna, DB and Lazar, JM and Avadhani, S and Kaplan, RC and Anastos, K and Gange, SJ and Holman, S and Minkoff, HL and Kizer, JR}, title = {Assessment of Different Classification Schemes for Identification of Diastolic Dysfunction in the Women's Interagency HIV Study.}, journal = {Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography}, volume = {32}, number = {4}, pages = {547-548}, doi = {10.1016/j.echo.2018.11.016}, pmid = {30665727}, issn = {1097-6795}, }
@article {pmid30664790, year = {2019}, author = {Carlson, P and Dasgupta, A and Grzelak, CA and Kim, J and Barrett, A and Coleman, IM and Shor, RE and Goddard, ET and Dai, J and Schweitzer, EM and Lim, AR and Crist, SB and Cheresh, DA and Nelson, PS and Hansen, KC and Ghajar, CM}, title = {Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy.}, journal = {Nature cell biology}, volume = {21}, number = {2}, pages = {238-250}, doi = {10.1038/s41556-018-0267-0}, pmid = {30664790}, issn = {1476-4679}, abstract = {The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascular endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand factor and vascular cell adhesion molecule 1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in prevention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.}, }
@article {pmid30664734, year = {2019}, author = {Newcomb, LF and Zheng, Y and Faino, AV and Bianchi-Frias, D and Cooperberg, MR and Brown, MD and Brooks, JD and Dash, A and Fabrizio, MD and Gleave, ME and Liss, M and Morgan, TM and Thompson, IM and Wagner, AA and Carroll, PR and Nelson, PS and Lin, DW}, title = {Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41391-018-0124-z}, pmid = {30664734}, issn = {1476-5608}, support = {R01 CA181605/CA/NCI NIH HHS/United States ; W81XWH1410595//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1110489//U.S. Department of Defense (United States Department of Defense)/ ; R01 CA181605//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {BACKGROUND: For men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.<br><br>METHODS: Urine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).<br><br>RESULTS: Seven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.<br><br>CONCLUSIONS: PCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies.}, }
@article {pmid30664659, year = {2019}, author = {Song, Y and Rongvaux, A and Taylor, A and Jiang, T and Tebaldi, T and Balasubramanian, K and Bagale, A and Terzi, YK and Gbyli, R and Wang, X and Fu, X and Gao, Y and Zhao, J and Podoltsev, N and Xu, M and Neparidze, N and Wong, E and Torres, R and Bruscia, EM and Kluger, Y and Manz, MG and Flavell, RA and Halene, S}, title = {A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {366}, doi = {10.1038/s41467-018-08166-x}, pmid = {30664659}, issn = {2041-1723}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; R01 HG008383/HG/NHGRI NIH HHS/United States ; U54 DK106857/DK/NIDDK NIH HHS/United States ; R01 CA156689/CA/NCI NIH HHS/United States ; R01 HL123851/HL/NHLBI NIH HHS/United States ; R21 CA120128/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antigens, CD/genetics/immunology ; Biomarkers/metabolism ; Cytokines/genetics/immunology ; *Disease Models, Animal ; Gene Expression ; Gene Knock-In Techniques ; *Graft Survival ; Hematopoietic Stem Cell Transplantation/*methods ; Hematopoietic Stem Cells/*immunology/pathology ; Humans ; Mice ; Mice, Transgenic ; Myelodysplastic Syndromes/*immunology/pathology ; Stem Cell Niche/*immunology ; Transplantation, Heterologous ; }, abstract = {Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient &quot;MISTRG&quot; mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients' dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample's genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.}, }
@article {pmid30664074, year = {2019}, author = {Long, JE and Montaño, M and Cabello, R and Sanchez, H and Lama, JR and Duerr, A}, title = {Brief Report: Comparing Sexual Risk Behavior in a High-Risk Group of Men Who Have Sex With Men and Transgender Women in Lima, Peru.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {80}, number = {5}, pages = {522-526}, doi = {10.1097/QAI.0000000000001966}, pmid = {30664074}, issn = {1944-7884}, support = {R01 DA032106/DA/NIDA NIH HHS/United States ; R01 DA040532/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: Transgender women (TW) and men who have sex with men (MSM) are often conflated in HIV research and prevention programs, despite clear differences that exist in culture and behavior.<br><br>METHODS: We examined baseline data from a large treatment-as-prevention study among TW and MSM in Lima, Peru, to assess differences in risk behavior. Baseline assessment included HIV testing and a questionnaire including sociodemographics, sexual behavior, social venue attendance, and drug and alcohol use. Poisson regression with robust standard errors was used to calculate prevalence ratios adjusted for confounding variables [adjusted prevalence ratio (aPR)] and 95% confidence intervals (CIs) comparing the prevalence of covariates related to HIV risk in MSM and TW.<br><br>RESULTS: Overall, 310 TW and 2807 MSM participated between July 2013 and September 2015 and were included in this analysis. TW engaged in some protective sexual health practices more than MSM, including HIV testing in the last year (aPR = 1.62; 95% CI: 1.42 to 1.84) and condom use at the last sexual encounter (aPR = 1.20; 95% CI: 1.06 to 1.36). TW were more likely to have sex while using alcohol (aPR 1.15, 95% CI: 1.01 to 1.31) or drugs (aPR 2.24, 95% CI: 1.47 to 3.41), have alcohol dependency (aPR 1.38, 95% CI: 1.15 to 1.66), engage in receptive anal sex (aPR 1.31, 95% CI: 1.26 to 1.36), and have received money, gifts, or favors in exchange of anal sex (1.96, 95% CI: 1.74 to 2.20).<br><br>CONCLUSIONS: TW and MSM exhibited distinct risk profiles, suggesting that interventions specifically targeted to each group may provide new opportunities for more effective HIV prevention programs.}, }
@article {pmid30663774, year = {2019}, author = {Smith, SD and Reddy, P and Sokolova, A and Chow, VA and Lynch, RC and Shadman, MA and Till, BG and Shustov, AR and Warren, EH and Ujjani, CS and Menon, MP and Tseng, YD and Gopal, AK}, title = {Eligibility for CAR T-cell therapy: An analysis of selection criteria and survival outcomes in chemorefractory DLBCL.}, journal = {American journal of hematology}, volume = {94}, number = {4}, pages = {E117-E116}, doi = {10.1002/ajh.25411}, pmid = {30663774}, issn = {1096-8652}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; 5K24CA184039//STTR/ ; //Seattle Cancer Care Alliance/ ; //Frank and Betty Vandermeer/ ; }, }
@article {pmid30662827, year = {2019}, author = {Wright, T and Coruh, B and Fredricks, D and Kim, N}, title = {Immune reconstitution inflammatory syndrome associated with disseminated histoplasmosis and TNF-alpha inhibition.}, journal = {Medical mycology case reports}, volume = {23}, number = {}, pages = {62-64}, doi = {10.1016/j.mmcr.2018.12.008}, pmid = {30662827}, issn = {2211-7539}, abstract = {Endemic fungal infections are a significant problem for patients on TNF-alpha inhibitors. Immune reconstitution inflammatory syndrome, IRIS, can present in patients with waning TNF-alpha inhibition and an endemic fungal infection. There may be a potential role that TNF-alpha inhibitors can play in mitigating IRIS related to disseminated endemic fungal infections.}, }
@article {pmid30661759, year = {2019}, author = {Sharon, N and Chawla, R and Mueller, J and Vanderhooft, J and Whitehorn, LJ and Rosenthal, B and Gürtler, M and Estanboulieh, RR and Shvartsman, D and Gifford, DK and Trapnell, C and Melton, D}, title = {A Peninsular Structure Coordinates Asynchronous Differentiation with Morphogenesis to Generate Pancreatic Islets.}, journal = {Cell}, volume = {176}, number = {4}, pages = {790-804.e13}, doi = {10.1016/j.cell.2018.12.003}, pmid = {30661759}, issn = {1097-4172}, abstract = {The pancreatic islets of Langerhans regulate glucose homeostasis. The loss of insulin-producing β cells within islets results in diabetes, and islet transplantation from cadaveric donors can cure the disease. In vitro production of whole islets, not just β cells, will benefit from a better understanding of endocrine differentiation and islet morphogenesis. We used single-cell mRNA sequencing to obtain a detailed description of pancreatic islet development. Contrary to the prevailing dogma, we find islet morphology and endocrine differentiation to be directly related. As endocrine progenitors differentiate, they migrate in cohesion and form bud-like islet precursors, or &quot;peninsulas&quot; (literally &quot;almost islands&quot;). α cells, the first to develop, constitute the peninsular outer layer, and β cells form later, beneath them. This spatiotemporal collinearity leads to the typical core-mantle architecture of the mature, spherical islet. Finally, we induce peninsula-like structures in differentiating human embryonic stem cells, laying the ground for the generation of entire islets in vitro.}, }
@article {pmid30659681, year = {2019}, author = {Lindström, S and Brody, JA and Turman, C and Germain, M and Bartz, TM and Smith, EN and Chen, MH and Puurunen, M and Chasman, D and Hassler, J and Pankratz, N and Basu, S and Guan, W and Gyorgy, B and Ibrahim, M and Empana, JP and Olaso, R and Jackson, R and Braekkan, SK and McKnight, B and Deleuze, JF and O'Donnell, CJ and Jouven, X and Frazer, KA and Psaty, BM and Wiggins, KL and Taylor, K and Reiner, AP and Heckbert, SR and Kooperberg, C and Ridker, P and Hansen, JB and Tang, W and Johnson, AD and Morange, PE and Trégouët, DA and Kraft, P and Smith, NL and Kabrhel, C and , }, title = {A large-scale exome array analysis of venous thromboembolism.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/gepi.22187}, pmid = {30659681}, issn = {1098-2272}, support = {HL053375//National Heart, Lung, and Blood Institute/ ; HHSN268201800001C//National Heart, Lung, and Blood Institute/ ; R01HL087652//National Heart, Lung, and Blood Institute/ ; HHSN268201200036C//National Heart, Lung, and Blood Institute/ ; HL043201//National Heart, Lung, and Blood Institute/ ; HL099355//National Heart, Lung, and Blood Institute/ ; R01CA67262//National Heart, Lung, and Blood Institute/ ; P01CA87969//National Cancer Institute/ ; N01HC85083//National Heart, Lung, and Blood Institute/ ; HL085251//National Heart, Lung, and Blood Institute/ ; HHSN268201600001C//National Heart, Lung, and Blood Institute/ ; DK063491//National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center/ ; HHSN268201700001I//National Heart, Lung, and Blood Institute/ ; HL68639//National Heart, Lung, and Blood Institute/ ; R01HL103612//National Heart, Lung, and Blood Institute/ ; R01HL130114//National Heart, Lung, and Blood Institute/ ; R01HL068986//National Heart, Lung, and Blood Institute/ ; UL1TR000124//National Center for Advancing Translational Sciences/ ; R01 HL116854/HL/NHLBI NIH HHS/United States ; N01HC85080//National Heart, Lung, and Blood Institute/ ; HL060739//National Heart, Lung, and Blood Institute/ ; HHSN268201700003I//National Heart, Lung, and Blood Institute/ ; ANR-10-IAHU//ICAN Institute for Cardiometabolism and Nutrition/ ; N01HC85086//National Heart, Lung, and Blood Institute/ ; HHSN268201600003C//National Heart, Lung, and Blood Institute/ ; HL043851//National Heart, Lung, and Blood Institute/ ; N01-HC-25195//National Heart, Lung, and Blood Institute/ ; R01HL105756//National Heart, Lung, and Blood Institute/ ; R01CA50385//National Heart, Lung, and Blood Institute/ ; R01CA49449//National Cancer Institute/ ; ANR-10-LABX-0013//GENMED Laboratory of Excellence on Medical Genomics/ ; HL095080//National Heart, Lung, and Blood Institute/ ; HL040628//National Heart, Lung, and Blood Institute/ ; UM1CA182913//National Cancer Institute/ ; R01HL034594//National Heart, Lung, and Blood Institute/ ; P01CA055075//National Heart, Lung, and Blood Institute/ ; U01HL080295//National Heart, Lung, and Blood Institute/ ; HL073410//National Heart, Lung, and Blood Institute/ ; 5RC2HL102419//NIH American Recovery and Reinvestment Act/ ; R01HL120393//National Heart, Lung, and Blood Institute/ ; CA047988//National Cancer Institute/ ; HHSN268201700005I//National Heart, Lung, and Blood Institute/ ; N01HC85079//National Heart, Lung, and Blood Institute/ ; N01HC85081//National Heart, Lung, and Blood Institute/ ; N01HC55222//National Heart, Lung, and Blood Institute/ ; HHSN268200800007C//National Heart, Lung, and Blood Institute/ ; R01HL35464//National Heart, Lung, and Blood Institute/ ; HL74745//National Heart, Lung, and Blood Institute/ ; HL080467//National Heart, Lung, and Blood Institute/ ; N01HC85082//National Heart, Lung, and Blood Institute/ ; S10 OD020069/OD/NIH HHS/United States ; R01HL116854//National Heart, Lung, and Blood Institute/ ; HL068986//National Heart, Lung, and Blood Institute/ ; R01AG023629//US Department of Health and Human Services, National Institutes of Health, National Institute of Aging/ ; HHSN268201600004C//National Heart, Lung, and Blood Institute/ ; HHSN268201700002I//National Heart, Lung, and Blood Institute/ ; R01HL59367//National Heart, Lung, and Blood Institute/ ; HHSN268201600002C//National Heart, Lung, and Blood Institute/ ; HHSN268201600018C//National Heart, Lung, and Blood Institute/ ; R01HL088521//National Heart, Lung, and Blood Institute/ ; }, abstract = {Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.}, }
@article {pmid30659131, year = {2019}, author = {Koh, WJ and Abu-Rustum, NR and Bean, S and Bradley, K and Campos, SM and Cho, KR and Chon, HS and Chu, C and Clark, R and Cohn, D and Crispens, MA and Damast, S and Dorigo, O and Eifel, PJ and Fisher, CM and Frederick, P and Gaffney, DK and Han, E and Huh, WK and Lurain, JR and Mariani, A and Mutch, D and Nagel, C and Nekhlyudov, L and Fader, AN and Remmenga, SW and Reynolds, RK and Tillmanns, T and Ueda, S and Wyse, E and Yashar, CM and McMillian, NR and Scavone, JL}, title = {Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {17}, number = {1}, pages = {64-84}, doi = {10.6004/jnccn.2019.0001}, pmid = {30659131}, issn = {1540-1413}, abstract = {Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.}, }
