@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}, 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}, 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}, 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}, 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 = {UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1AI106707//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 = {}, number = {}, pages = {}, 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}, 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}, 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, IGF-II) and IGFBPs (IGFBP-1, IGFBP-2, 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 non-smokers. 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. This article is protected by copyright. All rights reserved.}, }
@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 = {}, number = {}, pages = {}, doi = {10.1084/jem.20171452}, pmid = {30872361}, issn = {1540-9538}, 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) (BU/CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative anti-epileptic 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, 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT from 2004 through 2014. We found no differences suggesting decreased overall or relapse-free survival or increased risks of relapse, non-relapse mortality, acute or chronic GVHD, or regimen-related toxicity associated with the use of alternative AEMs as compared to 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 = {}, number = {}, pages = {}, 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 {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 {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/ ; //Division of AIDS, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068619//National Institutes of Health/ ; UM1-AI068613//National Institutes of Health/ ; UM1-AI068617//National Institutes of Health/ ; UM1-AI-068636//AIDS Clinical Trials Group/ ; //Gilead Sciences/ ; }, 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 = {UM1AI1068617//US National Institutes of Health/ ; UM1AI068619//US National Institutes of Health/ ; P30AI094189//US National Institutes of Health/ ; K01DA041259//US National Institutes of Health/ ; //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/ ; //National Institute of Mental Health/ ; //National Institute on Drug Abuse/ ; }, 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//National Institute of Environmental Health Sciences/ ; R01ES024731S1//National Institute of Environmental Health Sciences/ ; HHSN268201600018C//National Heart, Lung, and Blood Institute/ ; HHSN268201600001C//National Heart, Lung, and Blood Institute/ ; HHSN268201600002C//National Heart, Lung, and Blood Institute/ ; HHSN268201600003C//National Heart, Lung, and Blood Institute/ ; HHSN268201600004C//National Heart, Lung, and Blood Institute/ ; }, 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}, 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}, 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 {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 = {U01 HL098964//National Heart, Lung, and Blood Institute/ ; K24 HL087713//National Heart, Lung, and Blood Institute/ ; 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 {pmid30854504, year = {2018}, author = {Donahu, TF and Bagrodia, A and Audenet, F and Donoghue, MTA and Cha, EK and Sfakianos, JP and Sperling, D and Al-Ahmadie, H and Clendenning, M and Rosty, C and Buchanan, DD and Jenkins, M and Hopper, J and Winship, I and Templeton, AS and Walsh, MF and Stadler, ZK and Iyer, G and Taylor, B and Coleman, J and Lindor, NM and Solit, DB and Bochner, BH}, title = {Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome.}, journal = {JCO precision oncology}, volume = {2018}, number = {}, pages = {}, doi = {10.1200/PO.17.00143}, pmid = {30854504}, issn = {2473-4284}, abstract = {Purpose: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs.<br><br>Patients and Methods: We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC.<br><br>Results: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC.<br><br>Conclusion: LSand sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.}, }
@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}, 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 {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 = {}, number = {}, pages = {}, 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 {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}, 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}, 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 = {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 {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 = {}, number = {}, pages = {}, doi = {10.1007/s10552-019-01150-w}, pmid = {30830494}, issn = {1573-7225}, support = {U54CA153502//National Cancer Institute/ ; U53CA153502-05S1//National Cancer Institute/ ; U54CA132381//National Cancer Institute/ ; UL1RR025014//National Center for Research Resources/ ; }, 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}, 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}, 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 = {}, number = {}, pages = {}, 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}, 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, D 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 = {}, number = {}, pages = {}, doi = {10.1002/pon.5040}, pmid = {30817058}, issn = {1099-1611}, abstract = {OBJECTIVE: Sleep disorders are associated with psychological and physical health, though 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 five 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 = {UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //National Institute of Mental Health/ ; 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 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}, 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 {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}, 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 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 = {PURPOSE: The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCT) is well established. Optimal timing and number (single, ST vs. tandem, TT vs. three) of autoHCT are controversial with wide practice variation.<br><br>PATIENTS AND METHODS: We examined survival trends among 2,395 recipients of autoHCT for male GCT between 1990-2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplant for intervals 1990-94 (N = 288), 1995-99 (N = 351), 2000-04 (N = 376), 2005-09 (N = 509) and 2010-15 (N = 871). Multivariate analysis was restricted to the subset from 2000-2015 (n = 267) with research level data.<br><br>RESULTS: Median follow up was 51 months. Median age at autoHCT was 31 years; 633(26%) had primary extragonadal GCT and 1,167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24 (18-31)% and 35 (29-40)% in 1990-94 to 47 (43-50)% and 54 (50-57)% in 2010-15 (p < 0.0001), respectively. TT recipients were more likely to undergo autoHCT as first salvage treatment than ST recipients. The proportion of TT increased from 38% of all autoHCT in 2000-04 to 77% in 2010-15. Non-seminoma histology, residual disease at autoHCT, > 1 line of pre-transplant chemotherapy and ST versus TT were associated with inferior PFS and OS.<br><br>CONCLUSIONS: Post-transplant survival has improved significantly over time for relapsed/refractory male GCT and was associated with the increased use of TT (compared with ST) and earlier autoHCT 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, central nervous system demyelinating and degenerative disease. Approved disease modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. 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. Review of recent literature identified eight retrospective studies, eight clinical trials, and three 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 relapses, MRI lesion activity, and disability worsening, 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 transplant physicians with experience performing AHCT for autoimmune disease is crucial for appropriate patient selection and optimizing transplant procedures to improve patient outcomes. Transplant 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 = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2019.02.024}, pmid = {30794764}, issn = {1528-0012}, }
@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 = {}, number = {}, pages = {}, 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 T-cell therapy.}, journal = {Expert review of hematology}, volume = {}, number = {}, pages = {}, 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 asses 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 = {}, number = {}, pages = {}, 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 ; 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 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 presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (hsCRP, IL-6, sCD14, sCD163, Gal-3, 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% CI 1.06-14.07, 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 = {}, number = {}, pages = {}, 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 is available from a randomized trial or observational study. We distinguish between four different settings including (i) treatment selection when resources are constrained, (ii) treatment selection when resources are not constrained, (iii) treatment selection in the presence of side effects and costs, and (iv) 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 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 health care 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 = {}, number = {}, pages = {}, doi = {10.1038/s41416-019-0393-x}, pmid = {30787463}, issn = {1532-1827}, support = {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)/ ; 0000//Breast Cancer Now (BCN)/ ; 2010PR62, 2013PR044//Breast Cancer Campaign/United Kingdom ; 266528//Suomen Akatemia | Biotieteiden ja Ympäristön Tutkimuksen Toimikunta (Research Council for Biosciences and Environment)/ ; }, 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}, 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}, 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 ; }, 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 = {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 = {}, number = {}, pages = {}, 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}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2019.01.008}, pmid = {30773341}, issn = {1878-3686}, 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}, 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 two-decade period.}, 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.2019.02.010}, 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 = {Pediatric Cardio-Oncology: Epidemiology, Screening, Prevention, and Treatment.}, journal = {Cardiovascular research}, volume = {}, number = {}, pages = {}, doi = {10.1093/cvr/cvz031}, pmid = {30768157}, issn = {1755-3245}, abstract = {With five-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, dyslipidemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to pediatric 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 pediatric 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 = {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 = {}, number = {}, pages = {}, 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 = {P40 OD010440/OD/NIH HHS/United States ; R01 GM111566/GM/NIGMS NIH HHS/United States ; R15 AR068583/AR/NIAMS NIH HHS/United States ; T32 NS099578/NS/NINDS 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}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.humimm.2019.01.009}, pmid = {30738112}, issn = {1879-1166}, support = {RP-PG-0310-1003//Department of Health/United Kingdom ; }, 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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.clbc.2018.12.008}, pmid = {30737173}, issn = {1938-0666}, support = {P30 CA015704/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 {pmid30734822, year = {2019}, author = {Kreutz, JE and Wang, J and Sheen, AM and Thompson, AM and Staheli, JP and Dyen, MR and Feng, Q and Chiu, DT}, title = {Self-digitization chip for quantitative detection of human papillomavirus gene using digital LAMP.}, journal = {Lab on a chip}, volume = {}, number = {}, pages = {}, doi = {10.1039/c8lc01223g}, pmid = {30734822}, issn = {1473-0189}, support = {R01 EB021150/EB/NIBIB NIH HHS/United States ; }, abstract = {Digital nucleic acid amplification and detection methods provide excellent sensitivity and specificity and allow absolute quantification of target nucleic acids. Isothermal methods such as digital loop-mediated isothermal amplification (digital LAMP) have potential for use in rapid disease diagnosis in low-resource settings due to their speed and lack of thermal cycling. We previously developed a self-digitization (SD) chip, a simple microfluidics device that automatically digitizes a sample into an array of nanoliter wells, for use in digital LAMP. In this work, we improve the SD chip design to increase sample loading efficiency, speed, and completeness, and test a range of well volumes and numbers. We demonstrate the diagnostic capability of this platform by applying it to quantifying human papillomavirus 18 gene.}, }
@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}, 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 ; }, 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 = {}, number = {}, pages = {JCO1800969}, 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 = {//National Institutes of Health/ ; T32CA009515//National Cancer Institute/ ; P30 CA015704//Fred Hutch/University of Washington Cancer Consortium/ ; //Juno Therapeutics/Celgene/ ; 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 cells.}, journal = {Blood}, volume = {}, number = {}, pages = {}, 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 complete remission (MRD-negative CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR-T cells have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase I/II clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR-T cells (NCT01865617, www.clinicaltrials.gov) at our institution. Forty-five of 53 (85%) 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 to 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 lower pre-lymphodepletion LDH concentration (hazard ratio, HR 1.38 per 100U/L increment increase), higher pre-lymphodepletion 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 like allogeneic HCT.}, }
@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}, 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 = {}, number = {}, pages = {JCO1801896}, 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 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 post-transplantation compared to women in the general population, but less is known about the risk of uterine and ovarian cancers. This review will provide an overview of the epidemiology of gynecologic cancers after SOT, as well as their pathophysiology, management, and specific risk factors. 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. This article is protected by copyright. All rights reserved.}, }
@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 = {P30 MH058107//National Institute of Mental Health/ ; K01MH111374//National Institute of Mental Health/ ; K01AA025009//National Institute on Alcohol Abuse and Alcoholism/ ; R01 HD077891-04S1//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; T32 DA023356//National Institute on Drug Abuse/ ; 9K24DA040489//National Institute on Drug Abuse/ ; L60MD011184//National Institute on Minority Health and Health Disparities/ ; UM1 AI068619//National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, National Institute of Mental Health/ ; K01 AA025009/AA/NIAAA NIH HHS/United States ; L60 MD011184/MD/NIMHD NIH HHS/United States ; }, 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-Haghpeykar, 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 = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-18-0201}, pmid = {30723176}, issn = {1940-6215}, support = {HHSN268201600018C/HL/NHLBI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; R01 CA172880/CA/NCI NIH HHS/United States ; R01 CA220297/CA/NCI 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 pre-diagnostic sera collected one year before diagnosis in the Women's Health Initiative study. We used the liquid chromatography-mass spectrometry 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. False discovery rate (FDR) adjusted q-value < 0.25 was indicated statistically significant. Logistic regression model and receiver operating characteristic (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}, 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}, 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 pre-diagnostic autoantibody signatures in non-small cell lung cancer.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-18-1536}, pmid = {30723114}, issn = {1538-7445}, 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 pre-diagnostic 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 pre-diagnostic sera from NSCLC samples, of which 21 occurred in the immunoglobulin bound fraction. Additionally, 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.}, }
@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}, 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 ; }, 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 (OR) 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 OR 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 = {}, number = {}, pages = {}, 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}, 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 organism was coagulase-negative Staphylococcus (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 10 days ((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 ; }, 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 ; }, 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 CA204378/CA/NCI NIH HHS/United States ; 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 = {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 ; }, 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 = {}, number = {}, pages = {}, doi = {10.1093/annonc/mdz002}, pmid = {30698666}, issn = {1569-8041}, 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 5,323 incident lung cancer cases and 5,323 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, AC}, title = {ACUTE KIDNEY INJURY INDUCES DRAMATIC P21 UP-REGULATION VIA A NOVEL, GLUCOCORTICOID- ACTIVATED, P53 INDEPENDENT, PATHWAY.}, journal = {American journal of physiology. Renal physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajprenal.00571.2018}, pmid = {30698046}, issn = {1522-1466}, support = {R01 DK038432/DK/NIDDK NIH HHS/United States ; }, abstract = {P21, a cyclin kinase inhibitor, is acutely up-regulated during 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. Either 4 or 18 hrs later, plasma, urinary, and renal cortical p21 protein and mRNA levels were assessed. Renal p53 activation was gauged by measuring both total and activated p53 (p53-serine15p) and by measuring p53 mRNA. Glycerol evoked acute, progressive renal cortical p21 mRNA/ p21 protein increases. Corresponding plasma (~25x) and urinary (~75x) p21 elevations were also observed. Renal cortical p53/p53-ser15p rose 3-4-fold. However, the p53 inhibitor, pifithrin-α, failed to block glycerol-induced p21 gene induction, suggesting an alternative p21 activator might also be at play. To this end, it was established that glycerol AKI: i) dramatically increases plasma (~5x) and urinary (~75x) cortisol levels; ii) the glucocorticoid receptor (GCR) antagonist, mifepristone, blocked glycerol-induced p21mRNA/protein accumulation; and iii) dexamethasone or cortisol injections markedly increased p21 protein/p21 mRNA in both normal and glycerol-treated mice, although no discernible p53 protein/ mRNA increases were observed. We conclude that AKI-induced 'systemic stress' markedly increases plasma and urinary cortisol which can then activate renal p21 gene expression at least in part via a GCR-dependent signaling pathway. Discernible renal cortical p53 increases are not required for this DXM 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}, 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}, 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 ; }, 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 = {2018}, 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 ; 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 ; 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 ; 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 ; 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 ; 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 ; 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 ; 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 ; 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 = {R01 GM126479/GM/NIGMS NIH HHS/United States ; R21 DA040177/DA/NIDA NIH HHS/United States ; 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 ; R01 DA037904/DA/NIDA 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 = {R01 AI127893/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R35 GM119835/GM/NIGMS NIH HHS/United States ; }, 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 ; }, 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 ; G0700704//Medical 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}, 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}, 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 Calabrese, JM 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}, 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. This article is protected by copyright. All rights reserved.}, }
@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 = {}, number = {}, pages = {}, 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 = {W81XWH1410595//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1110489//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1410595//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1110489//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1410595//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1410595//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH1110489//U.S. Department of Defense (United States Department of Defense)/ ; 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)/ ; R01 CA181605//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 CA181605//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 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 = {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, J and Montaño, M and Cabello, R and Sanchez, H and Lama, JR and Duerr, A}, title = {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 = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000001966}, pmid = {30664074}, issn = {1944-7884}, support = {R01 DA032106/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 socio-demographics, 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 (aPR) and 95% confidence intervals (CI) comparing prevalence of covariates related to HIV risk in MSM and TW.<br><br>RESULTS: Overall, 310 TW and 2,807 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, 1.84) and condom use at last sexual encounter (aPR=1.20; 95% CI: 1.06, 1.36). TW were more likely to have sex while using alcohol (aPR 1.15, 95% CI 1.01, 1.31) or drugs (aPR 2.24, 95% CI 1.47, 3.41), have alcohol dependency (aPR 1.38, 95% CI 1.15, 1.66), engage in receptive anal sex (aPR 1.31, 95% CI 1.26, 1.36), and have received money, gifts, or favors in exchange of anal sex (1.96, 95% CI 1.74, 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 = {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/ ; 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/ ; 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 {pmid30649061, 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 = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000002142}, pmid = {30649061}, issn = {1473-5571}, support = {K01 HL129892/HL/NHLBI NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI 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- and C20:4-carnitines showed significantly lower levels comparing HIV-positive to HIV-negative individuals (FDR adjusted P < 0.05); and C20- and C26-carnitines showed significantly higher levels in HIV-positive using ART than those without ART (FDR 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 (RRs=1.22 [95% CI 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 CVD risk factors). This association was more evident in HIV-positive individuals without persistent viral suppression (RR = 1.37 [1.11-1.69]) compared to 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>CONCLUSIONS: 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 {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}, }
@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}, 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/ ; }, 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 ; R01 HG008983/HG/NHGRI NIH HHS/United States ; R01 DA042755/DA/NIDA NIH HHS/United States ; R01 DA037904/DA/NIDA NIH HHS/United States ; U01 DA046413/DA/NIDA NIH HHS/United States ; R01 AA023974/AA/NIAAA 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 ; U10 CA180899/CA/NCI 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 ; 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 = {}, number = {}, pages = {}, 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 ; 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 = {T32 GM007266/GM/NIGMS NIH HHS/United States ; R35 GM122543/GM/NIGMS NIH HHS/United States ; R01 AI051321/AI/NIAID NIH HHS/United States ; R01 AI051321/AI/NIAID NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/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}, 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}, 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)/ ; G1000861//Medical Research Council/United Kingdom ; MR/L01632X/1//Medical Research Council/United Kingdom ; MR/M013111/1//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 ; MC_UU_12015/1//Medical Research Council/United Kingdom ; RG/13/13/30194//British Heart Foundation (BHF)/ ; }, 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, CF 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 is a biomarker for PDAC that improves upon CA19-9.<br><br>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.<br><br>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 two versions of the sTRA assay, and another optimized for sensitivity, which included two 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 to 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker.<br><br>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.}, }
@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 = {}, number = {}, pages = {}, 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).Experimental Design: 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.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.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 ; R01 DA032106/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 = {}, number = {}, pages = {}, doi = {10.1111/jgs.15732}, pmid = {30614525}, issn = {1532-5415}, support = {HHSN268201600001C//U.S. Department of Health and Human Services/ ; 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/ ; HHSN268201600018C//U.S. Department of Health and Human Services/ ; 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.}, }
@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 = {}, number = {}, pages = {}, 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 specificity, pharmacodynamic properties, efficacy and safety remain.}, }
@article {pmid30608515, year = {2019}, author = {Weiss, NS}, title = {Observational Studies That Seek to Emulate a Randomized Trial of Screening to Reduce the Incidence of Cancer: Do They Address the Question to Which We'd Like to Have an Answer?.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwy286}, pmid = {30608515}, issn = {1476-6256}, abstract = {Some forms of cancer screening have the potential to reduce cancer incidence, if the screening modality can identify not only a malignancy but a treatable pre-malignant condition (such as a colon polyp) as well. Cohort studies of the efficacy of these forms of screening in reducing the incidence of cancer face many challenges, notably the difficulty in distinguishing whether a test performed in a given individual was screening or diagnostic in nature. Downward bias in the estimated efficacy of screening resulting from misclassification of test indication is a particular problem in cohort studies that seek to gauge cancer incidence beginning at the time of screening (and a corresponding point in time among unscreened persons). The downward bias is accentuated in those cohort studies that have sought to mimic the &quot;intention-to-treat&quot; analytic approach used in randomized trials, in which initially unscreened persons are retained in this category even if later they themselves undergo screening.}, }
@article {pmid30608197, year = {2018}, author = {Lemaitre, RN and McKnight, B and Sotoodehnia, N and Fretts, AM and Qureshi, WT and Song, X and King, IB and Sitlani, CM and Siscovick, DS and Psaty, BM and Mozaffarian, D}, title = {Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study.}, journal = {Journal of the American Heart Association}, volume = {7}, number = {21}, pages = {e010019}, doi = {10.1161/JAHA.118.010019}, pmid = {30608197}, issn = {2047-9980}, support = {U01 HL130114/HL/NHLBI NIH HHS/United States ; }, abstract = {Background Circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure (HF) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time-varying levels of the 3 major circulating VLSFAs , lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person-years among 4249 participants, we identified 1304 cases of incident HF , including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF (P trend≤0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95% confidence interval, 0.55-0.81) for 24:0, 0.72 (95% confidence interval, 0.60-0.87) for 22:0 and 0.72 (95% confidence interval, 0.59-0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF , including relevant new risk pathways. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00005133.}, }
@article {pmid30606716, year = {2019}, author = {Muller, DC and Larose, TL and Hodge, A and Guida, F and Langhammer, A and Grankvist, K and Meyer, K and Cai, Q and Arslan, AA and Zeleniuch-Jacquotte, A and Albanes, D and Giles, GG and Sesso, HD and Lee, IM and Gaziano, JM and Yuan, JM and Hoffman Bolton, J and Buring, JE and Visvanathan, K and Le Marchand, L and Purdue, MP and Caporaso, NE and Midttun, Ø and Ueland, PM and Prentice, RL and Weinstein, SJ and Stevens, VL and Zheng, W and Blot, WJ and Shu, XO and Zhang, X and Xiang, YB and Koh, WP and Hveem, K and Thomson, CA and Pettinger, M and Engström, G and Brunnström, H and Milne, RL and Stampfer, MJ and Han, J and Johansson, M and Brennan, P and Severi, G and Johansson, M}, title = {Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium.}, journal = {BMJ (Clinical research ed.)}, volume = {364}, number = {}, pages = {k4981}, doi = {10.1136/bmj.k4981}, pmid = {30606716}, issn = {1756-1833}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; UM1 CA182934/CA/NCI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVES: To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.<br><br>DESIGN: Nested case-control study.<br><br>SETTING: 20 population based cohort studies in Asia, Europe, Australia, and the United States.<br><br>PARTICIPANTS: 5299 patients with incident lung cancer, with individually incidence density matched controls.<br><br>EXPOSURE: Circulating hsCRP concentrations in prediagnostic serum or plasma samples.<br><br>MAIN OUTCOME MEASURE: Incident lung cancer diagnosis.<br><br>RESULTS: A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.<br><br>CONCLUSIONS: Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.}, }
@article {pmid30605731, year = {2018}, author = {Pulsipher, MA and Logan, BR and Kiefer, DM and Chitphakdithai, P and Riches, ML and Rizzo, JD and Anderlini, P and Leitman, SF and Varni, JW and Kobusingye, H and Besser, RM and Miller, JP and Drexler, RJ and Abdel-Mageed, A and Ahmed, IA and Ball, ED and Bolwell, BJ and Bunin, NJ and Cheerva, A and Delgado, DC and Dvorak, CC and Gillio, AP and Hahn, TE and Hale, GA and Haight, AE and Hayes-Lattin, BM and Kasow, KA and Linenberger, M and Magalhaes-Silverman, M and Mori, S and Prasad, VK and Quigg, TC and Sahdev, I and Schriber, JR and Shenoy, S and Tse, WT and Yanik, GA and Navarro, WH and Horowitz, MM and Confer, DL and Shaw, BE and Switzer, GE}, title = {Higher Risks of Toxicity and Incomplete Recovery in 13- to 17-Year-Old Females after Marrow Donation: RDSafe Peds Results.}, 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.2018.12.765}, pmid = {30605731}, issn = {1523-6536}, support = {R01 HL085707/HL/NHLBI NIH HHS/United States ; }, abstract = {Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation. Both older age (age 13 to 17 years versus younger) and female sex were associated with higher levels of pain peridonation, with the highest rates in older females (57% with grade 2-4 pain and 17% with grade 3-4 pain). Multivariate analyses showed a 4-fold increase in risk for older females compared with males age <13 years (P <.001). At 1 year, 11% of 13- to 17-year-old females reported grade 2-4 pain, compared with 3% of males age 13 to 17 years, 0% of females age <13 years, and 1% of males age <13 years (P = .01). Males and females age 13 to 17 years failed to return to predonation pain levels at 1 year 22% and 23% of the time, respectively, compared with 3% and 10% in males and females age <13 years (P = .002). Our data show that females age 13 to 17 years are at increased risk of grade 2-4 pain at 1 year and >20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.}, }
@article {pmid30605491, year = {2019}, author = {Johansson, M and Carreras-Torres, R and Scelo, G and Purdue, MP and Mariosa, D and Muller, DC and Timpson, NJ and Haycock, PC and Brown, KM and Wang, Z and Ye, Y and Hofmann, JN and Foll, M and Gaborieau, V and Machiela, MJ and Colli, LM and Li, P and Garnier, JG and Blanche, H and Boland, A and Burdette, L and Prokhortchouk, E and Skryabin, KG and Yeager, M and Radojevic-Skodric, S and Ognjanovic, S and Foretova, L and Holcatova, I and Janout, V and Mates, D and Mukeriya, A and Rascu, S and Zaridze, D and Bencko, V and Cybulski, C and Fabianova, E and Jinga, V and Lissowska, J and Lubinski, J and Navratilova, M and Rudnai, P and Benhamou, S and Cancel-Tassin, G and Cussenot, O and Weiderpass, E and Ljungberg, B and Tumkur Sitaram, R and Häggström, C and Bruinsma, F and Jordan, SJ and Severi, G and Winship, I and Hveem, K and Vatten, LJ and Fletcher, T and Larsson, SC and Wolk, A and Banks, RE and Selby, PJ and Easton, DF and Andreotti, G and Beane Freeman, LE and Koutros, S and Männistö, S and Weinstein, S and Clark, PE and Edwards, TL and Lipworth, L and Gapstur, SM and Stevens, VL and Carol, H and Freedman, ML and Pomerantz, MM and Cho, E and Wilson, KM and Gaziano, JM and Sesso, HD and Freedman, ND and Parker, AS and Eckel-Passow, JE and Huang, WY and Kahnoski, RJ and Lane, BR and Noyes, SL and Petillo, D and Teh, BT and Peters, U and White, E and Anderson, GL and Johnson, L and Luo, J and Buring, J and Lee, IM and Chow, WH and Moore, LE and Eisen, T and Henrion, M and Larkin, J and Barman, P and Leibovich, BC and Choueiri, TK and Lathrop, GM and Deleuze, JF and Gunter, M and McKay, JD and Wu, X and Houlston, RS and Chanock, SJ and Relton, C and Richards, JB and Martin, RM and Davey Smith, G and Brennan, P}, title = {The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.}, journal = {PLoS medicine}, volume = {16}, number = {1}, pages = {e1002724}, doi = {10.1371/journal.pmed.1002724}, pmid = {30605491}, issn = {1549-1676}, support = {MC_UU_12013/1//Medical Research Council/United Kingdom ; MC_UU_12013/2//Medical Research Council/United Kingdom ; MC_UU_12013/3//Medical Research Council/United Kingdom ; }, abstract = {BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.<br><br>METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.<br><br>CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.}, }
@article {pmid30604766, year = {2019}, author = {Morris, AP and Le, TH and Wu, H and Akbarov, A and van der Most, PJ and Hemani, G and Smith, GD and Mahajan, A and Gaulton, KJ and Nadkarni, GN and Valladares-Salgado, A and Wacher-Rodarte, N and Mychaleckyj, JC and Dueker, ND and Guo, X and Hai, Y and Haessler, J and Kamatani, Y and Stilp, AM and Zhu, G and Cook, JP and Ärnlöv, J and Blanton, SH and de Borst, MH and Bottinger, EP and Buchanan, TA and Cechova, S and Charchar, FJ and Chu, PL and Damman, J and Eales, J and Gharavi, AG and Giedraitis, V and Heath, AC and Ipp, E and Kiryluk, K and Kramer, HJ and Kubo, M and Larsson, A and Lindgren, CM and Lu, Y and Madden, PAF and Montgomery, GW and Papanicolaou, GJ and Raffel, LJ and Sacco, RL and Sanchez, E and Stark, H and Sundstrom, J and Taylor, KD and Xiang, AH and Zivkovic, A and Lind, L and Ingelsson, E and Martin, NG and Whitfield, JB and Cai, J and Laurie, CC and Okada, Y and Matsuda, K and Kooperberg, C and Chen, YI and Rundek, T and Rich, SS and Loos, RJF and Parra, EJ and Cruz, M and Rotter, JI and Snieder, H and Tomaszewski, M and Humphreys, BD and Franceschini, N}, title = {Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {29}, doi = {10.1038/s41467-018-07867-7}, pmid = {30604766}, issn = {2041-1723}, support = {P50 HD028138/HD/NICHD NIH HHS/United States ; R01 DK105124/DK/NIDDK NIH HHS/United States ; UL1 TR002736/TR/NCATS NIH HHS/United States ; R56 DK104806/DK/NIDDK NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; R37 NS029993/NS/NINDS NIH HHS/United States ; R01 DK113632/DK/NIDDK NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; //Wellcome Trust/United Kingdom ; }, abstract = {Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.}, }
@article {pmid30601989, year = {2019}, author = {Liu, C and Strnad, L and Beekmann, SE and Polgreen, PM and Chambers, HF}, title = {Clinical Practice Variation Among Adult Infectious Diseases Physicians in the Management of Staphylococcus aureus Bacteremia.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy1144}, pmid = {30601989}, issn = {1537-6591}, abstract = {Infectious disease management of Staphylococcus aureus bacteremia (SAB) was surveyed through the Emerging Infections Network. While there were areas of consensus, we found substantial practice variation in diagnostic evaluation and management of adult patients with SAB. These findings highlight opportunities for further research and guidance to define best practices.}, }
@article {pmid30600453, year = {2019}, author = {Fogel, JM and Zhang, Y and Palumbo, PJ and Guo, X and Clarke, W and Breaud, A and Richardson, P and Piwowar-Manning, E and Hamilton, EL and Ha, TV and Dumchev, K and Djoerban, Z and Hoffman, I and Hanscom, B and Miller, WC and Eshleman, SH}, title = {Use of Antiretroviral Drug Testing to Assess the Accuracy of Self-reported Data from HIV-Infected People Who Inject Drugs.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10461-018-2379-8}, pmid = {30600453}, issn = {1573-3254}, support = {UM1-AI068617//National Institutes of Health/ ; UM1-AI068619//National Institutes of Health/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1-AI068613//National Institutes of Health/ ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {We used antiretroviral (ARV) drug testing to evaluate the accuracy of self-reported data for HIV status and antiretroviral treatment (ART) among people who inject drugs enrolled in an HIV prevention trial. ARV drugs were detected in enrollment samples from 72/482 = 14.9% HIV-infected participants (39/52 = 75.0% who reported being on ART; 33/430 = 7.7% who reported not being on ART). Overall, 213/482 = 44.2% participants indicated that they were not aware of their HIV-positive status prior to study entry; of those, 30 had ARV drugs detected at enrollment, including 15 who also had ARV drugs detected at the screening visit. These participants were likely aware of their HIV-positive status at study entry but did not report this to study staff. This study shows that self-reported data on HIV testing history and ART may not be accurate and that ARV drug testing can help identify persons who are aware of their HIV-positive status and are on ART.}, }
@article {pmid30599207, year = {2018}, author = {Ueda, M and El-Jurdi, N and Cooper, B and Caimi, P and Baer, L and Kolk, M and Brister, L and Wald, DN and Otegbeye, F and Lazarus, HM and Sandmaier, BM and William, B and Saunthararajah, Y and Woost, P and Jacobberger, JW and de Lima, M}, title = {Low-Dose Azacitidine with DNMT1 Level Monitoring to Treat Post-Transplantation Acute Myelogenous Leukemia or Myelodysplastic Syndrome Relapse.}, 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.2018.12.764}, pmid = {30599207}, issn = {1523-6536}, abstract = {Patients with early relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) have a poor prognosis, and no standard treatment. Twenty-nine patients with early disease recurrence post-transplantation were treated with azacitidine (AZA; median dose, 40 mg/m2/day for 5 to 7 days). At a median follow-up of 6.3 months (range, 1.3 to 41.1 months), 7 patients (27%) had a response to AZA, defined as complete remission, hematologic improvement, or improved donor chimerism. Response occurred after a median of 3 cycles, and the median duration of response was 70 days (range, 26 to 464 days). Median survival was 6.8 months (95% confidence interval, 3.8 to 11.1 months). Survival was similar in the patients receiving an AZA dose ≤40 mg/m2 and those receiving an AZA dose >40 mg/m2. Six patients receiving donor lymphocyte infusion with AZA had a response or stable disease without worsening graft-versus-host-disease. We retrospectively used a flow cytometry assay to explore DNA-methyltransferase-1 in blood mononuclear cells as a potential pharmacodynamic marker to assess intracellular drug targeting in 8 patients. No correlation with AZA dose or response was observed. Low-dose AZA appears to have comparable efficacy to higher-dose AZA post-HCT. A significant proportion of this poor-risk population responded to low-dose AZA, suggesting a dose-independent, noncytotoxic mechanism for antileukemic activity.}, }
@article {pmid30598494, year = {2019}, author = {Hitzler, J and Estey, E}, title = {Gemtuzumab ozogamicin in acute myeloid leukemia: act 2, with perhaps more to come.}, journal = {Haematologica}, volume = {104}, number = {1}, pages = {7-9}, doi = {10.3324/haematol.2018.205948}, pmid = {30598494}, issn = {1592-8721}, }