@article {pmid30659125, year = {2019}, author = {Wierda, WG and Byrd, JC and Abramson, JS and Bilgrami, SF and Bociek, G and Brander, D and Brown, J and Chanan-Khan, AA and Chavez, JC and Coutre, SE and Davis, RS and Fletcher, CD and Hill, B and Kahl, BS and Kamdar, M and Kaplan, LD and Khan, N and Kipps, TJ and Ma, S and Malek, S and Mato, A and Mosse, C and Neppalli, VT and Shadman, M and Siddiqi, T and Stephens, D and Wagner, N and Dwyer, MA and Sundar, H}, title = {NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {17}, number = {1}, pages = {12-20}, doi = {10.6004/jnccn.2019.0002}, pmid = {30659125}, issn = {1540-1413}, abstract = {Chronic lymphocytic leukemia (CLL) is generally characterized by an indolent disease course. Histologic transformation (also known as Richter's transformation) to more aggressive lymphomas, such as diffuse large B-cell lymphoma or Hodgkin lymphoma, occurs in approximately 2% to 10% of patients and is associated with a poor prognosis. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with histologic transformation.}, }
@article {pmid30657904, year = {2019}, author = {McGuffin, SA and Bharadwaj, R and Gonzalez-Cuyar, LF and Schiffer, JT and Stacey, AW and Walter, RB and Duke, ER}, title = {In the Eye of the Beholder: A Conjunctival Lesion in a Woman With Acute Myelogenous Leukemia.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {68}, number = {3}, pages = {525-529}, doi = {10.1093/cid/ciy394}, pmid = {30657904}, issn = {1537-6591}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; }, }
@article {pmid30655571, year = {2019}, author = {Matejcic, M and Saunders, EJ and Dadaev, T and Brook, MN and Wang, K and Sheng, X and Olama, AAA and Schumacher, FR and Ingles, SA and Govindasami, K and Benlloch, S and Berndt, SI and Albanes, D and Koutros, S and Muir, K and Stevens, VL and Gapstur, SM and Tangen, CM and Batra, J and Clements, J and Gronberg, H and Pashayan, N and Schleutker, J and Wolk, A and West, C and Mucci, L and Kraft, P and Cancel-Tassin, G and Sorensen, KD and Maehle, L and Grindedal, EM and Strom, SS and Neal, DE and Hamdy, FC and Donovan, JL and Travis, RC and Hamilton, RJ and Rosenstein, B and Lu, YJ and Giles, GG and Kibel, AS and Vega, A and Bensen, JT and Kogevinas, M and Penney, KL and Park, JY and Stanford, JL and Cybulski, C and Nordestgaard, BG and Brenner, H and Maier, C and Kim, J and Teixeira, MR and Neuhausen, SL and De Ruyck, K and Razack, A and Newcomb, LF and Lessel, D and Kaneva, R and Usmani, N and Claessens, F and Townsend, PA and Gago-Dominguez, M and Roobol, MJ and Menegaux, F and Khaw, KT and Cannon-Albright, LA and Pandha, H and Thibodeau, SN and Schaid, DJ and ,  and Wiklund, F and Chanock, SJ and Easton, DF and Eeles, RA and Kote-Jarai, Z and Conti, DV and Haiman, CA}, title = {Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {382}, doi = {10.1038/s41467-019-08293-z}, pmid = {30655571}, issn = {2041-1723}, abstract = {The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.}, }
@article {pmid30655443, year = {2019}, author = {Martins, JP and Andoniou, CE and Fleming, P and Kuns, RD and Schuster, IS and Voigt, V and Daly, S and Varelias, A and Tey, SK and Degli-Esposti, MA and Hill, GR}, title = {Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation.}, journal = {Science (New York, N.Y.)}, volume = {363}, number = {6424}, pages = {288-293}, doi = {10.1126/science.aat0066}, pmid = {30655443}, issn = {1095-9203}, abstract = {Cytomegalovirus infection is a frequent and life-threatening complication that significantly limits positive transplantation outcomes. We developed preclinical mouse models of cytomegalovirus reactivation after transplantation and found that humoral immunity is essential for preventing viral recrudescence. Preexisting antiviral antibodies decreased after transplant in the presence of graft-versus-host disease and were not replaced, owing to poor reconstitution of donor B cells and elimination of recipient plasma cells. Viral reactivation was prevented by the transfer of immune serum, without a need to identify and target specific antigenic determinants. Notably, serotherapy afforded complete protection, provided that the serum was matched to the infecting viral strain. Thus, we define the mechanisms for cytomegalovirus reactivation after transplantation and identify a readily translatable strategy of exceptional potency, which avoids the constraints of cellular therapies.}, }
@article {pmid30653559, year = {2019}, author = {Olivier, M and Bouaoun, L and Villar, S and Robitaille, A and Cahais, V and Heguy, A and Byrnes, G and Le Calvez-Kelm, F and Torres-Mejía, G and Alvarado-Cabrero, I and Imani-Razavi, FS and Inés Sánchez, G and Jaramillo, R and Porras, C and Rodriguez, AC and Garmendia, ML and Soto, JL and Romieu, I and Porter, P and Guenthoer, J and Rinaldi, S and , }, title = {Molecular features of premenopausal breast cancers in Latin American women: Pilot results from the PRECAMA study.}, journal = {PloS one}, volume = {14}, number = {1}, pages = {e0210372}, doi = {10.1371/journal.pone.0210372}, pmid = {30653559}, issn = {1932-6203}, abstract = {BACKGROUND: In Latin America (LA), there is a high incidence rate of breast cancer (BC) in premenopausal women, and the genomic features of these BC remain unknown. Here, we aim to characterize the molecular features of BC in young LA women within the framework of the PRECAMA study, a multicenter population-based case-control study of BC in premenopausal women.<br><br>METHODS: Pathological tumor tissues were collected from incident cases from four LA countries. Immunohistochemistry (IHC) was performed centrally for ER, PR, HER2, Ki67, EGFR, CK5/6, and p53 protein markers. Targeted deep sequencing was done on genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissues and their paired blood samples to screen for somatic mutations in eight genes frequently mutated in BC. A subset of samples was analyzed by exome sequencing to identify somatic mutational signatures.<br><br>RESULTS: The majority of cases were positive for ER or PR (168/233; 72%), and 21% were triple-negative (TN), mainly of basal type. Most tumors were positive for Ki67 (189/233; 81%). In 126 sequenced cases, TP53 and PIK3CA were the most frequently mutated genes (32.5% and 21.4%, respectively), followed by AKT1 (9.5%). TP53 mutations were more frequent in HER2-enriched and TN IHC subtypes, whereas PIK3CA/AKT1 mutations were more frequent in ER-positive tumors, as expected. Interestingly, a higher proportion of G:C>T:A mutations was observed in TP53 in PRECAMA cases compared with TCGA and METABRIC BC series (27% vs 14%). Exome-wide mutational patterns in 10 TN cases revealed alterations in signal transduction pathways and major contributions of mutational signatures caused by altered DNA repair pathways.<br><br>CONCLUSIONS: These pilot results on PRECAMA tumors give a preview of the molecular features of premenopausal BC in LA. Although the overall mutation burden was as expected from data in other populations, mutational patterns observed in TP53 and exome-wide suggested possible differences in mutagenic processes giving rise to these tumors compared with other populations. Further -omics analyses of a larger number of cases in the near future will enable the investigation of relationships between these molecular features and risk factors.}, }
@article {pmid30653226, year = {2019}, author = {Ramsey, SD and Unger, JM and Baker, LH and Little, RF and Loomba, R and Hwang, JP and Chugh, R and Konerman, MA and Arnold, K and Menter, AR and Thomas, E and Michels, RM and Jorgensen, CW and Burton, GV and Bhadkamkar, NA and Hershman, DL}, title = {Prevalence of Hepatitis B Virus, Hepatitis C Virus, and HIV Infection Among Patients With Newly Diagnosed Cancer From Academic and Community Oncology Practices.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2018.6437}, pmid = {30653226}, issn = {2374-2445}, abstract = {Importance: Universal screening of patients with newly diagnosed cancer for hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV is not routine in oncology practice, and experts disagree about whether universal screening should be performed.<br><br>Objective: To estimate the prevalence of HBV, HCV, and HIV infection among persons with newly diagnosed cancer.<br><br>Multicenter prospective cohort study of patients with newly diagnosed cancer (ie, identified within 120 days of cancer diagnosis) at 9 academic and 9 community oncology institutions affiliated with SWOG (formerly the Southwest Oncology Group) Cancer Research Network, a member of the National Clinical Trials Network, with enrollment from August 29, 2013, through February 15, 2017. The data analysis was conducted using data available through August 17, 2017.<br><br>Main Outcomes and Measures: The accrual goal was 3000 patients and the primary end point was the presence of HBV infection (previous or chronic), HCV infection, or HIV infection at enrollment. Patients with previous knowledge of infection as well as patients with unknown viral viral status were evaluated.<br><br>Results: Of 3092 registered patients, 3051 were eligible and evaluable. Median (range) age was 60.6 (18.2-93.7) years, 1842 (60.4%) were female, 553 (18.1%) were black, and 558 (18.3%) were Hispanic ethnicity. Screened patients had similar clinical and demographic characteristics compared with those registered. The observed infection rate for previous HBV infection was 6.5% (95% CI, 5.6%-7.4%; n = 197 of 3050 patients); chronic HBV, 0.6% (95% CI, 0.4%-1.0%; n = 19 of 3050 patients); HCV, 2.4% (95% CI, 1.9%-3.0%; n = 71 of 2990 patients); and HIV, 1.1% (95% CI, 0.8%-1.6%; n = 34 of 3045). Among those with viral infections, 8 patients with chronic HBV (42.1%; 95% CI, 20.3%-66.5%), 22 patients with HCV (31.0%; 95% CI, 20.5%-43.1%), and 2 patients with HIV (5.9%; 95% CI, 0.7%-19.7%) were newly diagnosed through the study. Among patients with infections, 4 patients with chronic HBV (21.1%; 95% CI, 6.1%-45.6%), 23 patients with HCV (32.4%; 95% CI, 21.8%-44.5%), and 7 patients with HIV (20.6%; 95% CI, 8.7%-37.9%) had no identifiable risk factors.<br><br>Conclusions and Relevance: Results of this study found that a substantial proportion of patients with newly diagnosed cancer and concurrent HBV or HCV are unaware of their viral infection at the time of cancer diagnosis, and many had no identifiable risk factors for infection. Screening patients with cancer to identify HBV and HCV infection before starting treatment may be warranted to prevent viral reactivation and adverse clinical outcomes. The low rate of undiagnosed HIV infection may not support universal screening of newly diagnosed cancer patients.}, }
@article {pmid30651320, year = {2019}, author = {Barber, DL and Sakai, S and Kudchadkar, RR and Fling, SP and Day, TA and Vergara, JA and Ashkin, D and Cheng, JH and Lundgren, LM and Raabe, VN and Kraft, CS and Nieva, JJ and Cheever, MA and Nghiem, PT and Sharon, E}, title = {Tuberculosis following PD-1 blockade for cancer immunotherapy.}, journal = {Science translational medicine}, volume = {11}, number = {475}, pages = {}, doi = {10.1126/scitranslmed.aat2702}, pmid = {30651320}, issn = {1946-6242}, abstract = {Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be useful in infectious disease settings, including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical models, Mtb-infected PD-1-/- mice mount exaggerated TH1 responses that drive lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have been observed in patients with cancer, but in humans little is understood about Mtb-specific immune responses during checkpoint blockade-associated tuberculosis. Here, we report two more cases. We describe a patient who succumbed to disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel cell carcinoma who developed checkpoint blockade-associated tuberculosis and was successfully treated for the infection. After anti-PD-1 administration, interferon-γ-producing Mtb-specific CD4 T cells became more prevalent in the blood, and a tuberculoma developed a few months thereafter. Mtb-specific TH17 cells, CD8 T cells, regulatory T cells, and antibody abundance did not change before the appearance of the granuloma. These results are consistent with the murine model data and suggest that boosting TH1 function with PD-1 blockade may increase the risk or severity of tuberculosis in humans.}, }
@article {pmid30649998, year = {2019}, author = {Kerr, KF and Brown, MD and Marsh, TL and Janes, H}, title = {Assessing the Clinical Impact of Risk Models for Opting Out of Treatment.}, journal = {Medical decision making : an international journal of the Society for Medical Decision Making}, volume = {39}, number = {2}, pages = {86-90}, doi = {10.1177/0272989X18819479}, pmid = {30649998}, issn = {1552-681X}, support = {R01 CA152089/CA/NCI NIH HHS/United States ; R01 HL085757/HL/NHLBI NIH HHS/United States ; }, abstract = {Decision curves are a tool for evaluating the population impact of using a risk model for deciding whether to undergo some intervention, which might be a treatment to help prevent an unwanted clinical event or invasive diagnostic testing such as biopsy. The common formulation of decision curves is based on an opt-in framework. That is, a risk model is evaluated based on the population impact of using the model to opt high-risk patients into treatment in a setting where the standard of care is not to treat. Opt-in decision curves display the population net benefit of the risk model in comparison to the reference policy of treating no patients. In some contexts, however, the standard of care in the absence of a risk model is to treat everyone, and the potential use of the risk model would be to opt low-risk patients out of treatment. Although opt-out settings were discussed in the original decision curve paper, opt-out decision curves are underused. We review the formulation of opt-out decision curves and discuss their advantages for interpretation and inference when treat-all is the standard.}, }
@article {pmid30648524, year = {2019}, author = {Navarro, SL and Herrero, M and Martinez, H and Zhang, Y and Ladd, J and Lo, E and Shelley, D and Randolph, TW and Lampe, JW and Lampe, PD}, title = {Differences in serum biomarkers between combined glucosamine and chondroitin versus celecoxib in a randomized, double-blind trial in osteoarthritis patients.}, journal = {Anti-inflammatory &amp; anti-allergy agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/1871523018666190115094512}, pmid = {30648524}, issn = {1875-614X}, abstract = {BACKGROUND: Non-steroidal anti-inflammatory drugs, e.g., celecoxib, are commonly used for inflammatory conditions, but can be associated with adverse effects. Combined glucosamine hydrochloride plus chondroitin sulfate (GH+CS) are commonly used for joint pain and have no known adverse effects. Evidence from in vitro, animal and human studies suggests that GH+CS have anti-inflammatory activity, among other mechanisms of action.<br><br>OBJECTIVE: We evaluated the effects of GH+CS versus celecoxib on a panel of 20 serum proteins involved in inflammation and other metabolic pathways.<br><br>METHODS: Samples were from a randomized, parallel, double-blind trial of pharmaceutical grade 1500 mg GH + 1200 mg CS (n=96) versus 200 mg celecoxib daily (n=93) for 6-months in knee osteoarthritis (OA) patients. Linear mixed models adjusted for age, sex, body mass index, baseline serum protein values, and rescue medicine use assessed the intervention effects of each treatment arm adjusting for multiple testing.<br><br>RESULTS: All serum proteins except WNT16 were lower after treatment with GH+CS, while about half increased after celecoxib. Serum IL-6 was significantly reduced (by 9%, P=0.001) after GH+CS, and satisfied the FDR<0.05 threshold. CCL20, CSF3, and WNT16 increased after celecoxib (by 7%, 9% and 9%, respectively, P<0.05), but these serum proteins were no longer statistically significant after controlling for multiple testing.<br><br>CONCLUSION: The results of this study using samples from a previously conducted trial in OA patients, demonstrate that GH+CS reduces circulating IL-6, an inflammatory cytokine, but is otherwise comparable to celecoxib with regard to effects on other circulating protein biomarkers.}, }
@article {pmid30646272, year = {2018}, author = {Issaka, RB and Inadomi, JM}, title = {Low-Value Colorectal Cancer Screening: Too Much of a Good Thing?.}, journal = {JAMA network open}, volume = {1}, number = {8}, pages = {e185445}, doi = {10.1001/jamanetworkopen.2018.5445}, pmid = {30646272}, issn = {2574-3805}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, }
@article {pmid30646210, year = {2019}, author = {Goddard, ET and Bassale, S and Schedin, T and Jindal, S and Johnston, J and Cabral, E and Latour, E and Lyons, TR and Mori, M and Schedin, PJ and Borges, VF}, title = {Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk.}, journal = {JAMA network open}, volume = {2}, number = {1}, pages = {e186997}, doi = {10.1001/jamanetworkopen.2018.6997}, pmid = {30646210}, issn = {2574-3805}, abstract = {Importance: In women 45 years or younger, breast cancer diagnosis after childbirth increases the risk for metastasis and death, yet limited data exist to define this window of risk and associated prognostic factors.<br><br>Objective: To assess the window of elevated risk for metastasis following a postpartum breast cancer (PPBC) diagnosis and whether clinical prognostic factors are associated with the increased risk.<br><br>This multicenter cohort study conducted using cases from the Colorado Young Women's Breast Cancer Cohort diagnosed between January 1, 1981, and December 31, 2014, included 701 women 45 years or younger with stage I to III invasive breast cancer for whom parity data, including time of last childbirth, were available. Data analysis was conducted from July 1 to September 30, 2017. This study involved a tertiary care academic hospital-based breast center and its regional affiliates with cases from the greater Rocky Mountain region.<br><br>Exposures: Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, and time between breast cancer diagnosis and metastasis.<br><br>Main Outcomes and Measures: The primary outcome was distant metastasis-free survival.<br><br>Results: A total of 701 women 45 years or younger from the greater Rocky Mountain states region were included in the analysis; mean (SD) age at diagnosis was 37.9 (5.1) years. Breast cancer diagnosis within 10 years after parturition was associated with elevated risk for metastasis, particularly in women with stage I or II disease. In addition, women with PPBC diagnosed within 10 years of a completed pregnancy that was estrogen receptor-positive showed distant metastasis-free survival similar to that of nulliparous patients with estrogen receptor-negative cancer, and women with estrogen receptor-negative PPBC had further reduced metastasis-free survival. Moreover, women with PPBC had increased lymphovascular invasion and lymph node involvement. In addition, tumor-associated Ki67 positivity identified 129 patients with luminal B cancer in the cohort that, independent of parity status, had poorer prognosis compared with patients with luminal A cancer, although it did not reach statistical significance.<br><br>Conclusions and Relevance: Diagnosis of PPBC within 10 years post partum appears to be associated with an increased risk for metastasis. This increased risk was highest in stages I and II cancer at diagnosis and present in both patients with estrogen receptor-positive and estrogen receptor-negative cancer, persisting in estrogen receptor-positive cases for up to 15 years after diagnosis. Postpartum breast cancer diagnoses were not associated with increased Ki67 index but were associated with increased lymphovascular invasion and lymph node involvement compared with breast cancer in nulliparous patients.}, }
@article {pmid30646114, year = {2018}, author = {Unger, JM and Moseley, A and Symington, B and Chavez-MacGregor, M and Ramsey, SD and Hershman, DL}, title = {Geographic Distribution and Survival Outcomes for Rural Patients With Cancer Treated in Clinical Trials.}, journal = {JAMA network open}, volume = {1}, number = {4}, pages = {e181235}, doi = {10.1001/jamanetworkopen.2018.1235}, pmid = {30646114}, issn = {2574-3805}, abstract = {Importance: Studies showing that patients with cancer from rural areas have worse outcomes than their urban counterparts have relied on cancer population data and did not account for differences in access to care. Clinical trial patients receive protocol-directed care by design, so large clinical trial databases are ideal for examining the impact of rural vs urban residency on outcomes.<br><br>Objective: To compare the geographic distribution and survival outcomes for rural vs urban patients with cancer treated in clinical trials.<br><br>In this comparative effectiveness retrospective cohort analysis, 36 995 patients from all 50 states enrolled in 44 phase 3 and phase 2/3 SWOG (formerly the Southwest Oncology Group) treatment trials from January 1, 1986, to December 31, 2012, were examined. Seventeen different cancer-specific analysis cohorts were constructed. Data through January 30, 2018, were analyzed.<br><br>Main Outcomes and Measures: Rural vs urban residency was defined using the Rural-Urban Continuum Codes developed by the US Department of Agriculture. Multivariate Cox regression was used to estimate the association of residency with overall survival, progression-free survival, and cancer-specific survival, controlling for major disease-specific prognostic factors and demographic variables and stratifying by study. Different definitions of rurality were examined. The distribution of rural vs urban patients by geographic region was described.<br><br>Results: Overall, 27.7% of patients were 65 years or older (range across 17 cohort analyses, 7.8%-74.5%), 40.3% were female in the non-sex-specific analyses (range across 17 cohort analyses, 28.1%-45.9%), and 10.8% were black (range across 17 cohort analyses, 1.9%-22.4%). Overall, 19.4% of patients (7184 of 36 995) were from rural locations. Rural patients were more likely to be aged 65 years or older (rural, 30.7% aged ≥65 years vs urban, 27.0% aged ≥65 years; difference, 3.7%; 95% CI, 2.5%-4.9%; P < .001), were less likely to be black (rural, 5.4% vs urban, 12.1%; difference, 6.7%; 95% CI, 6.1%-7.3%; P < .001), were similar with respect to sex (rural, 40.4% female vs urban, 39.7% female; difference, 0.6%; 95% CI, -1.4% to 2.6%; P = .53), and were well represented within major US geographic regions (West, Midwest, South, and Northeast). Clinical prognostic factors were similar. In multivariable regression, rural patients with adjuvant-stage estrogen receptor-negative and progesterone receptor-negative breast cancer had worse overall survival (hazard ratio, 1.27; 95% CI, 1.06-1.51; P = .008) and cancer-specific survival (hazard ratio, 1.26; 95% CI, 1.04-1.52; P = .02). No other statistically significant differences for overall, progression-free, or cancer-specific survival were found. Results were consistent regardless of the definition of rurality.<br><br>Conclusions and Relevance: Rural and urban patients with uniform access to cancer care through participation in a SWOG clinical trial had similar outcomes. This finding suggests that improving access to uniform treatment strategies for patients with cancer may help resolve the disparity in cancer outcomes between rural and urban patients.}, }
@article {pmid30646111, year = {2018}, author = {Makarov, DV and Ciprut, S and Walter, D and Kelly, M and Gold, HT and Zhou, XH and Sherman, SE and Braithwaite, RS and Gross, C and Zeliadt, S}, title = {Association Between Guideline-Discordant Prostate Cancer Imaging Rates and Health Care Service Among Veterans and Medicare Recipients.}, journal = {JAMA network open}, volume = {1}, number = {4}, pages = {e181172}, doi = {10.1001/jamanetworkopen.2018.1172}, pmid = {30646111}, issn = {2574-3805}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; }, abstract = {Importance: Prostate cancer imaging rates appear to vary by health care setting. With the recent extension of the Veterans Access, Choice, and Accountability Act, the government has provided funds for veterans to seek care outside the Veterans Health Administration (VA). It is important to understand the difference in imaging rates and subsequent differences in patterns of care in the VA vs a traditional fee-for-service setting such as Medicare.<br><br>Objective: To assess the association between prostate cancer imaging rates and a VA vs fee-for-service health care setting.<br><br>This cohort study included data for men who received a diagnosis of prostate cancer from January 1, 2004, through March 31, 2008, that were collected from the VA Central Cancer Registry, linked to administrate claims and Medicare utilization records, and the Surveillance, Epidemiology, and End Results Program database. Three distinct nationally representative cohorts were constructed (use of VA only, use of Medicare only, and dual use of VA and Medicare). Men older than 85 years at diagnosis and men without high-risk features but missing any tumor risk characteristic (prostate-specific antigen, Gleason grade, or clinical stage) were excluded. Analysis of the data was completed from March 2016 to February 2018.<br><br>Exposures: Patient utilization of different health care delivery systems.<br><br>Main Outcomes and Measures: Rates of prostate cancer imaging were analyzed by health care setting (Medicare only, VA and Medicare, and VA only) among patients with low-risk prostate cancer and patients with high-risk prostate cancer.<br><br>Results: Of 98 867 men with prostate cancer (77.4% white; mean [SD] age, 70.26 [7.48] years) in the study cohort, 57.3% were in the Medicare-only group, 14.5% in the VA and Medicare group, and 28.1% in the VA-only group. Among men with low-risk prostate cancer, the Medicare-only group had the highest rate of guideline-discordant imaging (52.5%), followed by the VA and Medicare group (50.9%) and the VA-only group (45.9%) (P < .001). Imaging rates for men with high-risk prostate cancer were not significantly different among the 3 groups. Multivariable analysis showed that individuals in the VA and Medicare group (risk ratio [RR], 0.87; 95% CI, 0.76-0.98) and VA-only group (RR, 0.79; 95% CI, 0.67-0.92) were less likely to receive guideline-discordant imaging than those in the Medicare-only group.<br><br>Conclusions and Relevance: The results of this study suggest that patients with prostate cancer who use Medicare rather than the VA for health care could experience more utilization of health care services without an improvement in the quality of care.}, }
@article {pmid30644821, year = {2019}, author = {Jagannathan, S and Ogata, Y and Gafken, PR and Tapscott, SJ and Bradley, RK}, title = {Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy.}, journal = {eLife}, volume = {8}, number = {}, pages = {}, doi = {10.7554/eLife.41740}, pmid = {30644821}, issn = {2050-084X}, support = {P30 CA015704//National Institutes of Health/ ; FSHS-22014-01//FSH Society/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 NS069539/NS/NINDS NIH HHS/United States ; P01NS069539//National Institute of Neurological Disorders and Stroke/ ; S10 OD020069/OD/NIH HHS/United States ; }, abstract = {DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4's transcriptional activity has been extensively characterized, but the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein levels in DUX4-expressing cells via RNA-seq and quantitative mass spectrometry. DUX4 transcriptional targets were robustly translated, confirming the likely clinical relevance of proposed FSHD biomarkers. However, a multitude of mRNAs and proteins exhibited discordant expression changes upon DUX4 expression. Our dataset revealed unexpected proteomic, but not transcriptomic, dysregulation of diverse molecular pathways, including Golgi apparatus fragmentation, as well as extensive post-transcriptional buffering of stress-response genes. Key components of RNA degradation machineries, including UPF1, UPF3B, and XRN1, exhibited suppressed protein, but not mRNA, levels, explaining the build-up of aberrant RNAs that characterizes DUX4-expressing cells. Our results provide a resource for the FSHD community and illustrate the importance of post-transcriptional processes in DUX4-induced pathology.}, }