@article {pmid30596892, year = {2018}, author = {Ha, MJ and Sun, W}, title = {Estimation of high-dimensional directed acyclic graphs with surrogate intervention.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxy080}, pmid = {30596892}, issn = {1468-4357}, abstract = {Directed acyclic graphs (DAGs) have been used to describe causal relationships between variables. The standard method for determining such relations uses interventional data. For complex systems with high-dimensional data, however, such interventional data are often not available. Therefore, it is desirable to estimate causal structure from observational data without subjecting variables to interventions. Observational data can be used to estimate the skeleton of a DAG and the directions of a limited number of edges. We develop a Bayesian framework to estimate a DAG using surrogate interventional data, where the interventions are applied to a set of external variables, and thus such interventions are considered to be surrogate interventions on the variables of interest. Our work is motivated by expression quantitative trait locus (eQTL) studies, where the variables of interest are the expression of genes, the external variables are DNA variations, and interventions are applied to DNA variants during the process of a randomly selected DNA allele being passed to a child from either parent. Our method, surrogate intervention recovery of a DAG ($\texttt{sirDAG}$), first constructs a DAG skeleton using penalized regressions and the subsequent partial correlation tests, and then estimates the posterior probabilities of all the edge directions after incorporating DNA variant data. We demonstrate the utilities of $\texttt{sirDAG}$ by simulation and an application to an eQTL study for 550 breast cancer patients.}, }
@article {pmid30596402, year = {2018}, author = {Budde, LE and Wu, D and Martin, DB and Philip, M and Shustov, AR and Smith, SD and Gooley, TA and Chen, TL and Libby, EN and Chen, EY and Kojouri, K and Langerak, A and Roden, JE and Press, OW and Gopal, AK}, title = {Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial.}, journal = {British journal of haematology}, volume = {183}, number = {4}, pages = {601-607}, doi = {10.1111/bjh.15585}, pmid = {30596402}, issn = {1365-2141}, support = {K24CA184039//Leukemia and Lymphoma Society/ ; //Damon Runyon Cancer Research Foundation/ ; P01 CA044991/CA/NCI NIH HHS/United States ; //Clinical Investigator Award/ ; P50 CA107399//National Cancer Institute of the National Institutes of Health/ ; P01CA044991//Leukemia and Lymphoma Society/ ; K24 CA184039/CA/NCI NIH HHS/United States ; P50 CA107399/CA/NCI NIH HHS/United States ; }, abstract = {We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.}, }
@article {pmid30595435, year = {2019}, author = {Swygert, SG and Kim, S and Wu, X and Fu, T and Hsieh, TH and Rando, OJ and Eisenman, RN and Shendure, J and McKnight, JN and Tsukiyama, T}, title = {Condensin-Dependent Chromatin Compaction Represses Transcription Globally during Quiescence.}, journal = {Molecular cell}, volume = {73}, number = {3}, pages = {533-546.e4}, doi = {10.1016/j.molcel.2018.11.020}, pmid = {30595435}, issn = {1097-4164}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM111428/GM/NIGMS NIH HHS/United States ; R01 CA057138/CA/NCI NIH HHS/United States ; F32 GM120962/GM/NIGMS NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; R01 GM079205/GM/NIGMS NIH HHS/United States ; }, abstract = {Quiescence is a stress-resistant state in which cells reversibly exit the cell cycle and suspend most processes. Quiescence is essential for stem cell maintenance, and its misregulation is implicated in tumor formation. One of the hallmarks of quiescent cells is highly condensed chromatin. Because condensed chromatin often correlates with transcriptional silencing, it has been hypothesized that chromatin compaction represses transcription during quiescence. However, the technology to test this model by determining chromatin structure within cells at gene resolution has not previously been available. Here, we use Micro-C XL to map chromatin contacts at single-nucleosome resolution genome-wide in quiescent Saccharomyces cerevisiae cells. We describe chromatin domains on the order of 10-60 kilobases that, only in quiescent cells, are formed by condensin-mediated loops. Condensin depletion prevents the compaction of chromatin within domains and leads to widespread transcriptional de-repression. Finally, we demonstrate that condensin-dependent chromatin compaction is conserved in quiescent human fibroblasts.}, }
@article {pmid30594650, year = {2018}, author = {Ko, LK and Taylor, VM and Mohamed, FB and Do, HH and Gebeyaw, FA and Ibrahim, A and Ali, AA and Winer, RL}, title = {&quot;We brought our culture here with us&quot;: A qualitative study of perceptions of HPV vaccine and vaccine uptake among East African immigrant mothers.}, journal = {Papillomavirus research (Amsterdam, Netherlands)}, volume = {7}, number = {}, pages = {21-25}, doi = {10.1016/j.pvr.2018.12.003}, pmid = {30594650}, issn = {2405-8521}, support = {U48DP005013//ACL HHS/United States ; }, abstract = {BACKGROUND: HPV vaccine studies in East African communities are few and focus mainly on Somali women and girls. We examined how HPV vaccine perceptions and uptake are shaped among Somali, Ethiopian, and Eritrean mothers.<br><br>METHODS: We convened three focus groups in Somali, Amharic, and Tigrinya with mothers of 11-17 year old children. The Socio-Context Framework (social, cultural, and religious factors) and Andersen's Behavioral Model (predisposing, enabling, and need for care factors) informed question development.<br><br>RESULTS: Negative vaccine perceptions, lack of HPV vaccine knowledge, and concerns about side effects emerged as predisposing factors. Having a provider who engages parents on HPV vaccination and takes responsibility for vaccine-related risks emerged as enabling factors. Availability of vaccine information resources (e.g., person-to-person, word of mouth education for parents) were also enabling factors. Need for care factors included having comprehensive vaccine information, strong recommendation from a doctor, and validation from a co-ethnic medical professional. Women exerted strong social influence on vaccine uptake (social), had concerns about pork gelatin in vaccines (religious), and felt discussions about sex with children were culturally unacceptable (cultural).<br><br>CONCLUSION: Strategies for vaccine uptake among East African immigrants need to address factors that shape HPV vaccine perceptions for adolescents, caregivers, and providers.}, }
@article {pmid30594566, year = {2018}, author = {Doll, KM and Goff, BA and Ramsey, SD}, title = {Reply.}, journal = {American journal of obstetrics and gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajog.2018.12.036}, pmid = {30594566}, issn = {1097-6868}, }
@article {pmid30594542, year = {2018}, author = {Bachanova, V and Weisdorf, DJ and Wang, T and Marsh, SGE and Cereb, N and Haagenson, MD and Spellman, SR and Lee, SJ and Guethlein, LA and Parham, P and Miller, JS and Cooley, SA}, title = {Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.}, 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.2018.12.763}, pmid = {30594542}, issn = {1523-6536}, support = {P01 CA111412/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; UL1 TR000114/TR/NCATS NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.}, }
@article {pmid30593446, year = {2019}, author = {Brown, JR and O'Brien, S and Kingsley, CD and Eradat, H and Pagel, JM and Hirata, J and McIver, T and Morariu-Zamfir, R and Kipps, TJ}, title = {Durable remissions with obinutuzumab-based chemoimmunotherapy: long-term follow-up of the phase 1b GALTON trial in CLL.}, journal = {Blood}, volume = {133}, number = {9}, pages = {990-992}, doi = {10.1182/blood-2018-06-857714}, pmid = {30593446}, issn = {1528-0020}, }
@article {pmid30592986, year = {2018}, author = {Lee, DW and Santomasso, BD and Locke, FL and Ghobadi, A and Turtle, CJ and Brudno, JN and Maus, MV and Park, JH and Mead, E and Pavletic, S and Go, WY and Eldjerou, L and Gardner, RA and Frey, N and Curran, KJ and Peggs, K and Pasquini, M and DiPersio, JF and van den Brink, MRM and Komanduri, KV and Grupp, SA and Neelapu, SS}, title = {ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells.}, 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.2018.12.758}, pmid = {30592986}, issn = {1523-6536}, abstract = {Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia years &quot;?>and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.}, }
@article {pmid30592026, year = {2018}, author = {Poston, JN and Fromm, JR and Rasmussen, HA and Shustov, AR and Libby, EN and Smith, SD and Gooley, T and Gopal, AK}, title = {A pilot study of weekly brentuximab vedotin in patients with CD30+ malignancies resistant to brentuximab vedotin every 3 weeks.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.15742}, pmid = {30592026}, issn = {1365-2141}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 HL007093//National Heart, Lung, and Blood Institute/ ; //Seattle Genetics/ ; K24 CA184039/CA/NCI NIH HHS/United States ; P30 CA015704//National Cancer Institute/ ; }, }
@article {pmid30590810, year = {2018}, author = {McClure, JB and Bricker, J and Mull, K and Heffner, JL}, title = {Comparative-Effectiveness of Group-Delivered Acceptance and Commitment Therapy vs. Cognitive Behavioral Therapy for Smoking Cessation: A Randomized Controlled Trial.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/nty268}, pmid = {30590810}, issn = {1469-994X}, abstract = {Introduction: Preliminary trial data suggests group-delivered Acceptance and Commitment Therapy (ACT) might be effective for smoking cessation. If so, this could offer a viable alternative to mainstream behavioral therapies, such as those grounded in Cognitive Behavioral Therapy (CBT). The goal of the current study was to compare the effectiveness of group-delivered ACT versus group-delivered CBT in a rigorous randomized trial design with long term follow-up.<br><br>Methods: Participants (n = 450) were recruited from the Kaiser Permanente Washington health care system and randomized to either ACT-based group counseling or an attention-matched CBT-based group program. All were prescribed an 8-week course of nicotine patches. The primary outcome was self-reported 30-day point prevalence abstinence (PPA) at 12 months post-randomization assessed with missing values imputed as smoking. Sensitivity analyses using multiple imputation and complete cases were examined, as were biochemically-confirmed and 6-month outcomes.<br><br>Results: Thirty-day point prevalence abstinence rates at the 12-month follow up did not differ between study arms in the primary analysis (13.8% ACT vs. 18.1% CBT, adjusted OR 0.68 [0.35, 1.27], p = 0.23) or the sensitivity analyses.<br><br>Conclusions: Group-based ACT and CBT had similar long-term quit rates in this methodologically rigorous randomized trial. Group-based ACT is a reasonable alternative to group-based CBT for smoking cessation.<br><br>Implications: This study compared the effectiveness of group-based ACT with group-based CBT for smoking cessation using a rigorous, large-scale, attention-matched, randomized trial with one-year follow-up. One-year cessation rates did not differ between group-based ACT and CBT, suggesting ACT-based intervention is a reasonable alternative to CBT-based counseling for smoking cessation. The results add to the nascent but growing literature assessing ACT and other mindfulness-based treatments for smoking cessation.}, }
@article {pmid30590741, year = {2018}, author = {Rose, R and Hall, M and Redd, AD and Lamers, S and Barbier, AE and Porcella, SF and Hudelson, SE and Piwowar-Manning, E and McCauley, M and Gamble, T and Wilson, EA and Kumwenda, J and Hosseinipour, MC and Hakim, JG and Kumarasamy, N and Chariyalertsak, S and Pilotto, JH and Grinsztejn, B and Mills, LA and Makhema, J and Santos, BR and Chen, YQ and Quinn, TC and Fraser, C and Cohen, MS and Eshleman, SH and Laeyendecker, O}, title = {Phylogenetic methods inconsistently predict direction of HIV transmission among heterosexual pairs in the HPTN052 cohort.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiy734}, pmid = {30590741}, issn = {1537-6613}, support = {UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {Background: We evaluated use of phylogenetic methods to predict the direction of HIV transmission.<br><br>Methods: For 33 index-partner pairs with genetically-linked infection, samples were collected from partners and indexes close to time of partners' seroconversion (SC); 31 indexes also had an earlier sample. Phylogenies were inferred using env next-generation sequences (one tree per pair/subtype). Direction of transmission (DoT) predicted from each tree was classified as correct or incorrect based on which sequences (index or partner) were closest to the root. DoT was also assessed using maximum-parsimony to infer ancestral node states for 100 bootstrap trees.<br><br>Results: DoT was predicted correctly for both single pair and subtype-specific trees in 22 pairs (67%) using SC samples and 23 pairs (74%) using early index samples. DoT was predicted incorrectly for four pairs (15%) using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) using SC samples and 24 pairs (73%) using early index samples. DoT was predicted incorrectly for seven pairs (21%) using SC samples and four pairs (13%) using early index samples.<br><br>Conclusions: Phylogenetic methods based solely on tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.}, }
@article {pmid30590721, year = {2018}, author = {Chan, AK and Ammanuel, SG and Chan, AY and Oh, T and Skrehot, HC and Edwards, CS and Kondapavulur, S and Miller, CA and Nichols, AD and Liu, C and Dhall, SS and Clark, AJ and Chou, D and Ames, CP and Mummaneni, PV}, title = {Chlorhexidine Showers are Associated With a Reduction in Surgical Site Infection Following Spine Surgery: An Analysis of 4266 Consecutive Surgeries.}, journal = {Neurosurgery}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuros/nyy568}, pmid = {30590721}, issn = {1524-4040}, abstract = {BACKGROUND: Surgical site infection (SSI) is a common complication following spinal surgery. Prevention is critical to maintaining safe patient care and reducing additional costs associated with treatment.<br><br>OBJECTIVE: To determine the efficacy of preoperative chlorhexidine (CHG) showers on SSI rates following fusion and nonfusion spine surgery.<br><br>METHODS: A mandatory preoperative CHG shower protocol was implemented at our institution in November 2013. A cohort comparison of 4266 consecutive patients assessed differences in SSI rates for the pre- and postimplementation periods. Subgroup analysis was performed on the type of spinal surgery (eg, fusion vs nonfusion). Data represent all spine surgeries performed between April 2012 and April 2016.<br><br>RESULTS: The overall mean SSI rate was 0.4%. There was no significant difference between the pre- (0.7%) and postimplementation periods (0.2%; P = .08). Subgroup analysis stratified by procedure type showed that the SSI rate for the nonfusion patients was significantly lower in the post- (0.1%) than the preimplementation group (0.7%; P = .02). There was no significant difference between SSI rates for the pre- (0.8%) and postimplementation groups (0.3%) for the fusion cohort (P = .21). In multivariate analysis, the implementation of preoperative CHG showers were associated with significantly decreased odds of SSI (odds ratio = 0.15, 95% confidence interval [0.03-0.55], P < .01).<br><br>CONCLUSION: This is the largest study investigating the efficacy of preoperative CHG showers on SSI following spinal surgery. In adjusted multivariate analysis, CHG showering was associated with a significant decrease in SSI following spinal surgery.}, }
@article {pmid30590454, year = {2018}, author = {Wang, L and Luedtke, AR and Huang, Y}, title = {Assessing the incremental value of new biomarkers based on OR rules.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxy070}, pmid = {30590454}, issn = {1468-4357}, support = {R01 GM106177/GM/NIGMS NIH HHS/United States ; }, abstract = {In early detection of disease, a single biomarker often has inadequate classification performance, making it important to identify new biomarkers to combine with the existing marker for improved performance. A biologically natural method for combining biomarkers is to use logic rules, e.g., the OR/AND rules. In our motivating example of early detection of pancreatic cancer, the established biomarker CA19-9 is only present in a subclass of cancers; it is of interest to identify new biomarkers present in the other subclasses and declare disease when either marker is positive. While there has been research on developing biomarker combinations using the OR/AND rules, inference regarding the incremental value of the new marker within this framework is lacking and challenging due to statistical non-regularity. In this article, we aim to answer the inferential question of whether combining the new biomarker achieves better classification performance than using the existing biomarker alone, based on a nonparametrically estimated OR rule that maximizes the weighted average of sensitivity and specificity. We propose and compare various procedures for testing the incremental value of the new biomarker and constructing its confidence interval, using bootstrap, cross-validation, and a novel fuzzy p-value-based technique. We compare the performance of different methods via extensive simulation studies and apply them to the pancreatic cancer example.}, }
@article {pmid30590450, year = {2018}, author = {Juraska, M and Huang, Y and Gilbert, PB}, title = {Inference on treatment effect modification by biomarker response in a three-phase sampling design.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxy074}, pmid = {30590450}, issn = {1468-4357}, support = {R01 GM106177/GM/NIGMS NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; }, abstract = {An objective in randomized clinical trials is the evaluation of &quot;principal surrogates,&quot; which consists of analyzing how the treatment effect on a clinical endpoint varies over principal strata subgroups defined by an intermediate response outcome under both or one of the treatment assignments. The latter effect modification estimand has been termed the marginal causal effect predictiveness (mCEP) curve. This objective was addressed in two randomized placebo-controlled Phase 3 dengue vaccine trials for an antibody response biomarker whose sampling design rendered previously developed inferential methods highly inefficient due to a three-phase sampling design. In this design, the biomarker was measured in a case-cohort sample and a key baseline auxiliary strongly associated with the biomarker (the &quot;baseline surrogate measure&quot;) was only measured in a further sub-sample. We propose a novel approach to estimation of the mCEP curve in such three-phase sampling designs that avoids the restrictive &quot;placebo structural risk&quot; modeling assumption common to past methods and that further improves robustness by the use of non-parametric kernel smoothing for biomarker density estimation. Additionally, we develop bootstrap-based procedures for pointwise and simultaneous confidence intervals and testing of four relevant hypotheses about the mCEP curve. We investigate the finite-sample properties of the proposed methods and compare them to those of an alternative method making the placebo structural risk assumption. Finally, we apply the novel and alternative procedures to the two dengue vaccine trial data sets.}, }
@article {pmid30590447, year = {2018}, author = {Fong, Y and Huang, Y and Lemos, MP and Mcelrath, MJ}, title = {Response to Guo et al.'s Letter to the Editor.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxy061}, pmid = {30590447}, issn = {1468-4357}, 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 ; }, }
@article {pmid30590402, year = {2018}, author = {Dai, J and Li, Z and Amos, CI and Hung, RJ and Tardon, A and Andrew, A and Chen, C and Christiani, DC and Albanes, D and van der Heijden, EHFM and Duell, E and Rennert, G and James, MD and Yuan, JM and Field, JK and Jonas, M and Grankvist, K and Le Marchand, L and Teare, MD and Schabath, MB and Aldrich, MC and Tsao, MS and Lazarus, P and Stephen, L and Bojesen, SE and Susanne, A and Wu, X and Haugen, A and Vladimir, J and Johansson, M and Yonathan, B and Fernandez-Somoano, A and Kiemeney, LA and Davies, M and Zienolddiny, S and Hu, Z and Shen, H}, title = {Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci.}, journal = {Carcinogenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/carcin/bgy187}, pmid = {30590402}, issn = {1460-2180}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; P50 CA119997/CA/NCI NIH HHS/United States ; }, abstract = {DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In the current study, we performed a large-scale case-control study with 20,871 lung cancer cases and 15,971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The eQTL (expression quantitative trait loci) analysis and pathway enrichment analysis were performed to identify the possible target genes and pathways. Additionally, we performed motif-based analysis to explore the lung cancer related motifs using sequence kernel association test (SKAT). Two novel variants, rs186332 in 20q13.3 (C>T, OR = 1.17, 95% CI: 1.10-1.24, P = 8.45×10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02×10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1 respectively. What's more, the expression of both MRGBP and SLC16A1 were aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71×10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS related genetic variants for lung cancer.}, }
@article {pmid30590125, year = {2018}, author = {Sauter, CS and DeFilipp, Z and Inamoto, Y and Johnston, L and Nagler, A and Savani, BN and Carpenter, PA and Perales, MA}, title = {ASBMT Statement on Routine Prophylaxis for Central Nervous System Recurrence of Acute Lymphoblastic Leukemia following Allogeneic Hematopoietic Cell 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.2018.12.757}, pmid = {30590125}, issn = {1523-6536}, abstract = {Hematologic malignancies treated with allogeneic hematopoietic cell transplantation (allo-HCT) have a variable incidence of post-transplantation central nervous system (CNS) relapse, with acute lymphoblastic leukemia (ALL) representing the most common disease histology. Although data supporting post-transplantation CNS prophylaxis for ALL in the pre-CNS penetrant systemic therapy era established this as standard practice, controversy exists regarding the role of post-transplantation CNS prophylaxis in the contemporary era. Here we review the most relevant (albeit exclusively retrospective) literature to date on the role of post-transplantation CNS prophylaxis in ALL. Given the paucity of data supporting the routine practice of post-transplantation CNS prophylaxis for ALL in the contemporary era, this position statement is anticipated to further stoke controversy and discussion within the transplantation community. Ultimately, only well-designed prospective clinical studies will elucidate the role of routine post-transplantation CNS prophylaxis.}, }
@article {pmid30590092, year = {2019}, author = {Radtke, S and Chan, YY and Sippel, TR and Kiem, HP and Rongvaux, A}, title = {MISTRG mice support engraftment and assessment of nonhuman primate hematopoietic stem and progenitor cells.}, journal = {Experimental hematology}, volume = {70}, number = {}, pages = {31-41.e1}, doi = {10.1016/j.exphem.2018.12.003}, pmid = {30590092}, issn = {1873-2399}, abstract = {Preclinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large-animal models such as nonhuman primates (NHPs). Here, we wished to determine whether mouse models would allow engraftment of NHP HSPCs, which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34+ hematopoietic stem and progenitor cells (HSPCs). No engraftment of NHP HSPCs was observed in NSG mice, whereas the gene-humanized MISTRG model did demonstrate dose-dependent multilineage engraftment of NHP cells in the peripheral blood, bone marrow, spleen, and thymus. Most importantly, and closely mimicking the hematopoietic recovery of autologous stem cell transplantations in the NHP, only HSC-enriched CD34+CD90+CD45RA- cell fractions engrafted and reconstituted the bone marrow stem cell niche in MISTRG mice. In summary, we here report the first &quot;monkeynized&quot; mouse xenograft model that closely recapitulates the autologous hematopoietic reconstitution in the NHP stem and progenitor cell transplantation and gene therapy model. The availability of this model has the potential to pre-evaluate novel HSC-mediated gene therapy approaches, inform studies in the NHP, and improve the overall outcome of large-animal experiments.}, }
@article {pmid30586737, year = {2019}, author = {Sabater-Lleal, M and Huffman, JE and de Vries, PS and Marten, J and Mastrangelo, MA and Song, C and Pankratz, N and Ward-Caviness, CK and Yanek, LR and Trompet, S and Delgado, GE and Guo, X and Bartz, TM and Martinez-Perez, A and Germain, M and de Haan, HG and Ozel, AB and Polasek, O and Smith, AV and Eicher, JD and Reiner, AP and Tang, W and Davies, NM and Stott, DJ and Rotter, JI and Tofler, GH and Boerwinkle, E and de Maat, MPM and Kleber, ME and Welsh, P and Brody, JA and Chen, MH and Vaidya, D and Soria, JM and Suchon, P and van Hylckama Vlieg, A and Desch, KC and Kolcic, I and Joshi, PK and Launer, LJ and Harris, TB and Campbell, H and Rudan, I and Becker, DM and Li, JZ and Rivadeneira, F and Uitterlinden, AG and Hofman, A and Franco, OH and Cushman, M and Psaty, BM and Morange, PE and McKnight, B and Chong, MR and Fernandez-Cadenas, I and Rosand, J and Lindgren, A and ,  and Gudnason, V and Wilson, JF and Hayward, C and Ginsburg, D and Fornage, M and Rosendaal, FR and Souto, JC and Becker, LC and Jenny, NS and März, W and Jukema, JW and Dehghan, A and Trégouët, DA and Morrison, AC and Johnson, AD and O'Donnell, CJ and Strachan, DP and Lowenstein, CJ and Smith, NL}, title = {Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.}, journal = {Circulation}, volume = {139}, number = {5}, pages = {620-635}, doi = {10.1161/CIRCULATIONAHA.118.034532}, pmid = {30586737}, issn = {1524-4539}, support = {R01 HL059367/HL/NHLBI NIH HHS/United States ; R35 HL135793/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.<br><br>METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.<br><br>RESULTS: We identified 13 novel genome-wide significant (P≤2.5×10-8) associations, 7 with FVIII levels (FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels (PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.<br><br>CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.}, }
@article {pmid30586364, year = {2018}, author = {Kapadia, SN and Wu, C and Mayer, KH and Wilkin, TJ and Amico, KR and Landovitz, RJ and Andrade, A and Chen, YQ and Chege, W and McCauley, M and Gulick, RM and Schackman, BR}, title = {No change in health-related quality of life for at-risk U.S. women and men starting HIV pre-exposure prophylaxis (PrEP): Findings from HPTN 069/ACTG A5305.}, journal = {PloS one}, volume = {13}, number = {12}, pages = {e0206577}, doi = {10.1371/journal.pone.0206577}, pmid = {30586364}, issn = {1932-6203}, support = {UM1 AI069494/AI/NIAID NIH HHS/United States ; UM1 AI069423/AI/NIAID NIH HHS/United States ; UM1 AI069503/AI/NIAID NIH HHS/United States ; UM1 AI069501/AI/NIAID NIH HHS/United States ; UL1 TR001111/TR/NCATS NIH HHS/United States ; UL1 TR000005/TR/NCATS NIH HHS/United States ; UM1 AI069424/AI/NIAID NIH HHS/United States ; UL1 RR024153/RR/NCRR NIH HHS/United States ; UM1 AI069466/AI/NIAID NIH HHS/United States ; UL1 RR024996/RR/NCRR NIH HHS/United States ; P30 DA040500/DA/NIDA NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI069415/AI/NIAID NIH HHS/United States ; P30 AI045008/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; P30 AI117970/AI/NIAID NIH HHS/United States ; UM1 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI069465/AI/NIAID NIH HHS/United States ; UM1 AI069419/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: Tenofovir (TDF)-containing PrEP is effective for HIV prevention, but its effect on health-related quality of life (QOL) is unknown. Using data from HPTN 069/ACTG A5305, a randomized study of potential PrEP regimens comparing maraviroc alone, or together with TDF or emtricitabine (FTC), to TDF + FTC (control), we evaluated the impact of these regimens on QOL in at-risk HIV-uninfected U.S. women and men.<br><br>METHODS: QOL was measured at baseline (before starting medications) and every 8 weeks through week 48 using the EQ-5D-3L. Responses were converted to a scale from 0.0 (death) to 1.0 (perfect health), using published valuation weights. Mean scores were compared between groups at each time point using nonparametric testing. Multivariable linear regression was used to adjust for potential confounders.<br><br>RESULTS: We analyzed 186 women (median age 35 years, 65% black, 17% Hispanic) and 405 men (median age 30 years, 28% black, 22% Hispanic), including 9 transgender participants analyzed based on sex-at-birth. Mean baseline QOL was 0.91 for women and 0.95 for men. There were minimal changes in mean QOL over time for any regimen (women: p = 0.29; men: p = 0.14). There were no significant differences between participants who continued the regimen compared to participants who discontinued early (women: p = 0.61; men: p = 0.1). Mean QOL did not differ significantly by regimen at any time point, both unadjusted and after adjustment for age, race/ethnicity, adherence, and use of alcohol, marijuana, opiates, and other substances.<br><br>CONCLUSIONS: QOL in at-risk individuals starting candidate PrEP regimens in a clinical trial is similar to the general population and maintained over time. This finding did not vary among regimens or when adjusted for demographics, adherence, and substance use. Our findings are the first to show that starting a candidate PrEP regimen in at-risk HIV-uninfected U.S. women and men was not associated with significant changes in QOL.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov NCT01505114.}, }
@article {pmid30585971, year = {2019}, author = {Shore, RE and Beck, HL and Boice, JD and Caffrey, EA and Davis, S and Grogan, HA and Mettler, FA and Preston, RJ and Till, JE and Wakeford, R and Walsh, L and Dauer, LT}, title = {Recent Epidemiologic Studies and the Linear No-Threshold Model For Radiation Protection-Considerations Regarding NCRP Commentary 27.}, journal = {Health physics}, volume = {116}, number = {2}, pages = {235-246}, doi = {10.1097/HP.0000000000001015}, pmid = {30585971}, issn = {1538-5159}, abstract = {National Council on Radiation Protection and Measurements Commentary 27 examines recent epidemiologic data primarily from low-dose or low dose-rate studies of low linear-energy-transfer radiation and cancer to assess whether they support the linear no-threshold model as used in radiation protection. The commentary provides a critical review of low-dose or low dose-rate studies, most published within the last 10 y, that are applicable to current occupational, environmental, and medical radiation exposures. The strengths and weaknesses of the epidemiologic methods, dosimetry assessments, and statistical modeling of 29 epidemiologic studies of total solid cancer, leukemia, breast cancer, and thyroid cancer, as well as heritable effects and a few nonmalignant conditions, were evaluated. An appraisal of the degree to which the low-dose or low dose-rate studies supported a linear no-threshold model for radiation protection or on the contrary, demonstrated sufficient evidence that the linear no-threshold model is inappropriate for the purposes of radiation protection was also included. The review found that many, though not all, studies of solid cancer supported the continued use of the linear no-threshold model in radiation protection. Evaluations of the principal studies of leukemia and low-dose or low dose-rate radiation exposure also lent support for the linear no-threshold model as used in protection. Ischemic heart disease, a major type of cardiovascular disease, was examined briefly, but the results of recent studies were considered too weak or inconsistent to allow firm conclusions regarding support of the linear no-threshold model. It is acknowledged that the possible risks from very low doses of low linear-energy-transfer radiation are small and uncertain and that it may never be possible to prove or disprove the validity of the linear no-threshold assumption by epidemiologic means. Nonetheless, the preponderance of recent epidemiologic data on solid cancer is supportive of the continued use of the linear no-threshold model for the purposes of radiation protection. This conclusion is in accord with judgments by other national and international scientific committees, based on somewhat older data. Currently, no alternative dose-response relationship appears more pragmatic or prudent for radiation protection purposes than the linear no-threshold model.}, }
@article {pmid30585894, year = {2019}, author = {Halpern, AB and Walter, RB and Estey, EH}, title = {Outpatient induction and consolidation care strategies in acute myeloid leukemia.}, journal = {Current opinion in hematology}, volume = {26}, number = {2}, pages = {65-70}, doi = {10.1097/MOH.0000000000000481}, pmid = {30585894}, issn = {1531-7048}, abstract = {PURPOSE OF REVIEW: Patients with acute myeloid leukemia (AML) are almost invariably kept in the hospital until resolution of cytopenias following intensive induction chemotherapy. This care approach is costly and may further contribute to the reduced qualify of life of these patients. This has raised interest in moving at least part of this care to the outpatient setting. Reimbursement challenges for inpatient administration of some of the new drugs approved for AML in the last 2 years adds to this interest.<br><br>RECENT FINDINGS: Retrospective and smaller prospective studies have shown that outpatient management following intensive induction chemotherapy ('Early Hospital Discharge') is feasible and may be well tolerated and cost-effective. Reported experience is more limited regarding administration of intensive chemotherapy in the outpatient setting.<br><br>SUMMARY: Although of interest, barriers to the successful implementation of outpatient care models, such as limited outpatient infrastructure or geographical limitations, will have to be overcome in many cancer centers. Importantly, before wide-spread introduction, the safety and 'efficacy' (e.g. reduction in medical resources and/or cost and improvement in quality of life) of outpatient care strategies will need to be further evaluated in a prospective - and ideally randomized - manner across more heterogeneous types of oncology and geographical settings.}, }
@article {pmid30585824, year = {2018}, author = {Davis, JL and Lockwood, CM and Stohr, B and Boecking, C and Al-Ibraheemi, A and DuBois, SG and Vargas, SO and Black, JO and Cox, MC and Luquette, M and Turpin, B and Szabo, S and Laetsch, TW and Albert, CM and Parham, DM and Hawkins, DS and Rudzinski, ER}, title = {Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors.}, journal = {The American journal of surgical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1097/PAS.0000000000001203}, pmid = {30585824}, issn = {1532-0979}, abstract = {Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.}, }
@article {pmid30585505, year = {2019}, author = {Kraft, SA and Duenas, DM and Kublin, JG and Shipman, KJ and Murphy, SC and Shah, SK}, title = {Exploring Ethical Concerns About Human Challenge Studies: A Qualitative Study of Controlled Human Malaria Infection Study Participants' Motivations and Attitudes.}, journal = {Journal of empirical research on human research ethics : JERHRE}, volume = {14}, number = {1}, pages = {49-60}, doi = {10.1177/1556264618820219}, pmid = {30585505}, issn = {1556-2654}, abstract = {Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants' understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.}, }
@article {pmid30580725, year = {2018}, author = {Viscoli, CM and Kent, DM and Conwit, R and Dearborn, JL and Furie, KL and Gorman, M and Guarino, PD and Inzucchi, SE and Stuart, A and Young, LH and Kernan, WN and , }, title = {Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk.}, journal = {Stroke}, volume = {}, number = {}, pages = {STROKEAHA118022745}, doi = {10.1161/STROKEAHA.118.022745}, pmid = {30580725}, issn = {1524-4628}, support = {U01 NS044876/NS/NINDS NIH HHS/United States ; }, abstract = {Background and Purpose- The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy. Methods- IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack. Participants were recruited at 179 international centers from February 2005 to January 2013 and followed for a median of 4.8 years. Fracture risk models were developed from patient characteristics at entry. Within fracture risk strata, we quantified the effects of pioglitazone compared with placebo by estimating the relative risks and absolute 5-year risk differences for fracture and stroke or myocardial infarction. Results- The fracture risk model included points for age, race-ethnicity, sex, body mass index, disability, and medications. The relative increment in fracture risk with pioglitazone was similar in the lower (<median point score) and higher (≥ median point score) risk strata. However, the absolute risk difference (ARD) for fracture was less in the low-risk group (5.8% in pioglitazone group versus 4.0% in placebo group; ARD, 1.8%; 95% CI, -0.7% to 4.4%) compared with high-risk group (18.0% versus 11.6%; ARD, 6.4%; 95% CI, 3.2% to 9.6%). Reductions in risk for stroke or myocardial infarction did not vary by fracture risk (low-risk ARD, -3.7%; high-risk ARD, -3.5%). In low-risk patients, pioglitazone prevented 2.0 strokes or myocardial infarctions for each fracture caused, compared with 0.5 among those at high risk. Conclusions- A simple point score identifying patients at low risk for fracture may assist in selecting patients with a favorable benefit-risk profile for pioglitazone therapy after ischemic stroke or transient ischemic attack.}, }
@article {pmid30578684, year = {2019}, author = {Azenkot, T and Zaniello, B and Green, ML and Selke, S and Huang, ML and Magaret, A and Wald, A and Johnston, C}, title = {Cytomegalovirus shedding from breastmilk and mucosal sites in healthy postpartum women: A pilot study.}, journal = {Journal of medical virology}, volume = {91}, number = {5}, pages = {894-898}, doi = {10.1002/jmv.25386}, pmid = {30578684}, issn = {1096-9071}, support = {//University of California Davis Medical Student Research Fellowship/ ; AI030731//National Institute of Allergy and Infectious Diseases/ ; AI071113//National Institute of Allergy and Infectious Diseases/ ; P01 AI030731/AI/NIAID NIH HHS/United States ; K24 AI071113/AI/NIAID NIH HHS/United States ; }, abstract = {Mother-to-child cytomegalovirus (CMV) breastmilk transmission can occur in the postnatal period. In a pilot study, we measured daily CMV detection by polymerase chain reaction in breastmilk, vaginal, and saliva samples from nine healthy CMV-seropositive postpartum women for 28 days. CMV was found in seven of nine women and 171 of 253 breastmilk samples (67.6%). In four women, all breastmilk samples were positive. CMV was less frequently detected in the vagina (39 of 258, 15.1%) and saliva (53 of 258, 20.5%). Daily breastmilk, oral, and genital collection is feasible and demonstrates high variability between women. Further study of the dynamics of CMV in distinct anatomic compartments is warranted.}, }
@article {pmid30577869, year = {2018}, author = {Janssens, DH and Wu, SJ and Sarthy, JF and Meers, MP and Myers, CH and Olson, JM and Ahmad, K and Henikoff, S}, title = {Automated in situ chromatin profiling efficiently resolves cell types and gene regulatory programs.}, journal = {Epigenetics &amp; chromatin}, volume = {11}, number = {1}, pages = {74}, doi = {10.1186/s13072-018-0243-8}, pmid = {30577869}, issn = {1756-8935}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Binding Sites ; Chromatin/genetics ; Chromatin Immunoprecipitation/*methods ; DNA-Binding Proteins/analysis/classification/genetics ; Enhancer Elements, Genetic/genetics ; Gene Expression Profiling/*methods ; Gene Expression Regulation, Neoplastic/genetics ; High-Throughput Screening Assays/methods ; Histone Code/genetics ; Histones/genetics ; Humans ; In Situ Hybridization/methods ; K562 Cells ; Promoter Regions, Genetic/genetics ; Protein Binding/genetics ; Software ; Transcription Factors/genetics ; }, abstract = {BACKGROUND: Our understanding of eukaryotic gene regulation is limited by the complexity of protein-DNA interactions that comprise the chromatin landscape and by inefficient methods for characterizing these interactions. We recently introduced CUT&amp;RUN, an antibody-targeted nuclease cleavage method that profiles DNA-binding proteins, histones and chromatin-modifying proteins in situ with exceptional sensitivity and resolution.<br><br>RESULTS: Here, we describe an automated CUT&amp;RUN platform and apply it to characterize the chromatin landscapes of human cells. We find that automated CUT&amp;RUN profiles of histone modifications crisply demarcate active and repressed chromatin regions, and we develop a continuous metric to identify cell-type-specific promoter and enhancer activities. We test the ability of automated CUT&amp;RUN to profile frozen tumor samples and find that our method readily distinguishes two pediatric glioma xenografts by their subtype-specific gene expression programs.<br><br>CONCLUSIONS: The easy, cost-effective workflow makes automated CUT&amp;RUN an attractive tool for high-throughput characterization of cell types and patient samples.}, }
@article {pmid30577459, year = {2018}, author = {Pender, A and Jones, RL and Pollack, S}, title = {Optimising Cancer Vaccine Design in Sarcoma.}, journal = {Cancers}, volume = {11}, number = {1}, pages = {}, doi = {10.3390/cancers11010001}, pmid = {30577459}, issn = {2072-6694}, abstract = {Immunotherapeutics are increasingly recognized as a key tool in the armamentarium against malignancy. The success of immune checkpoint-targeting drugs and adoptive cell therapy has refocused attention on the potential anti-cancer effect of eliciting a tumour-specific immunological response. Sarcomas are a rare and diverse group of tumours with a limited prognosis in advanced disease despite systemic therapeutics. Various vaccine strategies including peptide vaccines against cancer testis antigens, dendritic cell vaccines, and viral vectors have been trialled in sarcoma with growing evidence of efficacy. Here, we review the principles of successful vaccine development and how these have been applied thus far to the treatment of sarcoma.}, }