@article {pmid30643251, year = {2019}, author = {Liu, M and Jiang, Y and Wedow, R and Li, Y and Brazel, DM and Chen, F and Datta, G and Davila-Velderrain, J and McGuire, D and Tian, C and Zhan, X and ,  and ,  and Choquet, H and Docherty, AR and Faul, JD and Foerster, JR and Fritsche, LG and Gabrielsen, ME and Gordon, SD and Haessler, J and Hottenga, JJ and Huang, H and Jang, SK and Jansen, PR and Ling, Y and Mägi, R and Matoba, N and McMahon, G and Mulas, A and Orrù, V and Palviainen, T and Pandit, A and Reginsson, GW and Skogholt, AH and Smith, JA and Taylor, AE and Turman, C and Willemsen, G and Young, H and Young, KA and Zajac, GJM and Zhao, W and Zhou, W and Bjornsdottir, G and Boardman, JD and Boehnke, M and Boomsma, DI and Chen, C and Cucca, F and Davies, GE and Eaton, CB and Ehringer, MA and Esko, T and Fiorillo, E and Gillespie, NA and Gudbjartsson, DF and Haller, T and Harris, KM and Heath, AC and Hewitt, JK and Hickie, IB and Hokanson, JE and Hopfer, CJ and Hunter, DJ and Iacono, WG and Johnson, EO and Kamatani, Y and Kardia, SLR and Keller, MC and Kellis, M and Kooperberg, C and Kraft, P and Krauter, KS and Laakso, M and Lind, PA and Loukola, A and Lutz, SM and Madden, PAF and Martin, NG and McGue, M and McQueen, MB and Medland, SE and Metspalu, A and Mohlke, KL and Nielsen, JB and Okada, Y and Peters, U and Polderman, TJC and Posthuma, D and Reiner, AP and Rice, JP and Rimm, E and Rose, RJ and Runarsdottir, V and Stallings, MC and Stančáková, A and Stefansson, H and Thai, KK and Tindle, HA and Tyrfingsson, T and Wall, TL and Weir, DR and Weisner, C and Whitfield, JB and Winsvold, BS and Yin, J and Zuccolo, L and Bierut, LJ and Hveem, K and Lee, JJ and Munafò, MR and Saccone, NL and Willer, CJ and Cornelis, MC and David, SP and Hinds, DA and Jorgenson, E and Kaprio, J and Stitzel, JA and Stefansson, K and Thorgeirsson, TE and Abecasis, G and Liu, DJ and Vrieze, S}, title = {Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.}, journal = {Nature genetics}, volume = {51}, number = {2}, pages = {237-244}, doi = {10.1038/s41588-018-0307-5}, pmid = {30643251}, issn = {1546-1718}, support = {R21 DA040177/DA/NIDA NIH HHS/United States ; MR/K023195/1//Medical Research Council/United Kingdom ; R01 HG008983/HG/NHGRI NIH HHS/United States ; R01 DA042755/DA/NIDA NIH HHS/United States ; MC_UU_12013/1//Medical Research Council/United Kingdom ; G0902144//Medical Research Council/United Kingdom ; R01 DA037904/DA/NIDA NIH HHS/United States ; U01 DA046413/DA/NIDA NIH HHS/United States ; R01 AA023974/AA/NIAAA NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; P2C HD066613/HD/NICHD NIH HHS/United States ; K01 MH109765/MH/NIMH NIH HHS/United States ; }, abstract = {Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.}, }
@article {pmid30643249, year = {2019}, author = {Gu, Z and Churchman, ML and Roberts, KG and Moore, I and Zhou, X and Nakitandwe, J and Hagiwara, K and Pelletier, S and Gingras, S and Berns, H and Payne-Turner, D and Hill, A and Iacobucci, I and Shi, L and Pounds, S and Cheng, C and Pei, D and Qu, C and Newman, S and Devidas, M and Dai, Y and Reshmi, SC and Gastier-Foster, J and Raetz, EA and Borowitz, MJ and Wood, BL and Carroll, WL and Zweidler-McKay, PA and Rabin, KR and Mattano, LA and Maloney, KW and Rambaldi, A and Spinelli, O and Radich, JP and Minden, MD and Rowe, JM and Luger, S and Litzow, MR and Tallman, MS and Racevskis, J and Zhang, Y and Bhatia, R and Kohlschmidt, J and Mrózek, K and Bloomfield, CD and Stock, W and Kornblau, S and Kantarjian, HM and Konopleva, M and Evans, WE and Jeha, S and Pui, CH and Yang, J and Paietta, E and Downing, JR and Relling, MV and Zhang, J and Loh, ML and Hunger, SP and Mullighan, CG}, title = {PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.}, journal = {Nature genetics}, volume = {51}, number = {2}, pages = {296-307}, doi = {10.1038/s41588-018-0315-5}, pmid = {30643249}, issn = {1546-1718}, support = {R35 CA197695/CA/NCI NIH HHS/United States ; RC1 CA145707/CA/NCI NIH HHS/United States ; R01 CA036401/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; P50 GM115279/GM/NIGMS NIH HHS/United States ; }, abstract = {Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.}, }
@article {pmid30642921, year = {2019}, author = {de Vries, PS and Sabater-Lleal, M and Huffman, JE and Marten, J and Song, C and Pankratz, N and Bartz, TM and de Haan, HG and Delgado, GE and Eicher, JD and Martinez-Perez, A and Ward-Caviness, CK and Brody, JA and Chen, MH and de Maat, MPM and Frånberg, M and Gill, D and Kleber, ME and Rivadeneira, F and Soria, JM and Tang, W and Tofler, GH and Uitterlinden, AG and van Hylckama Vlieg, A and Seshadri, S and Boerwinkle, E and Davies, NM and Giese, AK and Ikram, MK and Kittner, SJ and McKnight, B and Psaty, BM and Reiner, AP and Sargurupremraj, M and Taylor, KD and ,  and ,  and Fornage, M and Hamsten, A and März, W and Rosendaal, FR and Souto, JC and Dehghan, A and Johnson, AD and Morrison, AC and O'Donnell, CJ and Smith, NL}, title = {A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.}, journal = {Blood}, volume = {133}, number = {9}, pages = {967-977}, doi = {10.1182/blood-2018-05-849240}, pmid = {30642921}, issn = {1528-0020}, abstract = {Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.}, }
@article {pmid30642457, year = {2019}, author = {Horn, L and Bauml, J and Forde, PM and Davis, KL and Myall, NJ and Sasane, M and Dalal, A and Culver, K and Wozniak, AJ and Baik, CS and Mutebi, A and Zhang, P and Wakelee, HA and Johnson, BE}, title = {Real-world treatment patterns and survival of patients with BRAF V600-mutated metastatic non-small cell lung cancer.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {128}, number = {}, pages = {74-90}, doi = {10.1016/j.lungcan.2018.12.003}, pmid = {30642457}, issn = {1872-8332}, abstract = {INTRODUCTION: Clinical outcomes data on BRAF-mutated non-small cell lung cancer (NSCLC) patients treated in routine practice is limited. To address this gap, we described treatment patterns and survival in a cohort of these patients evaluated/treated at 7 US academic cancer centers during 2009-2016.<br><br>METHODS: This was a retrospective chart review. Patients with BRAF V600-mutated metastatic NSCLC were selected. Current/previous participants in BRAF-related trials were excluded. Onset of metastatic NSCLC defined a patient's index date, which had to occur ≥6 months before the chart review date. Analyses were descriptive, including Kaplan-Meier analyses for overall survival (OS).<br><br>RESULTS: The study included 72 patients. At index, median age (range) was 65 (44-90) years; 61.1% were female. Fifty-two patients received ≥1 line of systemic therapy for metastatic disease. Platinum-based doublet chemotherapy was the most common first-line (1 L) regimen (76.9% of 1 l recipients); no patient received 1 l targeted therapy (TT) with a BRAF/MEK inhibitor. In total, 20 patients received TT in any treatment line (2 l or later). At time of review, 38 patients were deceased. Median (95%CI) OS from index for all patients was 31.0 (14.5, 63.8) months. Median (95%CI) OS was 56.5 (13.4, 89.1) months from index for TT recipients and 27.2 (10.6, 64.6) months in patients not treated with TT.<br><br>CONCLUSION: Survival time in BRAF V600-mutated metastatic NSCLC patients studied here was higher than expected based on indirect comparisons with historical NSCLC cohorts for whom no oncogenic driver (BRAF or otherwise) was present. TT recipients had a numerically longer OS from metastatic onset than patients receiving usual care, further highlighting the importance of TT in BRAF V600-mutant NSCLC.}, }
@article {pmid30639324, year = {2019}, author = {Chen, H and Huffman, JE and Brody, JA and Wang, C and Lee, S and Li, Z and Gogarten, SM and Sofer, T and Bielak, LF and Bis, JC and Blangero, J and Bowler, RP and Cade, BE and Cho, MH and Correa, A and Curran, JE and de Vries, PS and Glahn, DC and Guo, X and Johnson, AD and Kardia, S and Kooperberg, C and Lewis, JP and Liu, X and Mathias, RA and Mitchell, BD and O'Connell, JR and Peyser, PA and Post, WS and Reiner, AP and Rich, SS and Rotter, JI and Silverman, EK and Smith, JA and Vasan, RS and Wilson, JG and Yanek, LR and ,  and ,  and Redline, S and Smith, NL and Boerwinkle, E and Borecki, IB and Cupples, LA and Laurie, CC and Morrison, AC and Rice, KM and Lin, X}, title = {Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.}, journal = {American journal of human genetics}, volume = {104}, number = {2}, pages = {260-274}, doi = {10.1016/j.ajhg.2018.12.012}, pmid = {30639324}, issn = {1537-6605}, support = {R35 CA197449/CA/NCI NIH HHS/United States ; R01 HL131136/HL/NHLBI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; R01 EB015611/EB/NIBIB NIH HHS/United States ; R01 HL139553/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL113338/HL/NHLBI NIH HHS/United States ; R01 HL137922/HL/NHLBI NIH HHS/United States ; P01 CA134294/CA/NCI NIH HHS/United States ; U01 HG009088/HG/NHGRI NIH HHS/United States ; P20 GM121334/GM/NIGMS NIH HHS/United States ; R00 HL130593/HL/NHLBI NIH HHS/United States ; }, abstract = {With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.}, }
@article {pmid30638028, year = {2019}, author = {McKinnon, LR and Achilles, SL and Bradshaw, CS and Burgener, A and Crucitti, T and Fredricks, DN and Jaspan, HB and Kaul, R and Kaushic, C and Klatt, N and Kwon, DS and Marrazzo, JM and Masson, L and McClelland, RS and Ravel, J and van de Wijgert, JHHM and Vodstrcil, LA and Tachedjian, G}, title = {The Evolving Facets of Bacterial Vaginosis: Implications for HIV Transmission.}, journal = {AIDS research and human retroviruses}, volume = {35}, number = {3}, pages = {219-228}, doi = {10.1089/AID.2018.0304}, pmid = {30638028}, issn = {1931-8405}, abstract = {Bacterial vaginosis (BV) is a common yet poorly understood vaginal condition that has become a major focus of HIV transmission and immunology research. Varied terminologies are used by clinicians and researchers to describe microbial communities that reside in the female reproductive tract (FRT), which is driven, in part, by microbial genetic and metabolic complexity, evolving diagnostic and molecular techniques, and multidisciplinary perspectives of clinicians, epidemiologists, microbiologists, and immunologists who all appreciate the scientific importance of understanding mechanisms that underlie BV. This Perspectives article aims to clarify the varied terms used to describe the cervicovaginal microbiota and its &quot;nonoptimal&quot; state, under the overarching term of BV. The ultimate goal is to move toward language standardization in future literature that facilitates a better understanding of the impact of BV on FRT immunology and risk of sexually transmitted infections, including HIV.}, }
@article {pmid30635626, year = {2019}, author = {Hoang, VT and Verma, D and Godavarthy, PS and Llavona, P and Steiner, M and Gerlach, K and Michels, BE and Bohnenberger, H and Wachter, A and Oellerich, T and Müller-Kuller, U and Weissenberger, E and Voutsinas, JM and Oehler, VG and Farin, HF and Zörnig, M and Krause, DS}, title = {The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-018-0358-8}, pmid = {30635626}, issn = {1476-5551}, support = {2015.039.1//Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)/ ; }, abstract = {The transcriptional regulator far upstream element binding protein 1 (FUBP1) acts as an oncoprotein in solid tumor entities and plays a role in the maintenance of hematopoietic stem cells. However, its potential function in leukemia is unknown. In murine models of chronic (CML) and acute myeloid leukemia (AML) induced by BCR-ABL1 and MLL-AF9, respectively, knockdown of Fubp1 resulted in prolonged survival, decreased numbers of CML progenitor cells, decreased cell cycle activity and increased apoptosis. Knockdown of FUBP1 in CML and AML cell lines recapitulated these findings and revealed enhanced DNA damage compared to leukemia cells expressing wild type FUBP1 levels. FUBP1 was more highly expressed in human CML compared to normal bone marrow cells and its expression correlated with disease progression. In AML, higher FUBP1 expression in patient leukemia cells was observed with a trend toward correlation with shorter overall survival. Treatment of mice with AML with irinotecan, known to inhibit topoisomerase I and FUBP1, significantly prolonged survival alone or in combination with cytarabine. In summary, our data suggest that FUBP1 acts as cell cycle regulator and apoptosis inhibitor in leukemia. We demonstrated that FUBP1 might play a role in DNA repair, and its inhibition may improve outcome in leukemia patients.}, }
@article {pmid30635271, year = {2019}, author = {Yusko, E and Vignali, M and Wilson, RK and Mardis, ER and Hodi, FS and Horak, C and Chang, H and Woods, DM and Robins, H and Weber, J}, title = {Association of Tumor Microenvironment T-cell Repertoire and Mutational Load with Clinical Outcome after Sequential Checkpoint Blockade in Melanoma.}, journal = {Cancer immunology research}, volume = {7}, number = {3}, pages = {458-465}, doi = {10.1158/2326-6066.CIR-18-0226}, pmid = {30635271}, issn = {2326-6074}, support = {R01 CA175732/CA/NCI NIH HHS/United States ; }, abstract = {To understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by IHC, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those parameters with response and overall survival. Immunosequencing of the T-cell receptor β-chain locus (TCRβ) from DNA of 91 pretreatment tumor samples and an additional 22 pairs of matched pre- and posttreatment samples from patients who received nivolumab followed by ipilimumab (nivo/ipi), or the reverse (ipi/nivo), was performed to measure T-cell clonality and fraction. Mutational and neoantigen load were also assessed by NGS in 82 of the 91 patients. Tumors were stained using IHC for PD-L1+ and CD8+ T cells. Pretreatment tumor TCR clonality and neoantigen load were marginally associated with best response with nivo/ipi (P = 0.04 and 0.05, respectively), but not with ipi/nivo. Amalgamated pretreatment mutational load and tumor T-cell fraction were significantly associated with best response with nivo/ipi (P = 0.002). Pretreatment PD-L1 staining intensity and CD8+ T-cell counts were correlated with T-cell fraction and clonality, but not mutational or neoantigen load. Patients with increased T-cell fraction posttreatment at week 13 had a 30-fold increased likelihood of survival (P = 0.002). Mutational and neoantigen load, and T-cell infiltrate within the tumor, were associated with outcome of sequential checkpoint inhibition using nivolumab then ipilimumab, but not when ipilimumab was administered before nivolumab.}, }