@article {pmid30576834, year = {2018}, 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, J 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 in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and 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.2018.12.068}, pmid = {30576834}, issn = {1523-6536}, abstract = {On August 30, 2017 the US Food and Drug Administration 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, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy 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 {pmid30576476, year = {2018}, author = {Ene, CI and Macomber, MW and Barber, JK and Ferreira, MJ and Ellenbogen, RG and Holland, EC and Rockhill, JK and Silbergeld, DL and Halasz, LM}, title = {Patterns of Failure After Stereotactic Radiosurgery for Recurrent High-Grade Glioma: A Single Institution Experience of 10 Years.}, journal = {Neurosurgery}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuros/nyy520}, pmid = {30576476}, issn = {1524-4040}, abstract = {BACKGROUND: Stereotactic radiosurgery (SRS) is a treatment modality that is frequently used as salvage therapy for small nodular recurrent high-grade gliomas (HGG). Due to the infiltrative nature of HGG, it is unclear if this highly focused technique provides a durable local control benefit.<br><br>OBJECTIVE: To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas.<br><br>METHODS: We retrospectively reviewed clinical, radiographic, and follow-up information for 47 consecutive patients receiving SRS for recurrent HGG at our institution between June 2006 and July 2016. All patients initially presented with an HGG (WHO grade III and IV). Following SRS for recurrence, all patients experienced treatment failure, and we evaluated patterns of local, regional, and distant failure in relation to the SRS 50% isodose line.<br><br>RESULTS: Most patients with recurrent HGG developed &quot;in-field&quot; treatment failure following SRS (n = 40; 85%). Higher SRS doses were associated with longer time to failure (hazards ratio = 0.80 per 1 Gy increase; 95% confidence interval 0.67-0.96; P = .016). There was a statistically significant increase in distant versus in-field failure among older patients (P = .035). This effect was independent of bevacizumab use (odds ratio = 0.54, P = 1.0).<br><br>CONCLUSION: Based on our experience, the majority of treatment failures after SRS for recurrent HGG were &quot;in-field.&quot; Older patients, however, presented with more distant failures. Our results indicate that higher SRS doses delivered to a larger area as fractioned or unfractioned regimen may prolong time to failure, especially in the older population.}, }
@article {pmid30576268, year = {2019}, author = {Halabi, S and Dutta, S and Tangen, CM and Rosenthal, M and Petrylak, DP and Thompson, IM and Chi, KN and Araujo, JC and Logothetis, C and Quinn, DI and Fizazi, K and Morris, MJ and Eisenberger, MA and George, DJ and De Bono, JS and Higano, CS and Tannock, IF and Small, EJ and Kelly, WK}, title = {Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {37}, number = {5}, pages = {403-410}, doi = {10.1200/JCO.18.01279}, pmid = {30576268}, issn = {1527-7755}, abstract = {PURPOSE: Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen.<br><br>METHODS: Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases).<br><br>RESULTS: Of 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men (P < .001).<br><br>CONCLUSION: When adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.}, }
@article {pmid30573517, year = {2019}, author = {Kuzma, JN and Hagman, DK and Cromer, G and Breymeyer, KL and Roth, CL and Foster-Schubert, KE and Holte, SE and Weigle, DS and Kratz, M}, title = {Intraindividual Variation in Markers of Intestinal Permeability and Adipose Tissue Inflammation in Healthy Normal-Weight to Obese Adults.}, 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 = {3}, pages = {610-615}, doi = {10.1158/1055-9965.EPI-18-0641}, pmid = {30573517}, issn = {1538-7755}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; R21 HL108257/HL/NHLBI NIH HHS/United States ; R25 CA094880/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Intestinal permeability and adipose tissue inflammation are considered mechanistic links in the relationship between diet, obesity, and chronic disease. However, methods to measure both are not well standardized, and the reliability of commonly used measures is not known.<br><br>METHODS: We calculated the intraclass correlation coefficient (ICC) for several common measures of intestinal permeability and adipose tissue inflammation from a randomized clinical trial of cross-over design in which normal-weight (n = 12) or overweight/obese (n = 12) individuals each completed three 8-day dietary intervention periods.<br><br>RESULTS: For biomarkers of intestinal permeability, plasma zonulin, and lipopolysaccharide-binding protein, ICCs were &quot;excellent&quot; (i.e., >0.9). The direct measure of intestinal permeability, the lactulose/mannitol test, exhibited &quot;fair&quot; reliability (ICC = 0.53). A wider range of ICCs (0.6-0.9), suggesting &quot;good&quot; to &quot;excellent&quot; reliability, were obtained for measures of adipose tissue expression of genes encoding major mediators of inflammation. Similarly, individual immune cell populations isolated from adipose tissue, expressed as a percentage of all CD45+ cells, also had &quot;good&quot; to &quot;excellent&quot; ICCs. However, when these populations were expressed as number of cells per gram of tissue, ICC values were &quot;fair,&quot; falling below 0.6.<br><br>CONCLUSIONS: Due to the repeated measures design, our study offered a unique opportunity to assess reliability of commonly used biomarkers of intestinal permeability and adipose tissue inflammation. Our findings suggest that these measures were generally highly reliable in the short-term.<br><br>IMPACT: Along with other factors, particularly validity, the demonstrated reliabilities can help inform the choice of endpoints in studies of intestinal permeability and adipose tissue inflammation.}, }
@article {pmid30572749, year = {2018}, author = {Chandrasekaran, S and Hunt, H and Melhorn, S and Gammill, HS and Schur, EA}, title = {Adipokine profiles in preeclampsia.}, journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians}, volume = {}, number = {}, pages = {1-121}, doi = {10.1080/14767058.2018.1562542}, pmid = {30572749}, issn = {1476-4954}, abstract = {OBJECTIVES: Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE), are associated with short- and long-term maternal health complications, and obesity is a leading attributable risk factor for HDP. Yet, most women identified as obese (by body mass index [BMI] ≥ 30 kg/m2) do not develop HDP, indicating limited predictability of BMI alone. In nonpregnant populations, increased visceral fat mass (VFM) is an obesity-associated phenotype increasing the risk for developing hypertension. We sought to assess whether in pregnancy, obese women with PE would have a higher circulating levels of adipokines preferential to VFM compared to obese women without PE.<br><br>STUDY DESIGN: We performed a case control study of women with and without PE, including obese (n = 65; BMI ≥ 30 kg/m2) and normal weight (n = 52; BMI 18.4-24.9 kg/m2) women. Plasma concentrations of adipokines preferential to VFM (visfatin, resistin), adipokines reflecting overall adiposity (leptin, adiponectin), and inflammatory cytokines were compared.<br><br>RESULTS: We found that among obese women, cases had significantly higher levels of visceral fat mass (VFM)-associated adipokines and cytokines compared to controls [visfatin (p < 0.01, t = -3.8), resistin (p = 0.002, t = 1.12), IFN gamma (p = 0.04, t = -2.0), IL-6 (p < 0.01, t = -2.65), IL1-beta (p < 0.01, t = -4.1), IL-2 (p < 0.01, t = -3.9)]. Interestingly, however, obese and normal weight cases had similar VFM-adipokine and cytokine levels [visfatin (p = 0.34, t = -0.35), resistin (p = 0.55, t = -0.25)], and inflammatory marker concentrations [IFN gamma (p = 0.86, t = -0.76), IL-6 (p = 0.91, t = -0.53), IL-1beta (p = 0.67, t = 1.18), and IL-2 (p = 0.45, t = -1.16)]. These data possibly suggest an association between VFM and preeclampsia (PE) that is present independent of BMI.<br><br>CONCLUSION: In summary, we demonstrated that, in normal-weight and obese women, PE was associated with higher concentrations of VFM-preferential adipokines compared to normal-weight and obese controls without PE.}, }
@article {pmid30571496, year = {2018}, author = {Jiang, X and Zeleznik, OA and Lindström, S and Lasky-Su, J and Hagan, K and Clish, CB and Eliassen, AH and Kraft, P and Kabrhel, C}, title = {Metabolites Associated With the Risk of Incident Venous Thromboembolism: A Metabolomic Analysis.}, journal = {Journal of the American Heart Association}, volume = {7}, number = {22}, pages = {e010317}, doi = {10.1161/JAHA.118.010317}, pmid = {30571496}, issn = {2047-9980}, support = {R01 HL141826/HL/NHLBI NIH HHS/United States ; }, abstract = {Background Venous thromboembolism (VTE) is a complex thrombotic disorder that constitutes a major source of mortality and morbidity. To improve understanding of the cause of VTE , we conducted a metabolomic analysis in a case-control study including 240 incident VTE cases and 6963 controls nested within 3 large prospective population-based cohorts, the Nurses' Health Study, the Nurses' Health Study II , and the Health Professionals Follow-Up Study. Methods and Results For each individual, we measured 211 metabolites and collected detailed information on lifestyle factors. We performed logistic regression and enrichment analysis to identify metabolites and biological categories associated with incident VTE risk, accounting for key confounders, such as age, sex, smoking, alcohol consumption, body mass index, and comorbid diseases (eg, cancers). We performed analyses of all VTEs and separate analyses of pulmonary embolism. Using the basic model controlling for age, sex, and primary disease, we identified 60 nominally significant VTE - or pulmonary embolism-associated metabolites (P<0.05). These metabolites were enriched for diacylglycerols (Ppermutation<0.05). However, after controlling for multiple testing, only 1 metabolite (C5 carnitine; odds ratio, 1.25; 95% confidence interval, 1.10-1.41; Pcorrected=0.03) remained significantly associated with VTE . After further adjustment for body mass index, no metabolites were significantly associated with disease after accounting for multiple testing, and no metabolite classes were enriched for nominally significant associations. Conclusions Although our findings suggest that circulating metabolites may influence the risk of incident VTE , the associations we observed were confounded by body mass index. Larger studies involving additional individuals and with broader metabolomics coverage are needed to confirm our findings.}, }
@article {pmid30566669, year = {2018}, author = {Day, AL and Greisen, P and Doyle, L and Schena, A and Stella, N and Johnsson, K and Baker, D and Stoddard, B}, title = {Unintended specificity of an engineered ligand-binding protein facilitated by unpredicted plasticity of the protein fold.}, journal = {Protein engineering, design &amp; selection : PEDS}, volume = {}, number = {}, pages = {}, doi = {10.1093/protein/gzy031}, pmid = {30566669}, issn = {1741-0134}, abstract = {Attempts to create novel ligand-binding proteins often focus on formation of a binding pocket with shape complementarity against the desired ligand (particularly for compounds that lack distinct polar moieties). Although designed proteins often exhibit binding of the desired ligand, in some cases they display unintended recognition behavior. One such designed protein, that was originally intended to bind tetrahydrocannabinol (THC), was found instead to display binding of 25-hydroxy-cholecalciferol (25-D3) and was subjected to biochemical characterization, further selections for enhanced 25-D3 binding affinity and crystallographic analyses. The deviation in specificity is due in part to unexpected altertion of its conformation, corresponding to a significant change of the orientation of an α-helix and an equally large movement of a loop, both of which flank the designed ligand-binding pocket. Those changes led to engineered protein constructs that exhibit significantly more contacts and complementarity towards the 25-D3 ligand than the initial designed protein had been predicted to form towards its intended THC ligand. Molecular dynamics simulations imply that the initial computationally designed mutations may contribute to the movement of the helix. These analyses collectively indicate that accurate prediction and control of backbone dynamics conformation, through a combination of improved conformational sampling and/or de novo structure design, represents a key area of further development for the design and optimization of engineered ligand-binding proteins.}, }
@article {pmid30566587, year = {2019}, author = {Webb, PM and Na, R and Weiderpass, E and Adami, HO and Anderson, KE and Bertrand, KA and Botteri, E and Brasky, TM and Brinton, LA and Chen, C and Doherty, JA and Lu, L and McCann, SE and Moysich, KB and Olson, S and Petruzella, S and Palmer, JR and Prizment, AE and Schairer, C and Setiawan, VW and Spurdle, AB and Trabert, B and Wentzensen, N and Wilkens, L and Yang, HP and Yu, H and Risch, HA and Jordan, SJ}, title = {Use of aspirin, other nonsteroidal anti-inflammatory drugs and acetaminophen and risk of endometrial cancer: the Epidemiology of Endometrial Cancer Consortium.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {30}, number = {2}, pages = {310-316}, doi = {10.1093/annonc/mdy541}, pmid = {30566587}, issn = {1569-8041}, support = {K05 CA092002/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; R01 CA105212/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA058420/CA/NCI NIH HHS/United States ; R01 CA047749/CA/NCI NIH HHS/United States ; R01 CA039742/CA/NCI NIH HHS/United States ; UM1 CA164974/CA/NCI NIH HHS/United States ; R01 CA098346/CA/NCI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; N01 HD023166/HD/NICHD NIH HHS/United States ; R03 CA169888/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited.<br><br>PATIENTS AND METHODS: We pooled individual-level data from seven cohort and five case-control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect.<br><br>RESULTS: At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 [95% CI 0.76-0.98] and 0.86 [95% CI 0.76-0.97], respectively, for aspirin; 0.87 [95% CI 0.76-1.00] and 0.84 [0.74-0.96], respectively, for non-aspirin NSAIDs). There was no association among women of normal weight (body mass index < 25 kg/m2, Pheterogeneity = 0.04 for aspirin, Pheterogeneity = 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2-6 times/week (OR = 0.81, 95% CI 0.68-0.96) than for daily use (0.91, 0.80-1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen.<br><br>CONCLUSION: Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.}, }
@article {pmid30565414, year = {2018}, author = {Triplette, M and Crothers, K and Mahale, P and Yanik, EL and Valapour, M and Lynch, CF and Schabath, MB and Castenson, D and Engels, EA}, title = {Risk of lung cancer in lung transplant recipients in the United States.}, 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.15181}, pmid = {30565414}, issn = {1600-6143}, support = {T32 HL007287/HL/NHLBI NIH HHS/United States ; T32 HL007287//National Heart, Lung, and Blood Institute/ ; //Intramural Research Program of the National Cancer Institute/ ; }, abstract = {Lung transplant recipients have an increased risk of lung cancer that is poorly understood. Prior studies are largely descriptive and single-center, and have not examined risk factors or outcomes in this population. This registry-linkage study utilized matched transplant and cancer registry data from 17 US states/regions during 1987-2012. We used standardized incidence ratios (SIRs) to compare incidence with the general population, Poisson models to identify lung cancer risk factors, and Cox models to compare survival after diagnosis. Lung cancer risk was increased among lung recipients (SIR 4.8, 95% confidence interval [CI] 4.1-5.5). Those with single lung transplant had 13-fold (95% CI 11-15) increased risk in the native lung. Native lung cancer risk factors included age, prior smoking, time since transplant, and idiopathic pulmonary fibrosis. Compared with cases in the general population, lung cancers in recipients were more frequently localized stage (P = .02) and treated surgically (P = .05). However, recipients had higher all-cause (adjusted hazard ratio 1.90, 95% CI 1.52-2.37) and cancer-specific mortality (adjusted hazard ratio 1.67, 95% CI 1.28-2.18). In conclusion, lung cancer risk is increased after lung transplant, especially in the native lung of single lung recipients. Traditional risk factors are associated with lung cancer in these patients. Lung cancer survival is worse among lung recipients despite earlier diagnosis.}, }
@article {pmid30564292, year = {2018}, author = {Halpern, AB and Walter, RB}, title = {CLAG-M with dose-escalated mitoxantrone for adults with acute myeloid leukemia.}, journal = {Oncotarget}, volume = {9}, number = {93}, pages = {36543-36544}, doi = {10.18632/oncotarget.26383}, pmid = {30564292}, issn = {1949-2553}, }
@article {pmid30564228, year = {2018}, author = {Collins, CJ and Chang, IJ and Jung, S and Dayuha, R and Whiteaker, JR and Segundo, GRS and Torgerson, TR and Ochs, HD and Paulovich, AG and Hahn, SH}, title = {Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2756}, doi = {10.3389/fimmu.2018.02756}, pmid = {30564228}, issn = {1664-3224}, support = {R01 AI123135/AI/NIAID NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; T32 GM007454/GM/NIGMS NIH HHS/United States ; U01 CA214114/CA/NCI NIH HHS/United States ; }, abstract = {Background: Primary immunodeficiency disorders (PIDD) comprise a group of life-threatening congenital diseases characterized by absent or impaired immune responses. Despite the fact that effective, curative treatments are available with optimal clinical outcomes when diagnosed early, newborn screening does not exist for the majority of these diseases due to the lack of detectable, specific biomarkers or validated methods for population-based screening. Peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno-SRM) is a sensitive proteomic assay, involving antibody-mediated peptide capture, that allows for concurrent quantification of multiple analytes. This assay has promise for use in potential newborn screening of PIDDs that lead to diminished or absent target proteins in the majority of cases. Objective: To determine and evaluate if a multiplex assay based on immuno-SRM is able to reliably and precisely distinguish affected patients with X-linked agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), and CD3ϵ-associated severe combined immunodeficiency (SCID) from one another and from unaffected normal control dried blood spot (DBS) samples. Methods: We performed a blinded, multiplexed analysis of proteolytically-generated peptides from WASp, BTK, and CD3ϵ (for WAS, XLA, and SCID, respectively) in DBS samples from 42 PIDD patients, 40 normal adult controls, and 62 normal newborns. The peptide ATPase copper transporting protein (ATP7B) 1056 was simultaneously monitored for quality assurance purposes. Results: The immuno-SRM assays reliably quantified the target peptides in DBS and accurately distinguished affected patients from normal controls. Analysis of signature peptides found statistically significant reduction or absence of peptide levels in affected patients compared to control groups in each case (WASp and BTK: p = 0.0001, SCID: p = 0.05). Intra and inter-assay precision ranged from 11 to 22% and 11 to 43% respectively; linearity (1.39-2000 fmol peptide), and stability (≤ 0.09% difference in 72 h) showed high precision for the multiplexed assay. Inter-laboratory assay comparison showed high concordance for measured peptide concentrations, with R2 linearity ≥ 0.97 for the WASp 274, CD3ϵ 197, BTK 407, and ATP7B 1056 peptides. Conclusion: Immuno-SRM-based quantification of proteotypic peptides from WASp, BTK, and CD3ϵ in DBS distinguishes relevant PIDD cases from one another and from controls, raising the possibility of employing this approach for large-scale multiplexed newborn screening of selective PIDDs.}, }
@article {pmid30561796, year = {2018}, author = {Fortner, RT and Poole, EM and Wentzensen, NA and Trabert, B and White, E and Arslan, AA and Patel, AV and Setiawan, VW and Visvanathan, K and Weiderpass, E and Adami, HO and Black, A and Bernstein, L and Brinton, LA and Buring, J and Clendenen, TV and Fournier, A and Fraser, G and Gapstur, SM and Gaudet, MM and Giles, GG and Gram, IT and Hartge, P and Hoffman-Bolton, J and Idahl, A and Kaaks, R and Kirsh, VA and Knutsen, S and Koh, WP and Lacey, JV and Lee, IM and Lundin, E and Merritt, MA and Milne, RL and Onland-Moret, NC and Peters, U and Poynter, JN and Rinaldi, S and Robien, K and Rohan, T and Sánchez, MJ and Schairer, C and Schouten, LJ and Tjonneland, A and Townsend, MK and Travis, RC and Trichopoulou, A and van den Brandt, PA and Vineis, P and Wilkens, L and Wolk, A and Yang, HP and Zeleniuch-Jacquotte, A and Tworoger, SS}, title = {Ovarian cancer risk factors by tumor aggressiveness: an analysis from the Ovarian Cancer Cohort Consortium.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.32075}, pmid = {30561796}, issn = {1097-0215}, support = {UM1 CA164917/CA/NCI NIH HHS/United States ; UM1 CA164973/CA/NCI NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; UM1 CA182934/CA/NCI NIH HHS/United States ; P30 ES000260/ES/NIEHS NIH HHS/United States ; R01 CA039742/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; }, abstract = {Ovarian cancer risk factors differ by histotype; however, within subtype there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n=864), very aggressive (death in 1-<3 years, n=1,390), moderately aggressive (death in 3-<5 years, n=639), and less aggressive (lived 5+ years, n=1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet =0.01), family history of ovarian cancer (phet =0.02), body mass index (BMI; phet ≤0.04) and smoking (phet <0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20-<25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted. This article is protected by copyright. All rights reserved.}, }
@article {pmid30561776, year = {2018}, author = {Cathcart-Rake, EJ and Zemla, T and Jatoi, A and Weaver, KE and Neuman, H and Kazak, AE and Carlos, R and Gansauer, L and Unger, JM and Pajewski, NM and Kamen, C}, title = {Acquisition of sexual orientation and gender identity data among NCI Community Oncology Research Program practice groups.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31925}, pmid = {30561776}, issn = {1097-0142}, support = {Institutional Funds//Mayo Clinic/ ; Community Oncology Program, based at the Universit//National Cancer Institute/ ; UG1 CA189828/CA/NCI NIH HHS/United States ; UG1 CA189961/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Sexual and gender minority individuals face numerous cancer-related inequities, many of which appear to be underreported. However, to the best of the authors' knowledge, no one has assessed rates of acquisition of sexual orientation and gender identity (SOGI) data within community oncology settings.<br><br>METHODS: Community oncology practices that were part of the NCI Community Oncology Research Program (NCORP) network were asked whether they routinely collected SOGI information and coded this information in their electronic medical records. The proportion of practice groups reporting routine collection of sexual and/or gender minority information was calculated. Potential associations between the collection of SOGI information and practice group-level and state-level characteristics (from Gallup poll data) were also provided.<br><br>RESULTS: Twenty-four percent of the responding NCORP practice groups reported routine collection of sexual orientation information, and 10% reported collection of gender identity information. Practices located in western regions of the United States, practices in states with higher proportions of sexual and gender minority-identifying individuals, and practices with lower proportions of non-Hispanic patients were more likely to ask patients about sexual orientation and/or gender identity.<br><br>CONCLUSIONS: US oncology practices that participate in research do not frequently collect SOGI information from patients with cancer. Educational initiatives should inform oncology staff and providers about the importance of collecting gender identity and sexual orientation information to improve existent disparities faced by sexual and gender minority patients.}, }
@article {pmid30559385, year = {2018}, author = {Zhang, X and Zhang, Y and Zhu, X and Purmann, C and Haney, MS and Ward, T and Khechaduri, A and Yao, J and Weissman, SM and Urban, AE}, title = {Local and global chromatin interactions are altered by large genomic deletions associated with human brain development.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {5356}, doi = {10.1038/s41467-018-07766-x}, pmid = {30559385}, issn = {2041-1723}, support = {UL1 RR025744/NH/NIH HHS/United States ; P50 HG007735/HG/NHGRI NIH HHS/United States ; UL1 RR025744/RR/NCRR NIH HHS/United States ; DP2 MH100010/MH/NIMH NIH HHS/United States ; HG007735-01/NH/NIH HHS/United States ; }, mesh = {Brain/*growth &amp; development ; Cell Line ; Chromatin/genetics/*metabolism ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 22/genetics ; Gene Dosage/*genetics ; Genome, Human/genetics ; Humans ; Mental Disorders/*genetics ; }, abstract = {Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.}, }
@article {pmid30559148, year = {2019}, author = {Yang, Y and Wu, L and Shu, X and Lu, Y and Shu, XO and Cai, Q and Beeghly-Fadiel, A and Li, B and Ye, F and Berchuck, A and Anton-Culver, H and Banerjee, S and Benitez, J and Bjørge, L and Brenton, JD and Butzow, R and Campbell, IG and Chang-Claude, J and Chen, K and Cook, LS and Cramer, DW and deFazio, A and Dennis, J and Doherty, JA and Dörk, T and Eccles, DM and Edwards, DV and Fasching, PA and Fortner, RT and Gayther, SA and Giles, GG and Glasspool, RM and Goode, EL and Goodman, MT and Gronwald, J and Harris, HR and Heitz, F and Hildebrandt, MA and Høgdall, E and Høgdall, CK and Huntsman, DG and Kar, SP and Karlan, BY and Kelemen, LE and Kiemeney, LA and Kjaer, SK and Koushik, A and Lambrechts, D and Le, ND and Levine, DA and Massuger, LF and Matsuo, K and May, T and McNeish, IA and Menon, U and Modugno, F and Monteiro, AN and Moorman, PG and Moysich, KB and Ness, RB and Nevanlinna, H and Olsson, H and Onland-Moret, NC and Park, SK and Paul, J and Pearce, CL and Pejovic, T and Phelan, CM and Pike, MC and Ramus, SJ and Riboli, E and Rodriguez-Antona, C and Romieu, I and Sandler, DP and Schildkraut, JM and Setiawan, VW and Shan, K and Siddiqui, N and Sieh, W and Stampfer, MJ and Sutphen, R and Swerdlow, AJ and Szafron, LM and Teo, SH and Tworoger, SS and Tyrer, JP and Webb, PM and Wentzensen, N and White, E and Willett, WC and Wolk, A and Woo, YL and Wu, AH and Yan, L and Yannoukakos, D and Chenevix-Trench, G and Sellers, TA and Pharoah, PDP and Zheng, W and Long, J}, title = {Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk.}, journal = {Cancer research}, volume = {79}, number = {3}, pages = {505-517}, doi = {10.1158/0008-5472.CAN-18-2726}, pmid = {30559148}, issn = {1538-7445}, support = {U01 CA069417/CA/NCI NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; UM1 CA164973/CA/NCI NIH HHS/United States ; N01 PC067010/PC/NCI NIH HHS/United States ; P50 CA159981/CA/NCI NIH HHS/United States ; P30 CA016056/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; R01 CA106414/CA/NCI NIH HHS/United States ; P30 CA072720/CA/NCI NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; K05 CA154337/CA/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 ; K22 CA138563/CA/NCI NIH HHS/United States ; R01 CA058860/CA/NCI NIH HHS/United States ; R01 CA080742/CA/NCI NIH HHS/United States ; S10 RR025141/RR/NCRR NIH HHS/United States ; R01 CA074850/CA/NCI NIH HHS/United States ; R01 CA063678/CA/NCI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; Z01 ES044005/ES/NIEHS NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; R03 CA115195/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; R01 CA122443/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA076016/CA/NCI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; U01 CA063464/CA/NCI NIH HHS/United States ; R01 CA160669/CA/NCI NIH HHS/United States ; U01 CA058860/CA/NCI NIH HHS/United States ; U19 CA148112/CA/NCI NIH HHS/United States ; R01 CA149429/CA/NCI NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; N01 CN025403/CA/NCI NIH HHS/United States ; R01 CA142081/CA/NCI NIH HHS/United States ; //Wellcome Trust/United Kingdom ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 CA063682/CA/NCI NIH HHS/United States ; K07 CA095666/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; R01 CA126841/CA/NCI NIH HHS/United States ; }, abstract = {: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.}, }
@article {pmid30558288, year = {2018}, author = {You, R and Dai, J and Zhang, P and Barding, GA and Raftery, D}, title = {Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells.}, journal = {Metabolites}, volume = {8}, number = {4}, pages = {}, doi = {10.3390/metabo8040095}, pmid = {30558288}, issn = {2218-1989}, support = {R01GM085291//National Institutes of Health/ ; P30CA015704//National Institutes of Health/ ; }, abstract = {Cellular senescence displays a heterogeneous set of phenotypes linked to tumor suppression; however, after drug treatment, senescence may also be involved in stable or recurrent cancer. Metabolic changes during senescence can provide detailed information on cellular status and may also have implications for the development of effective treatment strategies. The metabolic response to Adriamycin (ADR) treatment, which causes senescence as well as cell death, was obtained with the aid of metabolic profiling and isotope tracing in two human breast cancer cell lines, MCF7 and MDA-MB-231. After 5 days of ADR treatment, more than 60% of remaining, intact cells entered into a senescent state, characterized by enlarged and flattened morphology and positive blue staining using SA-β-gal. Metabolic trajectory analysis showed that the two cell lines' responses were significantly different and were divided into two distinct stages. The metabolic shift from the first stage to the second was reflected by a partial recovery of the TCA cycle, as well as amino acid and lipid metabolisms. Isotope tracing analysis indicated that the higher level of glutamine metabolism helped maintain senescence. The results suggest that the dynamic changes during senescence indicate a multi-step process involving important metabolic pathways which might allow breast cancer cells to adapt to persistent ADR treatment, while the higher level of anapleurosis may be important for maintaining the senescent state. Ultimately, a better understanding of metabolic changes during senescence might provide targets for cancer therapy and tumor eradication.}, }
@article {pmid30557332, year = {2018}, author = {Rose, TM and Bruce, AG and Barcy, S and Fitzgibbon, M and Matsumoto, LR and Ikoma, M and Casper, C and Orem, J and Phipps, W}, title = {Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter.}, journal = {PLoS pathogens}, volume = {14}, number = {12}, pages = {e1007441}, doi = {10.1371/journal.ppat.1007441}, pmid = {30557332}, issn = {1553-7374}, support = {P01 DE021954/DE/NIDCR NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 CA138165/CA/NCI NIH HHS/United States ; U54 CA190146/CA/NCI NIH HHS/United States ; }, mesh = {Gene Expression Profiling/methods ; Genes, Viral/genetics ; Herpesvirus 8, Human/*genetics ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Promoter Regions, Genetic/genetics ; Sarcoma, Kaposi/*genetics/virology ; Sequence Analysis, RNA ; Transcriptome/*genetics ; Uganda ; Virus Latency/*genetics ; }, abstract = {KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV transcriptome. Phylogenetic analysis of ORF75 sequences from 23 tumors revealed 6 distinct genetic clusters with KSHV strains exhibiting M, N or P alleles. RNA reads mapping to specific unique coding sequence (UCDS) features were quantitated using a gene feature file previously developed to globally analyze and quantitate KSHV transcription in infected endothelial cells. A pattern of high level expression was detected in the KSHV latency region that was common to all KS tumors. The clear majority of transcription was derived from the downstream latency transcript promoter P3(LTd) flanking ORF72, with little evidence of transcription from the P1(LTc) latency promoter, which is constitutive in KSHV-infected lymphomas and tissue-culture cells. RNAseq data provided evidence of alternate P3(LTd) transcript editing, splicing and termination resulting in multiple gene products, with 90% of the P3(LTd) transcripts spliced to release the intronic source of the microRNAs K1-9 and 11. The spliced transcripts encode a regulatory uORF upstream of Kaposin A with alterations in intervening repeat sequences yielding novel or deleted Kaposin B/C-like sequences. Hierarchical clustering and PCA analysis of KSHV transcripts revealed three clusters of tumors with different latent and lytic gene expression profiles. Paradoxically, tumors with a latent phenotype had high levels of total KSHV transcription, while tumors with a lytic phenotype had low levels of total KSHV transcription. Morphologically distinct KS tumors from the same individual showed similar KSHV gene expression profiles suggesting that the tumor microenvironment and host response play important roles in the activation level of KSHV within the infected tumor cells.}, }
@article {pmid30556054, year = {2018}, author = {Elmore, JG and Elder, DE and Barnhill, RL and Knezevich, SR and Longton, GM and Titus, LJ and Weinstock, MA and Pepe, MS and Nelson, HD and Reisch, LM and Radick, AC and Piepkorn, MW}, title = {Concordance and Reproducibility of Melanoma Staging According to the 7th vs 8th Edition of the AJCC Cancer Staging Manual.}, journal = {JAMA network open}, volume = {1}, number = {1}, pages = {}, doi = {10.1001/jamanetworkopen.2018.0083}, pmid = {30556054}, issn = {2574-3805}, support = {R01 CA151306/CA/NCI NIH HHS/United States ; R01 CA200690/CA/NCI NIH HHS/United States ; R01 CA201376/CA/NCI NIH HHS/United States ; }, abstract = {IMPORTANCE: The recently updated American Joint Committee on Cancer (AJCC) classification of cancer staging, the AJCC Cancer Staging Manual, 8th edition (AJCC 8), includes revisions to definitions of T1a vs T1b or greater. The Melanoma Pathology Study database affords a comparison,of pathologists' concordance and reproducibility in the microstaging of melanoma according to both the existing 7th edition (AJCC 7) and the new AJCC 8.<br><br>OBJECTIVE: To compare AJCC 7 and AJCC 8 to examine whether changes to the definitions of T1a and T1b or greater are associated with changes in concordance and reproducibility.<br><br>In this diagnostic study conducted as part of the national Melanoma Pathology Study across US states, 187 pathologists interpreting melanocytic skin lesions in practice completed 4342 independent case interpretations of 116 invasive melanoma cases. A consensus reference diagnosis and participating pathologists' interpretations were classified into the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis class IV (T1a) or class V (T1b) using both the AJCC 7 and AJCC 8 criteria.<br><br>MAIN OUTCOMES AND MEASURES: Concordance with consensus reference diagnosis, interobserver reproducibility, and intraobserver reproducibility.<br><br>RESULTS: For T1a diagnoses, participating pathologists' concordance with the consensus reference diagnosis increased from 44% (95% CI, 41%-48%) to 54% (95% CI, 51%-57%) using AJCC 7 and AJCC 8 criteria, respectively. The concordance for cases of T1b or greater increased from 72% (95% CI, 69%-75%) to 78% (95% CI, 75%-80%). Intraobserver reproducibility of diagnoses also improved, increasing from 59% (95% CI, 56%-63%) to 64% (95% CI, 62%-67%) for T1a invasive melanoma, and from 74% (95% CI, 71%-76%) to 77% (95% CI, 74%-79%) for T1b or greater invasive melanoma cases.<br><br>CONCLUSIONS AND RELEVANCE: Melanoma staging in AJCC 8 shows greater reproducibility and higher concordance with a reference standard. Improved classification of invasive melanoma can be expected after implementation of AJCC 8, suggesting a positive impact on patients. However, despite improvement, concordance and reproducibility remain low.}, }
@article {pmid30555194, year = {2018}, author = {Liu, D and Cai, T and Lok, A and Zheng, Y}, title = {Nonparametric Maximum Likelihood Estimators of Time-Dependent Accuracy Measures for Survival Outcome Under Two-Stage Sampling Designs.}, journal = {Journal of the American Statistical Association}, volume = {113}, number = {522}, pages = {882-892}, doi = {10.1080/01621459.2017.1295866}, pmid = {30555194}, issn = {0162-1459}, support = {P01 CA053996/CA/NCI NIH HHS/United States ; R01 GM079330/GM/NIGMS NIH HHS/United States ; R01 GM085047/GM/NIGMS NIH HHS/United States ; U01 CA086368/CA/NCI NIH HHS/United States ; }, abstract = {Large prospective cohort studies of rare chronic diseases require thoughtful planning of study designs, especially for biomarker studies when measurements are based on stored tissue or blood specimens. Two-phase designs, including nested case-control (Thomas, 1977) and case-cohort (Prentice, 1986) sampling designs, provide cost-effective strategies for conducting biomarker evaluation studies. Existing literature for biomarker assessment under two-phase designs largely focuses on simple inverse probability weighting (IPW) estimators (Cai and Zheng, 2011; Liu et al., 2012). Drawing on recent theoretical development on the maximum likelihood estimators for relative risk parameters in two-phase studies (Scheike and Martinussen, 2004; Zeng et al., 2006), we propose nonparametric maximum likelihood based estimators to evaluate the accuracy and predictiveness of a risk prediction biomarker under both types of two-phase designs. In addition, hybrid estimators that combine IPW estimators and maximum likelihood estimation procedure are proposed to improve efficiency and alleviate computational burden. We derive large sample properties of proposed estimators and evaluate their finite sample performance using numerical studies. We illustrate new procedures using a two-phase biomarker study aiming to evaluate the accuracy of a novel biomarker, des-γ-carboxy prothrombin, for early detection of hepatocellular carcinoma (Lok et al., 2010).}, }
@article {pmid30554944, year = {2019}, author = {Brahma, S and Henikoff, S}, title = {RSC-Associated Subnucleosomes Define MNase-Sensitive Promoters in Yeast.}, journal = {Molecular cell}, volume = {73}, number = {2}, pages = {238-249.e3}, doi = {10.1016/j.molcel.2018.10.046}, pmid = {30554944}, issn = {1097-4164}, support = {U01 CA200147/CA/NCI NIH HHS/United States ; }, abstract = {The classic view of nucleosome organization at active promoters is that two well-positioned nucleosomes flank a nucleosome-depleted region (NDR). However, this view has been recently disputed by contradictory reports as to whether wider (≳150 bp) NDRs instead contain unstable, micrococcal nuclease-sensitive (&quot;fragile&quot;) nucleosomal particles. To determine the composition of fragile particles, we introduce CUT&amp;RUN.ChIP, in which targeted nuclease cleavage and release is followed by chromatin immunoprecipitation. We find that fragile particles represent the occupancy of the RSC (remodeling the structure of chromatin) nucleosome remodeling complex and RSC-bound, partially unwrapped nucleosomal intermediates. We also find that general regulatory factors (GRFs) bind to partially unwrapped nucleosomes at these promoters. We propose that RSC binding and its action cause nucleosomes to unravel, facilitate subsequent binding of GRFs, and constitute a dynamic cycle of nucleosome deposition and clearance at the subset of wide Pol II promoter NDRs.}, }
@article {pmid30554720, year = {2019}, author = {Mavaddat, N and Michailidou, K and Dennis, J and Lush, M and Fachal, L and Lee, A and Tyrer, JP and Chen, TH and Wang, Q and Bolla, MK and Yang, X and Adank, MA and Ahearn, T and Aittomäki, K and Allen, J and Andrulis, IL and Anton-Culver, H and Antonenkova, NN and Arndt, V and Aronson, KJ and Auer, PL and Auvinen, P and Barrdahl, M and Beane Freeman, LE and Beckmann, MW and Behrens, S and Benitez, J and Bermisheva, M and Bernstein, L and Blomqvist, C and Bogdanova, NV and Bojesen, SE and Bonanni, B and Børresen-Dale, AL and Brauch, H and Bremer, M and Brenner, H and Brentnall, A and Brock, IW and Brooks-Wilson, A and Brucker, SY and Brüning, T and Burwinkel, B and Campa, D and Carter, BD and Castelao, JE and Chanock, SJ and Chlebowski, R and Christiansen, H and Clarke, CL and Collée, JM and Cordina-Duverger, E and Cornelissen, S and Couch, FJ and Cox, A and Cross, SS and Czene, K and Daly, MB and Devilee, P and Dörk, T and Dos-Santos-Silva, I and Dumont, M and Durcan, L and Dwek, M and Eccles, DM and Ekici, AB and Eliassen, AH and Ellberg, C and Engel, C and Eriksson, M and Evans, DG and Fasching, PA and Figueroa, J and Fletcher, O and Flyger, H and Försti, A and Fritschi, L and Gabrielson, M and Gago-Dominguez, M and Gapstur, SM and García-Sáenz, JA and Gaudet, MM and Georgoulias, V and Giles, GG and Gilyazova, IR and Glendon, G and Goldberg, MS and Goldgar, DE and González-Neira, A and Grenaker Alnæs, GI and Grip, M and Gronwald, J and Grundy, A and Guénel, P and Haeberle, L and Hahnen, E and Haiman, CA and Håkansson, N and Hamann, U and Hankinson, SE and Harkness, EF and Hart, SN and He, W and Hein, A and Heyworth, J and Hillemanns, P 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 Jakimovska, M and Jakubowska, A and Janni, W and John, EM and Johnson, N and Jones, ME and Jukkola-Vuorinen, A and Jung, A and Kaaks, R and Kaczmarek, K and Kataja, V and Keeman, R and Kerin, MJ and Khusnutdinova, E and Kiiski, JI and Knight, JA and Ko, YD and Kosma, VM and Koutros, S and Kristensen, VN and Krüger, U and Kühl, T and Lambrechts, D and Le Marchand, L and Lee, E and Lejbkowicz, F and Lilyquist, J and Lindblom, A and Lindström, S and Lissowska, J and Lo, WY and Loibl, S and Long, J and Lubiński, J and Lux, MP and MacInnis, RJ and Maishman, T and Makalic, E and Maleva Kostovska, I and Mannermaa, A and Manoukian, S and Margolin, S and Martens, JWM and Martinez, ME and Mavroudis, D and McLean, C and Meindl, A and Menon, U and Middha, P and Miller, N and Moreno, F and Mulligan, AM and Mulot, C and Muñoz-Garzon, VM and Neuhausen, SL and Nevanlinna, H and Neven, P and Newman, WG and Nielsen, SF and Nordestgaard, BG and Norman, A and Offit, K and Olson, JE and Olsson, H and Orr, N and Pankratz, VS and Park-Simon, TW and Perez, JIA and Pérez-Barrios, C and Peterlongo, P and Peto, J and Pinchev, M and Plaseska-Karanfilska, D and Polley, EC and Prentice, R and Presneau, N and Prokofyeva, D and Purrington, K and Pylkäs, K and Rack, B and Radice, P and Rau-Murthy, R and Rennert, G and Rennert, HS and Rhenius, V and Robson, M and Romero, A and Ruddy, KJ and Ruebner, M and Saloustros, E and Sandler, DP and Sawyer, EJ and Schmidt, DF and Schmutzler, RK and Schneeweiss, A and Schoemaker, MJ and Schumacher, F and Schürmann, P and Schwentner, L and Scott, C and Scott, RJ and Seynaeve, C and Shah, M and Sherman, ME and Shrubsole, MJ and Shu, XO and Slager, S and Smeets, A and Sohn, C and Soucy, P and Southey, MC and Spinelli, JJ and Stegmaier, C and Stone, J and Swerdlow, AJ and Tamimi, RM and Tapper, WJ and Taylor, JA and Terry, MB and Thöne, K and Tollenaar, RAEM and Tomlinson, I and Truong, T and Tzardi, M and Ulmer, HU and Untch, M and Vachon, CM and van Veen, EM and Vijai, J and Weinberg, CR and Wendt, C and Whittemore, AS and Wildiers, H and Willett, W and Winqvist, R and Wolk, A and Yang, XR and Yannoukakos, D and Zhang, Y and Zheng, W and Ziogas, A and ,  and ,  and ,  and Dunning, AM and Thompson, DJ and Chenevix-Trench, G and Chang-Claude, J and Schmidt, MK and Hall, P and Milne, RL and Pharoah, PDP and Antoniou, AC and Chatterjee, N and Kraft, P and García-Closas, M and Simard, J and Easton, DF}, title = {Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.}, journal = {American journal of human genetics}, volume = {104}, number = {1}, pages = {21-34}, doi = {10.1016/j.ajhg.2018.11.002}, pmid = {30554720}, issn = {1537-6605}, support = {P50 CA116201/CA/NCI NIH HHS/United States ; }, abstract = {Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.}, }