@article {pmid30630975, year = {2019}, author = {Monaco, F and Scott, BL and Chauncey, TR and Petersen, FB and Storer, BE and Baron, F and Flowers, ME and Deeg, HJ and Maloney, DG and Storb, R and Sandmaier, BM}, title = {Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.199398}, pmid = {30630975}, issn = {1592-8721}, abstract = {A nonmyeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive nonmyeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low-risk (n=36) and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 x3 days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary endpoint was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. Primary endpoint was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with nonmyeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease nonrelapse mortality, especially among patients with high-risk disease. Trial registered under ClinicalTrials.gov No. NCT00397813 .}, }
@article {pmid30630165, year = {2019}, author = {Smith, SD}, title = {Gemcitabine: End of a Chemotherapy's Era?.}, journal = {Acta haematologica}, volume = {141}, number = {2}, pages = {91-92}, doi = {10.1159/000496098}, pmid = {30630165}, issn = {1421-9662}, }
@article {pmid30629903, year = {2019}, author = {Greenlee, H and Shi, Z}, title = {Implementing Integrative Oncology: Hopes and Challenges.}, journal = {Journal of oncology practice}, volume = {15}, number = {1}, pages = {17-18}, doi = {10.1200/JOP.18.00755}, pmid = {30629903}, issn = {1935-469X}, }
@article {pmid30629898, year = {2019}, author = {Lyman, GH}, title = {Febrile Neutropenia: An Ounce of Prevention or a Pound of Cure.}, journal = {Journal of oncology practice}, volume = {15}, number = {1}, pages = {27-29}, doi = {10.1200/JOP.18.00750}, pmid = {30629898}, issn = {1935-469X}, }
@article {pmid30629263, year = {2019}, author = {Stoddard, BL and Fox, KR}, title = {Editorial: Preprints, citations and Nucleic Acids Research.}, journal = {Nucleic acids research}, volume = {47}, number = {1}, pages = {1-2}, doi = {10.1093/nar/gky1229}, pmid = {30629263}, issn = {1362-4962}, }
@article {pmid30629220, year = {2019}, author = {Reeves, KW and Santana, MD and Manson, JE and Hankinson, SE and Zoeller, RT and Bigelow, C and Sturgeon, SR and Spiegelman, D and Tinker, L and Luo, J and Chen, B and Meliker, J and Bonner, MR and Cote, ML and Cheng, TD and Calafat, AM}, title = {Urinary Phthalate Biomarker Concentrations and Postmenopausal Breast Cancer Risk.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djz002}, pmid = {30629220}, issn = {1460-2105}, abstract = {Background: Growing laboratory and animal model evidence supports the potentially carcinogenic effects of some phthalates, chemicals used as plasticizers in a wide variety of consumer products, including cosmetics, medications, and vinyl flooring. However, prospective data on whether phthalates are associated with human breast cancer risk are lacking.<br><br>Methods: We conducted a nested case-control study within the Women's Health Initiative (WHI) prospective cohort (N = 419 invasive cases and 838 controls). Controls were matched 2:1 to cases on age, enrollment date, follow-up time, and WHI study group. We quantified thirteen phthalate metabolites and creatinine in two or three urine samples per participant over one to three years. Multivariable conditional logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (OR, 95% CI) for breast cancer risk associated with each phthalate biomarker over up to 19 years of follow-up.<br><br>Results: Overall, we did not observe statistically significant positive associations between phthalate biomarkers and breast cancer risk in multivariable analyses (e.g. 4th vs 1st quartile of diethylhexyl phthalate OR 1.03, 95% CI 0.91 - 1.17). Results were generally similar in analyses restricted to disease subtypes, to non-users of postmenopausal hormone therapy, stratified by body mass index, or to cases diagnosed within three, five, or ten years.<br><br>Conclusions: In the first prospective analysis of phthalates and postmenopausal breast cancer, phthalate biomarker concentrations did not result in an increased risk of developing invasive breast cancer.}, }
@article {pmid30629092, year = {2019}, author = {Unger, JM and Hershman, DL and Fleury, ME and Vaidya, R}, title = {Association of Patient Comorbid Conditions With Cancer Clinical Trial Participation.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2018.5953}, pmid = {30629092}, issn = {2374-2445}, abstract = {Importance: The American Society of Clinical Oncology (ASCO), Friends of Cancer Research, and the US Food and Drug Administration recently recommended modernizing criteria related to comorbidities routinely used to exclude patients from cancer clinical trials. The goal was to design clinical trial eligibility such that trial results better reflect real-world cancer patient populations, to improve clinical trial participation, and to increase patient access to new treatments in trials. Yet despite the assumed influence of comorbidities on trial participation, the relationship between patients' comorbidity profile at diagnosis and trial participation has not been explicitly examined using patient-level data.<br><br>Objectives: To investigate the association between comorbidities, clinical trial decision-making, and clinical trial participation; and to estimate the potential impact of reducing comorbidity exclusion criteria on trial participation, to provide a benchmark for changing criteria.<br><br>A national survey was embedded within a web-based cancer treatment-decision tool accessible on multiple cancer-oriented websites. Participants must have received a diagnosis of breast, lung, colorectal, or prostate cancer. In total, 5499 surveyed patients who made a treatment decision within the past 3 months were analyzed using logistic regression analysis and simulations.<br><br>Exposures: Cancer diagnosis and 1 or more of 18 comorbidities.<br><br>Main Outcomes and Measures: Patient discussion of a clinical trial with their physician (yes vs no); if a trial was discussed, the offer of trial participation (yes vs no); and, if trial participation was offered, trial participation (yes vs no).<br><br>Results: Of the 5499 patients who participated in the survey, 3420 (62.6%) were women and 2079 (37.8%) were men (mean [SD] age, 56.63 [10.05] years). Most patients (65.6%; n = 3610) had 1 or more comorbidities. The most common comorbid condition was hypertension (35.0%; n = 1924). Compared with the absence of comorbidities, the presence of 1 or more comorbidities was associated with a decreased risk of trial discussions (44.1% vs 37.2%; OR, 0.86; 95% CI, 0.75-0.97; P = .02), trial offers (21.7% vs 15.7%; OR, 0.82; 95% CI, 0.70-0.96; P = .02), and trial participation (11.3% vs 7.8%; OR, 0.76; 95% CI, 0.61-0.94; P = .01). The removal of the ASCO-recommended comorbidity restrictions could generate up to 6317 additional patient trial registrations every year.<br><br>Conclusions and Relevance: Independent of sociodemographic variables, the presence of comorbidities is adversely associated with trial discussions, trial offers, and trial participation itself. Updating trial eligibility criteria could provide an opportunity for several thousand more patients with well-managed comorbidities to participate in clinical trials each year.}, }
@article {pmid30628928, year = {2019}, author = {Fries, CA and Lawson, SD and Wang, LC and Spencer, JR and Roth, M and Rickard, RF and Gorantla, VS and Davis, MR}, title = {Composite Graft Pretreatment With Hydrogen Sulfide Delays the Onset of Acute Rejection.}, journal = {Annals of plastic surgery}, volume = {82}, number = {4}, pages = {452-458}, doi = {10.1097/SAP.0000000000001693}, pmid = {30628928}, issn = {1536-3708}, abstract = {INTRODUCTION: Vascularized composite allotransplantation can reconstruct devastating tissue loss by replacing like-with-like tissues, most commonly in the form of hand or face transplantation. Unresolved technical and ethical challenges have meant that such transplants remain experimental treatments. The most significant barrier to expansion of this field is the requirement for systemic immunosuppression, its toxicity and effect on longevity.Hydrogen sulfide (H2S) has been shown experimentally to ameliorate the ischemia reperfusion injury associated with composite tissue autotransplantation, which has been linked to acute rejection in solid organ transplantation. In this protocol, a large-animal model was used to evaluate the effect of H2S on acute rejection after composite tissue allotransplantation.<br><br>MATERIALS AND METHODS: A musculocutaneous flap model in SLA-mismatched swine was used to evaluate acute rejection of allotransplants in 2 groups: control animals (n = 8) and a treatment group in which the allografts were pretreated with hydrogen sulfide (n = 8). Neither group was treated with systemic immunosuppression. Acute rejection was graded clinically and histopathologically by an independent, blinded pathologist. Data were analyzed by t tests with correction for multiple comparisons by the Holm-Šídák method.<br><br>RESULTS: Clinically, H2S-treated tissue composites showed a delay in the onset of rejection that was statistically significant from postoperative day 6. Histopathologically, this difference between groups was also apparent, although evidence of a difference in groups disappeared beyond day 10.<br><br>CONCLUSIONS: Targeted hydrogen sulfide treatment of vascularized composite allografts immediately before transplantation can delay acute rejection. This may, in turn, reduce or obviate the requirement for systemic immunosuppression.}, }
@article {pmid30628507, year = {2019}, author = {Estey, E}, title = {'Looking beyond survival to define therapeutic value in acute myeloid leukemia'.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/10428194.2018.1543886}, pmid = {30628507}, issn = {1029-2403}, }
@article {pmid30627300, year = {2018}, author = {Lange, JM and Gulati, R and Leonardson, AS and Lin, DW and Newcomb, LF and Trock, BJ and Carter, HB and Cooperberg, MR and Cowan, JE and Klotz, LH and Etzioni, R}, title = {ESTIMATING AND COMPARING CANCER PROGRESSION RISKS UNDER VARYING SURVEILLANCE PROTOCOLS.}, journal = {The annals of applied statistics}, volume = {12}, number = {3}, pages = {1773-1795}, doi = {10.1214/17-AOAS1130}, pmid = {30627300}, issn = {1932-6157}, support = {R01 CA183570/CA/NCI NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; U01 CA199338/CA/NCI NIH HHS/United States ; }, abstract = {Outcomes after cancer diagnosis and treatment are often observed at discrete times via doctor-patient encounters or specialized diagnostic examinations. Despite their ubiquity as endpoints in cancer studies, such outcomes pose challenges for analysis. In particular, comparisons between studies or patient populations with different surveillance schema may be confounded by differences in visit frequencies. We present a statistical framework based on multistate and hidden Markov models that represents events on a continuous time scale given data with discrete observation times. To demonstrate this framework, we consider the problem of comparing risks of prostate cancer progression across multiple active surveillance cohorts with different surveillance frequencies. We show that the different surveillance schedules partially explain observed differences in the progression risks between cohorts. Our application permits the conclusion that differences in underlying cancer progression risks across cohorts persist after accounting for different surveillance frequencies.}, }
@article {pmid30626941, year = {2019}, author = {Silva, DA and Yu, S and Ulge, UY and Spangler, JB and Jude, KM and Labão-Almeida, C and Ali, LR and Quijano-Rubio, A and Ruterbusch, M and Leung, I and Biary, T and Crowley, SJ and Marcos, E and Walkey, CD and Weitzner, BD and Pardo-Avila, F and Castellanos, J and Carter, L and Stewart, L and Riddell, SR and Pepper, M and Bernardes, GJL and Dougan, M and Garcia, KC and Baker, D}, title = {De novo design of potent and selective mimics of IL-2 and IL-15.}, journal = {Nature}, volume = {565}, number = {7738}, pages = {186-191}, doi = {10.1038/s41586-018-0830-7}, pmid = {30626941}, issn = {1476-4687}, support = {/HHMI/Howard Hughes Medical Institute/United States ; R37 AI051321/AI/NIAID NIH HHS/United States ; S10 OD021832/OD/NIH HHS/United States ; R01 AI051321/AI/NIAID NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; }, abstract = {We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγc heterodimer (IL-2Rβγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.}, }