@article {pmid30552419, year = {2019}, author = {Kisalu, NK and Idris, AH and Weidle, C and Flores-Garcia, Y and Flynn, BJ and Sack, BK and Murphy, S and Schön, A and Freire, E and Francica, JR and Miller, AB and Gregory, J and March, S and Liao, HX and Haynes, BF and Wiehe, K and Trama, AM and Saunders, KO and Gladden, MA and Monroe, A and Bonsignori, M and Kanekiyo, M and Wheatley, AK and McDermott, AB and Farney, SK and Chuang, GY and Zhang, B and Kc, N and Chakravarty, S and Kwong, PD and Sinnis, P and Bhatia, SN and Kappe, SHI and Sim, BKL and Hoffman, SL and Zavala, F and Pancera, M and Seder, RA}, title = {Author Correction: A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.}, journal = {Nature medicine}, volume = {25}, number = {1}, pages = {188-189}, doi = {10.1038/s41591-018-0315-0}, pmid = {30552419}, issn = {1546-170X}, abstract = {In the version of this article originally published, data were incorrectly ascribed to monoclonal antibody CIS34 because of a labeling error. The data were generated with monoclonal antibody CIS04. Full details can be found in the correction notice.}, }
@article {pmid30552400, year = {2019}, author = {Hourigan, CS and Gale, RP and Walter, RB}, title = {Refining AML outcome prediction.}, journal = {Leukemia}, volume = {33}, number = {2}, pages = {283-284}, doi = {10.1038/s41375-018-0317-4}, pmid = {30552400}, issn = {1476-5551}, support = {1ZIAHL006163//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, }
@article {pmid30552397, year = {2018}, author = {Sharifian, R and Okamura, DM and Denisenko, O and Zager, RA and Johnson, A and Gharib, SA and Bomsztyk, K}, title = {Distinct patterns of transcriptional and epigenetic alterations characterize acute and chronic kidney injury.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {17870}, doi = {10.1038/s41598-018-35943-x}, pmid = {30552397}, issn = {2045-2322}, support = {DK094934//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; GM111439//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R03 DK083648/DK/NIDDK NIH HHS/United States ; R01 DK038432/DK/NIDDK NIH HHS/United States ; DK38432//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R33 CA191135/CA/NCI NIH HHS/United States ; DK083648//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; CA191135//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 DK094934/DK/NIDDK NIH HHS/United States ; R21 GM111439/GM/NIGMS NIH HHS/United States ; DK073497//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; K08 DK073497/DK/NIDDK NIH HHS/United States ; }, abstract = {Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered early and late phases of a pathologic continuum of interconnected disease states. Although changes in gene expression patterns have recently been elucidated for the transition of AKI to CKD, the epigenetic regulation of key kidney injury related genes remains poorly understood. We used multiplex RT-qPCR, ChIP-qPCR and integrative analysis to compare transcriptional and epigenetic changes at renal disease-associated genes across mouse AKI and CKD models. These studies showed that: (i) there are subsets of genes with distinct transcriptional and epigenetically profiles shared by AKI and CKD but also subsets that are specific to either the early or late stages of renal injury; (ii) differences in expression of a small number of genes is sufficient to distinguish AKI from CKD; (iii) transcription plays a key role in the upregulation of both AKI and CKD genes while post-transcriptional regulation appears to play a more significant role in decreased expression of both AKI and CKD genes; and (iv) subsets of transcriptionally upregulated genes share epigenetic similarities while downregulated genes do not. Collectively, our study suggests that identified common transcriptional and epigenetic profiles of kidney injury loci could be exploited for therapeutic targeting in AKI and CKD.}, }
@article {pmid30552024, year = {2018}, author = {Bonsignori, M and Scott, E and Wiehe, K and Easterhoff, D and Alam, SM and Hwang, KK and Cooper, M and Xia, SM and Zhang, R and Montefiori, DC and Henderson, R and Nie, X and Kelsoe, G and Moody, MA and Chen, X and Joyce, MG and Kwong, PD and Connors, M and Mascola, JR and McGuire, AT and Stamatatos, L and Medina-Ramírez, M and Sanders, RW and Saunders, KO and Kepler, TB and Haynes, BF}, title = {Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier.}, journal = {Immunity}, volume = {49}, number = {6}, pages = {1162-1174.e8}, doi = {10.1016/j.immuni.2018.10.015}, pmid = {30552024}, issn = {1097-4180}, support = {R01 AI081625/AI/NIAID NIH HHS/United States ; T32 AI007392/AI/NIAID NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; }, abstract = {Elicitation of VRC01-class broadly neutralizing antibodies (bnAbs) is an appealing approach for a preventative HIV-1 vaccine. Despite extensive investigations, strategies to induce VRC01-class bnAbs and overcome the barrier posed by the envelope N276 glycan have not been successful. Here, we inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation. Env immunogens designed on reverted VRC01-class bnAbs bound to VRC01 UCA with affinity sufficient to activate naive B cells. Early mutations defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B cell maturation toward the development of neutralization breadth. Finally, VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan.}, }
@article {pmid30551258, year = {2018}, author = {Finak, G}, title = {The Computational article format: Software as a research output.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {93}, number = {12}, pages = {1187-1188}, doi = {10.1002/cyto.a.23691}, pmid = {30551258}, issn = {1552-4930}, support = {R01 GM118417/GM/NIGMS NIH HHS/United States ; R01GM118417-02/GM/NIGMS NIH HHS/United States ; }, }
@article {pmid30551257, year = {2018}, author = {Finak, G and Jiang, W and Gottardo, R}, title = {CytoML for cross-platform cytometry data sharing.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {93}, number = {12}, pages = {1189-1196}, doi = {10.1002/cyto.a.23663}, pmid = {30551257}, issn = {1552-4930}, support = {R01 GM118417/GM/NIGMS NIH HHS/United States ; OPP1032317//Bill and Melinda Gates Foundation/ ; UM1 AI068635//National Institute of Allergy and Infectious Diseases/ ; 1R01GM118417-01A1//National Institute of General Medical Sciences/ ; }, abstract = {CytoML is an R/Bioconductor package that enables cross-platform import, export, and sharing of gated cytometry data. It currently supports Cytobank, FlowJo, Diva, and R, allowing users to import gated cytometry data from commercial platforms into R. Once data are available in R, the data can be further manipulated. For example it can be combined with other computational and analytic approaches, and the results can be exported to FlowJo or Cytobank to be explored by researchers using those platforms. We demonstrate how CytoML and related R packages can be used as a tool to import, modify and export several samples stained with the T cell panel from the FlowCAP IV Lyoplate data set. Once imported, the gating is modified using computational approaches, and exported for visualization in Cytobank and FlowJo. We further show how CytoML can be used to import gated data from a publicly accessible mass cytometry experiment from Cytobank. CytoML is the only tool that allows such sharing of gated cytometry data between researchers working across different platforms, and it will serve as a useful tool for validating and verifying the reproducibility of analyses. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.}, }
@article {pmid30550782, year = {2018}, author = {Hahn, S}, title = {Phase Separation, Protein Disorder, and Enhancer Function.}, journal = {Cell}, volume = {175}, number = {7}, pages = {1723-1725}, doi = {10.1016/j.cell.2018.11.034}, pmid = {30550782}, issn = {1097-4172}, abstract = {New findings suggest that transcription enhancers work by recruitment of a large dynamic network of coactivators and other factors responsible for gene activation. Formation of these condensates is driven by DNA-bound transcription factors, their intrinsically disordered activation domains, and dynamic low-specificity interactions within the complex.}, }
@article {pmid30549412, year = {2019}, author = {Mair, F}, title = {Gate to the Future: Computational Analysis of Immunophenotyping Data.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {95}, number = {2}, pages = {147-149}, doi = {10.1002/cyto.a.23700}, pmid = {30549412}, issn = {1552-4930}, }
@article {pmid30549358, year = {2019}, author = {Zhang, QE and Wu, Q and Harari, PM and Rosenthal, DI}, title = {Randomized phase II/III confirmatory treatment selection design with a change of survival end points: Statistical design of Radiation Therapy Oncology Group 1216.}, journal = {Head &amp; neck}, volume = {41}, number = {1}, pages = {37-45}, doi = {10.1002/hed.25359}, pmid = {30549358}, issn = {1097-0347}, support = {U10 CA21661//Radiation Therapy Oncology Group (RTOG)/ ; U10 CA37422//National Cancer Institute (NCI)/ ; //National Cancer Institute/ ; U10 CA180868/CA/NCI NIH HHS/United States ; UG1 CA189867/CA/NCI NIH HHS/United States ; U10 CA037422/CA/NCI NIH HHS/United States ; U10 CA180822/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: To confirm the treatment effects of concurrent cetuximab plus docetaxel observed in Radiation Therapy Oncology Group (RTOG) 0234 and single out the effect of cetuximab, we designed RTOG 1216, a randomized phase II/III study, which uses an intermediate end point to select the best regimen for definitive testing of survival benefit.<br><br>METHODS: In phase II, the best regimen should demonstrate statistically significant efficacy against the control with predefined advantage over the competing arm regarding disease-free survival (DFS). We evaluate operating characteristics of the randomized II/III group sequential design through simulations and numerical integrations under the null and various alternative hypotheses.<br><br>RESULTS: Results show the randomized II/III design yields substantial savings on sample size and time with well-controlled type I and type II error rates.<br><br>CONCLUSION: Overall, the proposed randomized II/III design has desirable properties that offer cost effectiveness, operational efficiency, and, most importantly, scientific innovation that can be considered for similar clinical research settings.}, }
@article {pmid30549145, year = {2019}, author = {Lewis, FM and Griffith, KA and Alzawad, Z and Dawson, PL and Zahlis, EH and Shands, ME}, title = {Helping Her Heal: Randomized clinical trial to enhance dyadic outcomes in couples.}, journal = {Psycho-oncology}, volume = {28}, number = {2}, pages = {430-438}, doi = {10.1002/pon.4966}, pmid = {30549145}, issn = {1099-1611}, support = {R01-CA-114-561//National Cancer Institute/ ; R01 CA114561/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: The objective of this study was to test the short-term efficacy of a brief, fully manualized marital communication and interpersonal support intervention for couples facing recently diagnosed breast cancer.<br><br>METHODS: A total of 322 women diagnosed within 6 months with stages 0 to III breast cancer and their 322 spouse caregivers were enrolled. Spouses in the experimental group received five 30- to 60-minute intervention sessions at 2-week intervals by master's-prepared patient educators; controls received the booklet, &quot;What's Happening to the Woman I Love?&quot; Outcomes were assessed at 3, 6, and 9 months using the linear mixed models within an intent-to-treat analysis.<br><br>RESULTS: Compared with controls, at 3 months, spouse caregivers significantly improved on standardized measures of depressed mood, anxiety, cancer-related marital communication, interpersonal support, and self-care. All differences except depressed mood and anxiety were sustained at 9 months. Wives significantly improved at 3 months on marital communication and positive appraisal of spouses' interpersonal support; gains remained significant at 9 months. Compared with controls on chemotherapy, wives in the experimental group additionally improved on depressed mood and tended to improve on anxiety.<br><br>CONCLUSIONS: A brief, fully manualized intervention delivered directly to spouse caregivers early in the course of their wives' medical treatment improves caregivers' self-care and behavioral-emotional adjustment and wives' positive view of their spouses' support and communication. The brevity and manualized structure of the intervention argue strongly for its scalability, use in cost-sensitive settings, and its potential dissemination through e-health channels.}, }
@article {pmid30549014, year = {2018}, author = {Burhans, MS and Hagman, DK and Kuzma, JN and Schmidt, KA and Kratz, M}, title = {Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus.}, journal = {Comprehensive Physiology}, volume = {9}, number = {1}, pages = {1-58}, doi = {10.1002/cphy.c170040}, pmid = {30549014}, issn = {2040-4603}, abstract = {The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift toward more proinflammatory subtypes of leukocytes. The infiltration of proinflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, proinflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6 as well as reduced expression of the key insulin-sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are-almost without exception-associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie-diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues. © 2019 American Physiological Society. Compr Physiol 9:1-58, 2019.}, }
@article {pmid30548485, year = {2018}, author = {Calip, GS and Moran, KM and Sweiss, KI and Patel, PR and Wu, Z and Adimadhyam, S and Lee, TA and Ko, NY and Quigley, JG and Chiu, BC}, title = {Myelodysplastic syndrome and acute myeloid leukemia after receipt of granulocyte colony-stimulating factors in older patients with non-Hodgkin lymphoma.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31914}, pmid = {30548485}, issn = {1097-0142}, support = {UL1TR002003//National Center for Advancing Translational Sciences/ ; KL2 TR002002/TR/NCATS NIH HHS/United States ; U58DP003862-01//Centers for Disease Control and Prevention's National Program of Cancer Registries/ ; 103885//California Health and Safety/ ; HHSN261201000140C//National Cancer Institute's Surveillance, Epidemiology, and End Results Program/ ; R21 MD011439/MD/NIMHD NIH HHS/United States ; R21MD011439//National Institute on Minority Health and Health Disparities/ ; HHSN261201000035C//Prevention Institute of California/ ; //Public Health Institute/ ; //California Department of Public Health/ ; HHSN261201000034C//University of Southern California/ ; KL2TR000048//National Center for Advancing Translational Sciences/ ; }, abstract = {BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs), which are used for the prevention of complications from chemotherapy-related neutropenia, are linked to the risk of developing second primary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The objective of this study was to examine the correlation between using a specific G-CSF agent and the risk of MDS/AML among older patients with non-Hodgkin lymphoma (NHL).<br><br>METHODS: This was a retrospective cohort study of adults aged >65 years who were diagnosed with first primary NHL between 2001 and 2011. With data from the Surveillance, Epidemiology, and End Results-Medicare-linked database, adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the risk of MDS/AML associated with the receipt of G-CSF(filgrastim and pegfilgrastim) in Cox proportional-hazards models, which were stratified according to treatment accounting for confounding by indication.<br><br>RESULTS: Among 18,245 patients with NHL patients who had a median follow-up of 3.5 years, 56% received chemotherapy and/or immunotherapy, and G-CSF was most commonly used in those who received rituximab plus multiple chemotherapy regimens (77%). Subsequent MDS/AML diagnoses were identified in 666 patients (3.7%). A modest increased risk of MDS/AML was observed with the receipt of G-CSF (HR, 1.28; 95% CI, 1.01-1.62) and a trend was observed with increasing doses (Ptrend < .01). When specific agents were analyzed, an increased risk of MDS/AML was consistently observed with filgrastim (≥10 doses: HR, 1.67; 95% CI, 1.25-2.23), but not with pegfilgrastim (≥10 + doses: HR, 1.11; 95% CI, 0.84-1.45).<br><br>CONCLUSIONS: A higher of MDS/AML was observed in patients with NHL risk among those who received G-CSF that was specific to the use of filgrastim (≥10 doses), but not pegfilgrastim. Neutropenia prophylaxis is an essential component of highly effective NHL treatment regimens. The differential risk related to the types of G-CSF agents used warrants further study given their increasing use and newly available, US Food and Drug Administration-approved, biosimilar products.}, }
@article {pmid30547959, year = {2019}, author = {Kim, E and Andersen, MR and Standish, LJ}, title = {Comparison of Health-Related Quality of Life Between Adjuvant Breast Cancer Treatment Groups.}, journal = {Oncology nursing forum}, volume = {46}, number = {1}, pages = {59-70}, doi = {10.1188/19.ONF.59-70}, pmid = {30547959}, issn = {1538-0688}, support = {R01 AT005873/NH/NIH HHS/United States ; }, abstract = {OBJECTIVES: To compare the health-related quality of life (HRQOL) of women who did (receivers, n = 372) and did not (intentional nonreceivers, n = 46) receive all recommended adjuvant treatments for breast cancer.<br><br>SAMPLE &amp;AMP; SETTING: Women were recruited through integrative oncology clinics and the Cancer Surveillance System registry in western Washington.<br><br>METHODS &amp;AMP; VARIABLES: A cross-sectional and correlational study using secondary data was conducted. Self-reported data included involvement in treatment decision making (TDM) and HRQOL. Registry data included demographics, disease characteristics, and records on recommended treatments as well as receiving/not receiving them. Descriptive statistics, t tests, chi-square tests, correlations, and analysis of variance were used to compare receivers and intentional nonreceivers.<br><br>RESULTS: Among women who were &quot;very involved&quot; in TDM and those who reported their involvement as &quot;just right,&quot; intentional nonreceivers scored higher in role-physical, general health, and vitality than receivers after controlling for demographic and disease characteristics.<br><br>IMPLICATIONS FOR NURSING: Nurses need to be aware that intentional nonreceivers of adjuvant therapy, particularly if assessed as &quot;very involved&quot; and &quot;just right&quot; involvement in deciding to refuse treatment, may report better HRQOL than receivers, which could be attributed to lack of common side effects from adjuvant treatment.}, }
@article {pmid30545834, year = {2019}, author = {Thakar, MS and Broglie, L and Logan, B and Artz, A and Bunin, N and Burroughs, LM and Fretham, C and Jacobsohn, DA and Loren, AW and Kurtzberg, J and Martinez, CA and Mineishi, S and Nelson, AS and Woolfrey, A and Pasquini, MC and Sorror, ML}, title = {The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases.}, journal = {Blood}, volume = {133}, number = {7}, pages = {754-762}, doi = {10.1182/blood-2018-09-876284}, pmid = {30545834}, issn = {1528-0020}, support = {TL1 TR001437/TR/NCATS NIH HHS/United States ; U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; UL1 TR001436/TR/NCATS NIH HHS/United States ; }, abstract = {Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.}, }
@article {pmid30543657, year = {2018}, author = {Pasin, C and Halloran, ME and Gilbert, PB and Langevin, E and Ochiai, RL and Pitisuttithum, P and Capeding, MR and Carrasquilla, G and Frago, C and Cortés, M and Chambonneau, L and Moodie, Z}, title = {Periods of high dengue transmission defined by rainfall do not impact efficacy of dengue vaccine in regions of endemic disease.}, journal = {PloS one}, volume = {13}, number = {12}, pages = {e0207878}, doi = {10.1371/journal.pone.0207878}, pmid = {30543657}, issn = {1932-6203}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; }, abstract = {OBJECTIVE: To evaluate the association of rainy season with overall dengue disease incidence and with the efficacy of the Sanofi Pasteur recombinant, live, attenuated, tetravalent vaccine (CYD-TDV) in two randomized, controlled multicenter phase III clinical trials in Asia and Latin America.<br><br>METHODS: Rainy seasons were defined for each study site using climatological information from the World Meteorological Organization. The dengue attack rate in the placebo group for each study month was calculated as the number of symptomatic, virologically-confirmed dengue events in a given month divided by the number of participants at risk in the same month. Time-dependent Cox proportional hazard models were used to test whether rainy season was associated with dengue disease and whether it modified vaccine efficacy in each of the two trials and in both of the trials combined.<br><br>FINDINGS: Rainy season, country, and age were all significantly associated with dengue disease in both studies. Vaccine efficacy did not change during the rainy season in any of the analyses.<br><br>CONCLUSIONS: Although dengue transmission and exposure are expected to increase during the rainy season, our results indicate that CYD-TDV vaccine efficacy remains constant throughout the year in endemic regions.}, }
@article {pmid30542984, year = {2019}, author = {Mayer, SE and Weiss, NS and Chubak, J and Doody, DR and Carlson, CS and Makar, KW and Wurscher, MA and Malone, KE}, title = {CYP2D6-inhibiting medication use and inherited CYP2D6 variation in relation to adverse breast cancer outcomes after tamoxifen therapy.}, journal = {Cancer causes &amp; control : CCC}, volume = {30}, number = {1}, pages = {103-112}, doi = {10.1007/s10552-018-1117-x}, pmid = {30542984}, issn = {1573-7225}, support = {R01 CA192438/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; CA009168//National Cancer Institute/ ; R01 CA098858/CA/NCI NIH HHS/United States ; CA098858//National Cancer Institute/ ; CA173795//National Cancer Institute/ ; T32 CA009168/CA/NCI NIH HHS/United States ; CA015704//National Cancer Institute/ ; R03 CA173795/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Antineoplastic Agents, Hormonal/*therapeutic use ; Breast Neoplasms/*drug therapy/genetics ; Cohort Studies ; Cytochrome P-450 CYP2D6/*genetics ; Cytochrome P-450 CYP2D6 Inhibitors/pharmacology ; Disease-Free Survival ; Female ; Humans ; Middle Aged ; Neoplasm Recurrence, Local ; Phenotype ; Tamoxifen/*therapeutic use ; }, abstract = {PURPOSE: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications (&quot;inhibitors&quot;) is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen.<br><br>METHODS: The present cohort study of 960 women diagnosed with early-stage BC between 1993 and 1999 examined the association between concomitant use of CYP2D6 inhibitors and adjuvant tamoxifen and the risk of adverse BC outcomes (recurrence, second primary BC, BC mortality), both overall and according to CYP2D6 metabolic phenotype.<br><br>RESULTS: Six or more months of CYP2D6 inhibitor use concomitant with tamoxifen was not associated with any appreciable increase in risk of recurrence or second primary BC or BC mortality, and there was no clear evidence of variation by CYP2D6 metabolic phenotype.<br><br>CONCLUSIONS: These results are consistent with the relatively few other large, population-based studies conducted to date that have not observed an increased risk of adverse BC outcomes associated with CYP2D6 inhibition.}, }
@article {pmid30541882, year = {2019}, author = {Lindau, P and Mukherjee, R and Gutschow, MV and Vignali, M and Warren, EH and Riddell, SR and Makar, KW and Turtle, CJ and Robins, HS}, title = {Cytomegalovirus Exposure in the Elderly Does Not Reduce CD8 T Cell Repertoire Diversity.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {202}, number = {2}, pages = {476-483}, doi = {10.4049/jimmunol.1800217}, pmid = {30541882}, issn = {1550-6606}, abstract = {With age, the immune system becomes less effective, causing increased susceptibility to infection. Chronic CMV infection further impairs immune function and is associated with increased mortality in the elderly. CMV exposure elicits massive CD8+ T cell clonal expansions and diminishes the cytotoxic T cell response to subsequent infections, leading to the hypothesis that to maintain homeostasis, T cell clones are expelled from the repertoire, reducing T cell repertoire diversity and diminishing the ability to combat new infections. However, in humans, the impact of CMV infection on the structure and diversity of the underlying T cell repertoire remains uncharacterized. Using TCR β-chain immunosequencing, we observed that the proportion of the peripheral blood T cell repertoire composed of the most numerous 0.1% of clones is larger in the CMV seropositive and gradually increases with age. We found that the T cell repertoire in the elderly grows to accommodate CMV-driven clonal expansions while preserving its underlying diversity and clonal structure. Our observations suggest that the maintenance of large CMV-reactive T cell clones throughout life does not compromise the underlying repertoire. Alternatively, we propose that the diminished immunity in elderly individuals with CMV is due to alterations in cellular function rather than a reduction in CD8+ T cell repertoire diversity.}, }
@article {pmid30541786, year = {2018}, author = {Niño, DF and Zhou, Q and Yamaguchi, Y and Martin, LY and Wang, S and Fulton, WB and Jia, H and Lu, P and Prindle, T and Zhang, F and Crawford, J and Hou, Z and Mori, S and Chen, LL and Guajardo, A and Fatemi, A and Pletnikov, M and Kannan, RM and Kannan, S and Sodhi, CP and Hackam, DJ}, title = {Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain.}, journal = {Science translational medicine}, volume = {10}, number = {471}, pages = {}, doi = {10.1126/scitranslmed.aan0237}, pmid = {30541786}, issn = {1946-6242}, abstract = {Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.}, }
@article {pmid30523039, year = {2019}, author = {Ulrich, CM and Gigic, B and Böhm, J and Ose, J and Viskochil, R and Schneider, M and Colditz, GA and Figueiredo, JC and Grady, WM and Li, CI and Shibata, D and Siegel, EM and Toriola, AT and Ulrich, A}, title = {The ColoCare Study: A Paradigm of Transdisciplinary Science in Colorectal Cancer Outcomes.}, 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 = {3}, pages = {591-601}, doi = {10.1158/1055-9965.EPI-18-0773}, pmid = {30523039}, issn = {1538-7755}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA220004/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; P30 CA091842/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; U01 CA152756/CA/NCI NIH HHS/United States ; R01 CA194663/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Colorectal cancer is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether postdiagnosis diet and lifestyle can affect well-being and clinical outcomes. The international ColoCare Consortium aims to identify new biologic markers (e.g., metabolomic, transcriptomic, metagenomic, genetic, epigenetic, proteomic markers) that predict clinical outcomes, and to characterize associations between modifiable risk factors (e.g., diet, supplement use, physical activity) with short-term and long-term patient-reported and clinical outcomes among patients with colorectal cancer.Methods/Results: ColoCare is recruiting newly diagnosed patients with colorectal cancer across six sites in the United States and one site in Germany. As of April 2018, we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic patients with colorectal cancer. The study includes uniformly collected, comprehensive sets of data and biospecimens at multiple time points up to 5 years after diagnosis. Treatment and clinical data are abstracted from medical records and centrally harmonized. Biospecimens are archived according to standardized procedures. Our initial studies demonstrated metabolic differences in adipose tissue types. We further reported on associations of biological factors (e.g., inflammation, DNA methylation, metabolomics) with lifestyle factors (e.g., adiposity, smoking, physical activity, dietary supplement use) or joint associations with clinical outcomes.<br><br>CONCLUSIONS: ColoCare is a consortium for the investigation of multilevel factors relevant to colorectal cancer survivorship.<br><br>IMPACT: The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on colorectal cancer.}, }
@article {pmid30522836, year = {2018}, author = {Price, SA and Podczervinski, S and MacLeod, K and Helbert, L and Pergam, SA}, title = {Understanding influenza vaccination rates and reasons for refusal in caregivers and household contacts of cancer patients.}, journal = {American journal of infection control}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajic.2018.10.010}, pmid = {30522836}, issn = {1527-3296}, abstract = {Cancer patients are at increased risk for morbidity and mortality from seasonal influenza but are known to respond poorly to influenza vaccination. This single-center survey suggests that approximately one-third of cancer patients and their caregivers and family did not receive the vaccine in the prior season. Patients felt strongly that caregiver vaccination was important, whereas caregivers' decisions did not appear to be affected by the patients' disease.}, }
@article {pmid30541042, year = {2018}, author = {Walsh, N and Zhang, H and Hyland, PL and Yang, Q and Mocci, E and Zhang, M and Childs, EJ and Collins, I and Wang, Z and Arslan, AA and Beane-Freeman, L and Bracci, PM and Brennan, P and Canzian, F and Duell, EJ and Gallinger, S and Giles, GG and Goggins, M and Goodman, GE and Goodman, PJ and Hung, RJ and Kooperberg, C and Kurtz, RC and Malats, N and LeMarchand, L and Neale, RE and Olson, SH and Scelo, G and Shu, XO and Van Den Eeden, SK and Visvanathan, K and White, E and Zheng, W and ,  and Albanes, D and Andreotti, G and Babic, A and Bamlet, WR and Berndt, SI and Borgida, A and Boutron-Ruault, MC and Brais, L and Brennan, P and Bueno-de-Mesquita, B and Buring, J and Chaffee, KG and Chanock, S and Cleary, S and Cotterchio, M and Foretova, L and Fuchs, C and M Gaziano, JM and Giovannucci, E and Goggins, M and Hackert, T and Haiman, C and Hartge, P and Hasan, M and Helzlsouer, KJ and Herman, J and Holcatova, I and Holly, EA and Hoover, R and Hung, RJ and Janout, V and Klein, EA and Kurtz, RC and Laheru, D and Lee, IM and Lu, L and Malats, N and Mannisto, S and Milne, RL and Oberg, AL and Orlow, I and Patel, AV and Peters, U and Porta, M and Real, FX and Rothman, N and Sesso, HD and Severi, G and Silverman, D and Strobel, O and Sund, M and Thornquist, MD and Tobias, GS and Wactawski-Wende, J and Wareham, N and Weiderpass, E and Wentzensen, N and Wheeler, W and Yu, H and Zeleniuch-Jacquotte, A and Kraft, P and Li, D and Jacobs, EJ and Petersen, GM and Wolpin, BM and Risch, HA and Amundadottir, LT and Yu, K and Klein, AP and Stolzenberg-Solomon, RZ}, title = {Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djy155}, pmid = {30541042}, issn = {1460-2105}, support = {U01 CA063673/CA/NCI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; MC_UU_12015/1//Medical Research Council/United Kingdom ; R01 CA154823/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; }, abstract = {Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.<br><br>Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.<br><br>Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.<br><br>Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.}, }
@article {pmid30540700, year = {2019}, author = {Menon, U and Ashing, K and Chang, MW and Christy, SM and Friberg-Felsted, K and Rivas, VG and Gwede, CK and Lu, Q and Meade, CD and Sly, J and Wang, M and Yanez, B and Yeary, K and Yi, JC and Alcaraz, KI}, title = {Application of the ConNECT Framework to Precision Health and Health Disparities.}, journal = {Nursing research}, volume = {68}, number = {2}, pages = {99-109}, doi = {10.1097/NNR.0000000000000329}, pmid = {30540700}, issn = {1538-9847}, abstract = {BACKGROUND: An emphasis on precision health (PH) has stimulated precision medicine studies to focus on the interplay of biological, behavioral, and environmental factors with disease risks, treatments, prognoses, and outcomes affecting health disparities. It is imperative, as well, that improving health equity among underserved populations remains central to the efforts and aims of PH.<br><br>OBJECTIVES: The aim if this study was to apply the transdisciplinary ConNECT Framework: A Model for Advancing Behavioral Medicine Science and Practice to Foster Health Equity to PH by integrating a population health agenda for reducing health disparities.<br><br>METHODS: There are five ConNECT principles: (a) integrating context; (b) fostering a norm of inclusion; (c) ensuring equitable diffusion of innovations; (d) harnessing communication technology; and (e) prioritizing specialized training as an organizing framework to PH, including examples of how to integrate behavioral and socioecological determinants to better understand the contexts of individuals, systems, and place to design targeted treatments and interventions.<br><br>RESULTS: We describe proactive, actionable strategies for the systematic application of ConNECT Framework principles to address health equity via the PH initiative. Context and implications for nursing research and practice are also described.<br><br>DISCUSSION: The ConNECT Framework emphasizes that diversity inclusion is imperative for true population health benefit from PH, broadly in public health, behavioral medicine, medicine, and nursing, to equip health researchers and practitioners to account for contextual socioecologic data that can be aligned with biologic data for more population responsive and individually tailored interventions to prevent, diagnose, and treat diseases.}, }
@article {pmid30539318, year = {2019}, author = {Myerson, D and Parkin, RK}, title = {Donor-derived hepatocytes in human hematopoietic cell transplant recipients: evidence of fusion.}, journal = {Virchows Archiv : an international journal of pathology}, volume = {474}, number = {3}, pages = {365-374}, doi = {10.1007/s00428-018-2497-8}, pmid = {30539318}, issn = {1432-2307}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; 15074//National Cancer Institute/ ; 18029//National Cancer Institute/ ; 36444//National Heart, Lung, and Blood Institute/ ; P01 HL036444/HL/NHLBI NIH HHS/United States ; }, abstract = {Reconstitution of hepatocytes by hematopoietic stem cells-a phenomenon which occurs in rodents under highly selective conditions-results from infrequent fusion between incoming myelomonocytes and host hepatocytes, with subsequent proliferation. Human hematopoietic stem cell transplant recipients have been little studied, with some support for transdifferentiation (direct differentiation). We studied routinely obtained autopsy liver tissue of four female hematopoietic cell transplant recipients with male donors, using a highly specific conjoint immunohistochemistry in situ hybridization light microscopic technique. Hepatocyte nuclei were identified by cytokeratin (Cam5.2) staining and evaluated for X and Y chromosome content. Over 1.6 million hepatocytes were assessed for rare instances of donor origin, revealing a Y chromosome in 67. Mixed tetraploids (XXXY) and their nuclear truncation products (XXY, XY, Y) were directly demonstrated, with no detection of the male tetraploids (XXYY) that may result from transdifferentiation with subsequent tetraploidization, nor their unique truncation products (XYY, YY), implicating fusion as the mechanism. To determine whether it is the sole mechanism, we modeled the chromosome distribution based on the same probability of detection of each X chromosome, deriving parameters of sensitivity and female tetraploidy by best fit. We then hypothesized that the distribution of Y chromosome-containing cells could be predicted by a similar model. After modification to account for &quot;clumpy&quot; Y chromosomes, the observed results were in accord with the predicted results (p = 0.6). These results suggest that all the Y-containing cells, including apparent XY cells, derive from mixed tetraploids, consistent with fusion as the sole mechanism.}, }
@article {pmid30539315, year = {2019}, author = {Baglia, ML and Tang, MC and Malone, KE and Porter, P and Li, CI}, title = {Reproductive and menopausal factors and risk of second primary breast cancer after in situ breast carcinoma.}, journal = {Cancer causes &amp; control : CCC}, volume = {30}, number = {1}, pages = {113-120}, doi = {10.1007/s10552-018-1119-8}, pmid = {30539315}, issn = {1573-7225}, support = {R01 CA097271/CA/NCI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; R01-CA097271//National Cancer Institute/ ; }, mesh = {Aged ; Breast Feeding ; Breast Neoplasms/epidemiology/*pathology ; Case-Control Studies ; Female ; Humans ; Logistic Models ; Menarche ; *Menopause ; Middle Aged ; Neoplasms, Second Primary/*pathology ; Reproduction ; Reproductive History ; Risk Factors ; }, abstract = {PURPOSE: In situ breast cancer patients have a higher risk of developing a second primary breast cancer than women in the general population have of developing breast cancer. We have limited understanding of why some women with a previous in situ breast cancer develop second primary breast cancers while others do not.<br><br>METHODS: In this population-based nested case-control study, we evaluated the association between reproductive and menopausal factors and risk of developing a second primary breast cancer among women with a previous in situ breast cancer. Using conditional logistic regression, these associations were evaluated in 552 cases and 1032 individually matched controls.<br><br>RESULTS: Older age at menarche was associated with risk of second primary breast cancer among women with a previous in situ breast cancer (compared to age < 12, age 13: OR 0.60 (0.42, 0.85); age ≥ 14: OR 0.69 (0.47, 1.00); Ptrend = 0.07). Breastfeeding for > 12 months was associated with a decreased risk of developing a second primary breast cancer (OR 0.62 (0.39, 0.98)). No associations were observed for other reproductive or menopausal factors evaluated.<br><br>CONCLUSIONS: Results from this study suggest that reproductive factors may play a role in development of a second primary breast cancer after diagnosis of in situ breast carcinoma.}, }
@article {pmid30538099, year = {2019}, author = {Dai, JY and LeBlanc, M and Goodman, PJ and Lucia, MS and Thompson, IM and Tangen, CM}, title = {Case-only Methods Identified Genetic Loci Predicting a Subgroup of Men with Reduced Risk of High-grade Prostate Cancer by Finasteride.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {12}, number = {2}, pages = {113-120}, doi = {10.1158/1940-6207.CAPR-18-0284}, pmid = {30538099}, issn = {1940-6215}, support = {R01 CA222833/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; }, abstract = {In the Prostate Cancer Prevention Trial (PCPT), genotypes that may modify the effect of finasteride on the risk of prostate cancer have not been identified. Germline genetic data from 1,157 prostate cancer cases in PCPT were analyzed by case-only methods. Genotypes included 357 SNPs from 83 candidate genes in androgen metabolism, inflammation, circadian rhythm, and other pathways. Univariate case-only analysis was conducted to evaluate whether individual SNPs modified the finasteride effect on the risk of high-grade and low-grade prostate cancer. Case-only classification trees and random forests, which are powerful machine learning methods with resampling-based controls for model complexity, were employed to identify a predictive signature for genotype-specific treatment effects. Accounting for multiple testing, a single SNP in SRD5A1 gene (rs472402) significantly modified the finasteride effect on high-grade prostate cancer (Gleason score > 6) in PCPT (family-wise error rate < 0.05). Men carrying GG genotype at this locus had a 55% reduction of the risk in developing high-grade cancer when assigned to finasteride (RR = 0.45; 95% confidence interval, 0.27-0.75). Additional effect-modifying SNPs with moderate statistical significance were identified by case-only trees and random forests. A prediction model built by the case-only random forest method with 28 selected SNPs classified 37% of PCPT men to have reduced risk of high-grade prostate cancer when taking finasteride, while the others have increased risk. In conclusion, case-only methods identified SNPs that modified the effect of finasteride on the risk of high-grade prostate cancer and predicted a subgroup of men who had reduced cancer risk by finasteride.}, }
@article {pmid30537930, year = {2018}, author = {Kirsch, R and Seemann, SE and Ruzzo, WL and Cohen, SM and Stadler, PF and Gorodkin, J}, title = {Identification and characterization of novel conserved RNA structures in Drosophila.}, journal = {BMC genomics}, volume = {19}, number = {1}, pages = {899}, pmid = {30537930}, issn = {1471-2164}, support = {0603-00320B//Innovation Fund Denmark/ ; DFG SPP 1258 grant no. STA 850/10-2//Deutsche Forschungsgemeinschaft/ ; }, abstract = {BACKGROUND: Comparative genomics approaches have facilitated the discovery of many novel non-coding and structured RNAs (ncRNAs). The increasing availability of related genomes now makes it possible to systematically search for compensatory base changes - and thus for conserved secondary structures - even in genomic regions that are poorly alignable in the primary sequence. The wealth of available transcriptome data can add valuable insight into expression and possible function for new ncRNA candidates. Earlier work identifying ncRNAs in Drosophila melanogaster made use of sequence-based alignments and employed a sliding window approach, inevitably biasing identification toward RNAs encoded in the more conserved parts of the genome.<br><br>RESULTS: To search for conserved RNA structures (CRSs) that may not be highly conserved in sequence and to assess the expression of CRSs, we conducted a genome-wide structural alignment screen of 27 insect genomes including D. melanogaster and integrated this with an extensive set of tiling array data. The structural alignment screen revealed ∼30,000 novel candidate CRSs at an estimated false discovery rate of less than 10%. With more than one quarter of all individual CRS motifs showing sequence identities below 60%, the predicted CRSs largely complement the findings of sliding window approaches applied previously. While a sixth of the CRSs were ubiquitously expressed, we found that most were expressed in specific developmental stages or cell lines. Notably, most statistically significant enrichment of CRSs were observed in pupae, mainly in exons of untranslated regions, promotors, enhancers, and long ncRNAs. Interestingly, cell lines were found to express a different set of CRSs than were found in vivo. Only a small fraction of intergenic CRSs were co-expressed with the adjacent protein coding genes, which suggests that most intergenic CRSs are independent genetic units.<br><br>CONCLUSIONS: This study provides a more comprehensive view of the ncRNA transcriptome in fly as well as evidence for differential expression of CRSs during development and in cell lines.}, }
@article {pmid30537553, year = {2018}, author = {Askar, M and Sayer, D and Wang, T and Haagenson, M and Spellman, SR and Lee, SJ and Madbouly, A and Fleischhauer, K and Hsu, KC and Verneris, MR and Thomas, D and Zhang, A and Sobecks, RM and Majhail, NS and , }, title = {Analysis of Single Nucleotide Polymorphisms in the Gamma Block of the Major Histocompatibility Complex in Association with Clinical Outcomes of Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Study.}, 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.2018.12.008}, pmid = {30537553}, issn = {1523-6536}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {HLA haplotype mismatches have been associated with an elevated risk of acute graft-versus-host disease (aGVHD) in patients undergoing HLA-matched unrelated donor (URD) hematopoietic cell transplantation (HCT). The gamma block (GB) is located in the central MHC region between beta and delta blocks (encoding HLA-B and -C and HLA-DQ and -DR antigens, respectively) and contains numerous inflammatory and immune regulatory genes, including Bf, C2, and C4 genes. A single-center study showed that mismatches in SNPs c.2918+98G, c.3316C, and c.4385C in the GB block (C4 SNPs) were associated with higher risk of grade III-IV aGVHD. We investigated the association of GB SNP (GBS) mismatches with outcomes after 10/10 and 9/10 URD HCT (n = 714). The primary outcome was acute GVHD. Overall survival, disease-free survival, transplantation-related mortality, relapse, chronic GVHD, and engraftment were also analyzed. DNA samples were GBS genotyped by identifying 338 SNPs across 20 kb using the Illumina NGS platform. The overall 100-day incidence of aGVHD grade II-IV and II-IV were 41% and 17%, respectively. The overall incidence of matching at all GBSs tested and at the C4 SNPs were 23% and 81%, respectively. Neither being matched across all GB SNPs tested (versus mismatched) nor having a higher number of GBS mismatches was associated with transplantation outcomes. There was no association between C4 SNP mismatches and outcomes except for an unexpected significant association between having 2 C4 SNP mismatches and a higher hazard ratio (HR) for relapse (association seen in 15 patients only; HR, 3.38, 95% confidence interval, 1.75 to 6.53; P = .0003). These data do not support the hypothesis that mismatching at GB is associated with outcomes after HCT.}, }
@article {pmid30537551, year = {2018}, author = {Waghmare, A and Xie, H and Kuypers, J and Sorror, ML and Jerome, KR and Englund, JA and Boeckh, M and Leisenring, WM}, title = {Human Rhinovirus Infections in Hematopoietic Cell Transplant Recipients: Risk Score for Progression to Lower Respiratory Tract Infection.}, 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.2018.12.005}, pmid = {30537551}, issn = {1523-6536}, support = {K23 AI114844/AI/NIAID NIH HHS/United States ; K24 HL093294/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Human rhinovirus lower respiratory tract infection (LRTI) is associated with mortality after hematopoietic cell transplantation (HCT); however, risk factors for LRTI are not well characterized. We sought to develop a risk score for progression to LRTI from upper respiratory tract infection (URTI) in HCT recipients. Risk factors for LRTI within 90 days were analyzed using Cox regression among HCT recipients with rhinovirus URTI between January 2009 and March 2016. The final multivariable model included factors with a meaningful effect on the bootstrapped optimism corrected concordance statistic. Weighted score contributions based on hazard ratios were determined. Cumulative incidence curves estimated the probability of LRTI at various score cut-offs. Of 588 rhinovirus URTI events, 100 (17%) progressed to LRTI. In a final multivariable model allogeneic grafts, prior rhinovirus URTI, low lymphocyte count, low albumin, positive cytomegalovirus serostatus, recipient statin use, and steroid use ≥2 mg/kg/day were associated with progression to LRTI. A weighted risk score cut-off with the highest sensitivity and specificity was determined. Risk scores above this cut-off were associated with progression to LRTI (cumulative incidence 28% versus 11% below cut-off; P < .001). The weighted risk score for progression to rhinovirus LRTI can help identify and stratify patients for clinical management and for future clinical trials of therapeutics in HCT recipients.}, }
@article {pmid30537450, year = {2018}, author = {Panattoni, L and Fedorenko, C and Kreizenbeck, K and Sun, Q and Li, L and Conklin, T and Lyman, GH and Ramsey, SD}, title = {Lessons From Reporting National Performance Measures in a Regional Setting: Washington State Community Cancer Care Report.}, journal = {Journal of oncology practice}, volume = {14}, number = {12}, pages = {e801-e814}, doi = {10.1200/JOP.18.00410}, pmid = {30537450}, issn = {1935-469X}, abstract = {Regional public reporting of performance measures in oncology can facilitate local decision making across stakeholders, but small numbers of patients and clinics pose a challenge to creating statistically robust measures. In this article, we describe our development of the Community Cancer Care in Washington State: Quality and Cost Report, the first publicly available report showing clinic-level quality and cost measures at the regional level. We learned key lessons in how to adapt national performance reporting to our regional setting using a registry-linked multipayer claims database. In short, limited numbers of eligible patients for some nationally recognized metrics led us to group metrics and use a 3-year performance window. After completing clinic attribution and other requirements of metric construction, the final metrics included between 62.9% and 88.4% of the eligible patients. To link total costs to some quality measures, we had to define a treatment and surveillance episode of care. Risk adjustment was challenged by the ability to include a limited number of risk adjustors and their potential concentration in a few clinics. We used a different quality score than national performance reporting to account for variation in the range of risk-standardized rates. Current methodology does not permit us to determine whether clinically meaningful differences in quality or costs exist, which inhibits value comparisons. Stakeholder engagement was critical for providing methodologic feedback. In conclusion, we found that refining national metrics was necessary to facilitate public reporting in a regional setting. Further methodologic development can strengthen public reporting and future applications.}, }
@article {pmid30536628, year = {2018}, author = {Crandall, CJ and Larson, J and Manson, JE and Cauley, JA and LaCroix, AZ and Wactawski-Wende, J and Datta, M and Sattari, M and Schousboe, JT and Leslie, WD and Ensrud, KE}, title = {A Comparison of US and Canadian Osteoporosis Screening and Treatment Strategies in Postmenopausal Women.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {}, number = {}, pages = {}, doi = {10.1002/jbmr.3636}, pmid = {30536628}, issn = {1523-4681}, support = {HHSN268201600018C//US Department of Health and Human Services/ ; HHSN268201600001C//US Department of Health and Human Services/ ; HHSN268201600002C//US Department of Health and Human Services/ ; HHSN268201600003C//US Department of Health and Human Services/ ; HHSN268201600004C//US Department of Health and Human Services/ ; }, abstract = {The optimal approach to osteoporosis screening and treatment in postmenopausal women is unclear. We compared (i) the United States Preventive Services Task Force (USPSTF) and Osteoporosis Canada osteoporosis screening strategies; and (ii) the National Osteoporosis Foundation (NOF) and Canadian treatment strategies. We used data from the prospective Women's Health Initiative Observational Study and Clinical Trials of women aged 50 to 79 years at baseline (n = 117,707 followed for self-reported fractures; n = 8134 in bone mineral density [BMD] subset). We determined the yield of the screening and treatment strategies in identifying women who experienced major osteoporotic fractures (MOFs) during a 10-year follow-up. Among women aged 50 to 64 years, 23.1% of women were identified for BMD testing under the USPSTF strategy and 52.3% under the Canadian strategy. For women ≥65 years, 100% were identified for testing under the USPSTF and Canadian strategies, 35% to 74% were identified for treatment under NOF, and 16% to 37% were identified for treatment under CAROC (range among 5-year age subgroups). Among women who experienced MOF during follow-up, the USPSTF strategy identified 6.7% of women 50 to 54 years-old and 49.5% of women 60 to 64 years-old for BMD testing (versus 54.4% and 60.6% for the Canadian strategy, respectively). However, the specificity of the USPSTF strategy was higher than that of the Canadian strategy among women 50 to 64 years-old. Among women who experienced MOF during follow-up, sensitivity for identifying women as treatment candidates was lowest for both strategies in women aged 50 to 64 (NOF 10% to 38%; CAROC 1% to 15%) and maximal in 75-year-old to 79-year-old women (NOF 82.8%; 51.6% CAROC); specificity declined with advancing age and was lower with the NOF compared to the CAROC strategy. Among women aged 50 to 64 years, the screening and treatment strategies examined had low sensitivity for identifying those who subsequently experience MOF; sensitivity was higher among women ≥65 years than among younger women. New screening and treatment algorithms are needed. © 2018 American Society for Bone and Mineral Research.}, }
@article {pmid30535112, year = {2018}, author = {Prentice, RL}, title = {Intake biomarkers and the chronic disease nutritional epidemiology research agenda.}, journal = {The American journal of clinical nutrition}, volume = {108}, number = {3}, pages = {433-434}, doi = {10.1093/ajcn/nqy206}, pmid = {30535112}, issn = {1938-3207}, }
@article {pmid30535086, year = {2018}, author = {Gielen, M and Hageman, GJ and Antoniou, EE and Nordfjall, K and Mangino, M and Balasubramanyam, M and de Meyer, T and Hendricks, AE and Giltay, EJ and Hunt, SC and Nettleton, JA and Salpea, KD and Diaz, VA and Farzaneh-Far, R and Atzmon, G and Harris, SE and Hou, L and Gilley, D and Hovatta, I and Kark, JD and Nassar, H and Kurz, DJ and Mather, KA and Willeit, P and Zheng, YL and Pavanello, S and Demerath, EW and Rode, L and Bunout, D and Steptoe, A and Boardman, L and Marti, A and Needham, B and Zheng, W and Ramsey-Goldman, R and Pellatt, AJ and Kaprio, J and Hofmann, JN and Gieger, C and Paolisso, G and Hjelmborg, JBH and Mirabello, L and Seeman, T and Wong, J and van der Harst, P and Broer, L and Kronenberg, F and Kollerits, B and Strandberg, T and Eisenberg, DTA and Duggan, C and Verhoeven, JE and Schaakxs, R and Zannolli, R and Dos Reis, RMR and Charchar, FJ and Tomaszewski, M and Mons, U and Demuth, I and Iglesias Molli, AE and Cheng, G and Krasnienkov, D and D'Antono, B and Kasielski, M and McDonnell, BJ and Ebstein, RP and Sundquist, K and Pare, G and Chong, M and Zeegers, MP and , }, title = {Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.}, journal = {The American journal of clinical nutrition}, volume = {108}, number = {3}, pages = {453-475}, doi = {10.1093/ajcn/nqy107}, pmid = {30535086}, issn = {1938-3207}, support = {PG/12/9/29376//British Heart Foundation/United Kingdom ; RG/10/005/28296//British Heart Foundation/United Kingdom ; }, abstract = {Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes.<br><br>Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span.<br><br>Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories (&quot;young&quot;: 18-60 y; &quot;middle&quot;: 61-75 y; and &quot;old&quot;: >75 y), sex, and ethnicity.<br><br>Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10-3 unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10-3, -1.01 × 10-3) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10-3 unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10-3, -1.25 × 10-3). The associations were predominantly for the white pooled population. No sex differences were observed.<br><br>Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.}, }
@article {pmid30531955, 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 = {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/s41409-018-0339-6}, pmid = {30531955}, issn = {1476-5365}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.}, }
@article {pmid30531954, year = {2018}, author = {Inamoto, Y and Valdés-Sanz, N and Ogawa, Y and Alves, M and Berchicci, L and Galvin, J and Greinix, H and Hale, GA and Horn, B and Kelly, D and Liu, H and Rowley, S and Schoemans, H and Shah, A and Lupo Stanghellini, MT and Agrawal, V and Ahmed, I and Ali, A and Bhatt, N and Byrne, M and Chhabra, S and DeFilipp, Z and Fahnehjelm, K and Farhadfar, N and Horn, E and Lee, C and Nathan, S and Penack, O and Prasad, P and Rotz, S and Rovó, A and Yared, J and Pavletic, S and Basak, GW and Battiwalla, M and Duarte, R and Savani, BN and Flowers, MED and Shaw, BE and Petriček, I}, title = {Ocular graft-versus-host disease 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/s41409-018-0340-0}, pmid = {30531954}, issn = {1476-5365}, abstract = {Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.}, }
@article {pmid30531897, year = {2018}, author = {Becht, E and McInnes, L and Healy, J and Dutertre, CA and Kwok, IWH and Ng, LG and Ginhoux, F and Newell, EW}, title = {Dimensionality reduction for visualizing single-cell data using UMAP.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1038/nbt.4314}, pmid = {30531897}, issn = {1546-1696}, abstract = {Advances in single-cell technologies have enabled high-resolution dissection of tissue composition. Several tools for dimensionality reduction are available to analyze the large number of parameters generated in single-cell studies. Recently, a nonlinear dimensionality-reduction technique, uniform manifold approximation and projection (UMAP), was developed for the analysis of any type of high-dimensional data. Here we apply it to biological data, using three well-characterized mass cytometry and single-cell RNA sequencing datasets. Comparing the performance of UMAP with five other tools, we find that UMAP provides the fastest run times, highest reproducibility and the most meaningful organization of cell clusters. The work highlights the use of UMAP for improved visualization and interpretation of single-cell data.}, }
@article {pmid30530817, year = {2019}, author = {Mostaghel, EA}, title = {Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {25}, number = {4}, pages = {1139-1141}, doi = {10.1158/1078-0432.CCR-18-3410}, pmid = {30530817}, issn = {1078-0432}, support = {P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; }, abstract = {Castration-resistant prostate cancer is characterized by loss of the androgen inactivation enzyme HSD17B2, emphasizing the importance of intratumoral androgens in tumor progression. Inactive isoforms generated by alternative splicing destabilize the wild-type enzyme, adding steroidogenesis to other prostate cancer drivers that undergo oncogenic splicing, highlighting aberrant splicing as a therapeutic target.See related article by Gao et al., p. 1291.}, }
@article {pmid30530635, year = {2018}, author = {Lippman, SM and Abate-Shen, C and Colbert Maresso, KL and Colditz, GA and Dannenberg, AJ and Davidson, NE and Disis, ML and DuBois, RN and Szabo, E and Giuliano, AR and Hait, WN and Lee, JJ and Kensler, TW and Kramer, BS and Limburg, P and Maitra, A and Martinez, ME and Rebbeck, TR and Schmitz, KH and Vilar, E and Hawk, ET}, title = {AACR White Paper: Shaping the Future of Cancer Prevention - A Roadmap for Advancing Science and Public Health.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {11}, number = {12}, pages = {735-778}, doi = {10.1158/1940-6207.CAPR-18-0421}, pmid = {30530635}, issn = {1940-6215}, abstract = {The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold &quot;Cancer Interception&quot; initiative.}, }
@article {pmid30528801, year = {2019}, author = {Effinger, KE and Stratton, KL and Fisher, PG and Ness, KK and Krull, KR and Oeffinger, KC and Armstrong, GT and Robison, LL and Hudson, MM and Leisenring, WM and Nathan, PC}, title = {Long-term health and social function in adult survivors of paediatric astrocytoma: A report from the Childhood Cancer Survivor Study.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {106}, number = {}, pages = {171-180}, doi = {10.1016/j.ejca.2018.10.016}, pmid = {30528801}, issn = {1879-0852}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Although paediatric astrocytoma has an excellent 5-year survival rate, survivors remain at risk for morbidity and late mortality. This study aimed to estimate the risk of late mortality, chronic conditions, poor health status and social impairment in ageing paediatric astrocytoma survivors.<br><br>METHODS: We longitudinally evaluated 1182 5-year astrocytoma survivors diagnosed between 1970 and 1986 and 4023 siblings enrolled in a retrospective cohort study. Kaplan-Meier estimates of late mortality and cumulative incidence of serious chronic conditions were estimated. Cox regression models provided hazard ratios (HRs) with 95% confidence intervals (CIs) for development of chronic conditions, and generalised linear models provided relative risks (RRs) of the poor health status and social outcomes.<br><br>RESULTS: At 30 years from diagnosis, cumulative late mortality was 22.1% (CI 20.0-24.3%), primarily due to disease progression or recurrence. Compared with siblings, survivors were at increased risk of serious chronic conditions (HR 4.6, CI 3.8-5.5). Survivors reported higher rates of poor general health (RR 3.3, CI 2.8-3.8), poor mental health (RR 1.9, CI 1.7-2.1), functional impairment (RR 9.0, CI 7.7-10.5) and activity limitation (RR 3.6, CI 3.1-4.2) and lower rates of college graduation (RR 0.75, CI 0.69-0.82), marriage (RR 0.62, CI 0.58-0.66), employment (RR 0.75, CI 0.72-0.79) and household income ≥$40,000 (RR 0.68, CI 0.64-0.73). Even survivors without radiation exposure had elevated risk of chronic conditions, poor health status and social impairment compared with siblings.<br><br>CONCLUSIONS: Survivors of paediatric astrocytoma are at high risk for long-term complications of their disease and its treatment. They require lifelong monitoring for late effects.}, }
@article {pmid30526633, year = {2018}, author = {Brooks, JD and Comen, EA and Reiner, AS and Orlow, I and Leong, SF and Liang, X and Mellemkjær, L and Knight, JA and Lynch, CF and John, EM and Bernstein, L and Woods, M and Doody, DR and ,  and Malone, KE and Bernstein, JL}, title = {CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.}, journal = {Breast cancer research : BCR}, volume = {20}, number = {1}, pages = {149}, pmid = {30526633}, issn = {1465-542X}, support = {CA083178/CA/NCI NIH HHS/United States ; CA097397/CA/NCI NIH HHS/United States ; CA114236/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; CA129639/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.<br><br>METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.<br><br>RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02).<br><br>CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.}, }
@article {pmid30521975, year = {2018}, 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 Ahmed, 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 Hashmi, 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 = {Non-Graft-versus-Host Disease Ocular Complications after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European 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.2018.11.033}, pmid = {30521975}, issn = {1523-6536}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.}, }
@article {pmid30520941, year = {2018}, author = {Mueller, KAL and Hanna, DB and Ehinger, E and Xue, X and Baas, L and Gawaz, MP and Geisler, T and Anastos, K and Cohen, MH and Gange, SJ and Heath, SL and Lazar, JM and Liu, C and Mack, WJ and Ofotokun, I and Tien, PC and Hodis, HN and Landay, AL and Kaplan, RC and Ley, K}, title = {Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis.}, journal = {Cardiovascular research}, volume = {}, number = {}, pages = {}, doi = {10.1093/cvr/cvy292}, pmid = {30520941}, issn = {1755-3245}, abstract = {Aims: To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women.<br><br>Methods and Results: sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into 4 sets (n = 23 each) by HIV and sCVD status (HIV-/sCVD-, HIV-/sCVD+, HIV+/sCVD-, HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometery was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the 4 groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression (median fluorescence intensity, MFI) in non-classical monocytes was highest among HIV-/CVD- (628, IQR (295-1389)), followed by HIV+/CVD- (486, IQR (248-699)), HIV-/CVD + (398, IQR (89-901)), and lowest in HIV+/CVD+ women (226, IQR (73-519)), P = 0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV-CVD- vs HIV+CVD+ remained significant with P = 0.005 (HIV-CVD- vs HIV+CVD- P = 0.04, HIV-CVD- vs HIV-CVD+ P = 0.06, HIV+CVD+ vs HIV+CVD- P = 0.88, HIV+CVD+ vs HIV-CVD+ P = 0.81, HIV+CVD- vs HIV-CVD+, P = 0.99). All pairwise comparisons with HIV-CVD- were individually significant (P = 0.050 vs HIV-CVD+, P = 0.028 vs HIV+CVD-, P = 0.009 vs HIV+CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD- (501.5, IQR (249.5-887.3)) vs CVD + (297, IQR (81.75-626.8) individuals (P = 0.028, n = 46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV-related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P < 0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P = 0.003), but did not differ in classical or intermediate monocytes.<br><br>Conclusion: CXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes.}, }
@article {pmid30520725, year = {2018}, author = {OhAinle, M and Helms, L and Vermeire, J and Roesch, F and Humes, D and Basom, R and Delrow, JJ and Overbaugh, J and Emerman, M}, title = {A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV.}, journal = {eLife}, volume = {7}, number = {}, pages = {}, doi = {10.7554/eLife.39823}, pmid = {30520725}, issn = {2050-084X}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; CFAR New Investigator Award, P30 AI027757/AI/NIAID NIH HHS/United States ; DP1 DA039543/DA/NIDA NIH HHS/United States ; P30 CA015704-43/CA/NCI NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; R01 AI030927/AI/NIAID NIH HHS/United States ; CCEH Pilot Grant, DK56465/DK/NIDDK NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI30927/AI/NIAID NIH HHS/United States ; R37 AI030927/AI/NIAID NIH HHS/United States ; }, abstract = {Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced HIV restriction factors, we assembled a CRISPR sgRNA library of Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. A small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5alpha together explain the inhibitory effects of IFN on the CXCR4-tropic HIV-1 strain, HIV-1LAI, in THP-1 cells. A second screen with a CCR5-tropic primary strain, HIV-1Q23.BG505, described an overlapping, but non-identical, panel of restriction factors. Further, this screen also identifies HIV dependency factors. The ability of IFN-induced restriction factors to inhibit HIV strains to replicate in human cells suggests that these human restriction factors are incompletely antagonized.<br><br>Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).}, }
@article {pmid30520344, year = {2019}, author = {Melin, K and Moon, JY and Qi, Q and Hernandez-Suarez, DF and Duconge, J and Hua, S and Gonzalez, S and Zeng, D and Kaplan, RC}, title = {Prevalence of pharmacogenomic variants affecting the efficacy of clopidogrel therapy in the Hispanic Community Health Study/Study of Latinos cohort.}, journal = {Pharmacogenomics}, volume = {20}, number = {2}, pages = {75-83}, doi = {10.2217/pgs-2018-0148}, pmid = {30520344}, issn = {1744-8042}, abstract = {PURPOSE: Although clopidogrel is the most widely used oral P2Y12 receptor antagonist, up to 10% of acute coronary syndrome patients treated with clopidogrel will experience a recurrent myocardial infarction and 2-3% will experience stent thrombosis within 1 year. The purpose of this research is to describe the prevalence of pharmacogene variants associated with clopidogrel responsiveness (CYP2C19, B4GALT2, ABCB1, PON1, CES1 and P2RY12) in Hispanic/Latino patients of diverse backgrounds.<br><br>METHODS: Minor allele frequencies of nine variants from participants of Hispanic Community Health Study/Study of Latinos were compared between subpopulations as well as to continental ancestry references using z-test for independent proportions.<br><br>RESULTS: MAFs for six out of nine variants differed between Caribbean and Mainland subpopulations (p < 0.05). Compared with European reference group, MAFs of ABCB1, CES1 and PON1 were higher in Hispanic Community Health Study/Study of Latinos, whereas B4GALT2 and CYP2C19*2 and *17 were lower.<br><br>CONCLUSION: Significant differences in the prevalence of most pharmacogenomic variants related to clopidogrel response provide a foundation to better inform ongoing and future clinical studies of clopidogrel pharmacogenetics in the US Hispanic/Latino populations.}, }
@article {pmid30507409, year = {2018}, author = {Delany-Moretlwe, S and Lombard, C and Baron, D and Bekker, LG and Nkala, B and Ahmed, K and Sebe, M and Brumskine, W and Nchabeleng, M and Palanee-Philips, T and Ntshangase, J and Sibiya, S and Smith, E and Panchia, R and Myer, L and Schwartz, JL and Marzinke, M and Morris, L and Brown, ER and Doncel, GF and Gray, G and Rees, H}, title = {Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Infectious diseases}, volume = {18}, number = {11}, pages = {1241-1250}, doi = {10.1016/S1473-3099(18)30428-6}, pmid = {30507409}, issn = {1474-4457}, support = {P30 AI094189/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Young women in southern Africa have substantial risk of HIV acquisition. Female-controlled biomedical interventions are needed to mitigate this risk. We aimed to assess the safety and efficacy of a pericoitally applied tenofovir 1% gel.<br><br>METHODS: We did a phase 3, double-blind, randomised, placebo-controlled trial at nine community-based clinical trial sites in South Africa to evaluate the safety and efficacy of tenofovir 1% gel. Sexually active women who were HIV negative and aged 18-30 years were enrolled. Participants were randomly assigned (1:1) using sequential participant numbers to either tenofovir 1% gel or a placebo gel (one dose within 12 h before sex and one dose within 12 h after sex [BAT-24 regimen]), using dynamic permuted block sizes of 8 and 16 within each site. Women received monthly HIV-1 testing, risk reduction support, physical examinations, and product dispensing for up to 27 months. The primary efficacy outcome was incident HIV infection and the primary safety outcome was occurrence of grade 2-4 adverse events, both analysed in the modified intention-to-treat population. To assess the efficacy of tenofovir gel, the cumulative probability of HIV infection was calculated for each treatment using the Kaplan-Meier method. This trial is registered with ClinicalTrials.gov, number NCT01386294.<br><br>FINDINGS: From Oct 11, 2011, to Aug 29, 2014, 3844 women were screened, 2059 enrolled, and 2029 included in the primary analysis (1032 in the tenofovir group and 1027 in the placebo group); 39 (4%) in the tenofovir group and 36 (4%) in the placebo group were lost to follow-up. 123 HIV-1 infections occurred over 3036 woman-years of observation; 61 in the tenofovir group (HIV incidence 4·0 per 100 woman-years, 95% CI 3·1-5·2) and 62 in the placebo group (4·0 per 100 woman-years, 3·1-5·2; incidence rate ratio [IRR] 0·98, 95% CI 0·7-1·4). A higher incidence of grade 2 adverse events was observed in the tenofovir group than in the placebo group (IRR 1·09, 95% CI 1·0-1·2; p=0·02). The most common grade 2 or higher product-related adverse events were hypophosphataemia (n=22 for tenofovir vs n=22 for placebo), genital symptoms (n=6 for tenofovir vs n=2 for placebo), or elevated transaminases (n=2 for tenofovir vs n=2 for placebo). No product-related serious adverse events were reported, and no differences in product-related adverse events (p=0·78), grade 3 events (p=0·64), or grade 4 events (p=0·74) were observed between treatment groups.<br><br>INTERPRETATION: Overall, pericoital tenofovir gel did not prevent HIV-1 acquisition in this population of young women at risk of HIV infection in South Africa. Alternate safe and effective products that are less user dependent than this product or do not require high adherence are needed.<br><br>FUNDING: The US Agency for International Development (USAID), the Bill &amp; Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health.}, }
@article {pmid30506474, 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 = {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 = {661-674}, doi = {10.1007/s10461-018-2348-2}, pmid = {30506474}, issn = {1573-3254}, support = {K01 CA193918/CA/NCI NIH HHS/United States ; R01 DA032106/DA/NIDA NIH HHS/United States ; RO1DA032106//National Institutes on Drug Abuse/ ; }, abstract = {Experiencing HIV-related stigma has important impacts on the mental health of people living with HIV, which has implications for treatment adherence, disease progression, and health outcomes. The impacts of stigma are particularly important to consider among sexual and gender minorities, who often face a disproportionate burden of HIV. To address the implications of stigma in these key populations, we leveraged a longitudinal study conducted among Peruvian sexual and gender minorities to compare the relative effects of multiple mediators affecting the relationship between experienced HIV-related stigma and psychological distress: internalized HIV-related stigma, adaptive coping, and maladaptive coping. HIV-related stigma, coping, and distress were measured, respectively, at 24 weeks, 36 weeks, and 48 weeks post-diagnosis for 145 participants from the Sabes Study. HIV-related maladaptive coping largely mediated the relationship between experienced HIV-related stigma and distress. Our findings suggest interventions targeting maladaptive coping may alleviate the mental health consequences of experiencing HIV-related stigma.}, }
@article {pmid30504303, year = {2018}, author = {Baker, KS and Syrjala, KL}, title = {Long-term complications in adolescent and young adult leukemia survivors.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2018}, number = {1}, pages = {146-153}, pmid = {30504303}, issn = {1520-4383}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA201179/CA/NCI NIH HHS/United States ; R01 CA204378/CA/NCI NIH HHS/United States ; R01 CA215134/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Age Factors ; Cancer Survivors/*psychology ; Female ; Humans ; Leukemia/pathology/*psychology/*therapy ; Male ; Young Adult ; }, abstract = {Adolescents and young adults (AYAs) with cancer, defined by the National Cancer Institute as having been diagnosed between the ages of 15 and 39 years old, have not benefited from the same improvements in quality of outcomes and survival that have been seen for individuals diagnosed in childhood or as older adults. Although is leukemia composed of a diverse group of diagnoses, leukemia AYA survivors share unique vulnerabilities with other AYA diagnostic groups. They will spend the majority of their lives as survivors, with clear evidence of adverse medical conditions, health care requirements, and social and psychological needs that differ not only from their peers but also, from the needs of other cancer survivor populations. Furthermore, they share a developmental stage of life in which careers, finances, and family concerns are uniquely impacted by the cancer diagnosis and treatment. Leukemia in AYAs typically presents with higher-risk biologic features, and treatment requires multiagent chemotherapy, including alkylating agents, anthracyclines, high-dose steroids, frequently intrathecal chemotherapy, and sometimes, cranial radiation. Thus, AYAs have significant risks for long-term complications, subsequent malignancies, and accelerated development of usual age-related comorbid conditions, such as cardiovascular disease and dyslipidemias. AYAs require specialized health care monitoring, surveillance for late effects, and periodic evaluation of psychosocial, health behavior, and life goal outcomes.}, }
@article {pmid30504187, year = {2018}, author = {Okello, CD and Ddungu, H and Omoding, A and Towlerton, AMH and Pitorak, H and Maggard, K and Ewart, S and Phipps, WT and Uldrick, TS and Warren, EH and Orem, J}, title = {Capacity building for hematologic malignancies in Uganda: a comprehensive research, training, and care program through the Uganda Cancer Institute-Fred Hutchinson Cancer Research Center collaboration.}, journal = {Blood advances}, volume = {2}, number = {Suppl 1}, pages = {8-10}, doi = {10.1182/bloodadvances.2018GS111079}, pmid = {30504187}, issn = {2473-9537}, }
@article {pmid30502845, year = {2018}, author = {Yezefski, T and Schwemm, A and Lentz, M and Hone, K and Shankaran, V}, title = {Patient assistance programs: a valuable, yet imperfect, way to ease the financial toxicity of cancer care.}, journal = {Seminars in hematology}, volume = {55}, number = {4}, pages = {185-188}, doi = {10.1053/j.seminhematol.2017.07.004}, pmid = {30502845}, issn = {1532-8686}, abstract = {High out-of-pocket (OOP) spending on cancer drugs is a known contributor to &quot;financial toxicity&quot; among cancer patients. Many predict that this problem will only worsen as patients continue to bear more responsibility for the cost of their medical care and as the use of oral chemotherapeutic agents increases. Although foundations and pharmaceutical companies offer patient assistance programs (PAPs) to improve drug affordability, the degree to which these programs are used is poorly understood. There are several barriers to the use of PAPs that not only affect access to patients who may benefit but also create limitations on the research and study of these programs.}, }
@article {pmid30517204, year = {2018}, author = {Peebles, K and McClelland, RS and Overbaugh, J and Richardson, BA and Bosire, R and Kiarie, JN and Farquhar, C and Guthrie, BL}, title = {Higher prevalence of viral control in HIV-1-infected women in serodiscordant relationships.}, journal = {PloS one}, volume = {13}, number = {12}, pages = {e0208401}, doi = {10.1371/journal.pone.0208401}, pmid = {30517204}, issn = {1932-6203}, support = {R37 AI038518/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: HIV-1-discordant couples that remain discordant despite repeated exposure may differ from the general population in their distribution of transmission risk factors, including low plasma viral load (PVL) in the infected partner even in the absence of antiretroviral therapy (ART).<br><br>METHODS: We followed two cohorts of HIV-1-infected Kenyan women: females in discordant couples (FDC) and female sex workers (FSW). We compared the distribution of undetectable (<150 copies/mL) and low PVL (<1,000 copies/mL) between the cohorts using bootstrap methods and exact Poisson regression.<br><br>RESULTS: We evaluated 296 FDC and 220 FSW. At baseline, FDC were more likely to have undetectable (RR = 6.94, bootstrap 95% CI: 3.47, 20.81) and low PVL (RR = 3.53, bootstrap 95% CI: 2.57, 5.65) than FSW. Similarly, both repeat undetectable PVL (RR = 9.36, bootstrap 95% CI: 6.04, 10.97) and repeat low (RR = 4.99, bootstrap 95% CI: 2.33, 14.04) PVL were more likely among FDC than FSW during follow-up.<br><br>DISCUSSION: We observed higher prevalence of viral control in FDC compared to FSW in the absence of ART, suggesting potentially higher prevalence of biological HIV resistance factors among discordant couples.}, }
@article {pmid30517057, year = {2019}, author = {Huamani, KF and Metch, B and Broder, G and Andrasik, M}, title = {A Demographic Analysis of Racial/Ethnic Minority Enrollment Into HVTN Preventive Early Phase HIV Vaccine Clinical Trials Conducted in the United States, 2002-2016.}, journal = {Public health reports (Washington, D.C. : 1974)}, volume = {134}, number = {1}, pages = {72-80}, doi = {10.1177/0033354918814260}, pmid = {30517057}, issn = {1468-2877}, support = {P2C HD042828/HD/NICHD NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {OBJECTIVES:: Racial/ethnic minority communities in the United States are overrepresented among new HIV diagnoses, yet their inclusion in preventive HIV vaccine clinical trials is inadequate. An analysis of enrollment demographic characteristics from US preventive HIV vaccine clinical trials from 1988 through 2002 showed that enrollment of racial/ethnic minority groups increased. We analyzed enrollment in preventive HIV vaccine clinical trials from 2002 through 2016 and compared our data with data from the previous study, described demographic characteristics of trial participants, and assessed how well this distribution reflected the racial/ethnic distribution of new HIV diagnoses in the United States.<br><br>METHODS:: We examined data on demographic characteristics from 43 Phase 1 and Phase 2A preventive HIV vaccine clinical trials conducted in the United States and compared the results with those of the previous study. We also compared racial/ethnic distributions from 2011 through 2015 with Centers for Disease Control and Prevention data on the number of new HIV diagnoses during the same period.<br><br>RESULTS:: Of 3469 participants, 1134 (32.7%) identified as a racial/ethnic minority, a 94% increase from the previous period (634/3731; 17.0%). Percentage annual enrollment of all racial/ethnic minority participants fluctuated from 17% to 53% from mid-2002 to 2016. Percentages of new HIV diagnoses among the general population were 1.9 to 2.9 times the percentage enrollment of black participants and 1.3 to 6.6 times the percentage enrollment of Hispanic/Latino participants in clinical trials for the same period.<br><br>CONCLUSIONS:: Although enrollment of racial/ethnic minority groups into HIV vaccine clinical trials has increased, it is not proportional to the number of new HIV diagnoses among these groups. To enhance recruitment of racial/ethnic minority groups, the HIV Vaccine Trials Network has prioritized community partnerships and invested resources into staff training.}, }
@article {pmid30516725, year = {2018}, author = {Stoner, MCD and Dennis, AM and Hughes, JP and Eshleman, SH and Sivay, MV and Hudelson, SE and Kate Grabowski, M and Gomez-Olive, X and MacPhail, C and Piwowar-Manning, E and Kahn, K and Pettifor, A}, title = {Characteristics associated with HIV transmission networks involving adolescent girls and young women in HIV Prevention Trials Network (HPTN) 068 study.}, journal = {Sexually transmitted diseases}, volume = {}, number = {}, pages = {}, doi = {10.1097/OLQ.0000000000000954}, pmid = {30516725}, issn = {1537-4521}, abstract = {We combined behavioral survey data from the HIV Prevention Trials Network 068 study with phylogenetic information to determine if cluster membership was associated with characteristics of young women and their partners. Clusters were more likely to involve young women from specific villages and schools, indicating some localized transmission.}, }
@article {pmid30514795, year = {2018}, author = {Majhail, NS and Murphy, E and Laud, P and Preussler, JM and Denzen, EM and Abetti, B and Adams, A and Besser, R and Burns, LJ and Cerny, J and Drexler, R and Hahn, T and Idossa, L and Jahagirdar, B and Kamani, N and Loren, A and Mattila, D and McGuirk, J and Moore, H and Reynolds, J and Saber, W and Salazar, L and Schatz, B and Stiff, P and Wingard, JR and Syrjala, KL and Baker, KS}, title = {Randomized controlled trial of individualized treatment summary and survivorship care plans for hematopoietic cell transplantation survivors.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.203919}, pmid = {30514795}, issn = {1592-8721}, support = {R01 CA215134/CA/NCI NIH HHS/United States ; }, abstract = {Survivorship care plans may facilitate long-term care for cancer survivors, but their effectiveness has not been established in hematopoietic cell transplantation recipients. We evaluated the impact of individualized survivorship care plans on patient-reported outcomes among transplant survivors. Adult (≥18 years at transplant) survivors who were 1-5 years post-transplantation, proficient in English, and without relapse or secondary cancers were eligible for this multicenter randomized trial. Care plans were developed based on risk-factors and treatment exposures using patient data routinely submitted by transplant centers to the Center for International Blood and Marrow Transplant Research and published guidelines for long-term follow-up of transplant survivors. Phone surveys assessing patient-reported outcomes were conducted at baseline and 6-months. Primary endpoint was confidence in survivorship information, and secondary endpoints included cancer and treatment distress, knowledge of transplant exposures, health care utilization and health-related quality of life. Of 495 patients enrolled, 458 completed a baseline survey and were randomized (care plan=231, standard care=227); 200 (87%) and 199 (88%) completed the 6-month assessments, respectively. Patient characteristics were balanced in the two arms. Participants on care plan arm reported significantly lower distress scores at 6-months and an increase in the Mental Component Summary quality of life score assessed by the SF12 instrument. No effect was observed on the endpoint of confidence in survivorship information or other secondary outcomes. Provision of individualized survivorship care plans generated using registry data was associated with reduced distress and improved mental domain of quality of life among 1-5 year hematopoietic cell transplantation survivors. (clinicaltrials.gov NCT02200133).}, }
@article {pmid30514386, year = {2018}, author = {Boyiadzis, MM and Dhodapkar, MV and Brentjens, RJ and Kochenderfer, JN and Neelapu, SS and Maus, MV and Porter, DL and Maloney, DG and Grupp, SA and Mackall, CL and June, CH and Bishop, MR}, title = {Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance.}, journal = {Journal for immunotherapy of cancer}, volume = {6}, number = {1}, pages = {137}, pmid = {30514386}, issn = {2051-1426}, abstract = {Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.}, }