@article {pmid30625217, year = {2019}, author = {Burnett-Hartman, AN and Hua, X and Rue, TC and Golchin, N and Kessler, L and Rowhani-Rahbar, A}, title = {Risk interval analysis of emergency room visits following colonoscopy in patients with inflammatory bowel disease.}, journal = {PloS one}, volume = {14}, number = {1}, pages = {e0210262}, doi = {10.1371/journal.pone.0210262}, pmid = {30625217}, issn = {1932-6203}, abstract = {BACKGROUND AND AIMS: Prior studies suggest that colonoscopy may exacerbate inflammatory bowel disease (IBD) symptoms. Thus, our study aimed to determine risk of emergency room (ER) visits associated with colonoscopy among IBD patients and evaluate potential modifiers of this risk.<br><br>METHODS: The study population included IBD patients in the Multi-Payer Claims Database who were >20 years old and had a colonoscopy from 2007-2010. We used a self-controlled risk interval design and mixed-effects Poisson regression models to calculate risk ratios (RR) and 95% confidence intervals (CI) comparing the incidence of ER visits in the 1-4 weeks following colonoscopy (risk interval) to the incidence of ER visits in the 7-10 weeks after colonoscopy (control interval). We also conducted stratified analyses by patient characteristics, bowel preparation type, and medication.<br><br>RESULTS: There were 212,205 IBD patients with at least 1 colonoscopy from 2007-2010, and 3,699 had an ER visit during the risk and/or control interval. The risk of an ER visit was higher in the 4-week risk interval following colonoscopy compared to the control interval (RR = 1.24; 95% CI: 1.17-1.32). The effect was strongest in those <41 years old (RR = 1.60; 95% CI: 1.21-2.11), in women (RR = 1.32; 95% CI: 1.21-1.44), and in those with sodium phosphate bowel preparation (RR = 2.09; 95% CI: 1.02-4.29). Patients using immunomodulators had no increased risk of ER visits (RR = 0.75; 95% CI: 0.35-1.59).<br><br>CONCLUSIONS: Our results suggest that there is an increased risk of ER visits following colonoscopy among IBD patients, but that immunomodulators and mild bowel preparation agents may mitigate this risk.}, }
@article {pmid30624309, year = {2019}, author = {Peebles, K and Velloza, J and Balkus, JE and Scott McClelland, R and Barnabas, RV}, title = {High Global Burden and Costs of Bacterial Vaginosis: A Systematic Review and Meta-Analysis.}, journal = {Sexually transmitted diseases}, volume = {}, number = {}, pages = {}, doi = {10.1097/OLQ.0000000000000972}, pmid = {30624309}, issn = {1537-4521}, abstract = {BACKGROUND: Bacterial vaginosis (BV) is the most common vaginal infection among women of reproductive age and is associated with important adverse health outcomes. Estimates of the burden of BV and associated costs are needed to inform research priorities.<br><br>METHODS: We conducted a systematic review and meta-analysis of global BV prevalence among reproductive-aged women in the general population. We searched PubMed and Embase, and used random effects models to estimate BV prevalence by global regions. We estimated the direct medical costs of treating symptomatic BV. Assuming a causal relationship, we also estimated the potential costs of BV-associated preterm births and HIV cases in the United States.<br><br>RESULTS: General population prevalence of BV is high globally, ranging from 23% to 29% across regions (Europe and Central Asia: 23%; East Asia and Pacific: 24%; Latin America and Caribbean: 24%; Middle East and North Africa: 25%; sub-Saharan Africa: 25%; North America 27%; South Asia: 29%). Within North America, Black and Hispanic women have significantly higher (33% and 31%, respectively) prevalence compared to other racial groups (White: 23%; Asian: 11%) (p<0.01).The estimated annual global economic burden of treating symptomatic BV is $4.8 (95% CI: $3.7, $6.1) billion. The US economic burden of BV is nearly tripled when including costs of BV-associated preterm births and HIV cases.<br><br>CONCLUSIONS: BV prevalence is high globally, with a concomitant high economic burden and marked racial disparities in prevalence. Research to determine the etiology of BV and corresponding prevention and sustainable treatment strategies are urgently needed to reduce the burden of BV among women. Additionally, the exceptionally high cost of BV-associated sequelae highlights the need for research to understand potential causal linkages between BV and adverse health outcomes.}, }
@article {pmid30624099, year = {2019}, author = {Bennett, B and Workman, T and Smith, MN and Griffith, WC and Thompson, B and Faustman, EM}, title = {Longitudinal, Seasonal, and Occupational Trends of Multiple Pesticides in House Dust.}, journal = {Environmental health perspectives}, volume = {127}, number = {1}, pages = {17003}, doi = {10.1289/EHP3644}, pmid = {30624099}, issn = {1552-9924}, support = {HHSN267200700023C/HD/NICHD NIH HHS/United States ; P01 ES009601/ES/NIEHS NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; }, mesh = {Dust/*analysis ; Environmental Exposure/*analysis ; *Farmers ; Housing ; Humans ; Longitudinal Studies ; Occupational Exposure/analysis ; Pesticides/*analysis ; Seasons ; Washington ; }, abstract = {BACKGROUND: Children are especially vulnerable to pesticide exposure and can suffer lasting health effects. Because children of farmworkers are exposed to a variety of pesticides throughout development, it is important to explore temporal patterns of coexposures.<br><br>OBJECTIVES: The objectives of this study were to characterize the pesticide co-exposures, determine how they change over time, and assess differences between farmworker and nonfarmworker households.<br><br>METHODS: Dust collected from 40 farmworker and 35 nonfarmworker households in the Yakima Valley of the State of Washington in 2005 and then again in 2011 was analyzed for 99 pesticides. Eighty-seven pesticides representing over 28 classes were detected. Pesticides were grouped into classes using U.S. EPA pesticide chemical classifications, and trends in concentrations were analyzed at the class level.<br><br>RESULTS: Levels of organophosphates, pyridazinones, and phenols significantly decreased between 2005 and 2011 in both farmworker and nonfarmworker households. Levels of anilides, 2,6-dinitroanilines, chlorophenols, triclosan, and guanidines significantly increased in both farmworker and nonfarmworker households in 2011 vs. 2005. Among farmworkers alone, there were significantly lower levels of N-methyl carbamates and neonicotinoids in 2011.<br><br>CONCLUSIONS: We observed significant reductions in the concentrations of many pesticides over time in both farmworker and nonfarmworker households. Although nonfarmworker households generally had lower concentrations of pesticides, it is important to note that in comparison with NHANES participants, nonfarmworkers and their families still had significantly higher concentrations of urinary pesticide metabolites. This finding highlights the importance of detailed longitudinal exposure monitoring to capture changes in agricultural and residential pesticide use over time. This foundation provides an avenue to track longitudinal pesticide exposures in an intervention or regulatory context. https://doi.org/10.1289/EHP3644.}, }
@article {pmid30623732, year = {2019}, author = {Westling, T and Juraska, M and Seaton, KE and Tomaras, GD and Gilbert, PB and Janes, H}, title = {Methods for comparing durability of immune responses between vaccine regimens in early-phase trials.}, journal = {Statistical methods in medical research}, volume = {}, number = {}, pages = {962280218820881}, doi = {10.1177/0962280218820881}, pmid = {30623732}, issn = {1477-0334}, abstract = {The ability to produce a long-lasting, or durable, immune response is a crucial characteristic of many highly effective vaccines. A goal of early-phase vaccine trials is often to compare the immune response durability of multiple tested vaccine regimens. One parameter for measuring immune response durability is the area under the mean post-peak log immune response profile. In this paper, we compare immune response durability across vaccine regimens within and between two phase I trials of DNA-primed HIV vaccine regimens, HVTN 094 and HVTN 096. We compare four estimators of this durability parameter and the resulting statistical inferences for comparing vaccine regimens. Two of these estimators use the trapezoid rule as an empirical approximation of the area under the marginal log response curve, and the other two estimators are based on linear and nonlinear models for the marginal mean log response. We conduct a simulation study to compare the four estimators, provide guidance on estimator selection, and use the nonlinear marginal mean model to analyze immunogenicity data from the two HIV vaccine trials.}, }
@article {pmid30622541, year = {2018}, author = {Cassady, K and Martin, PJ and Zeng, D}, title = {Regulation of GVHD and GVL Activity via PD-L1 Interaction With PD-1 and CD80.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {3061}, doi = {10.3389/fimmu.2018.03061}, pmid = {30622541}, issn = {1664-3224}, support = {R01 CA228465/CA/NCI NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e. leukemia and lymphoma), because graft-versus-leukemia (GVL) activity mediated by alloreactive T cells can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells also mediate a severe side effect, graft-versus-host disease (GVHD), and prevention of GVHD while preserving GVL activity remains an elusive goal. The immune checkpoint molecule PD-L1 and its interaction with PD-1 receptor in regulating cancer immunity is under intensive and wide-spread study, but knowledge about this interaction in regulating GVHD and GVL activity is very limited. In this review, we summarize the literature exploring how PD-L1 interaction with its receptors PD-1 and CD80 regulate GVHD and GVL activities, how PD-L1 signaling regulates T cell metabolic profiles, and how a differential role of PD-L1 interaction with PD-1, CD80 or both may provide a novel avenue to prevent GVHD while preserving strong GVL effects.}, }
@article {pmid30622367, year = {2019}, author = {Schumacher, FR and Olama, AAA and Berndt, SI and Benlloch, S and Ahmed, M and Saunders, EJ and Dadaev, T and Leongamornlert, D and Anokian, E and Cieza-Borrella, C and Goh, C and Brook, MN and Sheng, X and Fachal, L and Dennis, J and Tyrer, J and Muir, K and Lophatananon, A and Stevens, VL and Gapstur, SM and Carter, BD and Tangen, CM and Goodman, PJ and Thompson, IM and Batra, J and Chambers, S and Moya, L and Clements, J and Horvath, L and Tilley, W and Risbridger, GP and Gronberg, H and Aly, M and Nordström, T and Pharoah, P and Pashayan, N and Schleutker, J and Tammela, TLJ and Sipeky, C and Auvinen, A and Albanes, D and Weinstein, S and Wolk, A and Håkansson, N and West, CML and Dunning, AM and Burnet, N and Mucci, LA and Giovannucci, E and Andriole, GL and Cussenot, O and Cancel-Tassin, G and Koutros, S and Beane Freeman, LE and Sorensen, KD and Orntoft, TF and Borre, M and Maehle, L and Grindedal, EM and Neal, DE and Donovan, JL and Hamdy, FC and Martin, RM and Travis, RC and Key, TJ and Hamilton, RJ and Fleshner, NE and Finelli, A and Ingles, SA and Stern, MC and Rosenstein, BS and Kerns, SL and Ostrer, H and Lu, YJ and Zhang, HW and Feng, N and Mao, X and Guo, X and Wang, G and Sun, Z and Giles, GG and Southey, MC and MacInnis, RJ and FitzGerald, LM and Kibel, AS and Drake, BF and Vega, A and Gómez-Caamaño, A and Szulkin, R and Eklund, M and Kogevinas, M and Llorca, J and Castaño-Vinyals, G and Penney, KL and Stampfer, M and Park, JY and Sellers, TA and Lin, HY and Stanford, JL and Cybulski, C and Wokolorczyk, D and Lubinski, J and Ostrander, EA and Geybels, MS and Nordestgaard, BG and Nielsen, SF and Weischer, M and Bisbjerg, R and Røder, MA and Iversen, P and Brenner, H and Cuk, K and Holleczek, B and Maier, C and Luedeke, M and Schnoeller, T and Kim, J and Logothetis, CJ and John, EM and Teixeira, MR and Paulo, P and Cardoso, M and Neuhausen, SL and Steele, L and Ding, YC and De Ruyck, K and De Meerleer, G and Ost, P and Razack, A and Lim, J and Teo, SH and Lin, DW and Newcomb, LF and Lessel, D and Gamulin, M and Kulis, T and Kaneva, R and Usmani, N and Singhal, S and Slavov, C and Mitev, V and Parliament, M and Claessens, F and Joniau, S and Van den Broeck, T and Larkin, S and Townsend, PA and Aukim-Hastie, C and Gago-Dominguez, M and Castelao, JE and Martinez, ME and Roobol, MJ and Jenster, G and van Schaik, RHN and Menegaux, F and Truong, T and Koudou, YA and Xu, J and Khaw, KT and Cannon-Albright, L and Pandha, H and Michael, A and Thibodeau, SN and McDonnell, SK and Schaid, DJ and Lindstrom, S and Turman, C and Ma, J and Hunter, DJ and Riboli, E and Siddiq, A and Canzian, F and Kolonel, LN and Le Marchand, L and Hoover, RN and Machiela, MJ and Cui, Z and Kraft, P and Amos, CI and Conti, DV and Easton, DF and Wiklund, F and Chanock, SJ and Henderson, BE and Kote-Jarai, Z and Haiman, CA and Eeles, RA and ,  and ,  and ,  and ,  and ,  and ,  and ,  and ,  and , }, title = {Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.}, journal = {Nature genetics}, volume = {51}, number = {2}, pages = {363}, doi = {10.1038/s41588-018-0330-6}, pmid = {30622367}, issn = {1546-1718}, support = {10119//Cancer Research UK/United Kingdom ; 10124//Cancer Research UK/United Kingdom ; }, abstract = {In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.}, }
@article {pmid30619245, year = {2018}, author = {Yang, J and Jing, L and James, EA and Gebe, JA and Koelle, DM and Kwok, WW}, title = {A Novel Approach of Identifying Immunodominant Self and Viral Antigen Cross-Reactive T Cells and Defining the Epitopes They Recognize.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2811}, doi = {10.3389/fimmu.2018.02811}, pmid = {30619245}, issn = {1664-3224}, support = {DP3 DK097653/DK/NIDDK NIH HHS/United States ; DP3 DK106909/DK/NIDDK NIH HHS/United States ; }, abstract = {Infection and vaccination can lead to activation of autoreactive T cells, including the activation of cross-reactive T cells. However, detecting these cross-reactive T cells and identifying the non-self and self-antigen epitopes is difficult. The current study demonstrates the utility of a novel approach that effectively accomplishes both. We utilized surface expression of CD38 on newly activated CD4 memory T cells as a strategy to identify type 1 diabetes associated autoreactive T cells activated by influenza vaccination in healthy subjects. We identified an influenza A matrix protein (MP) specific CD4+ T cell clone that cross-recognizes an immunodominant epitope from Glutamic Acid Decarboxylase 65 (GAD65) protein. The sequences of the MP and GAD65 peptides are rather distinct, with only 2 identical amino acids within the HLA-DR binding region. This result suggests that activation of autoreactive T cells by microbial infection under certain physiological conditions can occur amongst peptides with minimum amino acid sequence homology. This novel strategy also provides a new research pathway in which to examine activation of autoreactive CD4+ T cells after vaccination or natural infection.}, }