@article {pmid30513297, year = {2018}, author = {Wrenn, ED and Cheung, KJ}, title = {FoxP1 &quot;Tspans&quot; Quiescence and Activation of Mammary Stem Cells.}, journal = {Developmental cell}, volume = {47}, number = {5}, pages = {539-540}, doi = {10.1016/j.devcel.2018.11.017}, pmid = {30513297}, issn = {1878-1551}, abstract = {Stem cells can enter a reversible cell-cycle arrest state termed quiescence. In this issue of Developmental Cell, Fu et al. report that the transcription factor FoxP1 is necessary for postnatal mammary gland development and relieves Tspan8-dependent quiescence in basal mammary stem cells.}, }
@article {pmid30513095, year = {2018}, author = {Al-Rousan, T and Sparks, JA and Pettinger, M and Chlebowski, R and Manson, JE and Kauntiz, AM and Wallace, R}, title = {Menopausal hormone therapy and the incidence of carpal tunnel syndrome in postmenopausal women: Findings from the Women's Health Initiative.}, journal = {PloS one}, volume = {13}, number = {12}, pages = {e0207509}, doi = {10.1371/journal.pone.0207509}, pmid = {30513095}, issn = {1932-6203}, support = {K23 AR069688/AR/NIAMS NIH HHS/United States ; L30 AR066953/AR/NIAMS NIH HHS/United States ; }, abstract = {IMPORTANCE: Carpal tunnel syndrome (CTS) is a common and debilitating condition that commonly affects postmenopausal women.<br><br>OBJECTIVE: To determine the effect of menopausal hormone therapy (HT) in healthy postmenopausal women on CTS risk.<br><br>DESIGN: We conducted a secondary analysis of the Women's Health Initiative's (WHI) HT trials linked to Medicare claims data. Separate intention-to-treat analyses were performed for the two trials; the conjugated equine estrogens alone (CEE alone) and the trial of CEE plus medroxyprogesterone acetate (MPA) trial. (ClinicalTrials.gov, NCT number): NCT00000611.<br><br>SETTING: Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers.<br><br>PARTICIPANTS: The sample size included in the analysis was 16,053 community-dwelling women aged ≥65 years at study entry or those who later aged into Medicare eligibility, and who were enrolled in Medicare (including Part A and/or Part B coverage).<br><br>INTERVENTION: Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E+P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14203).<br><br>MAIN OUTCOME(S): The primary outcome was incident CTS and the secondary outcome was therapeutic CTS procedure occurring during the intervention phases of the trials.<br><br>RESULTS: A total of 16,053 women were randomized in both trials. During mean follow up of 4.5 ± 2.8 years in the CEE trial (n = 6,833), there were 203 incident CTS cases in the intervention and 262 incident CTS cases in the placebo group (HR, 0.78; 95% CI, 0.65-0.94; P = 0.009). The CEE+MPA trial (n = 9,220) followed participants for a mean of 3.7 ± 2.3 years. There were 173 incident CTS cases in the intervention compared to 203 cases in the placebo group (HR, 0.80, 95% CI, 0.65-0.97; P = 0.027).<br><br>CONCLUSIONS: These findings suggest a protective effect of menopausal HT on the incidence of CTS among postmenopausal women. A potential therapeutic role for other forms of estrogen therapy in the management of CTS warrants future research.}, }
@article {pmid30512095, year = {2018}, author = {Hershman, DL and Unger, JM and Crew, K}, title = {Acupuncture for Aromatase Inhibitor-Related Joint Pain Among Breast Cancer Patients.}, journal = {JAMA}, volume = {320}, number = {21}, pages = {2270-2271}, doi = {10.1001/jama.2018.16744}, pmid = {30512095}, issn = {1538-3598}, mesh = {Acupuncture Therapy ; *Aromatase Inhibitors ; *Arthralgia ; Breast Neoplasms ; Humans ; Personality ; }, }
@article {pmid30510914, year = {2018}, author = {Del Bene, G and Calabrò, F and Giannarelli, D and Plimack, ER and Harshman, LC and Yu, EY and Crabb, SJ and Pal, SK and Alva, AS and Powles, T and De Giorgi, U and Agarwal, N and Bamias, A and Ladoire, S and Necchi, A and Vaishampayan, UN and Niegisch, G and Bellmunt, J and Baniel, J and Galsky, MD and Sternberg, CN}, title = {Neoadjuvant vs. Adjuvant Chemotherapy in Muscle Invasive Bladder Cancer (MIBC): Analysis From the RISC Database.}, journal = {Frontiers in oncology}, volume = {8}, number = {}, pages = {463}, pmid = {30510914}, issn = {2234-943X}, abstract = {Background: MIBC is an aggressive disease, with 5-year survival rates ranging from 36 to 48% for p T3/p T4/p N+tumors. Perioperative treatment can improve overall survival, with more robust evidence in favor of neoadjuvant chemotherapy. Few randomized studies have compared neoadjuvant and adjuvant therapy in bladder cancer. Consequently, it has been difficult to establish the benefit of adjuvant chemotherapy (AC) in MIBC. Methods: Data from patients with muscle invasive bladder cancer (>pT2) collected from 2005 to 2012 within the RISC data base (Retrospective International Study of Cancers of the Urothelial Tract) were evaluated. Overall survival (OS), cancer specific survival (CSS), and disease-free survival (DFS) between NC and AC generated using the Kaplan-Meier method were compared for MIBC by log-rank test. All patients in this analysis received either NC or AC. Results: A total of 656 patients with MIBC (325 treated with AC and 331 with NC) were analyzed. The median DFS was 34.6 months (95% CI:25.3-43.9) for NC vs. 24.9 months (95% CI: 19.4-30.5) with AC, with a reduction in the risk of disease progression of 21% in favor of NC (HR: 0.78, 95% CI: 0.63-0.96, P = 0.02). There were no significant differences in terms of CSS (HR: 1.06, 95% CI: 0.79-1.43, P: 0.70), and OS (HR: 1.08, 95% CI: 0.83-1.39, P = 0.57). Conclusions: This study demonstrates superiority in DFS for NC compared to AC. The positive prognostic impact of complete pathological response to NC was confirmed.}, }
@article {pmid30510241, year = {2019}, author = {Huyghe, JR and Bien, SA and Harrison, TA and Kang, HM and Chen, S and Schmit, SL and Conti, DV and Qu, C and Jeon, J and Edlund, CK and Greenside, P and Wainberg, M and Schumacher, FR and Smith, JD and Levine, DM and Nelson, SC and Sinnott-Armstrong, NA and Albanes, D and Alonso, MH and Anderson, K and Arnau-Collell, C and Arndt, V and Bamia, C and Banbury, BL and Baron, JA and Berndt, SI and Bézieau, S and Bishop, DT and Boehm, J and Boeing, H and Brenner, H and Brezina, S and Buch, S and Buchanan, DD and Burnett-Hartman, A and Butterbach, K and Caan, BJ and Campbell, PT and Carlson, CS and Castellví-Bel, S and Chan, AT and Chang-Claude, J and Chanock, SJ and Chirlaque, MD and Cho, SH and Connolly, CM and Cross, AJ and Cuk, K and Curtis, KR and de la Chapelle, A and Doheny, KF and Duggan, D and Easton, DF and Elias, SG and Elliott, F and English, DR and Feskens, EJM and Figueiredo, JC and Fischer, R and FitzGerald, LM and Forman, D and Gala, M and Gallinger, S and Gauderman, WJ and Giles, GG and Gillanders, E and Gong, J and Goodman, PJ and Grady, WM and Grove, JS and Gsur, A and Gunter, MJ and Haile, RW and Hampe, J and Hampel, H and Harlid, S and Hayes, RB and Hofer, P and Hoffmeister, M and Hopper, JL and Hsu, WL and Huang, WY and Hudson, TJ and Hunter, DJ and Ibañez-Sanz, G and Idos, GE and Ingersoll, R and Jackson, RD and Jacobs, EJ and Jenkins, MA and Joshi, AD and Joshu, CE and Keku, TO and Key, TJ and Kim, HR and Kobayashi, E and Kolonel, LN and Kooperberg, C and Kühn, T and Küry, S and Kweon, SS and Larsson, SC and Laurie, CA and Le Marchand, L and Leal, SM and Lee, SC and Lejbkowicz, F and Lemire, M and Li, CI and Li, L and Lieb, W and Lin, Y and Lindblom, A and Lindor, NM and Ling, H and Louie, TL and Männistö, S and Markowitz, SD and Martín, V and Masala, G and McNeil, CE and Melas, M and Milne, RL and Moreno, L and Murphy, N and Myte, R and Naccarati, A and Newcomb, PA and Offit, K and Ogino, S and Onland-Moret, NC and Pardini, B and Parfrey, PS and Pearlman, R and Perduca, V and Pharoah, PDP and Pinchev, M and Platz, EA and Prentice, RL and Pugh, E and Raskin, L and Rennert, G and Rennert, HS and Riboli, E and Rodríguez-Barranco, M and Romm, J and Sakoda, LC and Schafmayer, C and Schoen, RE and Seminara, D and Shah, M and Shelford, T and Shin, MH and Shulman, K and Sieri, S and Slattery, ML and Southey, MC and Stadler, ZK and Stegmaier, C and Su, YR and Tangen, CM and Thibodeau, SN and Thomas, DC and Thomas, SS and Toland, AE and Trichopoulou, A and Ulrich, CM and Van Den Berg, DJ and van Duijnhoven, FJB and Van Guelpen, B and van Kranen, H and Vijai, J and Visvanathan, K and Vodicka, P and Vodickova, L and Vymetalkova, V and Weigl, K and Weinstein, SJ and White, E and Win, AK and Wolf, CR and Wolk, A and Woods, MO and Wu, AH and Zaidi, SH and Zanke, BW and Zhang, Q and Zheng, W and Scacheri, PC and Potter, JD and Bassik, MC and Kundaje, A and Casey, G and Moreno, V and Abecasis, GR and Nickerson, DA and Gruber, SB and Hsu, L and Peters, U}, title = {Discovery of common and rare genetic risk variants for colorectal cancer.}, journal = {Nature genetics}, volume = {51}, number = {1}, pages = {76-87}, doi = {10.1038/s41588-018-0286-6}, pmid = {30510241}, issn = {1546-1718}, support = {R01 CA059045/CA/NCI NIH HHS/United States ; R01 CA204279/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA160356/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; K23 DK103119/DK/NIDDK NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R21 CA191312/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; U01 CA185094/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; U01 CA152756/CA/NCI NIH HHS/United States ; R01 CA193677/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; }, abstract = {To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.}, }
@article {pmid30509329, year = {2018}, author = {Li, K and Anderson, G and Viallon, V and Arveux, P and Kvaskoff, M and Fournier, A and Krogh, V and Tumino, R and Sánchez, MJ and Ardanaz, E and Chirlaque, MD and Agudo, A and Muller, DC and Smith, T and Tzoulaki, I and Key, TJ and Bueno-de-Mesquita, B and Trichopoulou, A and Bamia, C and Orfanos, P and Kaaks, R and Hüsing, A and Fortner, RT and Zeleniuch-Jacquotte, A and Sund, M and Dahm, CC and Overvad, K and Aune, D and Weiderpass, E and Romieu, I and Riboli, E and Gunter, MJ and Dossus, L and Prentice, R and Ferrari, P}, title = {Risk prediction for estrogen receptor-specific breast cancers in two large prospective cohorts.}, journal = {Breast cancer research : BCR}, volume = {20}, number = {1}, pages = {147}, pmid = {30509329}, issn = {1465-542X}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; MR/M012190/1//Medical Research Council/United Kingdom ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C//Women's Health Initiative/International ; 14136//Cancer Research UK/United Kingdom ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; C570/A16491//Cancer Research UK/United Kingdom ; HHSN268201600001C//Women's Health Initiative/International ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; 1000143//Medical Research Council/United Kingdom ; HHSN268201600002C//Women's Health Initiative/International ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; C8221/A19170//Medical Research Council/United Kingdom ; HHSN268201600018C//Women's Health Initiative/International ; C8221/A19170//Cancer Research UK/United Kingdom ; HHSN268201600003C//Women's Health Initiative/International ; }, abstract = {BACKGROUND: Few published breast cancer (BC) risk prediction models consider the heterogeneity of predictor variables between estrogen-receptor positive (ER+) and negative (ER-) tumors. Using data from two large cohorts, we examined whether modeling this heterogeneity could improve prediction.<br><br>METHODS: We built two models, for ER+ (ModelER+) and ER- tumors (ModelER-), respectively, in 281,330 women (51% postmenopausal at recruitment) from the European Prospective Investigation into Cancer and Nutrition cohort. Discrimination (C-statistic) and calibration (the agreement between predicted and observed tumor risks) were assessed both internally and externally in 82,319 postmenopausal women from the Women's Health Initiative study. We performed decision curve analysis to compare ModelER+ and the Gail model (ModelGail) regarding their applicability in risk assessment for chemoprevention.<br><br>RESULTS: Parity, number of full-term pregnancies, age at first full-term pregnancy and body height were only associated with ER+ tumors. Menopausal status, age at menarche and at menopause, hormone replacement therapy, postmenopausal body mass index, and alcohol intake were homogeneously associated with ER+ and ER- tumors. Internal validation yielded a C-statistic of 0.64 for ModelER+ and 0.59 for ModelER-. External validation reduced the C-statistic of ModelER+ (0.59) and ModelGail (0.57). In external evaluation of calibration, ModelER+ outperformed the ModelGail: the former led to a 9% overestimation of the risk of ER+ tumors, while the latter yielded a 22% underestimation of the overall BC risk. Compared with the treat-all strategy, ModelER+ produced equal or higher net benefits irrespective of the benefit-to-harm ratio of chemoprevention, while ModelGail did not produce higher net benefits unless the benefit-to-harm ratio was below 50. The clinical applicability, i.e. the area defined by the net benefit curve and the treat-all and treat-none strategies, was 12.7 × 10- 6 for ModelER+ and 3.0 × 10- 6 for ModelGail.<br><br>CONCLUSIONS: Modeling heterogeneous epidemiological risk factors might yield little improvement in BC risk prediction. Nevertheless, a model specifically predictive of ER+ tumor risk could be more applicable than an omnibus model in risk assessment for chemoprevention.}, }
@article {pmid30500442, year = {2018}, author = {Elsawy, M and Storer, BE and Milano, F and Sandmaier, BM and Delaney, C and Salit, RB and Rashad, AH and Woolfrey, AE and Appelbaum, FR and Storb, R and Sorror, ML}, title = {Prognostic Performance of the Augmented Hematopoietic Cell Transplantation-Specific Comorbidity/Age Index in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation from Alternative Graft Sources.}, 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.2018.11.030}, pmid = {30500442}, issn = {1523-6536}, support = {P01 CA078902/CA/NCI NIH HHS/United States ; P01 HL122173/HL/NHLBI NIH HHS/United States ; R00 HL088021/HL/NHLBI NIH HHS/United States ; }, abstract = {The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplantation comorbidities and estimate their impact on post-transplantation risks of nonrelapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and the values of 3 markers: ferritin, albumin, and platelet count. So far, research involving The HCT-CI has been limited almost exclusively to recipients of allogeneic hematopoietic cell transplantation (HCT) from HLA-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (n = 345), haploidentical (n = 117), and umbilical cord blood (UCB; n = 262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared with the original HCT-CI (.63 versus .59). Findings were similar for recipients of HLA-mismatched (.62 versus .59), haploidentical (.60 versus .54), or UCB grafts (.65 versus .61). Compared with patients with an HCT-CI score ≥4, those with a score <4 had a higher survival rate among recipients of HLA-mismatched (55% versus 39%; P < .0008), HLA-haploidentical (58% versus 38%; P = .01), or UCB (67% versus 48%; P = .004) grafts. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources.}, }
@article {pmid30499236, year = {2019}, author = {Kim, S and Wang, M and Tyrer, JP and Jensen, A and Wiensch, A and Liu, G and Lee, AW and Ness, RB and Salvatore, M and Tworoger, SS and Whittemore, AS and Anton-Culver, H and Sieh, W and Olson, SH and Berchuck, A and Goode, EL and Goodman, MT and Doherty, JA and Chenevix-Trench, G and Rossing, MA and Webb, PM and Giles, GG and Terry, KL and Ziogas, A and Fortner, RT and Menon, U and Gayther, SA and Wu, AH and Song, H and Brooks-Wilson, A and Bandera, EV and Cook, LS and Cramer, DW and Milne, RL and Winham, SJ and Kjaer, SK and Modugno, F and Thompson, PJ and Chang-Claude, J and Harris, HR and Schildkraut, JM and Le, ND and Wentzensen, N and Trabert, B and Høgdall, E and Huntsman, D and Pike, MC and Pharoah, PDP and Pearce, CL and Mukherjee, B}, title = {A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.}, journal = {International journal of cancer}, volume = {144}, number = {9}, pages = {2192-2205}, doi = {10.1002/ijc.32029}, pmid = {30499236}, issn = {1097-0215}, support = {U01 CA069417/CA/NCI NIH HHS/United States ; M01-RR000056//National Center for Research Resources/ ; N01 PC067010/PC/NCI NIH HHS/United States ; P50 CA159981/CA/NCI NIH HHS/United States ; //Peter MacCallum Foundation/ ; R01 CA087538/CA/NCI NIH HHS/United States ; //Mermaid I project/ ; //State of Connecticut Department of Public Health/ ; //Connecticut Department of Public Health/ ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; M01 RR000056/RR/NCRR NIH HHS/United States ; U19-CA148112//National Cancer Institute's Genetic Associations and Mechanisms in Oncology/ ; P30 CA072720/CA/NCI NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; R03 CA113148/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; PPD/RPCI.074//Ovarian Cancer Research Fund/ ; K22 CA138563/CA/NCI NIH HHS/United States ; R01 CA058860/CA/NCI NIH HHS/United States ; 00-01389V-20170, 2II0200//California Cancer Center Research Program/ ; //Mayo Foundation/ ; //Fred C. and Katherine B. Andersen Foundation/ ; R01 CA080742/CA/NCI NIH HHS/United States ; 1043134, 199600, ID400281, ID400413, 209057, 396414, 1074383//National Health and Medical Research Council/ ; //Minnesota Ovarian Cancer Alliance/ ; R01 CA074850/CA/NCI NIH HHS/United States ; //National Institute for Health Research University College London Hospitals Biomedical Research Centre/ ; R01 CA063678/CA/NCI NIH HHS/United States ; 223175 HEALTH F2 2009-223175//Seventh Framework Programme/ ; P50 CA105009/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; 94 222 52//Kraeftens Bekaempelse/ ; P30 CA008748/CA/NCI NIH HHS/United States ; K22 CA193860/CA/NCI NIH HHS/United States ; Multi-State Applications 182, 191, 211//Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and The Cancer Foundation of Western Australia/ ; NSF DMS 1406712 BM//National Science Foundation/ ; 01 GB 9401//German Federal Ministry of Education and Research/ ; //Ovarian Cancer Australia/ ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; DAMD17-02-1-0666DAMD17-02-1-0669W81XWH-10-1-02802//U.S. Department of Defense/ ; R03 CA115195/CA/NCI NIH HHS/United States ; DAMD17-01-1-0729//Medical Research and Materiel Command/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; //Cancer Institute of New Jersey/ ; R01 CA054419/CA/NCI NIH HHS/United States ; //Intramural Research Program of the National Cancer Institute/ ; 6613-1415-53//National Health Research and Development Program, Health Canada/ ; R01 CA122443/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; //The Eve Appeal (The Oak Foundation)/ ; R01 CA076016/CA/NCI NIH HHS/United States ; R01 CA160669/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; R21 ES020811/ES/NIEHS NIH HHS/United States ; NIH ES 20811 BM//National Institute of Environmental Health Sciences/ ; U19 CA148112/CA/NCI NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; N01 CN025403/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; 1 R01CA160669-01A1, K07-CA080668, NIH-K07 CA095666, NIH-K22-CA138563, P30 CA04, P30 CA046592, P30-CA008748, P30-CA072720, P50-CA159981, R01 CA076016, R01-CA61107, R01-CA83918, R01-CA95023, R21-CA222867//National Cancer Institute/ ; K22 CA193860, N01-CN-55424, N01-PC-67001, N01CN025403, N01PC67010, P01 CA87969, P01CA17054, P30-CA15083, P30CA14089, P50-CA105009, P50-CA136393, R01 CA49449, R01-CA0568860, R01-CA063678, R01-CA074850, R01-CA080742, R01-CA112523, R01-CA122443, R01-CA54419, R01-CA58598, R01-CA67262, R01-CA76016, R01-CA87538, R01CA61132, R03CA113148, R03CA115195, T32 ES013678, U01 CA69417, U01 CA71966, UM1 CA176726, UM1 CA186107//National Institutes of Health/ ; MOP-86727//Canadian Institutes of Health Research/Canada ; //Deutsches Krebsforschungszentrum/ ; K07 CA095666/CA/NCI NIH HHS/United States ; LVS-39420//Lon V Smith Foundation/ ; R01 CA112523/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.}, }
@article {pmid30499135, year = {2018}, author = {Fanidi, A and Carreras-Torres, R and Larose, TL and Yuan, JM and Stevens, VL and Weinstein, SJ and Albanes, D and Prentice, R and Pettinger, M and Cai, Q and Blot, WJ and Arslan, AA and Zeleniuch-Jacquotte, A and McCullough, ML and Le Marchand, L and Wilkens, LR and Haiman, CA and Zhang, X and Stampfer, MJ and Smith-Warner, SA and Giovannucci, E and Giles, GG and Hodge, AM and Severi, G and Johansson, M and Grankvist, K and Langhammer, A and Brumpton, BM and Wang, R and Gao, YT and Ericson, U and Bojesen, SE and Arnold, SM and Koh, WP and Shu, XO and Xiang, YB and Li, H and Zheng, W and Lan, Q and Visvanathan, K and Hoffman-Bolton, J and Ueland, PM and Midttun, Ø and Caporaso, NE and Purdue, M and Freedman, ND and Buring, JE and Lee, IM and Sesso, HD and Michael Gaziano, J and Manjer, J and Relton, CL and Hung, RJ and Amos, CI and Johansson, M and Brennan, P and , }, title = {Is high vitamin B12 status a cause of lung cancer?.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.32033}, pmid = {30499135}, issn = {1097-0215}, support = {C18281/A19169//Cancer Research UK/United Kingdom ; 1U01CA155340-01//Division of Cancer Prevention, National Cancer Institute/ ; 267776/H10//The Research Council of Norway/ ; }, abstract = {Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.}, }
@article {pmid30488475, year = {2019}, author = {Turner, RM and Domínguez-Islas, CP and Jackson, D and Rhodes, KM and White, IR}, title = {Incorporating external evidence on between-trial heterogeneity in network meta-analysis.}, journal = {Statistics in medicine}, volume = {38}, number = {8}, pages = {1321-1335}, doi = {10.1002/sim.8044}, pmid = {30488475}, issn = {1097-0258}, support = {MC_U105260558//Medical Research Council/United Kingdom ; MC_UU_12023/21//Medical Research Council/United Kingdom ; }, abstract = {In a network meta-analysis, between-study heterogeneity variances are often very imprecisely estimated because data are sparse, so standard errors of treatment differences can be highly unstable. External evidence can provide informative prior distributions for heterogeneity and, hence, improve inferences. We explore approaches for specifying informative priors for multiple heterogeneity variances in a network meta-analysis. First, we assume equal heterogeneity variances across all pairwise intervention comparisons (approach 1); incorporating an informative prior for the common variance is then straightforward. Models allowing unequal heterogeneity variances are more realistic; however, care must be taken to ensure implied variance-covariance matrices remain valid. We consider three strategies for specifying informative priors for multiple unequal heterogeneity variances. Initially, we choose different informative priors according to intervention comparison type and assume heterogeneity to be proportional across comparison types and equal within comparison type (approach 2). Next, we allow all heterogeneity variances in the network to differ, while specifying a common informative prior for each. We explore two different approaches to this: placing priors on variances and correlations separately (approach 3) or using an informative inverse Wishart distribution (approach 4). Our methods are exemplified through application to two network metaanalyses. Appropriate informative priors are obtained from previously published evidence-based distributions for heterogeneity. Relevant prior information on between-study heterogeneity can be incorporated into network meta-analyses, without needing to assume equal heterogeneity across treatment comparisons. The approaches proposed will be beneficial in sparse data sets and provide more appropriate intervals for treatment differences than those based on imprecise heterogeneity estimates.}, }
@article {pmid30487530, year = {2018}, author = {Zhang, B and Whiteaker, JR and Hoofnagle, AN and Baird, GS and Rodland, KD and Paulovich, AG}, title = {Clinical potential of mass spectrometry-based proteogenomics.}, journal = {Nature reviews. Clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41571-018-0135-7}, pmid = {30487530}, issn = {1759-4782}, abstract = {Cancer genomics research aims to advance personalized oncology by finding and targeting specific genetic alterations associated with cancers. In genome-driven oncology, treatments are selected for individual patients on the basis of the findings of tumour genome sequencing. This personalized approach has prolonged the survival of subsets of patients with cancer. However, many patients do not respond to the predicted therapies based on the genomic profiles of their tumours. Furthermore, studies pairing genomic and proteomic analyses of samples from the same tumours have shown that the proteome contains novel information that cannot be discerned through genomic analysis alone. This observation has led to the concept of proteogenomics, in which both types of data are leveraged for a more complete view of tumour biology that might enable patients to be more successfully matched to effective treatments than they would using genomics alone. In this Perspective, we discuss the added value of proteogenomics over the current genome-driven approach to the clinical characterization of cancers and summarize current efforts to incorporate targeted proteomic measurements based on selected/multiple reaction monitoring (SRM/MRM) mass spectrometry into the clinical laboratory to facilitate clinical proteogenomics.}, }
@article {pmid30486865, year = {2018}, author = {Mongiovi, JM and Zirpoli, GR and Cannioto, R and Sucheston-Campbell, LE and Hershman, DL and Unger, JM and Moore, HCF and Stewart, JA and Isaacs, C and Hobday, TJ and Salim, M and Hortobagyi, GN and Gralow, JR and Thomas Budd, G and Albain, KS and Ambrosone, CB and McCann, SE}, title = {Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).}, journal = {Breast cancer research : BCR}, volume = {20}, number = {1}, pages = {146}, pmid = {30486865}, issn = {1465-542X}, support = {N01 CA004919/CA/NCI NIH HHS/United States ; T32CA113951/CA/NCI NIH HHS/United States ; UG1CA189974/CA/NCI NIH HHS/United States ; U10 CA004919/CA/NCI NIH HHS/United States ; P30 CA016056/CA/NCI NIH HHS/United States ; T32 CA113951/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; CA68183/CA/NCI NIH HHS/United States ; CA139426/CA/NCI NIH HHS/United States ; CA189953/CA/NCI NIH HHS/United States ; U10 CA180858/CA/NCI NIH HHS/United States ; CA46282/CA/NCI NIH HHS/United States ; CA116395/CA/NCI NIH HHS/United States ; CA180858/CA/NCI NIH HHS/United States ; CA04919/CA/NCI NIH HHS/United States ; CA180828/CA/NCI NIH HHS/United States ; U10 CA046282/CA/NCI NIH HHS/United States ; CA180888/CA/NCI NIH HHS/United States ; U10 CA180828/CA/NCI NIH HHS/United States ; CA180819/CA/NCI NIH HHS/United States ; P30CA016056/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; UG1 CA189953/CA/NCI NIH HHS/United States ; U10 CA068183/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment.<br><br>METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900).<br><br>RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05).<br><br>CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.}, }
@article {pmid30485471, year = {2019}, author = {Zhou, J and Han, J and Nutescu, EA and Patel, PR and Sweiss, K and Calip, GS}, title = {Discontinuation and Nonadherence to Medications for Chronic Conditions after Hematopoietic Cell Transplantation: A 6-Year Propensity Score-Matched Cohort Study.}, journal = {Pharmacotherapy}, volume = {39}, number = {1}, pages = {55-66}, doi = {10.1002/phar.2197}, pmid = {30485471}, issn = {1875-9114}, support = {UL1TR002003//National Center for Advancing Translational Sciences/ ; UL1TR002003//National Institutes of Health/ ; //UIC-AbbVie Fellowship in Health Economics and Outcomes Research/ ; //National Center for Advancing Translational Sciences/ ; KL2TR002002//National Institutes of Health/ ; KL2TR000048//National Institutes of Health/ ; }, abstract = {INTRODUCTION: Hematopoietic cell transplantation (HCT) is an established curative option for patients with hematological malignancies and other life-threatening conditions. Evidence on nonpersistence and nonadherence to oral medications for chronic conditions among patients following HCT is lacking.<br><br>OBJECTIVES: This study aims to examine patterns of oral medication use for chronic conditions following HCT in the U.S.<br><br>METHODS: Nonpersistence and nonadherence to oral medications for diabetes, hypertension, and dyslipidemia among HCT recipients were assessed in a cohort that included 1382 autologous and 650 allogeneic HCT recipients with hematological malignancies using the Truven Health MarketScan Research Database between 2009 and 2014. Recipients of HCT were compared to propensity score-matched cancer patients receiving chemotherapy without transplantation. Multivariable Cox proportional hazards models and generalized estimating equations were used to determine characteristics associated with nonpersistence and nonadherence to oral chronic medications, respectively.<br><br>RESULTS: Recipients of HCT had higher risks of discontinuing medication for diabetes mellitus (allogeneic HCT hazard ratio [HR] = 1.93, 95% confidence interval [CI] 1.10-3.39; autologous HCT HR = 1.49, 95% CI 1.04-2.15); hypertension (allogeneic HCT HR = 1.75, 95% CI 1.21-2.53; autologous HCT HR = 1.32, 95% CI 1.07-1.62), and dyslipidemia (allogeneic HCT HR = 2.02, 95% CI 1.39-2.93; autologous HCT, HR = 1.26, 95% CI 0.98-1.61) compared to patients treated with only chemotherapy. Lower odds of adherence to antihypertensive medications (odds ratio [OR] = 0.58, 95% CI 0.38-0.89) and to lipid-lowering medications (OR = 0.38, 95% CI 0.22-0.65) were observed in allogeneic HCT recipients compared with propensity score-matched patients who underwent chemotherapy only.<br><br>CONCLUSIONS: Poor medication persistence and adherence to chronic disease medications are common after HCT. Further research to improve long-term outcomes following HCT should include management of medication therapy for chronic comorbid conditions.}, }
@article {pmid30482247, year = {2018}, author = {Miller, NJ and Church, CD and Fling, SP and Kulikauskas, R and Ramchurren, N and Shinohara, MM and Kluger, HM and Bhatia, S and Lundgren, L and Cheever, MA and Topalian, SL and Nghiem, P}, title = {Merkel cell polyomavirus-specific immune responses in patients with Merkel cell carcinoma receiving anti-PD-1 therapy.}, journal = {Journal for immunotherapy of cancer}, volume = {6}, number = {1}, pages = {131}, pmid = {30482247}, issn = {2051-1426}, support = {P30 CA015704//National Cancer Institute/ ; K24 CA139052//National Cancer Institute/ ; R01 CA162522//National Cancer Institute/ ; 15CHAS04//Prostate Cancer Foundation/ ; }, abstract = {BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. MCC is associated with sun exposure and, in 80% of cases, Merkel cell polyomavirus (MCPyV). MCPyV-specific T and B cell responses provide a unique opportunity to study cancer-specific immunity throughout PD-1 blockade therapy.<br><br>METHODS: Immune responses were assessed in patients (n = 26) with advanced MCC receiving pembrolizumab. Peripheral blood mononuclear cells (PBMC) were collected at baseline and throughout treatment. MCPyV-oncoprotein antibodies were quantified and T cells were assessed for MCPyV-specificity via tetramer staining and/or cytokine secretion. Pre-treatment tumor biopsies were analyzed for T cell receptor clonality.<br><br>RESULTS: MCPyV oncoprotein antibodies were detectable in 15 of 17 (88%) of virus-positive MCC (VP-MCC) patients. Antibodies decreased in 10 of 11 (91%) patients with responding tumors. Virus-specific T cells decreased over time in patients who had a complete response, and increased in patients who had persistent disease. Tumors that were MCPyV(+) had a strikingly more clonal (less diverse) intratumoral TCR repertoire than virus-negative tumors (p = 0.0001).<br><br>CONCLUSIONS: Cancer-specific T and B cell responses generally track with disease burden during PD-1 blockade, in proportion to presence of antigen. Intratumoral TCR clonality was significantly greater in VP-MCC than VN-MCC tumors, suggesting expansion of a limited number of dominant clones in response to fewer immunogenic MCPyV antigens. In contrast, VN-MCC tumors had lower clonality, suggesting a diverse T cell response to numerous neoantigens. These findings reveal differences in tumor-specific immunity for VP-MCC and VN-MCC, both of which often respond to anti-PD-1 therapy.}, }
@article {pmid30481594, year = {2019}, author = {Inamoto, Y and Valdés-Sanz, N and Ogawa, Y and Alves, M and Berchicci, L and Galvin, J and Greinix, H and Hale, GA and Horn, B and Kelly, D and Liu, H and Rowley, S and Schoemans, H and Shah, A and Lupo Stanghellini, MT and Agrawal, V and Ahmed, I and Ali, A and Bhatt, N and Byrne, M and Chhabra, S and DeFilipp, Z and Fahnehjelm, K and Farhadfar, N and Horn, E and Lee, C and Nathan, S and Penack, O and Prasad, P and Rotz, S and Rovó, A and Yared, J and Pavletic, S and Basak, GW and Battiwalla, M and Duarte, R and Savani, BN and Flowers, MED and Shaw, BE and Petriček, I}, title = {Ocular Graft-versus-Host Disease after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {25}, number = {2}, pages = {e46-e54}, doi = {10.1016/j.bbmt.2018.11.021}, pmid = {30481594}, issn = {1523-6536}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care.}, }
@article {pmid30481098, year = {2018}, author = {Beaber, EF and Sprague, BL and Tosteson, ANA and Haas, JS and Onega, T and Schapira, MM and McCarthy, AM and Li, CI and Herschorn, SD and Lehman, CD and Wernli, KJ and Barlow, WE}, title = {Multilevel Predictors of Continued Adherence to Breast Cancer Screening Among Women Ages 50-74 Years in a Screening Population.}, journal = {Journal of women's health (2002)}, volume = {}, number = {}, pages = {}, doi = {10.1089/jwh.2018.6997}, pmid = {30481098}, issn = {1931-843X}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; U01 CA163304/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: U.S. women of ages 50-74 years are recommended to receive screening mammography at least biennially. Our objective was to evaluate multilevel predictors of nonadherence among screened women, as these are not well known.<br><br>MATERIALS AND METHODS: A cohort study was conducted among women of ages 50-74 years with a screening mammogram in 2011 with a negative finding (Breast Imaging-Reporting and Data System 1 or 2) within Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium research centers. We evaluated the association between woman-level factors, radiology facility, and PROSPR research center, and nonadherence to breast cancer screening guidelines, defined as not receiving breast imaging within 27 months of an index screening mammogram. Multilevel mixed-effects logistic regression was used to calculate odds ratios and 95% confidence intervals.<br><br>RESULTS: Nonadherence to guideline-recommended screening interval was 15.5% among 51,241 women with a screening mammogram. Non-Hispanic Asian/Pacific Islander women, women of other races, heavier women, and women of ages 50-59 years had a greater odds of nonadherence. There was no association with ZIP code median income. Nonadherence varied by research center and radiology facility (variance = 0.10, standard error = 0.03). Adjusted radiology facility nonadherence rates ranged from 10.0% to 26.5%. One research center evaluated radiology facility communication practices for screening reminders and scheduling, but these were not associated with nonadherence.<br><br>CONCLUSIONS: Breast cancer screening interval nonadherence rates in screened women varied across radiology facilities even after adjustment for woman-level characteristics and research center. Future studies should investigate other characteristics of facilities, practices, and health systems to determine factors integral to increasing continued adherence to breast cancer screening.}, }
@article {pmid30478421, year = {2018}, author = {Rotinen, M and You, S and Yang, J and Coetzee, SG and Reis-Sobreiro, M and Huang, WC and Huang, F and Pan, X and Yáñez, A and Hazelett, DJ and Chu, CY and Steadman, K and Morrissey, CM and Nelson, PS and Corey, E and Chung, LWK and Freedland, SJ and Di Vizio, D and Garraway, IP and Murali, R and Knudsen, BS and Freeman, MR}, title = {ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis.}, journal = {Nature medicine}, volume = {24}, number = {12}, pages = {1887-1898}, doi = {10.1038/s41591-018-0241-1}, pmid = {30478421}, issn = {1546-170X}, support = {R01 CA220327/CA/NCI NIH HHS/United States ; }, abstract = {Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.}, }
@article {pmid30476588, year = {2018}, author = {Carr, PR and Banbury, B and Berndt, SI and Campbell, PT and Chang-Claude, J and Hayes, RB and Howard, BV and Jansen, L and Jacobs, E and Lane, DS and Nishihara, R and Ogino, S and Phipps, AI and Slattery, ML and Stefanick, ML and Wallace, R and Walter, V and White, E and Wu, K and Peters, U and Chan, AT and Newcomb, PA and Brenner, H and Hoffmeister, M}, title = {Association Between Intake of Red and Processed Meat and Survival in Patients With Colorectal Cancer in a Pooled Analysis.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cgh.2018.11.036}, pmid = {30476588}, issn = {1542-7714}, support = {R01 CA059045/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; R01 CA176272/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; UM1 CA167551/CA/NCI NIH HHS/United States ; P50 CA127003/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND &amp; AIMS: Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis.<br><br>METHODS: We pooled data from 7627 patients with stage I-IV CRC from 10 studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of intake of red and processed meat before diagnosis with overall and CRC-specific survival.<br><br>RESULTS: Among 7627 patients with CRC, 2338 died, including 1576 from CRC, over a median follow-up time of 5.1 years. In multivariable-adjusted analyses, higher intake of red or processed meat was not associated with overall survival of patients with stage I-III CRC: Q4 vs Q1 red meat hazard ratio [HR], 1.08 (95% CI, 0.93-1.26) and Q4 vs Q1 processed meat HR, 1.10 (95% CI, 0.93-1.32) or with CRC-specific survival: Q4 vs Q1 red meat HR, 1.09 (95% CI, 0.89-1.33) and Q4 vs Q1 processed meat HR, 1.11 (95% CI, 0.87-1.42). Results were similar for patients with stage IV CRC. However, patients with stage I-III CRC who reported an intake of processed meat above the study-specific medians had a higher risk of death from any cause (HR, 1.12; 95% CI, 1.01-1.25) than patients who reported eating at or less than the median.<br><br>CONCLUSION: In this large consortium of CRC patient cohorts, intake of red and processed meat before a diagnosis of CRC was not associated with shorter survival time after diagnosis, although a possible weak adverse association cannot be excluded. Studies that evaluate dietary data from several time points before and after cancer diagnosis are required to confirm these findings.}, }
@article {pmid30476131, year = {2018}, author = {Wang, X and Dai, JY and Albanes, D and Arndt, V and Berndt, SI and Bézieau, S and Brenner, H and Buchanan, DD and Butterbach, K and Caan, B and Casey, G and Campbell, PT and Chan, AT and Chen, Z and Chang-Claude, J and Cotterchio, M and Easton, DF and Giles, GG and Giovannucci, E and Grady, WM and Hoffmeister, M and Hopper, JL and Hsu, L and Jenkins, MA and Joshi, AD and Lampe, JW and Larsson, SC and Lejbkowicz, F and Li, L and Lindblom, A and Le Marchand, L and Martin, V and Milne, RL and Moreno, V and Newcomb, PA and Offitt, K and Ogino, S and Pharoah, PDP and Pinchev, M and Potter, JD and Rennert, HS and Rennert, G and Saliba, W and Schafmayer, C and Schoen, RE and Schrotz-King, P and Slattery, ML and Song, M and Stegmaier, C and Weinstein, SJ and Wolk, A and Woods, MO and Wu, AH and Gruber, SB and Peters, U and White, E}, title = {Mendelian randomization analysis of C-reactive protein on colorectal cancer risk.}, journal = {International journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ije/dyy244}, pmid = {30476131}, issn = {1464-3685}, support = {U01 CA152756/CA/NCI NIH HHS/United States ; }, abstract = {Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach.<br><br>Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk.<br><br>Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors.<br><br>Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.}, }
@article {pmid30475957, year = {2018}, author = {Schübel, R and Nattenmüller, J and Sookthai, D and Nonnenmacher, T and Graf, ME and Riedl, L and Schlett, CL and von Stackelberg, O and Johnson, T and Nabers, D and Kirsten, R and Kratz, M and Kauczor, HU and Ulrich, CM and Kaaks, R and Kühn, T}, title = {Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial.}, journal = {The American journal of clinical nutrition}, volume = {108}, number = {5}, pages = {933-945}, doi = {10.1093/ajcn/nqy196}, pmid = {30475957}, issn = {1938-3207}, abstract = {Background: Although preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies.<br><br>Objective: We conducted a randomized controlled trial to test whether ICR, operationalized as the &quot;5:2 diet,&quot; has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen.<br><br>Design: One hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) ≥25 to <40, 50% women], aged 35-65 y, were randomly assigned to an ICR group (5 d without energy restriction and 2 d with 75% energy deficit, net weekly energy deficit ∼20%), a CCR group (daily energy deficit ∼20%), or a control group (no advice to restrict energy) and participated in a 12-wk intervention phase, a 12-wk maintenance phase, and a 26-wk follow-up phase.<br><br>Results: Loge relative weight change over the intervention phase was -7.1% ± 0.7% (mean ± SEM) with ICR, -5.2% ± 0.6% with CCR, and -3.3% ± 0.6% with the control regimen (Poverall < 0.001, PICR vs. CCR = 0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was -5.2% ± 1.2% with ICR, -4.9% ± 1.1% with CCR, and -1.7% ± 0.8% with the control regimen (Poverall = 0.01, PICR vs. CCR = 0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers.<br><br>Conclusion: Our results on the effects of the &quot;5:2 diet&quot; indicate that ICR may be equivalent but not superior to CCR for weight reduction and prevention of metabolic diseases. This trial was registered at clinicaltrials.gov as NCT02449148.}, }