@article {pmid30617281, year = {2019}, author = {Skapek, SX and Ferrari, A and Gupta, AA and Lupo, PJ and Butler, E and Shipley, J and Barr, FG and Hawkins, DS}, title = {Rhabdomyosarcoma.}, journal = {Nature reviews. Disease primers}, volume = {5}, number = {1}, pages = {1}, doi = {10.1038/s41572-018-0051-2}, pmid = {30617281}, issn = {2056-676X}, abstract = {Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. Decades of clinical and basic research have gradually improved our understanding of the pathophysiology of RMS and helped to optimize clinical care. The two major subtypes of RMS, originally characterized on the basis of light microscopic features, are driven by fundamentally different molecular mechanisms and pose distinct clinical challenges. Curative therapy depends on control of the primary tumour, which can arise at many distinct anatomical sites, as well as controlling disseminated disease that is known or assumed to be present in every case. Sophisticated risk stratification for children with RMS incorporates various clinical, pathological and molecular features, and that information is used to guide the application of multifaceted therapy. Such therapy has historically included cytotoxic chemotherapy as well as surgery, ionizing radiation or both. This Primer describes our current understanding of RMS epidemiology, disease susceptibility factors, disease mechanisms and elements of clinical care, including diagnostics, risk-based care of newly diagnosed and relapsed disease and the prevention and management of late effects in survivors. We also outline potential opportunities to further translate new biological insights into improved clinical outcomes.}, }
@article {pmid30617275, year = {2019}, author = {Erzurumluoglu, AM and Liu, M and Jackson, VE and Barnes, DR and Datta, G and Melbourne, CA and Young, R and Batini, C and Surendran, P and Jiang, T and Adnan, SD and Afaq, S and Agrawal, A and Altmaier, E and Antoniou, AC and Asselbergs, FW and Baumbach, C and Bierut, L and Bertelsen, S and Boehnke, M and Bots, ML and Brazel, DM and Chambers, JC and Chang-Claude, J and Chen, C and Corley, J and Chou, YL and David, SP and de Boer, RA and de Leeuw, CA and Dennis, JG and Dominiczak, AF and Dunning, AM and Easton, DF and Eaton, C and Elliott, P and Evangelou, E and Faul, JD and Foroud, T and Goate, A and Gong, J and Grabe, HJ and Haessler, J and Haiman, C and Hallmans, G and Hammerschlag, AR and Harris, SE and Hattersley, A and Heath, A and Hsu, C and Iacono, WG and Kanoni, S and Kapoor, M and Kaprio, J and Kardia, SL and Karpe, F and Kontto, J and Kooner, JS and Kooperberg, C and Kuulasmaa, K and Laakso, M and Lai, D and Langenberg, C and Le, N and Lettre, G and Loukola, A and Luan, J and Madden, PAF and Mangino, M and Marioni, RE and Marouli, E and Marten, J and Martin, NG and McGue, M and Michailidou, K and Mihailov, E and Moayyeri, A and Moitry, M and Müller-Nurasyid, M and Naheed, A and Nauck, M and Neville, MJ and Nielsen, SF and North, K and Perola, M and Pharoah, PDP and Pistis, G and Polderman, TJ and Posthuma, D and Poulter, N and Qaiser, B and Rasheed, A and Reiner, A and Renström, F and Rice, J and Rohde, R and Rolandsson, O and Samani, NJ and Samuel, M and Schlessinger, D and Scholte, SH and Scott, RA and Sever, P and Shao, Y and Shrine, N and Smith, JA and Starr, JM and Stirrups, K and Stram, D and Stringham, HM and Tachmazidou, I and Tardif, JC and Thompson, DJ and Tindle, HA and Tragante, V and Trompet, S and Turcot, V and Tyrrell, J and Vaartjes, I and van der Leij, AR and van der Meer, P and Varga, TV and Verweij, N and Völzke, H and Wareham, NJ and Warren, HR and Weir, DR and Weiss, S and Wetherill, L and Yaghootkar, H and Yavas, E and Jiang, Y and Chen, F and Zhan, X and Zhang, W and Zhao, W and Zhao, W and Zhou, K and Amouyel, P and Blankenberg, S and Caulfield, MJ and Chowdhury, R and Cucca, F and Deary, IJ and Deloukas, P and Di Angelantonio, E and Ferrario, M and Ferrières, J and Franks, PW and Frayling, TM and Frossard, P and Hall, IP and Hayward, C and Jansson, JH and Jukema, JW and Kee, F and Männistö, S and Metspalu, A and Munroe, PB and Nordestgaard, BG and Palmer, CNA and Salomaa, V and Sattar, N and Spector, T and Strachan, DP and ,  and van der Harst, P and Zeggini, E and Saleheen, D and Butterworth, AS and Wain, LV and Abecasis, GR and Danesh, J and Tobin, MD and Vrieze, S and Liu, DJ and Howson, JMM}, title = {Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-018-0313-0}, pmid = {30617275}, issn = {1476-5578}, support = {RG/13/13/30194//British Heart Foundation/United Kingdom ; SP/09/002//British Heart Foundation (BHF)/ ; 268834//EC | European Research Council (ERC)/ ; MC_QA137853//Medical Research Council/United Kingdom ; G1000861//Medical Research Council/United Kingdom ; MR/L01632X/1//Medical Research Council/United Kingdom ; MC_PC_12010//Medical Research Council/United Kingdom ; MR/L01341X/1//Medical Research Council/United Kingdom ; MR/K026992/1//Medical Research Council/United Kingdom ; MR/L003120/1//Medical Research Council/United Kingdom ; MC_UU_12015/1//Medical Research Council/United Kingdom ; RG/13/13/30194//British Heart Foundation (BHF)/ ; 10119//Cancer Research UK/United Kingdom ; RG/14/5/30893//British Heart Foundation/United Kingdom ; BB/F019394/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; 10124//Cancer Research UK/United Kingdom ; }, abstract = {Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.}, }
@article {pmid30617132, year = {2019}, author = {Staal, B and Liu, Y and Barnett, D and Hsueh, P and He, Z and Gao, C and Partyka, K and Hurd, MW and Singhi, AD and Drake, RR and Huang, Y and Maitra, A and Brand, RE and Haab, BB}, title = {The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-18-3310}, pmid = {30617132}, issn = {1078-0432}, support = {P30 CA138313/CA/NCI NIH HHS/United States ; U01 CA152653/CA/NCI NIH HHS/United States ; U01 CA168896/CA/NCI NIH HHS/United States ; U01 CA200466/CA/NCI NIH HHS/United States ; }, abstract = {Purpose: The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9.Experimental Design: We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case-control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set.Results: The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 2 versions of the sTRA assay, and another optimized for sensitivity, which included 2 sTRA assays. Both panels achieved statistical improvement (P < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (P < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared with 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker.Conclusions: sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.Significance: No serological biomarkers have been validated to improve upon CA19-9 for pancreatic cancer diagnostics. We show that a glycan called sTRA forms that basis for a biomarker that could meet clinical requirements for surveillance or differential diagnosis of pancreatic cancer.}, }
@article {pmid30617130, year = {2019}, author = {Ramchandren, R and Advani, RH and Ansell, SM and Bartlett, NL and Chen, R and Connors, JM and Feldman, T and Forero-Torres, A and Friedberg, JW and Gopal, AK and Gordon, LI and Kuruvilla, J and Savage, KJ and Younes, A and Engley, G and Manley, TJ and Fenton, K and Straus, DJ}, title = {Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {25}, number = {6}, pages = {1718-1726}, doi = {10.1158/1078-0432.CCR-18-2435}, pmid = {30617130}, issn = {1078-0432}, abstract = {PURPOSE: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).<br><br>PATIENTS AND METHODS: ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.<br><br>RESULTS: The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.<br><br>CONCLUSIONS: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.}, }
@article {pmid30616442, year = {2019}, author = {Stone, SA and Han, CJ and Senn, T and Korde, LA and Allott, K and Reding, S and Whittington, D and Reding, KW}, title = {Sex Hormones in Women With Elevated Breast Cancer Risk Undergoing Weight Loss.}, journal = {Western journal of nursing research}, volume = {}, number = {}, pages = {193945918820672}, doi = {10.1177/0193945918820672}, pmid = {30616442}, issn = {1552-8456}, support = {R00 NR012232/NR/NINR NIH HHS/United States ; T32 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {Sedentary lifestyles and obesity are known risk factors for breast cancer. Elevated estrogen levels correlate with obesity and, independently, with increased breast cancer risk. Lifestyle interventions that reduce obesity may mitigate this risk, potentially via estrogen pathways. In a 6-month lifestyle intervention, overweight/obese women with high breast cancer risk were randomized to control (n = 7) or intervention (n = 6) and analyzed for sex hormone levels. Serum and urine hormones were evaluated by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and sex hormone binding globulin (SHBG) by enzyme-linked immunosorbent assay (ELISA). Serum estrone (E1) and estradiol (E2) were reduced by 12.1% and 50.8%, respectively, at 9 months in the intervention group, which differed from controls (p = .043 and .020). This contrasted with a 73.3% increase in urine E1 at 6 months in the intervention group (p = .035). These results suggest that a lifestyle intervention led to a favorable estrogen profile in relation to breast cancer risk.}, }
@article {pmid30616390, year = {2019}, author = {Andersen, MR and Sweet, E and Hager, S and Gaul, M and Dowd, F and Standish, LJ}, title = {Effects of Vitamin D Use on Health-Related Quality of Life of Breast Cancer Patients in Early Survivorship.}, journal = {Integrative cancer therapies}, volume = {18}, number = {}, pages = {1534735418822056}, doi = {10.1177/1534735418822056}, pmid = {30616390}, issn = {1552-695X}, abstract = {BACKGROUND: Vitamin D supplements may prevent recurrence, prolong survival, and improve mood for women with breast cancer, although evidence for these effects is preliminary.<br><br>METHODS: This report describes vitamin D supplement use by 553 breast cancer patient/survivors (193 who used a naturopathic oncology [NO] provider and 360 who did not) participating in a matched cohort study of breast cancer outcomes.<br><br>RESULTS: We found that more than half of breast cancer patients reported using vitamin D supplements. Women who received care from NO providers in early survivorship may be more likely to use vitamin D supplements (P < .05). Approximately 30% of breast cancer patients with blood levels recorded in their medical chart were potentially vitamin D deficient (<30 ng/mL). Vitamin D supplement use at study enrollment was associated with higher levels of self-reported health-related quality of life (HRQOL) at enrollment (P < .05) and predicted better HRQOL at 6-month follow-up (P < .05). Sufficient blood levels of vitamin D recorded between enrollment and follow-up were also associated with better HRQOL at follow-up (P < .05).<br><br>CONCLUSIONS: Vitamin D supplementation by breast cancer patients is common both during and after treatment for breast cancer, but deficiency may also be common. NO and conventional providers may be able to promote vitamin D sufficiency through vitamin D supplementation and by encouraging healthy solar exposure. Further studies should be undertaken examining whether vitamin D supplementation and higher blood levels might improve HRQOL among women with breast cancer in early survivorship.}, }
@article {pmid30616376, year = {2019}, author = {Molina, Y and Ulrich, A and Greer, AC and Primbas, A and Wandell, G and Sanchez, H and Bain, C and Konda, KA and Clark, JL and De la Grecca, R and Villarán, MV and Pasalar, S and Lama, JR and Duerr, AC}, title = {Impact of pre-diagnosis awareness of HIV-related stigma and dispositional coping on linkage to HIV care among newly diagnosed HIV+ Peruvian patients.}, journal = {AIDS care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/09540121.2018.1563282}, pmid = {30616376}, issn = {1360-0451}, support = {K01 CA193918/CA/NCI NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 DA032106/DA/NIDA NIH HHS/United States ; R01 DA040532/DA/NIDA NIH HHS/United States ; }, abstract = {A substantial body of literature has characterized how psychosocial factors, including HIV-related stigma and coping, are associated with HIV testing and HIV care utilization post-diagnosis. Less is known about if certain psychosocial characteristics pre-diagnosis may also predict linkage to care among individuals who receive an HIV-positive diagnosis. We examined if pre-diagnosis awareness/perception about HIV-related stigma and dispositional coping styles predicted linkage to HIV care within three months post-diagnosis with a secondary analysis of 604 patients from a randomized controlled trial (Sabes Study). Awareness/perception about HIV-related stigma, dispositional maladaptive and adaptive coping were measured before patients underwent an HIV test. Linkage to care was measured as receipt of care within three months of receiving the diagnosis. After adjusting for covariates, individuals who reported greater dispositional maladaptive coping pre-diagnosis had lower odds of linking to care, OR = 0.82, 95%CI [0.67, 1.00], p = .05. There was also a non-significant inverse association between dispositional adaptive coping pre-diagnosis and linkage to care. These preliminary data suggest the need for further longitudinal research and highlight the potential utility of pre-diagnosis psychosocial assessment and tailored counseling when providing positive HIV diagnosis results.}, }
@article {pmid30615169, year = {2019}, author = {Hightow-Weidman, LB and Magnus, M and Beauchamp, G and Hurt, CB and Shoptaw, S and Emel, L and Piwowar-Manning, E and Mayer, KH and Nelson, LE and Wilton, L and Watkins, P and Whitfield, D and Fields, SD and Wheeler, D}, title = {Incidence and Correlates of STIs among Black Men who have Sex with Men Participating in the HPTN 073 PrEP Study.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy1141}, pmid = {30615169}, issn = {1537-6591}, support = {P30 AI117970/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {Background: HPTN 073 assessed the feasibility, acceptability, and safety of pre-exposure prophylaxis (PrEP) for Black men who have sex with men (BMSM). The purpose of this analysis was to characterize the relationship between PrEP uptake and use, and incident STIs among participants enrolled in HPTN 073.<br><br>Methods: 226 HIV-uninfected BMSM were enrolled in three US cities; all participants received client-centered care coordination (C4) and were offered daily oral PrEP. Participants were followed for 12 months with STI testing (rectal and urine NAAT for gonorrhea and chlamydia, RPR for syphilis) conducted at baseline, week 26 and week 52. Logistic regression was used to examine associations between STI incidence and PrEP uptake. Generalized estimating equations (GEE) evaluated associations between age, PrEP acceptance, sexual behaviors, and incident STI cases.<br><br>Results: Baseline STI prevalence was 14.2%. Men <25 were more likely to have a baseline STI (25.3% vs. 6.7%; OR 4.39; 95% CI: 1.91, 10.11). Sixty participants (26.5%) acquired ≥1 STI during follow-up; the incidence rate was 34.2 cases per 100 person-years (95% CI: 27.4, 42.9). In adjusted analyses, baseline STI diagnosis (OR 4.23, 95% CI: 1.82, 9.87; p<0.001) and additional C4 time (OR 1.03, 95% CI: 1.00, 1.06; p=0.027) were associated with having an incident STI. STI incidence was not associated with PrEP acceptance or adherence.<br><br>Discussion: While we found higher rates of STIs in younger BMSM, the overall rates of STI in this trial were lower than in prior PrEP trials with no increase over time. BMSM with STIs at PrEP initiation may require additional interventions targeting STI acquisition risk.}, }
@article {pmid30615138, year = {2019}, author = {Galldiks, N and Langen, KJ and Albert, NL and Chamberlain, M and Soffietti, R and Kim, MM and Law, I and Le Rhun, E and Chang, S and Schwarting, J and Combs, SE and Preusser, M and Forsyth, P and Pope, W and Weller, M and Tonn, JC}, title = {PET Imaging in Patients with Brain Metastasis - Report of the RANO/PET Group.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noz003}, pmid = {30615138}, issn = {1523-5866}, abstract = {Brain metastases (BM) from extracranial cancer are associated with significant morbidity and mortality. Effective local treatment options are stereotactic radiotherapy, including radiosurgery or fractionated external beam radiotherapy, and surgical resection. The use of systemic treatment for intracranial disease control also is improving. BM diagnosis, treatment planning and follow-up is most often based on contrast-enhanced magnetic resonance imaging (MRI). However, anatomic imaging modalities including standard MRI have limitations in accurately characterizing post-therapeutic reactive changes and treatment response. Molecular imaging techniques such as positron emission tomography (PET) characterize specific metabolic and cellular features of metastases, potentially providing clinically relevant information supplementing anatomic MRI. Here, the RANO working group provides recommendations for the use of PET imaging in the clinical management of patients with BM based on evidence from studies validated by histology and/or clinical outcome.}, }
@article {pmid30615119, year = {2019}, author = {Spearman, P and Tomaras, GD and Montefiori, DC and Huang, Y and Elizaga, ML and Ferrari, G and Alam, SM and Isaacs, A and Ahmed, H and Hural, J and McElrath, MJ and Ouedraogo, L and Pensiero, M and Butler, C and Kalams, SA and Overton, ET and Barnett, SW and ,  and , }, title = {Rapid Boosting of HIV-1 Neutralizing Antibody Responses in Humans Following a Prolonged Immunologic Rest.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiz008}, pmid = {30615119}, issn = {1537-6613}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Background: Durability and breadth of HIV-1-specific immune responses elicited through vaccination are important considerations in the development of an effective HIV-1 vaccine. Responses to HIV-1 envelope subunit protein (Env) immunization in humans are often described as short-lived.<br><br>Methods: We identified 16 healthy volunteers who had received priming with an HIV-1 subtype B Env protein vaccine given with MF59 adjuvant 5-17 years previously, and administered three booster immunizations with a heterologous subtype C trimeric gp140 protein vaccine. We enrolled 20 healthy unprimed volunteers and administered the same vaccination regimen.<br><br>Results: Binding antibodies and neutralizing antibodies to Tier 1 viral isolates were detected in the majority of previously-primed subjects. Remarkably, a single dose of protein boosted binding and neutralizing antibody titers in 100% of primed subjects following this prolonged immunologic rest period, and CD4+ T cell responses were boosted in 75% of primed individuals.<br><br>Conclusions: These results demonstrate that HIV-1 protein immunogens can elicit durable memory T and B cell responses, and that strong Tier 1 virus neutralizing responses can be elicited by a single booster dose of protein following a long immunologic rest period. However, we found no evidence that cross-clade boosting led to a significantly broadened neutralizing antibody response.}, }
@article {pmid30614525, year = {2019}, author = {Margolis, KL and Buchner, DM and LaMonte, MJ and Zhang, Y and Di, C and Rillamas-Sun, E and Hunt, J and Ikramuddin, F and Li, W and Marshall, S and Rosenberg, D and Stefanick, ML and Wallace, R and LaCroix, AZ}, title = {Hypertension Treatment and Control and Risk of Falls in Older Women.}, journal = {Journal of the American Geriatrics Society}, volume = {67}, number = {4}, pages = {726-733}, doi = {10.1111/jgs.15732}, pmid = {30614525}, issn = {1532-5415}, support = {HHSN268201600001C//U.S. Department of Health and Human Services/ ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C//U.S. Department of Health and Human Services/ ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; //National Institutes of Health/ ; R01HL105065//National Heart, Lung, and Blood Institute/ ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C//U.S. Department of Health and Human Services/ ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C//U.S. Department of Health and Human Services/ ; HHSN268201600002C//U.S. Department of Health and Human Services/ ; R01 HL105065/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND/OBJECTIVES: A lower risk of falls is commonly cited as a reason to treat hypertension conservatively in older individuals. We examined the effect of hypertension treatment and control status and measured blood pressure (BP) level on the risk of falls in older women.<br><br>DESIGN/SETTING: Prospective cohort study.<br><br>PARTICIPANTS: A total of 5971 women (mean age 79 years; 50.4% white, 33.1% black, 16.5% Hispanic/Latina) enrolled in the Women's Health Initiative and Objective Physical Activity and Cardiovascular Health study.<br><br>MEASUREMENTS: BP was measured by trained nurses, and hypertension treatment was assessed by medication inventory. Participants mailed in monthly calendars to self-report falls for 1 year.<br><br>RESULTS: Overall, 70% of women had hypertension at baseline (53% treated and controlled, 12% treated and uncontrolled, 5% untreated). There were 2582 women (43%) who reported falls in the 1 year of surveillance. Compared with nonhypertensive women, when adjusted for fall risk factors and lower limb physical function, the incidence rate ratio (IRR) for falls was 0.82 (confidence interval [CI] = 0.74-0.92) in women with treated controlled hypertension (p = .0008) and 0.73 (CI = 0.62-0.87) in women with treated uncontrolled hypertension (p = .0004). Neither measured systolic nor diastolic BP was associated with falls in the overall cohort. In women treated with antihypertensive medication, higher diastolic BP was associated with a lower risk of falls in a model adjusted for fall risk factors (IRR = 0.993 per mm Hg; 95% CI = 0.987-1.000; p = .04). The only class of antihypertensive medication associated with an increased risk of falls compared with all other types of antihypertensive drugs was β-blockers.<br><br>CONCLUSION: Women in this long-term research study with treated hypertension had a lower risk of falls compared with nonhypertensive women. Diastolic BP (but not systolic BP) is weakly associated with fall risk in women on antihypertensive treatment (<1% decrease in risk per mm Hg increase). J Am Geriatr Soc, 2019. J Am Geriatr Soc 67:726-733, 2019.}, }
@article {pmid30614479, year = {2019}, author = {Martins, F and Sykiotis, GP and Maillard, M and Fraga, M and Ribi, C and Kuntzer, T and Michielin, O and Peters, S and Coukos, G and Spertini, F and Thompson, JA and Obeid, M}, title = {New therapeutic perspectives to manage refractory immune checkpoint-related toxicities.}, journal = {The Lancet. Oncology}, volume = {20}, number = {1}, pages = {e54-e64}, doi = {10.1016/S1470-2045(18)30828-3}, pmid = {30614479}, issn = {1474-5488}, abstract = {Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.}, }
@article {pmid30613635, year = {2018}, author = {Kennedy, LC and Gadi, V}, title = {Dasatinib in breast cancer: Src-ing for response in all the wrong kinases.}, journal = {Annals of translational medicine}, volume = {6}, number = {Suppl 1}, pages = {S60}, doi = {10.21037/atm.2018.10.26}, pmid = {30613635}, issn = {2305-5839}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, }
@article {pmid30611192, year = {2019}, author = {Bajema, KL and Bassett, IV and Coleman, SM and Ross, D and Freedberg, KA and Wald, A and Drain, PK}, title = {Subclinical tuberculosis among adults with HIV: clinical features and outcomes in a South African cohort.}, journal = {BMC infectious diseases}, volume = {19}, number = {1}, pages = {14}, doi = {10.1186/s12879-018-3614-7}, pmid = {30611192}, issn = {1471-2334}, support = {R01AI058736//National Institute of Allergy and Infectious Diseases/ ; K23 AI108293//National Institute of Allergy and Infectious Diseases/ ; P30 AI060354//Harvard University Center for AIDS Research/ ; R01 MH090326/MH/NIMH NIH HHS/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; T32 AI007433//National Institutes of Health (US)/ ; K23 AI108293/AI/NIAID NIH HHS/United States ; R01 MH090326//National Institute of Mental Health/ ; R24 TW007988//Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University/ ; R01 AI058736/AI/NIAID NIH HHS/United States ; T32 AI007044//National Institutes of Health/ ; T32 AI007433/AI/NIAID NIH HHS/United States ; R37 AI058736/AI/NIAID NIH HHS/United States ; P30 AI060354/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; African Continental Ancestry Group/statistics &amp; numerical data ; Anti-Retroviral Agents/therapeutic use ; Antitubercular Agents/therapeutic use ; Asymptomatic Infections/*epidemiology/mortality/therapy ; Cohort Studies ; Female ; Follow-Up Studies ; HIV ; HIV Infections/complications/diagnosis/drug therapy/*epidemiology ; Humans ; Infection Control/methods ; Male ; Middle Aged ; Prevalence ; Prognosis ; South Africa/epidemiology ; Survival Analysis ; Tuberculosis/complications/diagnosis/drug therapy/*epidemiology ; Young Adult ; }, abstract = {BACKGROUND: Subclinical tuberculosis is an asymptomatic disease phase with important relevance to persons living with HIV. We describe the prevalence, clinical characteristics, and risk of mortality for HIV-infected adults with subclinical tuberculosis.<br><br>METHODS: Untreated adults with HIV presenting for outpatient care in Durban, South Africa were screened for tuberculosis-related symptoms and had sputum tested by acid-fast bacilli smear and tuberculosis culture. Active tuberculosis and subclinical tuberculosis were defined as having any tuberculosis symptom or no tuberculosis symptoms with culture-positive sputum. We evaluated the association between tuberculosis disease category and 12-month survival using Cox regression, adjusting for age, sex, and CD4 count.<br><br>RESULTS: Among 654 participants, 96 were diagnosed with active tuberculosis disease and 28 with subclinical disease. The median CD4 count was 68 (interquartile range 39-161) cells/mm3 in patients with active tuberculosis, 136 (72-312) cells/mm3 in patients with subclinical disease, and 249 (125-394) cells/mm3 in those without tuberculosis disease (P < 0.001). The proportion of smear positive cases did not differ significantly between the subclinical (29%) and active tuberculosis groups (14%, P 0.08). Risk of mortality was not increased in individuals with subclinical tuberculosis relative to no tuberculosis (adjusted hazard ratio 0.84, 95% confidence interval 0.26-2.73).<br><br>CONCLUSIONS: Nearly one-quarter of tuberculosis cases among HIV-infected adults were subclinical, which was characterized by an intermediate degree of immunosuppression. Although there was no significant difference in survival, anti-tuberculous treatment of subclinical cases was common.<br><br>TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov , NCT01188941 (August 26, 2010).}, }
@article {pmid30610225, year = {2019}, author = {Cuadrado, A and Rojo, AI and Wells, G and Hayes, JD and Cousin, SP and Rumsey, WL and Attucks, OC and Franklin, S and Levonen, AL and Kensler, TW and Dinkova-Kostova, AT}, title = {Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.}, journal = {Nature reviews. Drug discovery}, volume = {18}, number = {4}, pages = {295-317}, doi = {10.1038/s41573-018-0008-x}, pmid = {30610225}, issn = {1474-1784}, support = {10268//Cancer Research UK/United Kingdom ; }, abstract = {The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target s