@article {pmid30470817, year = {2018}, author = {Ryser, MD and Yu, M and Grady, W and Siegmund, K and Shibata, D}, title = {Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {17292}, pmid = {30470817}, issn = {2045-2322}, support = {U54 CA217376/CA/NCI NIH HHS/United States ; U54CA217376//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P300P2-154583//Schweizerischer Nationalfonds zur F&amp;#x00F6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; K99 CA207872/CA/NCI NIH HHS/United States ; P30CA014089//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA196569//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; K99CA207872//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Genomic intratumoral heterogeneity (ITH) is common in cancers, but the extent of phenotypic ITH is uncertain because most subclonal mutations are passengers. Since tumor phenotypes are largely driven by epigenetics, methylomic analyses can provide insights into phenotypic ITH. Following this principle, we determined the extent of epigenetic ITH in 16 human colorectal tumors by comparing the methylomes from spatially separated regions in each tumor. Methylomes from opposite tumor sides were similar (Pearson correlation >0.95) with little evidence of ITH or stepwise selection during growth, suggesting that the epigenome of a sampled tumor largely reflects that of its founder cell. Epigenetic conservation was functional, with higher conservation at promoters and expressed genes compared to non-coding regions. Despite epigenomic conservation, RNA expression varied between individual tumor glands, indicating continued adaption during growth. Because many promoters and enhancers were unmethylated, continued adaptation may be due to phenotypic plasticity. Gene enrichment analyses identified that interferon signaling and antigen-processing and presenting pathways were strongly conserved during tumor growth, suggesting a mechanism for immune evasion. In summary, our findings suggest that epigenomes are preferentially conserved during tumor growth and that early tumor cells are poised for rapid growth, phenotypic adaptation, and immune evasion.}, }
@article {pmid30470782, year = {2018}, author = {Gyanchandani, R and Kvam, E and Heller, R and Finehout, E and Smith, N and Kota, K and Nelson, JR and Griffin, W and Puhalla, S and Brufsky, AM and Davidson, NE and Lee, AV}, title = {Whole genome amplification of cell-free DNA enables detection of circulating tumor DNA mutations from fingerstick capillary blood.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {17313}, pmid = {30470782}, issn = {2045-2322}, abstract = {The ability to measure mutations in plasma cell-free DNA (cfDNA) has the potential to revolutionize cancer surveillance and treatment by enabling longitudinal monitoring not possible with solid tumor biopsies. However, obtaining sufficient quantities of cfDNA remains a challenge for assay development and clinical translation; consequently, large volumes of venous blood are typically required. Here, we test proof-of-concept for using smaller volumes via fingerstick collection. Matched venous and fingerstick blood were obtained from seven patients with metastatic breast cancer. Fingerstick blood was separated at point-of-care using a novel paper-based concept to isolate plasma centrifuge-free. Patient cfDNA was then analyzed with or without a new method for whole genome amplification via rolling-circle amplification (WG-RCA). We identified somatic mutations by targeted sequencing and compared the concordance of mutation detection from venous and amplified capillary samples by droplet-digital PCR. Patient mutations were detected with 100% concordance after WG-RCA, although in some samples, allele frequencies showed greater variation likely due to differential amplification or primer inaccessibility. These pilot findings provide physiological evidence that circulating tumor DNA is accessible by fingerstick and sustains presence/absence of mutation detection after whole-genome amplification. Further refinement may enable simpler and less-invasive methods for longitudinal or theranostic surveillance of metastatic cancer.}, }
@article {pmid30466891, year = {2018}, author = {Mahon, KL and Qu, W and Lin, HM and Spielman, C and Cain, D and Jacobs, C and Stockler, MR and Higano, CS and de Bono, JS and Chi, KN and Clark, SJ and Horvath, LG}, title = {Serum Free Methylated Glutathione S-transferase 1 DNA Levels, Survival, and Response to Docetaxel in Metastatic, Castration-resistant Prostate Cancer: Post Hoc Analyses of Data from a Phase 3 Trial.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2018.11.001}, pmid = {30466891}, issn = {1873-7560}, abstract = {BACKGROUND: Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts.<br><br>OBJECTIVE: To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC.<br><br>Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients.<br><br>Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods.<br><br>RESULTS AND LIMITATIONS: Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data.<br><br>CONCLUSIONS: This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool.<br><br>PATIENT SUMMARY: In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.}, }
@article {pmid30466757, year = {2018}, author = {Appelbaum, FR}, title = {Hematopoietic cell transplantation as treatment of patients with acute myeloid leukemia with measurable residual disease after consolidation therapy.}, journal = {Best practice &amp; research. Clinical haematology}, volume = {31}, number = {4}, pages = {405-409}, doi = {10.1016/j.beha.2018.09.009}, pmid = {30466757}, issn = {1532-1924}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {The persistence of measurable residual disease (MRD) following induction chemotherapy is the single most powerful prognostic factor available to clinicians treating patients with acute myeloid leukemia (AML). How to use this information to guide subsequent therapy is complex, and influenced by the category of AML being treated, the assays used to measure MRD, MRD levels and kinetics, and the spectrum of therapies available to the patient. In this literature-based review, each of these issues will be discussed, with a particular emphasis on the role of hematopoietic cell transplantation in the treatment of MRD-positive patients.}, }
@article {pmid30462654, year = {2018}, author = {Pavía-Ruz, N and Barrera-Fuentes, GA and Villanueva-Jorge, S and Che-Mendoza, A and Campuzano-Rincón, JC and Manrique-Saide, P and Rojas, DP and Vazquez-Prokopec, GM and Halloran, ME and Longini, IM and Gómez-Dantés, H}, title = {Dengue seroprevalence in a cohort of schoolchildren and their siblings in Yucatan, Mexico (2015-2016).}, journal = {PLoS neglected tropical diseases}, volume = {12}, number = {11}, pages = {e0006748}, pmid = {30462654}, issn = {1935-2735}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; U54 GM111274/GM/NIGMS NIH HHS/United States ; }, mesh = {Adolescent ; Antibodies, Viral/*blood ; Child ; Child, Preschool ; Cohort Studies ; Dengue/*blood/epidemiology/virology ; Dengue Virus/genetics/immunology/physiology ; Female ; Humans ; Infant ; Male ; Mexico/epidemiology ; Seroepidemiologic Studies ; Siblings ; Students/statistics &amp; numerical data ; }, abstract = {BACKGROUND: The implementation of vector control interventions and potential introduction new tools requires baseline data to evaluate their direct and indirect effects. The objective of the study is to present the seroprevalence of dengue infection in a cohort of children 0 to 15 years old followed during 2015 to 2016, the risk factors and the role of enhanced surveillance strategies in three urban sites (Merida, Ticul and Progreso) in Yucatan, Mexico.<br><br>METHODS: A cohort of school children and their family members was randomly selected in three urban areas with different demographic, social conditions and levels of transmission. We included results from 1,844 children aged 0 to 15 years. Serum samples were tested for IgG, NS1 and IgM. Enhanced surveillance strategies were established in schools (absenteeism) and cohort families (toll-free number).<br><br>RESULTS: Seroprevalence in children 0 to 15 years old was 46.8 (CI 95% 44.1-49.6) with no difference by sex except in Ticul. Prevalence increased with age and was significantly lower in 0 to 5 years old (26.9%, 95% CI:18.4-35.4) compared with 6 to 8 years old (43.9%, 95% CI:40.1-47.7) and 9 to 15 years old (61.4%, 95% CI:58.0-64.8). Sharing the domestic space with other families increased the risk 1.7 times over the individual families that own or rented their house, while risk was significantly higher when kitchen and bathroom were outside. Complete protection with screens in doors and windows decreased risk of infection. Seroprevalence was significantly higher in the medium and high risk areas.<br><br>CONCLUSIONS: The prevalence of antibodies in children 0 to 15 years in three urban settings in the state of Yucatan describe the high exposure and the heterogenous transmission of dengue virus by risk areas and between schools in the study sites. The enhanced surveillance strategy was useful to improve detection of dengue cases with the coincident transmission of chikungunya and Zika viruses.}, }
@article {pmid30462635, year = {2018}, author = {Rojas, DP and Barrera-Fuentes, GA and Pavia-Ruz, N and Salgado-Rodriguez, M and Che-Mendoza, A and Manrique-Saide, P and Vazquez-Prokopec, GM and Halloran, ME and Longini, IM and Gomez-Dantes, H}, title = {Epidemiology of dengue and other arboviruses in a cohort of school children and their families in Yucatan, Mexico: Baseline and first year follow-up.}, journal = {PLoS neglected tropical diseases}, volume = {12}, number = {11}, pages = {e0006847}, pmid = {30462635}, issn = {1935-2735}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; U54 GM111274/GM/NIGMS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Arbovirus Infections/*epidemiology/virology ; Arboviruses/physiology ; Child ; Child, Preschool ; Cohort Studies ; Dengue/*epidemiology/virology ; Dengue Virus/physiology ; Family ; Female ; Follow-Up Studies ; Humans ; Male ; Mexico/epidemiology ; Middle Aged ; Prevalence ; Students/statistics &amp; numerical data ; Young Adult ; }, abstract = {Dengue is the most prevalent mosquito-borne viral disease of humans and is caused by the four serotypes of dengue virus. To estimate the incidence of dengue and other arboviruses, we analyzed the baseline and first year follow-up of a prospective school-based cohort study and their families in three cities in the state of Yucatan, Mexico. Through enhanced surveillance activities, acute febrile illnesses in the participants were detected and yearly blood samples were collected to evaluate dengue infection incidence. A Cox model was fitted to identify hazard ratios of arboviral infections in the first year of follow-up of the cohort. The incidence of dengue symptomatic infections observed during the first year of follow-up (2015-2016) was 3.5 cases per 1,000 person-years (95% CI: 1.9, 5.9). The incidence of dengue infections was 33.9 infections per 1,000 person-years (95% CI: 31.7, 48.0). The majority of dengue infections and seroconversions were observed in the younger age groups (≤ 14 years old). Other arboviruses were circulating in the state of Yucatan during the study period. The incidence of symptomatic chikungunya infections was 8.6 per 1,000 person-years (95% CI: 5.8, 12.3) and the incidence of symptomatic Zika infections was 2.3 per 1,000 person-years (95% CI: 0.9, 4.5). Our model shows that having a dengue infection during the first year of follow-up was significantly associated with being female, living in Ticul or Progreso, and being dengue naïve at baseline. Age was not significantly associated with the outcome, it was confounded by prior immunity to dengue that increases with age. This is the first report of a cohort in Latin America that provides incidence estimates of the three arboviruses co-circulating in all age groups. This study provides important information for understanding the epidemiology of dengue and other arboviruses and better informing public health policies.}, }
@article {pmid30461557, year = {2018}, author = {Duggan, C and Tapsoba, JD and Stanczyk, F and Wang, CY and Schubert, KF and McTiernan, A}, title = {Long-term weight loss maintenance, sex steroid hormones, and sex hormone-binding globulin.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/GME.0000000000001250}, pmid = {30461557}, issn = {1530-0374}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA105204/CA/NCI NIH HHS/United States ; U54 CA116847/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: We tested the effects of weight loss on serum estradiol, estrone, testosterone, and sex hormone-binding globulin (SHBG) in overweight/obese women 18 months after completing a year-long, 4-arm, randomized-controlled dietary weight loss and/or exercise trial.<br><br>METHODS: From 2005 to 2008, 439 overweight/obese, postmenopausal women (BMI >25 kg/m), 50 to 75 years, were randomized to a year-long intervention: diet (reduced calorie, 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). At 12 months, 399 women provided blood; of these, 156 returned at 30 months and gave a blood sample. Hormones and SHBG were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for confounders.<br><br>RESULTS: At 30 months, participants randomized to the diet + exercise intervention had statistically significant increases in SHBG levels versus controls (P = 0.001). There was no statistically significant change in SHBG in the exercise or diet intervention arms. Hormone levels did not vary by intervention arm from baseline to 30 months. Participants who maintained weight loss at 30 months had statistically significantly greater decreases in free estradiol and free testosterone (Ptrend = 0.02 and Ptrend = 0.04, respectively) and increases in SHBG (Ptrend < 0.0001) versus those who did not have sustained weight loss. Levels of other analytes did not vary by weight loss at 30 months.<br><br>CONCLUSIONS: Sustained weight loss results in reductions in free estradiol and testosterone and increases in SHBG 18-month post-intervention.}, }
@article {pmid30459208, year = {2019}, author = {Chubak, J and McLerran, D and Zheng, Y and Singal, AG and Corley, DA and Doria-Rose, VP and Doubeni, CA and Kamineni, A and Haas, JS and Halm, EA and Skinner, CS and Zauber, AG and Wernli, KJ and Beaber, EF and , }, title = {Receipt of Colonoscopy Following Diagnosis of Advanced Adenomas: An Analysis within Integrated Healthcare Delivery Systems.}, 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 = {1}, pages = {91-98}, doi = {10.1158/1055-9965.EPI-18-0452}, pmid = {30459208}, issn = {1538-7755}, support = {UM1 CA222035/CA/NCI NIH HHS/United States ; U54 CA163307/CA/NCI NIH HHS/United States ; U54 CA163261/CA/NCI NIH HHS/United States ; U54 CA163262/CA/NCI NIH HHS/United States ; U54 CA163308/CA/NCI NIH HHS/United States ; U01 CA163304/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: To reduce colorectal cancer incidence and mortality, experts recommend surveillance colonoscopy 3 years after advanced adenoma removal. Little is known about adherence to that interval.<br><br>METHODS: We describe patterns of and factors associated with subsequent colonoscopy among persons with ≥3 adenomas and/or ≥1 adenoma with villous/tubulovillous histology in four U.S. integrated healthcare delivery systems. We report Kaplan-Meier estimators of the cumulative percentage of patients undergoing colonoscopy 6 months to 3.5 years after an index colonoscopy with high-risk findings. Combining data from three healthcare systems, we used multivariable logistic regression with inverse probability of censoring weights to estimate ORs and 95% confidence intervals (CI) for associations between patient characteristics and receipt of subsequent colonoscopy.<br><br>RESULTS: Among 6,909 persons with advanced adenomas, the percent receiving a subsequent colonoscopy 6 months to 3.5 years later ranged from 18.3% (95% CI: 11.7%-27.8%) to 59.5% (95% CI: 53.8%-65.2%) across healthcare systems. Differences remained significant in the multivariable model. Patients with ≥3 adenomas were more likely than those with 1 to 2 villous/tubulovillous adenomas to undergo subsequent colonoscopy. Subsequent colonoscopy was also more common for patients ages 60-74 and less common for patients ages 80 to 89 compared with those ages 50 to 54 years at their index colonoscopy. Sex, race/ethnicity, and comorbidity index score were generally not associated with subsequent colonoscopy receipt.<br><br>CONCLUSIONS: Colonoscopy within the recommended interval following advanced adenoma was underutilized and varied by healthcare system, age, and number of adenomas.<br><br>IMPACT: Strategies to improve adherence to surveillance colonoscopy following advanced adenomas are needed.}, }
@article {pmid30454872, year = {2018}, author = {Puronen, CE and Cassaday, RD and Stevenson, PA and Sandmaier, BM and Flowers, ME and Green, DJ and Maloney, DG and Storb, RF and Press, OW and Gopal, AK}, title = {Long-Term Follow-Up of 90Y-Ibritumomab Tiuxetan, Fludarabine, and Total Body Irradiation-Based Nonmyeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B Cell Lymphoma.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {24}, number = {11}, pages = {2211-2215}, pmid = {30454872}, issn = {1523-6536}, support = {K24 CA184039/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) can provide prolonged remissions in patients with advanced B cell lymphoma (B-NHL) via the graft-versus-lymphoma effect, although inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy can safely induce responses in B-NHL with minimal nonhematologic toxicity. Initial results of 90Y-ibritumomab tiuxetan-based allografting demonstrated early safety and disease control in nonremission patients but with short follow-up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2). Fourteen (35%) deaths were due to disease progression and 14 (35%) deaths to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year overall and progression-free survival for patients with indolent B-NHL was 40% and 27.5%, respectively. None of the patients with diffuse large B cell lymphoma was a long-term disease-free survivor regardless of early remission status. 90Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392.}, }
@article {pmid30452727, year = {2018}, author = {Byrne, EM and Ferreira, MAR and Xue, A and Lindström, S and Jiang, X and Yang, J and Easton, DF and Wray, NR and Chenevix-Trench, G}, title = {Is Schizophrenia a Risk Factor for Breast Cancer?-Evidence From Genetic Data.}, journal = {Schizophrenia bulletin}, volume = {}, number = {}, pages = {}, doi = {10.1093/schbul/sby162}, pmid = {30452727}, issn = {1745-1701}, abstract = {Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.}, }
@article {pmid30451992, year = {2018}, author = {Bentzen, AK and Such, L and Jensen, KK and Marquard, AM and Jessen, LE and Miller, NJ and Church, CD and Lyngaa, R and Koelle, DM and Becker, JC and Linnemann, C and Schumacher, TNM and Marcatili, P and Nghiem, P and Nielsen, M and Hadrup, SR}, title = {T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide-MHC complexes.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {30451992}, issn = {1546-1696}, abstract = {The promiscuous nature of T-cell receptors (TCRs) allows T cells to recognize a large variety of pathogens, but makes it challenging to understand and control T-cell recognition. Existing technologies provide limited information about the key requirements for T-cell recognition and the ability of TCRs to cross-recognize structurally related elements. Here we present a 'one-pot' strategy for determining the interactions that govern TCR recognition of peptide-major histocompatibility complex (pMHC). We measured the relative affinities of TCRs to libraries of barcoded peptide-MHC variants and applied this knowledge to understand the recognition motif, here termed the TCR fingerprint. The TCR fingerprints of 16 different TCRs were identified and used to predict and validate cross-recognized peptides from the human proteome. The identified fingerprints differed among TCRs recognizing the same epitope, demonstrating the value of this strategy for understanding T-cell interactions and assessing potential cross-recognition before selection of TCRs for clinical development.}, }
@article {pmid30448105, year = {2019}, author = {Kearns, JT and Winters, BD and Holt, SK and Mossanen, M and Lin, DW and Wright, JL}, title = {Pathologic Nodal Involvement in Patients With Penile Cancer With Cavernosal Versus Spongiosal Involvement.}, journal = {Clinical genitourinary cancer}, volume = {17}, number = {1}, pages = {e156-e161}, doi = {10.1016/j.clgc.2018.10.004}, pmid = {30448105}, issn = {1938-0682}, abstract = {BACKGROUND: The American Joint Committee on Cancer recently proposed new TNM staging for penile cancer, with proposed T2 as spongiosal invasion and T3 as cavernosal invasion. We sought to validate the proposed staging system for predicting pathologic nodal involvement using the National Cancer Data Base.<br><br>PATIENTS AND METHODS: Invasive penile cancer cases from 2010 to 2012 were identified. Differences in demographic and pathologic factors between T2 and T3 tumors were compared using χ2 and t tests. Logistic regression was performed to determine the odds of pathologically involved lymph nodes (pN+) by T classification.<br><br>RESULTS: There were 378 T2 and 524 T3 patients with penile cancer. Compared with T2 tumors, T3 tumors were larger (mean size, 5.8 cm vs. 4.3 cm), had higher positive surgical margin rates (12% vs. 9%), and were more likely to have lymphovascular invasion (42% vs. 31%) (all P < .05). In multivariable analysis, both T2 (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.3) and T3 (OR, 2.3; 95% CI, 1.4-3.6) remained significantly associated with risk of positive lymph nodes compared with T1 disease, but there was no increase in risk between T2 and T3 disease (OR, 1.1; 95% CI, 0.7-1.8; P = .56).<br><br>CONCLUSION: The proposed new American Joint Committee on Cancer staging system for the penile cancer distinguishes spongiosal (T2) from cavernosal (T3) involvement. There does not appear to be a difference in positive lymph node status between the 2 grades when other clinical and pathologic variables are considered.}, }
@article {pmid30447499, year = {2019}, author = {Reeves, KW and Santana, MD and Manson, JE and Hankinson, SE and Zoeller, RT and Bigelow, C and Hou, L and Wactawski-Wende, J and Liu, S and Tinker, L and Calafat, AM}, title = {Predictors of urinary phthalate biomarker concentrations in postmenopausal women.}, journal = {Environmental research}, volume = {169}, number = {}, pages = {122-130}, doi = {10.1016/j.envres.2018.10.024}, pmid = {30447499}, issn = {1096-0953}, support = {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: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear.<br><br>OBJECTIVES: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI).<br><br>MATERIALS AND METHODS: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics.<br><br>RESULTS: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP.<br><br>CONCLUSION: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations.}, }
@article {pmid30447393, year = {2018}, author = {Rozmus, J and Kariminia, A and Abdossamadi, S and Storer, BE and Martin, PJ and Lee, SJ and Wolff, D and Arora, M and Cutler, C and Schultz, KR}, title = {Comprehensive B Cell Phenotyping Profile for Chronic Graft-versus-Host Disease Diagnosis.}, 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.2018.11.007}, pmid = {30447393}, issn = {1523-6536}, abstract = {Previous studies have reported single B cell-related chronic graft-versus-host disease diagnostic (cGVHD) biomarkers, such as B cell-activating factor (BAFF), CD21low, and immature B cells, but research on the performance of biomarker combinations and the covariate effect of steroids is lacking. The primary objective of this study was to determine the most accurate combination of B cell populations using cell surface staining flow cytometry in an independent cohort of patients with cGVHD. Secondary objectives included assessing the effect of corticosteroid use at sample collection on the makeup and accuracy of the diagnostic panel and identifying the mechanism underlying low surface expression of BAFF receptor (BAFF-R) on B cells in cGVHD. Flow cytometry analysis was performed in an adult cohort of post-HCT patients with cGVHD onset (n = 44) and time-matched recipients without cGVHD (n = 63). We confirmed that the onset of cGVHD was associated with higher soluble BAFF (sBAFF) levels, elevated CD27-CD10-CD21low CD19+ B cell and classical switched memory B cell counts, and reduced transitional and naïve B cell counts. The highest single B cell population area under the receiver operating characteristic (ROC) curve (AUC) was .72 for transitional type 1 CD21low B cells. We also showed a significant inverse relationship between sBAFF and surface BAFF-R expression caused by sBAFF modulation of BAFF-R. Steroid use at sample collection influenced the significance of the sBAFF:B cell ratio, naïve and marginal zone-like B cells. The optimal combination of B cell subsets most significantly associated with cGVHD onset with or without concurrent corticosteroid use resulted in ROC AUCs of .87 and .84, respectively. Transitional and CD21low B cells were the only populations present in both panels; however, analyzing only these populations resulted in ROC AUCs of .79 and .78, respectively. This suggests that the inclusion of other populations and use of different panels depending on steroid use is necessary to achieve better accuracy. sBAFF was not a component of either panel. These novel B cell profiles could be tested prospectively in patients post-HSCT and could lead to focused mechanistic studies.}, }
@article {pmid30446650, year = {2018}, author = {Reeves, DB and Duke, ER and Wagner, TA and Palmer, SE and Spivak, AM and Schiffer, JT}, title = {A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {4811}, pmid = {30446650}, issn = {2041-1723}, support = {R01 AI121129/AI/NIAID NIH HHS/United States ; P01 AI030371-24, U19 AI113173-02, R01 AI121129-01, UM1 AI126623, UM1 AI068635//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/International ; U19 AI096109/AI/NIAID NIH HHS/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; KL2 TR002317//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/International ; U19 AI113173/AI/NIAID NIH HHS/United States ; Postdoctoral Fellowship//Washington Research Foundation (WRF)/International ; UM1 AI126611/AI/NIAID NIH HHS/United States ; UM1 AI126623/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Anti-HIV Agents/*therapeutic use ; Antiretroviral Therapy, Highly Active ; CD4-Positive T-Lymphocytes/*drug effects/immunology/virology ; Cell Proliferation ; Computer Simulation ; Female ; HIV Infections/*drug therapy/immunology/virology ; HIV-1/*drug effects/growth &amp; development/immunology ; Humans ; Male ; *Models, Statistical ; Treatment Failure ; Viral Load/drug effects ; Virus Latency/drug effects ; Virus Replication/drug effects ; }, abstract = {Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been attributed to viral replication in an ART sanctuary and long-lived and/or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a fossil record of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure.}, }
@article {pmid30446494, year = {2019}, author = {Qu, X and Li, H and Braziel, RM and Passerini, V and Rimsza, LM and Hsi, ED and Leonard, JP and Smith, SM and Kridel, R and Press, O and Weigert, O and LeBlanc, M and Friedberg, JW and Fang, M}, title = {Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016.}, journal = {Blood}, volume = {133}, number = {1}, pages = {81-93}, doi = {10.1182/blood-2018-07-865428}, pmid = {30446494}, issn = {1528-0020}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, abstract = {Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P = .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P = .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P = .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P = .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P = .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.}, }
@article {pmid30445587, year = {2018}, author = {Heuvel, AVD and Mahfouz, A and Kloet, SL and Balog, J and Engelen, BGMV and Tawil, R and Tapscott, SJ and Maarel, SMV}, title = {Single-cell RNA-sequencing in facioscapulohumeral muscular dystrophy disease etiology and development.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddy400}, pmid = {30445587}, issn = {1460-2083}, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is characterized by sporadic de-repression of the transcription factor DUX4 in skeletal muscle. DUX4 activates a cascade of muscle disrupting events, eventually leading to muscle atrophy and apoptosis. Yet, how sporadic DUX4 expression leads to the generalized muscle wasting remains unclear. Transcriptome analyses have systematically been challenged by the majority of nuclei being DUX4neg, weakening the DUX4 transcriptome signature. Moreover, DUX4 has been shown to be expressed in a highly dynamic burst-like manner, likely resulting in the detection of the downstream cascade of events long after DUX4 expression itself has faded. Identifying the FSHD-transcriptome in individual cells and unraveling the cascade of events leading to FSHD development, may therefore provide important insights in the disease process.We employed single-cell RNA-sequencing, combined with pseudotime trajectory modeling, to study FSHD disease etiology and cellular progression in human primary myocytes. We identified a small FSHD-specific cell population in all tested patient-derived cultures and detected new genes associated with DUX4 de-repression. We furthermore generated an FSHD cellular progression model, reflecting both the early burst-like DUX4 expression as well as the downstream activation of various FSHD-associated pathways, which allowed us to correlate DUX4 expression signature dynamics with that of regulatory complexes, thereby facilitating the prioritization of epigenetic targets for DUX4 silencing.Single-cell transcriptomics combined with pseudotime modeling thus holds valuable information on FSHD disease etiology and progression which can potentially guide biomarker and target selection for therapy.}, }
@article {pmid30445486, year = {2019}, author = {Amundsen, SK and Smith, GR}, title = {The RecB helicase-nuclease tether mediates Chi hotspot control of RecBCD enzyme.}, journal = {Nucleic acids research}, volume = {47}, number = {1}, pages = {197-209}, doi = {10.1093/nar/gky1132}, pmid = {30445486}, issn = {1362-4962}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM031693/GM/NIGMS NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; }, abstract = {In bacteria, repair of DNA double-strand breaks uses a highly conserved helicase-nuclease complex to unwind DNA from a broken end and cut it at specific DNA sequences called Chi. In Escherichia coli the RecBCD enzyme also loads the DNA strand-exchange protein RecA onto the newly formed end, resulting in a recombination hotspot at Chi. Chi hotspots regulate multiple RecBCD activities by altering RecBCD's conformation, which is proposed to include the swinging of the RecB nuclease domain on the 19-amino-acid tether connecting the helicase and nuclease domains. Here, we altered the tether and tested multiple RecBCD activities, genetically in cells and enzymatically in cell-free extracts. Randomizing the amino-acid sequence or lengthening it had little effect. However, shortening it by as little as two residues or making substitutions of ≥10 proline or ≥9 glycine residues dramatically lowered Chi-dependent activities. These results indicate that proper control of RecBCD by Chi requires that the tether be long enough and appropriately flexible. We discuss a model in which the swing-time of the nuclease domain determines the position of Chi-dependent and Chi-independent cuts and Chi hotspot activity.}, }
@article {pmid30445012, year = {2018}, author = {Lim, U and Monroe, KR and Buchthal, S and Fan, B and Cheng, I and Kristal, BS and Lampe, JW and Hullar, MA and Franke, AA and Stram, DO and Wilkens, LR and Shepherd, J and Ernst, T and Le Marchand, L}, title = {Propensity for Intra-abdominal and Hepatic Adiposity Varies Among Ethnic Groups.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2018.11.021}, pmid = {30445012}, issn = {1528-0012}, support = {P01 CA168530/CA/NCI NIH HHS/United States ; P30 CA071789/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; UL1 TR000130/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND &amp; AIMS: We compared fat storage in the abdominal region among individuals from 5 different ethnic-racial groups to determine whether fat storage is associated with disparities observed in metabolic syndrome and other obesity-associated diseases.<br><br>METHODS: We collected data from 1794 participants in the Multiethnic Cohort Study (60-77 years old; of African, European [white], Japanese, Latino, or Native Hawaiian ancestry) with body mass index values of 17.1-46.2 kg/m2. From May 2013 through April 2016, participants visited the study clinic to undergo body measurements, an interview, and a blood collection. Participants were evaluated by dual-energy x-ray absorptiometry and abdominal magnetic resonance imaging. Among ethnic groups, we compared adiposity of the trunk, intra-abdominal visceral cavity, and liver, adjusting for total fat mass; we evaluated the association of adult weight change with abdominal adiposity; and we examined the prevalence of metabolic syndrome mediated by abdominal adiposity.<br><br>RESULTS: Relative amounts of trunk, visceral, and liver fat varied significantly with ethnicity-they were highest in Japanese Americans, lowest in African Americans, and intermediate in the other groups. Compared with African Americans, the mean visceral fat area was 45% and 73% greater in Japanese American men and women, respectively, and the mean measurements of liver fat were 61% and 122% greater in Japanese American men and women. The visceral and hepatic adiposity associated with weight gain since participants were 21 years old varied in a similar pattern among ethnic-racial groups. In the mediation analysis, visceral and liver fat jointly accounted for a statistically significant fraction of the difference in metabolic syndrome prevalence, compared with white persons, for African Americans, Japanese Americans, and Native Hawaiian women, independently of total fat mass.<br><br>CONCLUSIONS: In an analysis of data from the participants in the Multiethnic Cohort Study, we found extensive differences among ethnic-racial groups in the propensity to store fat intra-abdominally. This observation should be considered by clinicians in the prevention and early detection of metabolic disorders.}, }
@article {pmid30442800, year = {2018}, author = {Ludwig, DS and Willett, WC and Volek, JS and Neuhouser, ML}, title = {Dietary fat: From foe to friend?.}, journal = {Science (New York, N.Y.)}, volume = {362}, number = {6416}, pages = {764-770}, doi = {10.1126/science.aau2096}, pmid = {30442800}, issn = {1095-9203}, support = {K24 DK082730/DK/NIDDK NIH HHS/United States ; }, abstract = {For decades, dietary advice was based on the premise that high intakes of fat cause obesity, diabetes, heart disease, and possibly cancer. Recently, evidence for the adverse metabolic effects of processed carbohydrate has led to a resurgence in interest in lower-carbohydrate and ketogenic diets with high fat content. However, some argue that the relative quantity of dietary fat and carbohydrate has little relevance to health and that focus should instead be placed on which particular fat or carbohydrate sources are consumed. This review, by nutrition scientists with widely varying perspectives, summarizes existing evidence to identify areas of broad consensus amid ongoing controversy regarding macronutrients and chronic disease.}, }
@article {pmid30442764, year = {2018}, author = {Patel, AB and Louder, RK and Greber, BJ and Grünberg, S and Luo, J and Fang, J and Liu, Y and Ranish, J and Hahn, S and Nogales, E}, title = {Structure of human TFIID and mechanism of TBP loading onto promoter DNA.}, journal = {Science (New York, N.Y.)}, volume = {362}, number = {6421}, pages = {}, doi = {10.1126/science.aau8872}, pmid = {30442764}, issn = {1095-9203}, support = {R35 GM127018/GM/NIGMS NIH HHS/United States ; T32 GM008295/GM/NIGMS NIH HHS/United States ; P01 GM051487/GM/NIGMS NIH HHS/United States ; R01 GM053451/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; P50 GM076547/GM/NIGMS NIH HHS/United States ; R01 GM063072/GM/NIGMS NIH HHS/United States ; R21 CA175849/CA/NCI NIH HHS/United States ; }, mesh = {Cross-Linking Reagents/chemistry ; Cryoelectron Microscopy ; DNA/chemistry/metabolism ; Humans ; *Promoter Regions, Genetic ; Protein Binding ; Protein Domains ; Protein Multimerization ; Protein Stability ; TATA-Box Binding Protein/*chemistry ; Transcription Factor TFIID/*chemistry ; *Transcription Initiation, Genetic ; }, abstract = {The general transcription factor IID (TFIID) is a critical component of the eukaryotic transcription preinitiation complex (PIC) and is responsible for recognizing the core promoter DNA and initiating PIC assembly. We used cryo-electron microscopy, chemical cross-linking mass spectrometry, and biochemical reconstitution to determine the complete molecular architecture of TFIID and define the conformational landscape of TFIID in the process of TATA box-binding protein (TBP) loading onto promoter DNA. Our structural analysis revealed five structural states of TFIID in the presence of TFIIA and promoter DNA, showing that the initial binding of TFIID to the downstream promoter positions the upstream DNA and facilitates scanning of TBP for a TATA box and the subsequent engagement of the promoter. Our findings provide a mechanistic model for the specific loading of TBP by TFIID onto the promoter.}, }
@article {pmid30442722, year = {2018}, author = {Fatobene, G and Storer, BE and Salit, RB and Lee, SJ and Martin, PJ and Cheng, GS and Carpenter, PA and Balgansuren, G and Petersdorf, EW and Delaney, C and Sandmaier, BM and Milano, F and Flowers, ME}, title = {Disability related to chronic graft-versus-host disease after alternative donor hematopoietic cell transplantation.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.202754}, pmid = {30442722}, issn = {1592-8721}, abstract = {We determined the incidence of disability related to chronic graft-versus-host disease (bronchiolitis obliterans, grade ≥ 2 keratoconjunctivitis sicca, sclerotic features or esophageal stricture) for 3 categories of alternative donor: cord blood, haplorelated marrow or peripheral blood with posttransplant cyclophosphamide, and unrelated single HLA-allele mismatched peripheral blood. Among 396 consecutive hematopoietic cell transplantation recipients, 129 developed chronic graft-versus-host disease with incidences in each group of 18% for cord blood, 24% for haplorelated, and 55% for unrelated single HLA-allele mismatched peripheral blood; after a median follow-up of 48, 60, and 46 months, respectively, from diagnosis. Disability rates were significantly lower for cord blood (hazard ratio 0.13; 95% cumulative incidence (CI): 0.1-0.4) and for the haplorelated group (HR 0.31; 95%CI: 0.1-0.7) compared to unrelated single HLA-allele mismatched peripheral blood. Cord blood recipients were also >2-fold more likely to return to work/school by 3 years from chronic graft-versus-host disease onset (HR 2.54; 95%CI: 1.1-5.7, p=.02), and the haplorelated group trended similarly (HR 2.38; 95%CI: 1.0-5.9, p=.06). Cord blood recipients were more likely to discontinue immunosuppression than unrelated single HLA-allele mismatched peripheral blood (HR 3.96; 95%CI: 1.9-8.4, p=.0003), similar to the haplorelated group (HR 4.93; 95%CI: 2.2-11.1, p=.0001). Progression-free survival and non-relapse mortality did not differ between donor groups. Our observations that compared to unrelated single HLA-allele mismatched peripheral blood, recipients of cord blood and haplorelated grafts less often developed disability related to chronic graft-versus-host disease, and more likely resumed work/school, should help better counsel pre-hematopoietic cell transplant candidates.}, }
@article {pmid30442493, year = {2018}, author = {Piper, CL and Scheel, JR and Lee, CI and Forman, HP}, title = {Representation of Women on Radiology Journal Editorial Boards: A 40-Year Analysis.}, journal = {Academic radiology}, volume = {25}, number = {12}, pages = {1640-1645}, doi = {10.1016/j.acra.2018.03.031}, pmid = {30442493}, issn = {1878-4046}, abstract = {RATIONALE AND OBJECTIVES: We examined female representation on editorial boards of four prominent radiology journals. We compared editorial board representation to female academic radiology career advancement and the proportion of female authorship in three journals over four decades.<br><br>METHODS: We collected data on the gender of editorial board members as listed on mastheads of Radiology, American Journal of Roentgenology (AJR), Academic Radiology, and the Journal of the American College of Radiology in 5-year intervals plus the most recent year available (1973-2017), and the gender of their editors-in-chief for all years since each journal's inception. We compared Radiology, AJR, and Academic Radiology data to published data on gender of the journals' authors, all US medical students, and academic radiologists over time.<br><br>RESULTS: Gender was determined for 171 editors-in-chief (100%) and 2139 (100%) editorial board members listed in the selected journals for each of the study years. The proportion of women on editorial boards increased from 1.4% (1 of 69) in 1978 to 18.8% (73 of 388) in 2013 (P < .001), but remained below the proportion of female first authors (7.5% in 1978 and 27.1% in 2013) and female faculty in radiology (11.5% in 1978 and 28.1% in 2013). None of the four general radiology journals had a female editor-in-chief during the study period.<br><br>CONCLUSIONS: Female representation on editorial boards has increased over time, but still lags behind increases seen in female first authorship in radiology journals and radiology faculty appointments over the last four decades. There was no female editor-in-chief during the study period.}, }
@article {pmid30439709, year = {2019}, author = {Iovino, L and Mazziotta, F and Buda, G and Orciuolo, E and Caracciolo, F and Pelosini, M and Morganti, R and Galimberti, S and Benedetti, E and Petrini, M}, title = {The Onset of Monoclonal and Oligoclonal Gammopathies Is a Good Prognostic Factor after Allogeneic Stem Cell Transplantation.}, journal = {Acta haematologica}, volume = {141}, number = {1}, pages = {7-11}, doi = {10.1159/000493416}, pmid = {30439709}, issn = {1421-9662}, }
@article {pmid30439517, year = {2019}, author = {Borges, KA and Dai, J and Parikh, ND and Schwartz, M and Nguyen, MH and Roberts, LR and Befeler, AS and Srivastava, S and Rinaudo, JA and Feng, Z and Marrero, JA and Reddy, KR}, title = {Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's Early Detection Research Network.}, journal = {Contemporary clinical trials}, volume = {76}, number = {}, pages = {49-54}, doi = {10.1016/j.cct.2018.11.008}, pmid = {30439517}, issn = {1559-2030}, abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity.<br><br>METHODS: The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository.<br><br>RESULTS: The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis.<br><br>CONCLUSIONS: The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy.}, }
@article {pmid30439335, year = {2018}, author = {Koch, MA}, title = {Sex Bias in Sepsis.}, journal = {Cell host &amp; microbe}, volume = {24}, number = {5}, pages = {613-615}, doi = {10.1016/j.chom.2018.10.014}, pmid = {30439335}, issn = {1934-6069}, abstract = {Though critical for preventing fatal sepsis, the mechanisms mediating the capture of bloodstream bacteria are incompletely understood. New work by Zeng et al. (2018) demonstrates that estrogen-regulated innate antibodies protect females and newborns from death following bloodstream infection with enteropathogenic Eschericia coli.}, }
@article {pmid30431292, year = {2019}, author = {Andersen, MR and Karlan, BY and Drescher, CW and Paley, P and Hawley, S and Palomares, M and Daly, MB and Urban, N}, title = {False-positive screening events and worry influence decisions about surgery among high-risk women.}, journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association}, volume = {38}, number = {1}, pages = {43-52}, doi = {10.1037/hea0000647}, pmid = {30431292}, issn = {1930-7810}, support = {//Canary Foundation, Marsha Rivkin Center for EOC Research/ ; //National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS)/ ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Anxiety/*psychology ; Decision Making ; Early Detection of Cancer/*psychology ; Female ; Humans ; Middle Aged ; Neoplasms/pathology/*psychology/*surgery ; }, abstract = {OBJECTIVE: Studies of cancer screening have found that false positive screening events (FPSE) can affect worry about cancer risk and screening program use, we sought to further explore this.<br><br>METHOD: In a study of 1,100 women at high risk for ovarian cancer who participated in a previously published randomized controlled trial (RCT), we sought to explore whether worry might also influence the use of risk-reducing surgical procedures by women. Participants included 234 women with BRCA1/2 mutations and 866 women with high-risk pedigrees. We followed the women for up to 6 years.<br><br>RESULTS: Worry predicted risk reducing prophylactic bilateral salpingo-oophorectomy (pBSO) for both mutation carriers (HR = 1.74; p = .02), and women with high-risk pedigree (HR = 3.41; p < .001). FPSE also predicted subsequent pBSO among women with a high-risk pedigree (HR 2.31; p < .01). While screening may reduce worry among those who never receive a positive result, FPSE increase worry at least temporarily. Worry about ovarian cancer risk predicted use of preventative pBSO among high-risk women including those with BRCA1/2 mutations enrolled in an ovarian cancer-screening program. FPSE also predicted risk-reducing ovarian surgery among high-risk women without a known mutation at the time of screening program enrollment.<br><br>CONCLUSIONS: Physicians who offer screening should know that false positive results may increase use of pBSO, how this should effect clinical practice is unclear. (PsycINFO Database Record (c) 2018 APA, all rights reserved).}, }
@article {pmid30430548, year = {2018}, author = {Zhao, N and Zhang, H and Clark, JJ and Maity, A and Wu, MC}, title = {Composite Kernel Machine Regression based on Likelihood Ratio Test for Joint Testing of Genetic and Gene-environment Interaction Effect.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13003}, pmid = {30430548}, issn = {1541-0420}, abstract = {Most common human diseases are a result from the combined effect of genes, the environmental factors and their interactions such that including gene-environment (GE) interactions can improve power in gene mapping studies. The standard strategy is to test the SNPs, one-by-one, using a regression model that includes both the SNP effect and the GE interaction. However, the SNP-by-SNP approach has serious limitations, such as the inability to model epistatic SNP effects, biased estimation and reduced power. Thus, in this paper, we develop a kernel machine regression framework to model the overall genetic effect of a SNP-set, considering the possible GE interaction. Specifically, we use a composite kernel to specify the overall genetic effect via a nonparametric function and we model additional covariates parametrically within the regression framework. The composite kernel is constructed as a weighted average of two kernels, one corresponding to the genetic main effect and one corresponding to the GE interaction effect. We propose a likelihood ratio test (LRT) and a restricted likelihood ratio test (RLRT) for statistical significance. We derive a Monte Carlo approach for the finite sample distributions of LRT and RLRT statistics. Extensive simulations and real data analysis show that our proposed method has correct type I error and can have higher power than score-based approaches under many situations. This article is protected by copyright. All rights reserved.}, }
@article {pmid30429847, year = {2018}, author = {Davidsen, K and Matsen, FA}, title = {Benchmarking Tree and Ancestral Sequence Inference for B Cell Receptor Sequences.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2451}, pmid = {30429847}, issn = {1664-3224}, abstract = {B cell receptor sequences evolve during affinity maturation according to a Darwinian process of mutation and selection. Phylogenetic tools are used extensively to reconstruct ancestral sequences and phylogenetic trees from affinity-matured sequences. In addition to using general-purpose phylogenetic methods, researchers have developed new tools to accommodate the special features of B cell sequence evolution. However, the performance of classical phylogenetic techniques in the presence of B cell-specific features is not well understood, nor how much the newer generation of B cell specific tools represent an improvement over classical methods. In this paper we benchmark the performance of classical phylogenetic and new B cell-specific tools when applied to B cell receptor sequences simulated from a forward-time model of B cell receptor affinity maturation toward a mature receptor. We show that the currently used tools vary substantially in terms of tree structure and ancestral sequence inference accuracy. Furthermore, we show that there are still large performance gains to be achieved by modeling the special mutation process of B cell receptors. These conclusions are further strengthened with real data using the rules of isotype switching to count possible violations within each inferred phylogeny.}, }
@article {pmid30429343, year = {2019}, author = {Asbach, B and Kibler, KV and Köstler, J and Perdiguero, B and Yates, NL and Stanfield-Oakley, S and Tomaras, GD and Kao, SF and Foulds, KE and Roederer, M and Seaman, MS and Montefiori, DC and Parks, R and Ferrari, G and Forthal, DN and Phogat, S and Tartaglia, J and Barnett, SW and Self, SG and Gottardo, R and Cristillo, AD and Weiss, DE and Galmin, L and Ding, S and Heeney, JL and Esteban, M and Jacobs, BL and Pantaleo, G and Wagner, R}, title = {Priming with a Potent HIV-1 DNA Vaccine Frames the Quality of Immune Responses prior to a Poxvirus and Protein Boost.}, journal = {Journal of virology}, volume = {93}, number = {3}, pages = {}, doi = {10.1128/JVI.01529-18}, pmid = {30429343}, issn = {1098-5514}, abstract = {The use of heterologous immunization regimens and improved vector systems has led to increases in immunogenicity of HIV-1 vaccine candidates in nonhuman primates. In order to resolve interrelations between different delivery modalities, three different poxvirus boost regimens were compared. Three groups of rhesus macaques were each primed with the same DNA vaccine encoding Gag, Pol, Nef, and gp140. The groups were then boosted with either the vaccinia virus strain NYVAC or a variant with improved replication competence in human cells, termed NYVAC-KC. The latter was administered either by scarification or intramuscularly. Finally, macaques were boosted with adjuvanted gp120 protein to enhance humoral responses. The regimen elicited very potent CD4+ and CD8+ T cell responses in a well-balanced manner, peaking 2 weeks after the boost. T cells were broadly reactive and polyfunctional. All animals exhibited antigen-specific humoral responses already after the poxvirus boost, which further increased following protein administration. Polyclonal reactivity of IgG antibodies was highest against HIV-1 clade C Env proteins, with considerable cross-reactivity to other clades. Substantial effector functional activities (antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated virus inhibition) were observed in serum obtained after the last protein boost. Notably, major differences between the groups were absent, indicating that the potent priming induced by the DNA vaccine initially framed the immune responses in such a way that the subsequent boosts with NYVAC and protein led only to an increase in the response magnitudes without skewing the quality. This study highlights the importance of selecting the best combination of vector systems in heterologous prime-boost vaccination regimens.IMPORTANCE The evaluation of HIV vaccine efficacy trials indicates that protection would most likely correlate with a polyfunctional immune response involving several effector functions from all arms of the immune system. Heterologous prime-boost regimens have been shown to elicit vigorous T cell and antibody responses in nonhuman primates that, however, qualitatively and quantitatively differ depending on the respective vector systems used. The present study evaluated a DNA prime and poxvirus and protein boost regimen and compared how two poxvirus vectors with various degrees of replication capacity and two different delivery modalities-conventional intramuscular delivery and percutaneous delivery by scarification-impact several immune effectors. It was found that despite the different poxvirus boosts, the overall immune responses in the three groups were similar, suggesting the potent DNA priming as the major determining factor of immune responses. These findings emphasize the importance of selecting optimal priming agents in heterologous prime-boost vaccination settings.}, }
@article {pmid30429340, year = {2019}, author = {Kibler, KV and Asbach, B and Perdiguero, B and García-Arriaza, J and Yates, NL and Parks, R and Stanfield-Oakley, S and Ferrari, G and Montefiori, DC and Tomaras, GD and Roederer, M and Foulds, KE and Forthal, DN and Seaman, MS and Self, S and Gottardo, R and Phogat, S and Tartaglia, J and Barnett, S and Cristillo, AD and Weiss, D and Galmin, L and Ding, S and Heeney, JL and Esteban, M and Wagner, R and Pantaleo, G and Jacobs, BL}, title = {Replication-Competent NYVAC-KC Yields Improved Immunogenicity to HIV-1 Antigens in Rhesus Macaques Compared to Nonreplicating NYVAC.}, journal = {Journal of virology}, volume = {93}, number = {3}, pages = {}, doi = {10.1128/JVI.01513-18}, pmid = {30429340}, issn = {1098-5514}, abstract = {As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here, we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a nonhuman primate study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140, and Gag/Gag-Pol-Nef-derived virus-like particles (VLPs) from clade C and were used as the prime, with recombinant virus plus envelope protein used as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.IMPORTANCE Though the RV144 phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 study. With that goal in mind, we have tested in nonhuman primates an attenuated but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 study. The results of this study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate.}, }
@article {pmid30429336, year = {2019}, author = {Hill, JA and Ikoma, M and Zerr, DM and Basom, RS and Peddu, V and Huang, ML and Hall Sedlak, R and Jerome, KR and Boeckh, M and Barcy, S}, title = {RNA Sequencing of the In Vivo Human Herpesvirus 6B Transcriptome To Identify Targets for Clinical Assays Distinguishing between Latent and Active Infections.}, journal = {Journal of virology}, volume = {93}, number = {3}, pages = {}, doi = {10.1128/JVI.01419-18}, pmid = {30429336}, issn = {1098-5514}, abstract = {Human herpesvirus 6B (HHV-6B) DNA is frequently detected in human samples. Diagnostic assays distinguishing HHV-6B reactivation from latency are limited. This has impaired strategies to diagnose and treat HHV-6B-associated diseases. We used RNA sequencing to characterize and compare the HHV-6B transcriptome in multiple sample types, including (i) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia, (ii) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B, (iii) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B, and (iv) HHV-6B Z29 infected SupT1 CD4+ T cells. We demonstrated substantial overlap in the HHV-6B transcriptome observed in in vivo and in vitro samples, although there was variability in the breadth and quantity of gene expression across samples. The HHV-6B viral polymerase gene U38 was the only HHV-6B transcript detected in all next-generation RNA sequencing (RNA-seq) data sets and was one of the most highly expressed genes. We developed a novel reverse transcription-PCR assay targeting HHV-6B U38, which identified U38 mRNA in all tested whole-blood samples from patients with concurrent HHV-6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or reverse transcription-real-time quantitative PCR (RT-qPCR) in whole-blood samples from subjects without HHV-6B plasma detection or from latently infected LCLs. A RT-qPCR assay for HHV-6B U38 may be useful to identify lytic HHV-6B infection in nonplasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses for HCT recipients.IMPORTANCE Human herpesvirus 6B (HHV-6B) is a DNA virus that infects most children within the first few years of life. After primary infection, HHV-6B persists as a chronic, latent infection in many cell types. Additionally, HHV-6B can integrate into germ line chromosomes, resulting in individuals with viral DNA in every nucleated cell. Given that PCR to detect viral DNA is the mainstay for diagnosing HHV-6B infection, the characteristics of HHV-6B infection complicate efforts to distinguish between latent and active viral infection, particularly in immunocompromised patients who have frequent HHV-6B reactivation. In this study, we used RNA sequencing to characterize the HHV-6B gene expression profile in multiple sample types, and our findings identified evidence-based targets for diagnostic tests that distinguish between latent and active viral infection.}, }
@article {pmid30427551, year = {2018}, author = {Munshi, PN and Ujjani, C}, title = {The acceleration of CAR-T therapy in non-Hodgkin lymphoma.}, journal = {Hematological oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/hon.2568}, pmid = {30427551}, issn = {1099-1069}, abstract = {Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19-directed CAR-T cell therapy in aggressive B-cell non-Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients. The cost of this remarkable therapy, however, includes cytokine release syndrome and neurotoxicity shortly after administration as well as delayed infectious complications due to B-cell aplasia. Future investigations are focused on the optimizing both safety and efficacy of CAR-T cell therapy.}, }
@article {pmid30425841, year = {2018}, author = {Hilton, SK and Bloom, JD}, title = {Modeling site-specific amino-acid preferences deepens phylogenetic estimates of viral sequence divergence.}, journal = {Virus evolution}, volume = {4}, number = {2}, pages = {vey033}, pmid = {30425841}, issn = {2057-1577}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; R35 GM126911/GM/NIGMS NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, abstract = {Molecular phylogenetics is often used to estimate the time since the divergence of modern gene sequences. For highly diverged sequences, such phylogenetic techniques sometimes estimate surprisingly recent divergence times. In the case of viruses, independent evidence indicates that the estimates of deep divergence times from molecular phylogenetics are sometimes too recent. This discrepancy is caused in part by inadequate models of purifying selection leading to branch-length underestimation. Here we examine the effect on branch-length estimation of using models that incorporate experimental measurements of purifying selection. We find that models informed by experimentally measured site-specific amino-acid preferences estimate longer deep branches on phylogenies of influenza virus hemagglutinin. This lengthening of branches is due to more realistic stationary states of the models, and is mostly independent of the branch-length extension from modeling site-to-site variation in amino-acid substitution rate. The branch-length extension from experimentally informed site-specific models is similar to that achieved by other approaches that allow the stationary state to vary across sites. However, the improvements from all of these site-specific but time homogeneous and site independent models are limited by the fact that a protein's amino-acid preferences gradually shift as it evolves. Overall, our work underscores the importance of modeling site-specific amino-acid preferences when estimating deep divergence times-but also shows the inherent limitations of approaches that fail to account for how these preferences shift over time.}, }
@article {pmid30425058, year = {2019}, author = {Travis, RC and Perez-Cornago, A and Appleby, PN and Albanes, D and Joshu, CE and Lutsey, PL and Mondul, AM and Platz, EA and Weinstein, SJ and Layne, TM and Helzlsouer, KJ and Visvanathan, K and Palli, D and Peeters, PH and Bueno-de-Mesquita, B and Trichopoulou, A and Gunter, MJ and Tsilidis, KK and Sánchez, MJ and Olsen, A and Brenner, H and Schöttker, B and Perna, L and Holleczek, B and Knekt, P and Rissanen, H and Yeap, BB and Flicker, L and Almeida, OP and Wong, YYE and Chan, JM and Giovannucci, EL and Stampfer, MJ and Ursin, G and Gislefoss, RE and Bjørge, T and Meyer, HE and Blomhoff, R and Tsugane, S and Sawada, N and English, DR and Eyles, DW and Heath, AK and Williamson, EJ and Manjer, J and Malm, J and Almquist, M and Marchand, LL and Haiman, CA and Wilkens, LR and Schenk, JM and Tangen, CM and Black, A and Cook, MB and Huang, WY and Ziegler, RG and Martin, RM and Hamdy, FC and Donovan, JL and Neal, DE and Touvier, M and Hercberg, S and Galan, P and Deschasaux, M and Key, TJ and Allen, NE}, title = {A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk.}, journal = {Cancer research}, volume = {79}, number = {1}, pages = {274-285}, doi = {10.1158/0008-5472.CAN-18-2318}, pmid = {30425058}, issn = {1538-7445}, abstract = {: Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (Pheterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.}, }
@article {pmid30423481, year = {2018}, author = {Brunstein, CG and Pasquini, MC and Kim, S and Fei, M and Adekola, K and Ahmed, I and Aljurf, M and Agrawal, V and Auletta, JJ and Battiwalla, M and Bejanyan, N and Bubalo, J and Cerny, J and Chee, L and Ciurea, SO and Freytes, C and Gadalla, SM and Gale, RP and Ganguly, S and Hashmi, SK and Hematti, P and Hildebrandt, G and Holmberg, LA and Lahoud, OB and Landau, H and Lazarus, HM and de Lima, M and Mathews, V and Maziarz, R and Nishihori, T and Norkin, M and Olsson, R and Reshef, R and Rotz, S and Savani, B and Schouten, HC and Seo, S and Wirk, BM and Yared, J and Mineishi, S and Rogosheske, J and Perales, MA}, title = {Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell 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.2018.11.005}, pmid = {30423481}, issn = {1523-6536}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing ≥ 20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.}, }
@article {pmid30423480, year = {2018}, author = {Pulsipher, MA and Logan, BR and Chitphakdithai, P and Kiefer, DM and Riches, ML and Rizzo, JD and Anderlini, P and Leitman, SF and Varni, JW and Kobusingye, H and Besser, RM and Miller, JP and Drexler, RJ and Abdel-Mageed, A and Ahmed, IA and Akard, LP and Artz, AS and Ball, ED and Bayer, RL and Bigelow, C and Bolwell, BJ and Broun, ER and Bunin, NJ and Delgado, DC and Duckworth, K and Dvorak, CC and Hahn, TE and Haight, AE and Hari, PN and Hayes-Lattin, BM and Jacobsohn, DA and Jakubowski, AA and Kasow, KA and Lazarus, HM and Liesveld, JL and Linenberger, M and Litzow, MR and Longo, W and Magalhaes-Silverman, M and McCarty, JM and McGuirk, JP and Mori, S and Prasad, VK and Rowley, SD and Rybka, WB and Sahdev, I and Schriber, JR and Selby, GB and Shaughnessy, PJ and Shenoy, S and Spitzer, T and Tse, WT and Uberti, JP and Vusirikala, M and Waller, EK and Weisdorf, DJ and Yanik, GA and Navarro, WH and Horowitz, MM and Switzer, GE and Shaw, BE and Confer, DL}, title = {Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.}, 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.2018.11.004}, pmid = {30423480}, issn = {1523-6536}, support = {R01 HL085707/HL/NHLBI NIH HHS/United States ; UG1 HL069254/HL/NHLBI NIH HHS/United States ; }, abstract = {The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3 days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.}, }
@article {pmid30422669, year = {2018}, author = {Lastwika, KJ and Kargl, J and Zhang, Y and Zhu, X and Lo, E and Shelley, D and Ladd, JJ and Wu, W and Kinahan, P and Pipavath, SNJ and Randolph, TW and Shipley, M and Lampe, PD and Houghton, AM}, title = {Tumor-Derived Autoantibodies Identify Malignant Pulmonary Nodules.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1164/rccm.201804-0628OC}, pmid = {30422669}, issn = {1535-4970}, support = {U01 CA185097/CA/NCI NIH HHS/United States ; U01 CA186157/CA/NCI NIH HHS/United States ; }, abstract = {RATIONALE: Screening for non-small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm due to invasive follow up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor specific biomarkers.<br><br>OBJECTIVES: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules.<br><br>METHODS: High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule controls. Promising autoantibodies were further analyzed in an independent cohort of 250 nodule positive patients.<br><br>MEASUREMENTS AND MAIN RESULTS: Thirteen tumor B cell-derived autoantibodies isolated ex vivo showed ≥50% sensitivity and ≥70% specificity for lung cancer. ‎In plasma, 11/13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5/13 tumor-derived autoantibodies remained significantly elevated in cancers. A combination of 4 of these autoantibodies could detect malignant nodules with an AUC=0.74 and had an AUC=0.78 in a sub-cohort of indeterminate (8-20mm in the longest diameter) pulmonary nodules.<br><br>CONCLUSIONS: Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost-effective and non-invasive approach to determine nodule malignancy for widespread LDCT screening.}, }
@article {pmid30416076, year = {2018}, author = {Gibson, TM and Mostoufi-Moab, S and Stratton, KL and Leisenring, WM and Barnea, D and Chow, EJ and Donaldson, SS and Howell, RM and Hudson, MM and Mahajan, A and Nathan, PC and Ness, KK and Sklar, CA and Tonorezos, ES and Weldon, CB and Wells, EM and Yasui, Y and Armstrong, GT and Robison, LL and Oeffinger, KC}, title = {Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort.}, journal = {The Lancet. Oncology}, volume = {19}, number = {12}, pages = {1590-1601}, doi = {10.1016/S1470-2045(18)30537-0}, pmid = {30416076}, issn = {1474-5488}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.<br><br>METHODS: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.<br><br>FINDINGS: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p<0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p<0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; pmediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; pmediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p<0·0001).<br><br>INTERPRETATION: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.<br><br>FUNDING: National Cancer Institute and the American Lebanese-Syrian Associated Charities.}, }
@article {pmid30415231, year = {2019}, author = {Welch, LS and Dement, JM and Cranford, K and Shorter, J and Quinn, PS and Madtes, DK and Ringen, K}, title = {Early detection of lung cancer in a population at high risk due to occupation and smoking.}, journal = {Occupational and environmental medicine}, volume = {76}, number = {3}, pages = {137-142}, doi = {10.1136/oemed-2018-105431}, pmid = {30415231}, issn = {1470-7926}, abstract = {OBJECTIVE: The US National Comprehensive Cancer Network (NCCN) recommends two pathways for eligibility for Early Lung Cancer Detection (ELCD) programmes. Option 2 includes individuals with occupational exposures to lung carcinogens, in combination with a lesser requirement on smoking. Our objective was to determine if this algorithm resulted in a similar prevalence of lung cancer as has been found using smoking risk alone, and if so to present an approach for lung cancer screening in high-risk worker populations.<br><br>METHODS: We enrolled 1260 former workers meeting NCCN criteria, with modifications to account for occupational exposures in an ELCD programme.<br><br>RESULTS: At baseline, 1.6% had a lung cancer diagnosed, a rate similar to the National Lung Cancer Screening Trial (NLST). Among NLST participants, 59% were current smokers at the time of baseline scan or had quit smoking fewer than 15 years prior to baseline; all had a minimum of 30 pack-years of smoking. Among our population, only 24.5% were current smokers and 40.1% of our participants had smoked fewer than 30 pack-years; only 43.5% would meet entry criteria for the NLST. The most likely explanation for the high prevalence of screen-detected lung cancers in the face of a reduced risk from smoking is the addition of occupational risk factors for lung cancer.<br><br>CONCLUSION: Occupational exposures to lung carcinogens should be incorporated into criteria used for ELCD programmes, using the algorithm developed by NCCN or with an individualised risk assessment; current risk assessment tools can be modified to incorporate occupational risk.}, }
@article {pmid30414446, year = {2019}, author = {Iovino, L and Taddei, R and Bindi, ML and Morganti, R and Ghinolfi, D and Petrini, M and Biancofiore, G}, title = {Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study.}, journal = {Transplant immunology}, volume = {52}, number = {}, pages = {45-52}, doi = {10.1016/j.trim.2018.11.001}, pmid = {30414446}, issn = {1878-5492}, abstract = {Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs. We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (-226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV- patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.}, }
@article {pmid30412361, year = {2019}, author = {Elbing, KL and Brent, R}, title = {Recipes and Tools for Culture of Escherichia coli.}, journal = {Current protocols in molecular biology}, volume = {125}, number = {1}, pages = {e83}, doi = {10.1002/cpmb.83}, pmid = {30412361}, issn = {1934-3647}, support = {R21 CA223901/GF/NIH HHS/United States ; R21 CA223901/CA/NCI NIH HHS/United States ; }, abstract = {In this article, we provide information about culture media, including minimal liquid media, rich liquid media, solid media, top agar, and stab agar. We also provide descriptions and useful information about tools used with growth media such as inoculating loops, sterile toothpicks, and spreaders. © 2018 by John Wiley &amp; Sons, Inc.}, }
@article {pmid30412224, year = {2018}, author = {Chang, K and Willis, JA and Reumers, J and Taggart, MW and San Lucas, FA and Thirumurthi, S and Kanth, P and Delker, DA and Hagedorn, CH and Lynch, PM and Ellis, LM and Hawk, ET and Scheet, PA and Kopetz, S and Arts, J and Guinney, J and Dienstmann, R and Vilar, E}, title = {Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {29}, number = {10}, pages = {2061-2067}, pmid = {30412224}, issn = {1569-8041}, support = {T32 CA009666/CA/NCI NIH HHS/United States ; }, abstract = {Background: Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown.<br><br>Patients and methods: We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier.<br><br>Results: Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations.<br><br>Conclusions: Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.}, }
@article {pmid30411258, year = {2018}, author = {Pisarsky, L and Ghajar, CM}, title = {Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence?.}, journal = {Advances in experimental medicine and biology}, volume = {1100}, number = {}, pages = {19-45}, doi = {10.1007/978-3-319-97746-1_2}, pmid = {30411258}, issn = {0065-2598}, abstract = {Anti-angiogenic therapy was conceived originally as a silver bullet able to maintain tumor dormancy indefinitely. By targeting new blood vessel formation, anti-angiogenic agents were expected to suppress the growth of any type of primary or metastatic tumor, independent of their subtype or genetic landscape. However, more that 20 years after the first anti-angiogenic preclinical trial, the astonishing inhibition of metastatic outgrowth originally observed in mouse models never translated into clinics. Indeed, whereas anti-angiogenic agents (sometimes) prolong progression-free survival, they fail to impact overall survival, particularly in breast cancer. This observation revealed to be true in early- and advanced-stage breast cancer patients treated either in adjuvant or neo-adjuvant settings, suggesting that the effect of anti-angiogenic therapy on repressing growth of overt metastases - and also on preventing outgrowth of disseminated tumor cells and micrometastases - is limited. What are the reasons underlying this failure? And, more importantly, is there still room for improvement?}, }
@article {pmid30409798, year = {2018}, author = {Halpern, AB and Othus, M and Huebner, EM and Scott, BL and Hendrie, PC and Percival, MM and Becker, PS and Smith, HA and Oehler, VG and Orozco, JJ and Cassaday, RD and Gardner, KM and Chen, TL and Buckley, SA and Orlowski, KF and Anwar, A and Estey, EH and Walter, RB}, title = {Phase 1/2 trial of cladribine, high-dose cytarabine, mitoxantrone, and G-CSF with dose-escalated mitoxantrone for relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.204792}, pmid = {30409798}, issn = {1592-8721}, }
@article {pmid30409719, year = {2019}, author = {Smith, SD and Gandhy, S and Gopal, AK and Reddy, P and Shadman, M and Till, BG and Lynch, RC and Kanan, S and Cowan, A and Low, L and Hill, BT}, title = {Modified VR-CAP, Alternating With Rituximab and High-dose Cytarabine: An Effective Pre-transplant Induction Regimen for Mantle Cell Lymphoma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {19}, number = {1}, pages = {48-52}, doi = {10.1016/j.clml.2018.10.006}, pmid = {30409719}, issn = {2152-2669}, abstract = {BACKGROUND: Initial treatment of mantle cell lymphoma (MCL) incorporating autologous stem cell transplantation affords long-term remissions, but relapses still occur. Optimal pretransplant therapy will afford high complete response rates and not impair stem cell collection. Incorporation of bortezomib represents a natural evolution of pretransplant therapy, given its proven first-line efficacy and minimal impact on stem cell collection.<br><br>PATIENTS AND METHODS: At the University of Washington/Seattle Cancer Care Alliance and the Cleveland Clinic Foundation, we developed modified VR-CAP/R+ara-C (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone, alternating with rituximab and high-dose cytarabine), for transplant-eligible patients with MCL. This regimen was administered as standard-of-care, pretransplant therapy to consecutive patients with MCL from April 2015 to the present.<br><br>RESULTS: A total of 37 patients were treated with this regimen, including 18 at the University of Washington/Seattle Cancer Care Alliance and 19 at the Cleveland Clinic Foundation. Most patients had intermediate- or high-risk disease by both (mantle-cell lymphoma international prognostic index (MIPI)-B and MIPI-C category. Complete response to induction was achieved in 32 (86%) of 37 evaluable patients; 2 achieved partial response, and 3 had primary refractory disease. Stem cell collection was successful in 1 attempt in 30 of 32 patients. The median follow-up of survivors measured from start of treatment is 17.4 months. Five patients have progressed, and 4 have died (2 owing to lymphoma, 2 from toxicity).<br><br>CONCLUSION: Modified VR-CAP/R+ara-C is feasible pretransplant therapy for patients with MCL and is associated with a high rate of complete response and eligibility for autologous stem cell transplantation.}, }
@article {pmid30409315, year = {2018}, author = {Cannon, RB and Houlton, JJ and Patel, S and Raju, S and Noble, A and Futran, ND and Parvathaneni, U and Méndez, E}, title = {Patterns of cervical node positivity, regional failure rates, and fistula rates for HPV+ oropharyngeal squamous cell carcinoma treated with transoral robotic surgery (TORS).}, journal = {Oral oncology}, volume = {86}, number = {}, pages = {296-300}, doi = {10.1016/j.oraloncology.2018.10.001}, pmid = {30409315}, issn = {1879-0593}, abstract = {OBJECTIVES: (1) Report the patterns of cervical node positivity for HPV + oropharyngeal squamous cell carcinoma (OPSCC) treated with transoral robotic surgery (TORS) and a unilateral level II-IV node dissection. (2) Investigate the regional failure rate following this operation. (3) Report the rate of pharyngocutaneous fistula (PCF) formation intraoperatively and postoperatively following TORS/neck dissection.<br><br>METHODS: Retrospective case series of 88 patients with HPV+ OPSCC treated with TORS and simultaneous neck dissection levels II-IV at the University of Washington from 2010 to 2016. Primary endpoints were PCF, regional recurrence, disease-free survival (DFS), and overall survival (OS).<br><br>RESULTS: The overall frequency of cervical node positivity was 93%, with 84% in level IIa, 7% in IIb, 23% in III, and 13% in IV. Two patients developed PCF intraoperatively, repaired with a local digastric flap, and no postoperative PCF occurred. Sixteen patients (18%) received surgery alone, 49 patients (56%) received adjuvant radiation, and 23 patients (26%) underwent adjuvant chemoradiation. DFS at 2 years was 95% and OS at 2 years was 100%. No concerning level Ib nodes were identified preoperatively or during surgery, and no regional failures occurred in this location.<br><br>CONCLUSION: Our data suggests, in TORS for HPV+ OPSCC, neck dissection of levels II-IV accurately stages the neck pathologically and prevents regional recurrences, with adjuvant therapy when indicated, and survival outcomes are excellent. Single-staged operations did not result in any postoperative PCF. Avoiding dissection of level Ib with TORS oropharyngectomy limits morbidity to the marginal mandibular nerve and salivary function, and resulted in no postoperative fistulas with minimal reconstruction interventions.}, }
@article {pmid30408115, year = {2018}, author = {Landovitz, RJ and Li, S and Grinsztejn, B and Dawood, H and Liu, AY and Magnus, M and Hosseinipour, MC and Panchia, R and Cottle, L and Chau, G and Richardson, P and Marzinke, MA and Hendrix, CW and Eshleman, SH and Zhang, Y and Tolley, E and Sugarman, J and Kofron, R and Adeyeye, A and Burns, D and Rinehart, AR and Margolis, D and Spreen, WR and Cohen, MS and McCauley, M and Eron, JJ}, title = {Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial.}, journal = {PLoS medicine}, volume = {15}, number = {11}, pages = {e1002690}, pmid = {30408115}, issn = {1549-1676}, support = {P30 AI094189/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States.<br><br>METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population.<br><br>CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.}, }
@article {pmid30407609, year = {2018}, author = {Hay, KA}, title = {Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy.}, journal = {British journal of haematology}, volume = {183}, number = {3}, pages = {364-374}, doi = {10.1111/bjh.15644}, pmid = {30407609}, issn = {1365-2141}, abstract = {Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.}, }
@article {pmid30406840, year = {2019}, author = {Jones, RL and Mo, G and Baldwin, JR and Peterson, PM and Ilaria, RL and Conti, I and Cronier, DM and Tap, WD}, title = {Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma.}, journal = {Cancer chemotherapy and pharmacology}, volume = {83}, number = {1}, pages = {191-199}, doi = {10.1007/s00280-018-3723-4}, pmid = {30406840}, issn = {1432-0843}, abstract = {PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure-response relationship for progression-free survival (PFS), overall survival (OS), and safety.<br><br>METHODS: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (Cmin1) and the average concentration throughout treatment (Cavg). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles.<br><br>RESULTS: PFS and OS were described by models with an exponential hazard function and inhibitory EMAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (ECmin150 = 82.0 µg/mL, ECavg50 = 179 µg/mL) and OS (ECmin150 = 66.1 µg/mL, ECavg50 = 134 µg/mL) corresponded to the median and 25th percentile of Cmin1/Cavg in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels.<br><br>CONCLUSIONS: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.}, }
@article {pmid30404870, year = {2019}, author = {Greenlee, H and Shi, Z and Hibshoosh, H and Giri, DD and Ahmed, A and Williams, S and Falcone, DJ and Winston, LA and Zhou, XK and Hudis, CA and Hershman, DL and Dannenberg, AJ and Iyengar, NM}, title = {Obesity-associated Breast Inflammation among Hispanic/Latina Breast Cancer Patients.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {12}, number = {1}, pages = {21-30}, doi = {10.1158/1940-6207.CAPR-18-0207}, pmid = {30404870}, issn = {1940-6215}, abstract = {Breast white adipose tissue inflammation (BWATi) is associated with obesity and higher breast cancer risk among non-Hispanic white women. Obesity is prevalent in Hispanic/Latina patients with breast cancer, and the occurrence of BWATi in this population is not well-characterized. The association between BWATi and body mass index (BMI) was evaluated in Hispanic/Latina patients with breast cancer who underwent mastectomy. BWATi was defined as the presence of crown-like structures of the breast (CLS-B), detected by CD68 IHC in nontumor breast tissue. BWATi severity was quantified as number of CLS-B/cm2 Adipocyte diameter was measured using hematoxylin and eosin-stained breast tissue sections. Preoperative BMI (within 1 week prior to mastectomy) was categorized as normal (18.5-<25.0 kg/m2), overweight (25.0-<30.0 kg/m2), class I obesity (30.0-<35.0 kg/m2), and class II-III obesity (35.0 kg/m2 or above). Patient charts were abstracted to record clinicopathologic features and liver function tests <90 days before mastectomy. The study included 91 women (mean age 69 years; range 36-96 years). Prevalence of BWATi increased with BMI (24% in normal weight, 34% in overweight, 57% in class I obesity, and 65% in class II-III obesity; Ptrend <0.01). Severe BWATi (>0.27 CLS-B/cm2) was associated with higher BMI (Ptrend = 0.046) and greater adipocyte diameter (P = 0.04). Adjusting for BMI, neoadjuvant chemotherapy, and elevated alanine aminotransferase were associated with severe BWATi, and current smoking was associated with mild BWATi (all P < 0.05). BWATi was associated with higher BMI in Hispanic/Latina patients with breast cancer, consistent with previously described associations in other populations.}, }
@article {pmid30403372, year = {2018}, author = {Borst, AJ and Weidle, CE and Gray, MD and Frenz, B and Snijder, J and Joyce, MG and Georgiev, IS and Stewart-Jones, GB and Kwong, PD and McGuire, AT and DiMaio, F and Stamatatos, L and Pancera, M and Veesler, D}, title = {Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core.}, journal = {eLife}, volume = {7}, number = {}, pages = {}, pmid = {30403372}, issn = {2050-084X}, support = {U19 AI109632//National Institute of Allergy and Infectious Diseases/International ; P01 AI094419//National Institute of Allergy and Infectious Diseases/International ; R01 GM120553/GM/NIGMS NIH HHS/United States ; U19 AI109632/AI/NIAID NIH HHS/United States ; R01 AI081625/AI/NIAID NIH HHS/United States ; R01AI081625//National Institute of Allergy and Infectious Diseases/International ; R01GM120553/GM/NIGMS NIH HHS/United States ; S10 OD018111/OD/NIH HHS/United States ; T32GM008268/GM/NIGMS NIH HHS/United States ; R01 AI104384/AI/NIAID NIH HHS/United States ; U24 GM116792/GM/NIGMS NIH HHS/United States ; R01 AI104384//National Institute of Allergy and Infectious Diseases/International ; S10 RR023057/RR/NCRR NIH HHS/United States ; R01 AI081625//National Institute of Allergy and Infectious Diseases/International ; T32 GM008268/GM/NIGMS NIH HHS/United States ; P01 AI094419/AI/NIAID NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Antibodies/chemistry/*metabolism/ultrastructure ; Germ Cells/*metabolism ; Glycosylation ; HEK293 Cells ; HIV Envelope Protein gp120/*metabolism ; HIV-1/*metabolism ; Humans ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin G/metabolism ; Models, Molecular ; Polysaccharides/metabolism ; Protein Binding ; *Protein Multimerization ; Protein Structure, Secondary ; }, abstract = {VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1-3 in the presence and absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.}, }
@article {pmid30401586, year = {2019}, author = {Morsink, LM and Walter, RB and Ossenkoppele, GJ}, title = {Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia.}, journal = {Blood reviews}, volume = {34}, number = {}, pages = {26-33}, doi = {10.1016/j.blre.2018.10.003}, pmid = {30401586}, issn = {1532-1681}, abstract = {CLEC12A has recently been identified as an antigen, expressed on leukemic stem cells and leukemic blasts. Given the fact that this expression profile seems stable throughout diagnosis, treatment and relapse on leukemic blasts and leukemic stem cells, CLEC12A can be considered a highly potent and reliable marker for the detection of measurable residual disease and therefore applicable for risk stratification and prognostication in AML. Low CLEC12A expression on leukemic blasts seems to be independently associated with lower likelihood of achieving complete remission after 1 cycle of induction chemotherapy, shorter event free survival, as well as overall survival, indicating potential prognostic properties of CLEC12A expression itself. Lack of expression on the normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, might result in less toxicity regarding cytopenias, making CLEC12A an interesting target for innovating immunotherapies, including monoclonal and bispecific antibodies, antibody-drug conjugates and CAR-T cells therapy.}, }
@article {pmid30400834, year = {2018}, author = {Hirsch, A and Katz, MA and Laufer Peretz, A and Greenberg, D and Wendlandt, R and Shemer Avni, Y and Newes-Adeyi, G and Gofer, I and Leventer-Roberts, M and Davidovitch, N and Rosenthal, A and Gur-Arie, R and Hertz, T and Glatman-Freedman, A and Monto, AS and Azziz-Baumgartner, E and Ferdinands, JM and Martin, ET and Malosh, RE and Neyra Quijandría, JM and Levine, M and Campbell, W and Balicer, R and Thompson, MG and , }, title = {Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol.}, journal = {BMC infectious diseases}, volume = {18}, number = {1}, pages = {550}, pmid = {30400834}, issn = {1471-2334}, mesh = {Absenteeism ; Adult ; Cohort Studies ; Female ; Health Personnel/*statistics &amp; numerical data ; Hospitals/statistics &amp; numerical data ; Humans ; Influenza Vaccines/*therapeutic use ; Influenza, Human/*epidemiology/*prevention &amp; control ; Israel/epidemiology ; Male ; Middle Aged ; Respiratory Syncytial Virus, Human/immunology ; Respiratory Tract Infections/*epidemiology/virology ; Surveys and Questionnaires ; Treatment Outcome ; Vaccination/*statistics &amp; numerical data ; Virus Diseases/*epidemiology ; Young Adult ; }, abstract = {BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospec