@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.
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.
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.
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.
Objective: To estimate the prevalence of HBV, HCV, and HIV infection among persons with newly diagnosed cancer.
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.
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.
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.
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 = {}, number = {}, pages = {272989X18819479}, doi = {10.1177/0272989X18819479}, pmid = {30649998}, issn = {1552-681X}, 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}, abstract = {OBJECTIVE: To evaluate plasma acylcarnitine profiles and their relationships with progression of carotid artery atherosclerosis among individuals with and without HIV-infection.
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.
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.
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]).
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 & 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.
OBJECTIVE: We evaluated the effects of GH+CS versus celecoxib on a panel of 20 serum proteins involved in inflammation and other metabolic pathways.
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.
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.
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.
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.
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.
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.
Main Outcomes and Measures: The primary outcome was distant metastasis-free survival.
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.
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.
Objective: To compare the geographic distribution and survival outcomes for rural vs urban patients with cancer treated in clinical trials.
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.
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.
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.
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.
Objective: To assess the association between prostate cancer imaging rates and a VA vs fee-for-service health care setting.
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.
Exposures: Patient utilization of different health care delivery systems.
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.
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.
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 FSHD.}, journal = {eLife}, volume = {8}, number = {}, pages = {}, doi = {10.7554/eLife.41740}, pmid = {30644821}, issn = {2050-084X}, support = {P01NS069539//National Institute of Neurological Disorders and Stroke/ ; FSHS-22014-01//FSH Society/ ; P30 CA015704//National Institutes of Health/ ; }, abstract = {DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). While DUX4's transcriptional activity has been extensively characterized, 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 to 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 = {}, number = {}, pages = {}, doi = {10.1038/s41588-018-0307-5}, pmid = {30643251}, issn = {1546-1718}, 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 = {}, number = {}, pages = {}, doi = {10.1038/s41588-018-0315-5}, pmid = {30643249}, issn = {1546-1718}, 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 {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.
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).
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.
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 {pmid30530817, year = {2018}, 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 = {}, number = {}, pages = {}, 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.}, }
@article {pmid30639324, year = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2018.12.012}, pmid = {30639324}, issn = {1537-6605}, 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, S 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, S 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 = {}, number = {}, pages = {}, 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, 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 "non-optimal" 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 female reproductive tract 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 {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 {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.
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.
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.
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.
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.
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.
Exposures: Cancer diagnosis and 1 or more of 18 comorbidities.
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).
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.
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.
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.
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.
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 & 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}, 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}, 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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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}, 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 = {}, number = {}, pages = {}, 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}, 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 = {SP/09/002//British Heart Foundation (BHF)/ ; RG/13/13/30194//British Heart Foundation (BHF)/ ; 268834//EC | European Research Council (ERC)/ ; }, 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 = {Haab, BB and Staal, B 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 Liu, Y and Brand, RE and Maitra, A}, 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}, 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.
EXPERIMENTAL DESIGN: We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case/control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set.
RESULTS: The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 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.
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, 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 Patients 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 3 study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD+bleomycin) as frontline 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=.012). For PFS, the risk of progression or death was also reduced (HR=0.50; P=.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 to 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 Stage III or IV cHL patients.}, }
@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}, 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 = {}, 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.
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.
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).
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}, 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 {pmid30333223, year = {2019}, author = {Himbert, C and Ose, J and Nattenmüller, J and Warby, CA and Holowatyj, AN and Böhm, J and Lin, T and Haffa, M and Gigic, B and Hardikar, S and Scherer, D and Zielske, L and Schrotz-King, P and Kölsch, T and Siegel, EM and Shibata, D and Ulrich, A and Schneider, M and Hursting, SD and Kauczor, HU and Ulrich, CM}, title = {Body Fatness, Adipose Tissue Compartments, and Biomarkers of Inflammation and Angiogenesis in Colorectal Cancer: The ColoCare Study.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {28}, number = {1}, pages = {76-82}, doi = {10.1158/1055-9965.EPI-18-0654}, pmid = {30333223}, issn = {1538-7755}, support = {R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R35 CA197627/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R01 CA211705/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Adiposity has been linked to both risk and prognosis of colorectal cancer; however, the impact of different fat areas [visceral (VFA) vs. subcutaneous fat area (SFA)] is unclear. We investigated associations between adiposity and biomarkers of inflammation and angiogenesis among patients with colorectal cancer.
METHODS: Preoperative serum samples and computed tomography scans were obtained from 188 patients diagnosed with primary invasive stage I-IV colorectal cancer enrolled in the ColoCare Study. Adiposity was assessed by area-based quantification of VFA, SFA, and VFA:SFA ratio on spinal levels L3/L4 and L4/L5. Circulating levels of inflammation (CRP, SAA, sICAM-1, and sVCAM-1) and angiogenesis (VEGF-A and VEGF-D) were assessed from patient sera on the Meso Scale Discovery platform. Partial correlations and regression analyses, adjusted for age, sex, and tumor stage, were performed.
RESULTS: VFA was moderately correlated with CRP and SAA (CRP: L3/L4 and L4/L5:r = 0.21, P = 0.01; SAA: L3/L4:r = 0.17, P = 0.04). The correlation between SFA and the measured biomarkers were weak (r ≤ 0.13, not significant). The ratio of VFA:SFA at L3/L4 was moderately correlated with VEGF-A (r = 0.28, P = 0.0008) and SAA (r = 0.24, P = 0.006), and less so with CRP (r = 0.18, P = 0.04) and sICAM-1 (r = 0.18, P = 0.04). Similar correlations were found for the VFA:SFA ratio at L4/L5.
CONCLUSIONS: We observed an association between visceral adiposity and biomarkers of inflammation and angiogenesis in colorectal cancer. In particular, the VFA:SFA ratio was correlated with circulating levels of the proangiogenic biomarker VEGF-A.
IMPACT: Our findings support a direct association of visceral adipose tissue with inflammatory and angiogenic processes, which play fundamental roles in the development and progression of colorectal cancer.}, }
@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}, 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.
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.
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.
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}, 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.
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.
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.
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 = {R01HL105065//National Heart, Lung, and Blood Institute/ ; //National Institutes of Health/ ; HHSN268201600018C//U.S. Department of Health and Human Services/ ; HHSN268201600001C//U.S. Department of Health and Human Services/ ; HHSN268201600002C//U.S. Department of Health and Human Services/ ; HHSN268201600003C//U.S. Department of Health and Human Services/ ; HHSN268201600004C//U.S. Department of Health and Human Services/ ; }, 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.
DESIGN/SETTING: Prospective cohort study.
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.
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.
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.
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}, }
@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 = {T32 AI007044//National Institutes of Health/ ; R24 TW007988//Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University/ ; T32 AI007433//National Institutes of Health (US)/ ; P30 AI060354//Harvard University Center for AIDS Research/ ; K23 AI108293//National Institute of Allergy and Infectious Diseases/ ; R01AI058736//National Institute of Allergy and Infectious Diseases/ ; R01 MH090326//National Institute of Mental Health/ ; }, 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.
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.
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).
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.
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}, 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 "intention-to-treat" 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}, 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}, pmid = {30606716}, issn = {1756-1833}, 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.
DESIGN: Nested case-control study.
SETTING: 20 population based cohort studies in Asia, Europe, Australia, and the United States.
PARTICIPANTS: 5299 patients with incident lung cancer, with individually incidence density matched controls.
EXPOSURE: Circulating hsCRP concentrations in prediagnostic serum or plasma samples.
MAIN OUTCOME MEASURE: Incident lung cancer diagnosis.
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.
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 13-17 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}, abstract = {Although donation of bone marrow (BM) or peripheral blood stem cells (PBSC) 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, we prospectively enrolled 294 donors age <18 at 25 pediatric transplant centers in North America, assessing them pre-donation, peri-donation, 1 month, 6 months, and 1 year after donation. We noted that 71% of children reported pain and 59% other symptoms peri-donation, with resolution to 14% and 12% at 1 month. Both older age (age 13-17 vs. younger) and female sex were associated with higher levels of pain peri-donation, with the highest rates in older females (57% and 17% reporting grades 2-4 and 3-4 pain, respectively). Multivariate analyses showed a 4-fold increase in risk for older females compared to males <13 (p<0.001)). At 1 year, 11% of 13-17 year old females reported grade 2-4 pain compared to 3%, 0%, and 1% of males aged 13-17, females <13, and males <13 (p=0.01). Males and females 13-17 years old failed to return to pre-donation pain levels at 1 year 22% and 23% of the time compared to 3% and 10% in males and females <13 (p=0.002). In conclusion, females age 13-17 are at increased risk for grade 2-4 pain at 1 year and more than 20% of females and males 13-17 do not return to baseline pain levels 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}, 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.
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.
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}, 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-AI068613//National Institutes of Health/ ; UM1-AI068617//National Institutes of Health/ ; UM1-AI068619//National Institutes of Health/ ; }, 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 posttransplant AML or MDS 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 AML/MDS relapse after hematopoietic cell transplantation have poor prognosis and no standard treatment. Twenty-nine patients with early disease recurrence posttransplant were treated with azacitidine (median dose 40 mg/m2/day x 5-7 days). At a median follow-up of 6.3 (range 1.3-41.1) months, 7 (27%) had response to azacitidine defined as complete remission, hematologic improvement, or improved donor chimerism. Response occurred at a median of 3 cycles, and median duration of response was 70 (range 26-464) days. Median survival was 6.8 months (95% CI 3.8-11.1). Patients receiving azacitidine dose ≤40 or >40 mg/m2 had similar survival. Six patients receiving donor lymphocyte infusion with azacitidine had 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 azacitidine dose or response was observed. Low-dose azacitidine appears to be comparable to higher doses in efficacy posttransplant. A significant proportion of this poor-risk population responded to low-dose azacitidine, suggesting a dose-independent, non-cytotoxic mechanism for anti-leukemic 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 = {Jin Ha, M 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 = {//Damon Runyon Cancer Research Foundation/ ; //Clinical Investigator Award/ ; P50 CA107399//National Cancer Institute of the National Institutes of Health/ ; P01CA044991//Leukemia and Lymphoma Society/ ; K24CA184039//Leukemia and Lymphoma Society/ ; }, 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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2018.11.020}, pmid = {30595435}, issn = {1097-4164}, 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 Hoai Do, H and Gebeyaw, FA and Ibrahim, A and Ali, AA and Winer, RL}, title = {"We brought our culture here with us": A qualitative study of perceptions of HPV vaccine and vaccine uptake among East African immigrant mothers.}, journal = {Papillomavirus research (Amsterdam, Netherlands)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pvr.2018.12.003}, pmid = {30594650}, issn = {2405-8521}, 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.
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.
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).
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 = {In Reply: Are early screening biomarkers for endometrial cancer needed to reduce health disparities?.}, 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 (KIR) genotype does not improve graft-versus-leukemia responses in chronic lymphocytic leukemia (CLL) after unrelated donor transplant: a CIBMTR 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}, abstract = {Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with CLL leading to 40-45% long-term survival. The impact of donor KIR genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown.
METHODS: 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.
RESULTS: 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 OS were reduced intensity conditioning (HR of death 0.76) and good performance status (HR 0.46), while allo-HCT in non-remission (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 vs B/x KIR haplotypes and those with KIR gene content scores of 0 vs 1 vs ≥2 yielded similar rates of non-relapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival (PFS) and overall survival (OS). Relapse risk was not different with grafts from donors with KIR3DL1 transplanted into HLA C1/1 vs C2 recipients.
CONCLUSION: This large analysis failed to demonstrate an association between unrelated donor 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 = {2018}, 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 = {}, number = {}, pages = {}, 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 Neurological 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 hematological malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia up to the age of 25 years 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 neurological toxicity. The assessment and grading of these toxicities have varied considerably across clinical trials and across institutions, making it difficult to compare 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 widely 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 20-21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here, we report the consensus of the group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to use, 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 post-approval 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 = {//Seattle Genetics/ ; T32 HL007093//National Heart, Lung, and Blood Institute/ ; 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 & 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.
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.
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.
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.
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}, abstract = {Background: We evaluated use of phylogenetic methods to predict the direction of HIV transmission.
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.
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.
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.
OBJECTIVE: To determine the efficacy of preoperative chlorhexidine (CHG) showers on SSI rates following fusion and nonfusion spine surgery.
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.
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).
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}, 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}, abstract = {An objective in randomized clinical trials is the evaluation of "principal surrogates," 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 "baseline surrogate measure") 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 "placebo structural risk" 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}, }
@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}, 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 varying incidences of posttransplant central nervous system (CNS) relapse, with acute lymphoblastic leukemia (ALL) representing the most common disease histology. While data supporting posttransplant CNS prophylaxis for ALL in the pre-CNS penetrant systemic therapy-era established this as standard practice, controversy exists regarding the role of posttransplant CNS prophylaxis in the contemporary era. Herein we review the most relevant, albeit exclusively retrospective, literature to date for the role of posttransplant CNS prophylaxis in ALL. Given the paucity of data supporting the routine practice of posttransplant 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 posttransplant CNS prophylaxis.}, }
@article {pmid30590092, year = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.exphem.2018.12.003}, pmid = {30590092}, issn = {1873-2399}, abstract = {Pre-clinical 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. No engraftment of NHP HSPCs was observed in NSG mice, whereas the 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 transplants in the NHP, only HSC-enriched CD34+CD90+CD45RA- cell fractions did engraft and reconstituted the bone marrow stem cell niche in MISTRG mice. In summary, we here report the first "monkeynized" mouse xenograft model that closely recapitulates the autologous hematopoietic reconstitution in the NHP stem and progenitor cell transplantation and gene therapy model. 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 {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}, 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.
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.
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, 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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {1556264618820219}, 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}, 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 (
RESULTS: Here, we describe an automated CUT&RUN platform and apply it to characterize the chromatin landscapes of human cells. We find that automated CUT&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&RUN to profile frozen tumor samples and find that our method readily distinguishes two pediatric glioma xenografts by their subtype-specific gene expression programs.
CONCLUSIONS: The easy, cost-effective workflow makes automated CUT&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 Receptors T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL) - an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT).}, journal = {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 U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor - T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.}, }
@article {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.
OBJECTIVE: To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas.
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.
RESULTS: Most patients with recurrent HGG developed "in-field" 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).
CONCLUSION: Based on our experience, the majority of treatment failures after SRS for recurrent HGG were "in-field." 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 = {2018}, 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 = {}, number = {}, pages = {JCO1801279}, 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.
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).
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).
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 = {2018}, 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 = {Intra-individual variation in markers of intestinal permeability and adipose tissue inflammation in healthy normal weight to obese adults.}, journal = {Cancer epidemiology, biomarkers & 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-18-0641}, pmid = {30573517}, issn = {1538-7755}, 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.
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.
RESULTS: For biomarkers of intestinal permeability, plasma zonulin and lipopolysaccharide binding protein, ICCs were 'excellent' (i.e., > 0.9). The direct measure of intestinal permeability, the lactulose/mannitol test, exhibited 'fair' reliability (ICC=0.53). A wider range of ICCs (0.6-0.9), suggesting 'good' to 'excellent' 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 'good' to 'excellent' ICCs. However, when these populations were expressed as number of cells per gram of tissue, ICC values were 'fair', falling below 0.6.
CONCLUSION: 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.
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 & 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.
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.
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.
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}, 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 & 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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1093/annonc/mdy541}, pmid = {30566587}, issn = {1569-8041}, 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.
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 7,120 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.
Results: At least weekly use of aspirin and non-aspirin (NA) 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 [0.76-0.97], respectively, for aspirin; 0.87 [0.76-1.00] and 0.84 [0.74-0.96], respectively, for NA-NSAIDs). There was no association among women of normal weight (BMI <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.
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//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}, 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}, 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/ ; }, 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.
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.
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.
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}, 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 = {2018}, 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 Dork, T and Eccles, DM and Velez Edwards, D 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, MAT 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, LFAG 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 Rodríguez-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 = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-18-2726}, pmid = {30559148}, issn = {1538-7445}, 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.}, }
@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 {pmid30404870, year = {2018}, 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 = {}, number = {}, pages = {}, 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 {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}, 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}, 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.
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.
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.
MAIN OUTCOMES AND MEASURES: Concordance with consensus reference diagnosis, interobserver reproducibility, and intraobserver reproducibility.
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.
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}, 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 = {2018}, author = {Brahma, S and Henikoff, S}, title = {RSC-Associated Subnucleosomes Define MNase-Sensitive Promoters in Yeast.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2018.10.046}, pmid = {30554944}, issn = {1097-4164}, 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 ("fragile") nucleosomal particles. To determine the composition of fragile particles, we introduce CUT&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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2018.11.002}, pmid = {30554720}, issn = {1537-6605}, 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 = {2018}, 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 = {}, number = {}, pages = {}, 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 = {2018}, author = {Hourigan, CS and Gale, RP and Walter, RB}, title = {Refining AML outcome prediction.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-018-0317-4}, pmid = {30552400}, issn = {1476-5551}, support = {1ZIAHL006163//U.S. Department of Health & 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 = {DK073497//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; DK083648//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; DK38432//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; DK094934//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; GM111439//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; CA191135//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2018.10.015}, pmid = {30552024}, issn = {1097-4180}, 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 = {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 = {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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1002/cyto.a.23700}, pmid = {30549412}, issn = {1552-4930}, }
@article {pmid30549358, year = {2018}, 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 & neck}, volume = {}, number = {}, pages = {}, 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/ ; }, 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.
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1002/pon.4966}, pmid = {30549145}, issn = {1099-1611}, abstract = {OBJECTIVE: To test the short-term efficacy of a brief, fully manualized marital communication and interpersonal support intervention for couples facing recently diagnosed breast cancer.
METHODS: A total of 322 women diagnosed within 6 months with Stage 0-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 Masters prepared patient educators; controls received the booklet, "What's Happening to the Woman I Love?" Outcomes were assessed at 3, 6 and 9 months using Linear Mixed Models within an intent to treat analysis.
RESULTS: Compared to 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 to controls on chemotherapy, wives in the experimental group additionally improved on depressed mood and tended to improve on anxiety.
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/ ; KL2TR000048//National Center for Advancing Translational Sciences/ ; R21MD011439//National Institute on Minority Health and Health Disparities/ ; //California Department of Public Health/ ; 103885//California Health and Safety/ ; HHSN261201000140C//National Cancer Institute's Surveillance, Epidemiology, and End Results Program/ ; HHSN261201000035C//Prevention Institute of California/ ; HHSN261201000034C//University of Southern California/ ; //Public Health Institute/ ; U58DP003862-01//Centers for Disease Control and Prevention's National Program of Cancer Registries/ ; }, 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).
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.
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).
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}, 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.
SAMPLE & SETTING: Women were recruited through integrative oncology clinics and the Cancer Surveillance System registry in western Washington.
METHODS & 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.
RESULTS: Among women who were "very involved" in TDM and those who reported their involvement as "just right," intentional nonreceivers scored higher in role-physical, general health, and vitality than receivers after controlling for demographic and disease characteristics.
IMPLICATIONS FOR NURSING: Nurses need to be aware that intentional nonreceivers of adjuvant therapy, particularly if assessed as "very involved" and "just right" 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 = {2018}, author = {Thakar, M 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 non-malignant diseases.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood-2018-09-876284}, pmid = {30545834}, issn = {1528-0020}, abstract = {Despite overall improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for non-malignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI), predicts probability of post-transplant survival in these patients. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 4,083 patients with non-malignant diseases transplanted between 2007-2014. Primary outcome was overall survival (OS), estimated using the Kaplan-Meier method. Hazard ratios (HR) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, 55.8% for patients with HCT-CI scores of 0, 1-2, 3-4, ≥5, respectively (log-rank p<0.001), regardless of conditioning intensity. HCT-CI scores of 1-2 did not differ relative to scores of 0, [HR 1.12 (0.93-1.34, p=0.218)], but HCT-CI of 3-4 and ≥5 posed significantly greater risks of mortality [HR 1.33 (95% CI 1.09-1.63), p=0.004; HR 2.31 (95% CI 1.79-2.96), p<0.0001, respectively). The impact of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores of ≥3 had increased risk of death after HCT (p<0.001). However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk (p=0.11). In conclusion, this is the largest study to date reporting on patients with non-malignant diseases, demonstrating HCT-CI scores ≥ 3 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 non-malignant 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}, 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.
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.
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.
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 = {2018}, 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 & control : CCC}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10552-018-1117-x}, pmid = {30542984}, issn = {1573-7225}, support = {CA173795//National Cancer Institute/ ; CA098858//National Cancer Institute/ ; CA015704//National Cancer Institute/ ; CA009168//National Cancer Institute/ ; }, 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 ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen.
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, 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 = {2018}, 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 & 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-18-0773}, pmid = {30523039}, issn = {1538-7755}, abstract = {BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether post-diagnosis 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) 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 CRC patients.
METHODS/RESULTS: ColoCare is recruiting newly diagnosed CRC patients across six sites in the U.S. and one in Germany. As of April 2018 we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic CRC patients. 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.
CONCLUSION: ColoCare is a consortium for the investigation of multi-level factors relevant to CRC survivorship.
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 CRC.}, }
@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}, 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.
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, 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.
OBJECTIVES: 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.
METHODS: Describe the 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.
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.
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 socio-ecologic 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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1007/s00428-018-2497-8}, pmid = {30539318}, issn = {1432-2307}, support = {18029//National Cancer Institute/ ; 15074//National Cancer Institute/ ; 36444//National Heart, Lung, and Blood Institute/ ; }, 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 "clumpy" 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 = {2018}, 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 & control : CCC}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10552-018-1119-8}, pmid = {30539315}, issn = {1573-7225}, support = {R01-CA097271//National Cancer Institute/ ; }, 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.
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-18-0284}, pmid = {30538099}, issn = {1940-6215}, 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 1157 prostate cancer cases in PCPT were analyzed by case-only methods. Genotypes included 357 single nucleotide polymorphisms (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% C.I. [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}, doi = {10.1186/s12864-018-5234-4}, 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.
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.
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 CIBMTR 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}, abstract = {HLA haplotype mismatches have been associated with higher risk of acute graft versus host disease (aGVHD) in patients receiving HLA matched unrelated donor (URD) hematopoietic cell transplant (HCT) unrelated donors. The Gamma block (GB) is located in the central MHC region between beta and delta blocks (encoding C & B and DR & DQ antigens, respectively). GB contains many inflammatory and immune regulatory genes such as Bf, C2 and C4 genes. A single center study showed that mismatches in SNP c.2918+98G, c.3316C, and c.4385C in the GB block (C4 SNP) were associated with higher risk of grades 3-4 aGVHD. We investigated the association of GB SNP (GBS) mismatches with outcomes after 10/10 & 9/10 URD HCT (n=714). The primary outcome was aGVHD. OS, DFS, TRM, relapse, cGVHD, and engraftment were also analyzed. DNA samples were GBS genotyped by identifying 338 SNPs across 20kb using the Illumina NGS platform. The overall 100 day incidence of aGVHD grades 2-4 & 3-4 were 41% and 17%, respectively. The overall incidence of matching at all GBS tested and at C4 SNP were 23% & 81%, respectively. Neither being matched across all GB SNP tested (vs. mismatched) nor having higher number of GBS mismatches was associated with transplant outcomes. There was no association between C4 SNP mismatches and outcomes except an unexpected significant association between having 2 C4 SNP mismatches and higher hazard ratio for relapse (association seen in 15 patients only, HR: 3.38, 95% CI: 1.75-6.53, p=0.0003). These data did 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}, abstract = {Human rhinovirus lower respiratory tract infection is associated with mortality following hematopoietic cell transplantation; however, risk factors for lower respiratory tract infection are not well characterized. We sought to develop a risk score for progression to lower respiratory tract infection from upper respiratory tract infection in hematopoietic cell transplantation recipients. Risk factors for lower respiratory tract infection within 90 days were analyzed using Cox regression among hematopoietic cell transplantation recipients with rhinovirus upper respiratory tract infection between 1/2009-3/2016. 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 lower respiratory tract infection at various score cutoffs. Of 588 rhinovirus upper respiratory tract infection events, 100 (17%) progressed to lower respiratory tract infection. In a final multivariable model, allogeneic grafts, prior rhinovirus upper respiratory tract infection, low lymphocyte count, low albumin, positive cytomegalovirus serostatus, recipient statin use, and steroid use ≥2 mg/kg/day were associated with progression to lower respiratory tract infection. A weighted risk score cutoff with the highest sensitivity and specificity was determined. Risk scores above this cutoff were associated with progression to lower respiratory tract infection (cumulative incidence 28% vs. 11% below cutoff; p<0.001). The weighted risk score for progression to rhinovirus lower respiratory tract infection can help identify and stratify patients for clinical management and for future clinical trials of therapeutics in hematopoietic cell transplantation 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, A and Wactawski-Wende, J and Datta, M and Sattari, M and Schousboe, JT and Leslie, WD and Ensrud, KE}, title = {A Comparison of U.S. 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}, abstract = {The optimal approach to osteoporosis screening and treatment in postmenopausal women is unclear. We compared 1) the United States Preventive Services Task Force (USPSTF) and Osteoporosis Canada osteoporosis screening strategies; and 2) 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 50-79 years at baseline (n = 117,707 followed for self-reported fractures; n = 8,134 in bone mineral density [BMD] subset). We determined the yield of the screening and treatment strategies in identifying women who experienced major osteoporotic fractures (MOF) during 10-year follow-up. Among women aged 50-64 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, 35-74% were identified for treatment under NOF, and 16-37% 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 50-54 years-old and 49.5% of women 60-64 years-old for BMD testing (versus 54.4% and 60.6% for the Canadian strategy, respectively). However, specificity of the USPSTF strategy was higher than that of the Canadian strategy among women 50-64 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 50-64 (NOF 10-38%; CAROC 1-15%) and maximal in 75- to 79-year-old women (NOF 82.8%; 51.6% CAROC); specificity declined with advancing age and was lower with the NOF than the CAROC strategy. Among women aged 50-64 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. This article is protected by copyright. All rights reserved.}, }
@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 Molli, AEI 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}, 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.
Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span.
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 ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity.
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.
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 = {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 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}, 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 {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 "Cancer Interception" initiative.}, }
@article {pmid30528801, year = {2018}, 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}, 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.
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.
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.
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}, doi = {10.1186/s13058-018-1083-y}, pmid = {30526633}, issn = {1465-542X}, support = {CA129639//National Cancer Institute/ ; CA083178//National Cancer Institute/ ; CA097397//National Cancer Institute/ ; CA114236//National Cancer Institute/ ; P30 CA008748//National Cancer Institute/ ; }, 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.
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.
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).
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 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, ME 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 = {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}, abstract = {Non-graft-versus-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 complications 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 {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.
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.
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 = {CFAR New Investigator Award, P30 AI027757//National Institute of Allergy and Infectious Diseases/ ; P30 CA015704-43//National Cancer Institute/ ; CCEH Pilot Grant, DK56465//National Institute of Diabetes and Digestive and Kidney Diseases/ ; Postdoctoral Fellowship//Belgian American Educational Foundation/ ; DP1 DA039543//National Institute on Drug Abuse/ ; R01 AI30927//National Institute of Allergy and Infectious Diseases/ ; }, 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.
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 = {2018}, 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 = {}, number = {}, pages = {}, 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.
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.
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.
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}, 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.
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.
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.
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.
FUNDING: The US Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health.}, }
@article {pmid30506474, year = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1007/s10461-018-2348-2}, pmid = {30506474}, issn = {1573-3254}, support = {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}, doi = {10.1182/asheducation-2018.1.146}, pmid = {30504303}, issn = {1520-4383}, 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 "financial toxicity" 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}, 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).
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {33354918814260}, doi = {10.1177/0033354918814260}, pmid = {30517057}, issn = {1468-2877}, 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.
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.
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.
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}, 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}, doi = {10.1186/s40425-018-0460-5}, 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 "Tspans" 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}, abstract = {IMPORTANCE: Carpal tunnel syndrome (CTS) is a common and debilitating condition that commonly affects postmenopausal women.
OBJECTIVE: To determine the effect of menopausal hormone therapy (HT) in healthy postmenopausal women on CTS risk.
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.
SETTING: Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers.
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).
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).
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.
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).
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}, }
@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}, doi = {10.3389/fonc.2018.00463}, 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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1038/s41588-018-0286-6}, pmid = {30510241}, issn = {1546-1718}, 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}, doi = {10.1186/s13058-018-1073-0}, pmid = {30509329}, issn = {1465-542X}, support = {PI13/00061//Fundación Canaria de Investigación y Salud/ ; PI13/01162//Fundación Canaria de Investigación y Salud/ ; 14136//Cancer Research UK/United Kingdom ; C570/A16491//Cancer Research UK/United Kingdom ; C8221/A19170//Cancer Research UK/United Kingdom ; 1000143//Medical Research Council/United Kingdom ; C570/A16491//Medical Research Council/United Kingdom ; C8221/A19170//Medical Research Council/United Kingdom ; MR/M012190/1//Medical Research Council/United Kingdom ; HHSN268201600018C//Women's Health Initiative/ ; HHSN268201600001C//Women's Health Initiative/ ; HHSN268201600002C//Women's Health Initiative/ ; HHSN268201600003C//Women's Health Initiative/ ; HHSN268201600004C//Women's Health Initiative/ ; }, 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.
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.
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.
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}, abstract = {The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplant comorbidities and estimate their impact on post-transplant risks of non-relapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and values of three markers namely, ferritin, albumin, and platelet count. The HCT-CI research so far has been almost exclusively limited to recipients of allogeneic HCT from human leucocyte antigen (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 (MM, 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 to the original HCT-CI (0.63 versus 0.59). Findings were similar for recipients of HLA-mismatched (0.62 versus 0.59), HLA-haploidentical (0.60 versus 0.54), or UCB grafts (0.65 versus 0.61). Patients with scores of <4 had higher survival rates compared to those with scores of ≥4 and received HLA-mismatched (55% versus 39%, p<0.0008), HLA-haploidentical (58% versus 38%, p=0.01), or UCB grafts (67% versus 48%, p=0.004), respectively. 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 = {2018}, 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 = {}, number = {}, pages = {}, doi = {10.1002/ijc.32029}, pmid = {30499236}, issn = {1097-0215}, abstract = {As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), this 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 9,971 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 x 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. This article is protected by copyright. All rights reserved.}, }
@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 Gaziano, JM 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}, 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 aetiology 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 5,183 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. This article is protected by copyright. All rights reserved.}, }
@article {pmid30488475, year = {2018}, 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 = {}, number = {}, pages = {}, 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}, doi = {10.1186/s13058-018-1077-9}, pmid = {30486865}, issn = {1465-542X}, support = {CA180888//National Cancer Institute/ ; CA180819//National Cancer Institute/ ; CA180828//National Cancer Institute/ ; CA180858//National Cancer Institute/ ; CA189953//National Cancer Institute/ ; UG1CA189974//National Cancer Institute/ ; T32CA113951//National Cancer Institute/ ; P30CA016056//National Cancer Institute/ ; CA68183//National Cancer Institute/ ; CA04919//National Cancer Institute/ ; CA46282//National Cancer Institute/ ; CA116395//National Cancer Institute/ ; CA139426//National Cancer Institute/ ; }, 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.
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).
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).
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.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.}, }
@article {pmid30485471, year = {2018}, 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 Six-Year Propensity Score-Matched Cohort Study.}, journal = {Pharmacotherapy}, volume = {}, number = {}, pages = {}, doi = {10.1002/phar.2197}, pmid = {30485471}, issn = {1875-9114}, 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.
OBJECTIVES: This study aims to examine patterns of oral medication use for chronic conditions following HCT in the United States population.
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.
RESULTS: Recipients of HCT had higher risks of discontinuing medication for diabetes mellitus (allogeneic HCT hazard ratio (HR)=1.93, 95% Confidence Incidence (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.
CONCLUSIONS: Poor medication persistence and adherence to chronic disease medications are common post HCT. Further research to improve long-term outcomes following HCT should include management of medication therapy for chronic comorbid conditions. This article is protected by copyright. All rights reserved.}, }
@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}, doi = {10.1186/s40425-018-0450-7}, 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.
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.
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).
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 = {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 Stanghellini, MTL 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, ME 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 = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2018.11.021}, pmid = {30481594}, issn = {1523-6536}, 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 {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}, 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.
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.
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.
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 = {}, number = {}, pages = {}, doi = {10.1038/s41591-018-0241-1}, pmid = {30478421}, issn = {1546-170X}, 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}, abstract = {BACKGROUND & 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 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.
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.
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}, 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.
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.
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.
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.
Objective: We conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen.
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.
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.
Conclusion: Our results on the effects of the "5:2 diet" 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}, doi = {10.1038/s41598-018-35621-y}, pmid = {30470817}, issn = {2045-2322}, support = {K99CA207872//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA196569//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA014089//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA014089//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; U54CA217376//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA196569//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P300P2-154583//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; }, 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}, doi = {10.1038/s41598-018-35470-9}, 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.
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.
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.
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.
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.
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.
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 & research. Clinical haematology}, volume = {31}, number = {4}, pages = {405-409}, doi = {10.1016/j.beha.2018.09.009}, pmid = {30466757}, issn = {1532-1924}, 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 {pmid30464020, year = {2018}, author = {Dai, JY and Wang, B and Wang, X and Cheng, A and Kolb, S and Stanford, JL and Wright, JL}, title = {Vigorous physical activity is associated with metastatic-lethal progression in prostate cancer and differential tumor DNA methylation in the CRACR2A gene.}, journal = {Cancer epidemiology, biomarkers & 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-18-0622}, pmid = {30464020}, issn = {1538-7755}, support = {R01 CA222833/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: There is preliminary evidence linking physical activity to better prostate cancer (PCa) outcomes, though the molecular mechanisms underlying this association are not clear.
METHODS: In a Seattle-based cohort of patients diagnosed with clinically localized PCa and prospective follow-up for outcomes (n=1354), we studied the association between self-reported vigorous physical activity and PCa progression to a metastatic-lethal phenotype. A subset of patients have prostate cancer tissue samples available for investigating DNA methylation (Infinium® HumanMethylation450 BeadChip array) and exercise (n=524).
RESULTS: Patients who had vigorous physical activity at least once per week during the year before diagnosis (~79% of the cohort) were significantly less likely to progress to metastatic-lethal PCa compared to those who had vigorous physical activity less frequently (adjusted hazard ratio =0.63, p-value=0.029). Among the subset of men who had radical prostatectomy as primary treatment and tumor tissue available, a differentially methylated region (DMR) was identified (family-wise error rate=0.03, hypo-methylated in the weekly exercise group), with 9 methylation probes located in the promoter region of CRACR2A. This gene encodes a calcium binding protein involved in innate immune response. The methylation level of the nine CpGs was inversely correlated with CRACR2A gene expression (average correlation coefficient= - 0.35).
CONCLUSIONS: Vigorous physical activity before diagnosis is associated with epigenetic alterations of CRACR2A and PCa metastatic lethal progression.
IMPACT: This analysis provides strong evidence for the association between vigorous physical activity and a less likelihood to develop metastatic lethal progression, and a suggestive link between exercise and DNA methylation in CRACRA2A gene.}, }
@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}, doi = {10.1371/journal.pntd.0006748}, pmid = {30462654}, issn = {1935-2735}, 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.
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).
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.
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}, doi = {10.1371/journal.pntd.0006847}, pmid = {30462635}, issn = {1935-2735}, 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.
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.
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.
CONCLUSIONS: Sustained weight loss results in reductions in free estradiol and testosterone and increases in SHBG 18-month post-intervention.}, }
@article {pmid30459208, year = {2018}, 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 & 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-18-0452}, pmid = {30459208}, issn = {1538-7755}, support = {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.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.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.Conclusions: Colonoscopy within the recommended interval following advanced adenoma was underutilized and varied by healthcare system, age, and number of adenomas.Impact: Strategies to improve adherence to surveillance colonoscopy following advanced adenomas are needed. Cancer Epidemiol Biomarkers Prev; 1-8. ©2018 AACR.}, }
@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}, doi = {10.1016/j.bbmt.2018.06.033}, 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 = {}, doi = {10.1038/nbt.4303}, 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 = {2018}, 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 = {}, number = {}, pages = {}, 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.
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.
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).
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 = {2018}, 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}, 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.
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).
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.
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.
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 cGvHD cohort. Secondary objectives included assessing the effect of corticosteroid use at sample collection on the make-up 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 cytometric 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 numbers of CD27-CD10-CD21low CD19+ B cells and classical switched memory B cells, and reduced numbers of transitional and naïve B cells. The highest single B cell population area under the Receiver Operator Characteristic (ROC) curve (AUC) was 0.72 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 AUC of 0.87 and 0.84 respectively. Transitional and CD21low B cells were the only populations present in both panels; however only analyzing them resulted in ROC AUC of 0.79 and 0.78 respectively. This suggests that the inclusion of other populations and use of different panels depending on steroid use is necessary to achieve better accuracy. Soluble BAFF was not part of either panel. These novel B cell profiles could be prospectively tested in patients post-HSCT and 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}, doi = {10.1038/s41467-018-06843-5}, pmid = {30446650}, issn = {2041-1723}, support = {R01 AI121129/AI/NIAID NIH HHS/United States ; KL2 TR002317//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; U19 AI096109/AI/NIAID NIH HHS/United States ; P01 AI030371-24, U19 AI113173-02, R01 AI121129-01, UM1 AI126623, UM1 AI068635//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U19 AI113173/AI/NIAID NIH HHS/United States ; Postdoctoral Fellowship//Washington Research Foundation (WRF)/ ; 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 ; }, 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 = {2018}, 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 on SWOG study S0016.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood-2018-07-865428}, pmid = {30446494}, issn = {1528-0020}, 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 SWOG 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 (i.e., 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: while early progression was correlated with 2p gain [P=0.007, OR=2.55 (1.29, 5.03)] and 2p cnLOH [P=0.005, OR=10.9 (2.08, 57.2)], 2p gain specifically encompassing VRK2 and FANCL predicted PFS [P=0.01, HR=1.80 (1.14, 2.68)] as well as OS [P=0.005, 2.40 (1.30, 4.40)]; CDKN2A/B (9p) deletion correlated with worse PFS [P=0.004, 3.50 (1.51, 8.28)]; whereas CREBBP (16p) [P<0.001, 6.70 (2.52, 17.58)] and TP53 (17p) [P<0.001, 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 = {2018}, author = {Amundsen, SK and Smith, GR}, title = {The RecB helicase-nuclease tether mediates Chi hotspot control of RecBCD enzyme.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gky1132}, pmid = {30445486}, issn = {1362-4962}, 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}, abstract = {BACKGROUND & 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 the metabolic syndrome and other obesity-associated diseases.
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 the ethnic groups, we compared adiposity of 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 the metabolic syndrome mediated by abdominal adiposity.
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, in comparison to white persons, for African Americans, Japanese Americans, and Native Hawaiian women, independently of total fat mass.
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 = {}, number = {}, pages = {}, doi = {10.1126/science.aau8872}, pmid = {30442764}, issn = {1095-9203}, 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 (cryo-EM), chemical crosslinking-mass spectrometry (CX-MS) 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 {pmid30442731, year = {2018}, author = {Streiff, MB and Holmstrom, B and Angelini, D and Ashrani, A and Bockenstedt, PL and Chesney, C and Fanikos, J and Fenninger, RB and Fogerty, AE and Gao, S and Goldhaber, SZ and Gundabolu, K and Hendrie, P and Lee, AI and Lee, JT and Mann, J and McMahon, B and Millenson, MM and Morton, C and Ortel, TL and Ozair, S and Paschal, R and Shattil, S and Siddiqi, T and Smock, KJ and Soff, G and Wang, TF and Williams, E and Zakarija, A and Hammond, L and Dwyer, MA and Engh, AM}, title = {NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {16}, number = {11}, pages = {1289-1303}, doi = {10.6004/jnccn.2018.0084}, pmid = {30442731}, issn = {1540-1413}, abstract = {Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.}, }
@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.
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.
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.
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 = {2018}, 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 = {2018}, 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.
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.
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.
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 & 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 = {2018}, 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 = {}, number = {}, pages = {}, 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)/ ; }, 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.
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.
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.
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}, doi = {10.3389/fimmu.2018.02451}, 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 = {2018}, 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 = {}, number = {}, 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 non-human 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 for Gag, PolNef, and gp140. The groups were then boosted either with the vaccinia virus strain NYVAC or a variant with improved replication competence in human cells termed NYVAC-KC. The latter was either administered 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 two weeks after the boost. T cells were broadly reactive and polyfunctional. All animals exhibited antigen-specific humoral responses already after the poxvirus boost that 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 (ADCC and ADCVI) were observed in sera 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 only led 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.ImportanceThe 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 non-human primates that, however, qualitatively and quantitatively differ depending on the respective vector systems used. The present study evaluated a DNA prime, poxvirus and protein boost regimen, and compared how two poxvirus vectors with varying 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 = {2018}, 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 non-replicating NYVAC.}, journal = {Journal of virology}, volume = {}, number = {}, 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 non-human 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 VLPs from clade C and were used as the prime, with recombinant virus plus envelope protein 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 did NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.ImportanceThough 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 non-human 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 = {2018}, author = {Hill, JA and Ikoma, M and Zerr, DM and Basom, RS and Peddu, V and Huang, ML and Sedlak, RH 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 = {}, number = {}, 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 1) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia; 2) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B; 3) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B; and 4) 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 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 messenger RNA in all tested whole blood samples from patients with concurrent HHV-6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or 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 non-plasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses in 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 germline 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}, doi = {10.1093/ve/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 = {2018}, 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 Sanchez, 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 Le Marchand, L 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 = {}, number = {}, pages = {}, 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 pre-diagnostic concentrations of 25-hydroxyvitamin D (25(OH)D) and 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. Odds ratios (OR) 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 versus lowest study-specific fifth was 1.22, 95% CI 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 non-aggressive 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 non-aggressive prostate cancer may be influenced by detection bias.}, }
@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 = {nThe 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}, abstract = {There are limited data on whether to adjust high-dose chemotherapy prior to 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 of ≥ 20%, based on ideal, reported dosing and actual weights. We included two 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 we included patients with Hodgkin or non-Hodgkin lymphomas (n=781) who received carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning. Chemotherapy dose was adjusted in 1324 (78%) patients with MM and 608 (78%) patients with lymphoma. Age, sex, BMI, race, performance score, co-morbidity 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=0.894) and treatment-related mortality (TRM) (p=0.62), progression (p=0.12), and progression-free survival (p=0.178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (p=0.176), TRM (p=0.802), relapse (p=0.633) or PFS (p=0.812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose prior to 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 = {The Effect of Aging and Pre-Donation Comorbidities on the Related PBSC Donor Experience: A Report from the Related Donor Safety Study (RDSafe).}, 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}, abstract = {The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). RD >60 had a lower median CD34+ level pre-apheresis compared to younger RD (age >60, 59 × 106/L; age 41-60, 81 × 106/L; age 18-40, 121 × 106/L; p<0.001). This resulted in older donors undergoing more apheresis procedures (49% vs. 30% ≥2 collections, p<0.001) and higher collection volumes (52% vs. 32% >24L, p<0.001), leading to high percentages of donors >60 with post-collection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3 days of collection, respectively). RD age 18-40 had a higher risk of grade 2-4 pain and symptoms peri-collection, but donors above age 40 had more persistent pain at 1, 6, and 12 months (OR1.7, p=0.02) and a higher rate of non-recovery to pre-donation levels (OR 1.7, p=0.01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by NMDP unrelated donor standards had an increased risk for persistent grade 2-4 pain (OR=2.41, p<0.001) and failure to recover to pre-donation baseline for other symptoms (OR=2.34, p=0.004). This information should be used in counseling RD 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}, 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.
OBJECTIVES: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules.
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.
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.
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.
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.
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).
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.
FUNDING: National Cancer Institute and the American Lebanese-Syrian Associated Charities.}, }
@article {pmid30415231, year = {2018}, 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 = {}, number = {}, pages = {}, 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.
METHODS: We enrolled 1260 former workers meeting NCCN criteria, with modifications to account for occupational exposures in an ELCD programme.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, 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 = {2018}, author = {Elbing, KL and Brent, R}, title = {Recipes and Tools for Culture of Escherichia coli.}, journal = {Current protocols in molecular biology}, volume = {}, number = {}, pages = {e83}, doi = {10.1002/cpmb.83}, pmid = {30412361}, issn = {1934-3647}, support = {R21 CA223901/GF/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 & 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}, doi = {10.1093/annonc/mdy337}, pmid = {30412224}, issn = {1569-8041}, 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.
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.
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.
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 = {2018}, 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 & leukemia}, volume = {}, number = {}, pages = {}, 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.
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.
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).
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.
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).
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.
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}, doi = {10.1371/journal.pmed.1002690}, pmid = {30408115}, issn = {1549-1676}, 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.
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.
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.
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 = {2018}, 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 = {}, number = {}, pages = {}, 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.
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.
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.
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 {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 = {}, doi = {10.7554/eLife.37688}, 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 ; }, 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 = {2018}, author = {Morsink, LM and Walter, RB and Ossenkoppele, GJ}, title = {Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia.}, journal = {Blood reviews}, volume = {}, number = {}, pages = {}, 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}, doi = {10.1186/s12879-018-3444-7}, pmid = {30400834}, issn = {1471-2334}, abstract = {BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work.
METHODS: Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum.
DISCUSSION: SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients.
TRIAL REGISTRATION: NCT03331991 . Registered on November 6, 2017.}, }
@article {pmid30397198, year = {2018}, 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 Dominguez, MG 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 = {Germline variation at 8q24 and prostate cancer risk in men of European ancestry.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {4616}, doi = {10.1038/s41467-018-06863-1}, pmid = {30397198}, issn = {2041-1723}, support = {U01 CA188392/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; U19 CA148537/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; C5047/A7357//Cancer Research UK (CRUK)/ ; }, abstract = {Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.}, }
@article {pmid30396912, year = {2018}, author = {Chhabra, S and Ahn, KW and Hu, ZH and Jain, S and Assal, A and Cerny, J and Copelan, EA and Daly, A and DeFilipp, Z and Gadalla, SM and Gale, RP and Ganguly, S and Hamilton, BK and Hildebrandt, GC and Hsu, JW and Inamoto, Y and Kanate, AS and Khoury, HJ and Lazarus, HM and Litzow, MR and Nathan, S and Olsson, RF and Pawarode, A and Ringden, O and Rowe, JM and Saad, A and Savani, BN and Schouten, HC and Seo, S and Shah, NN and Solh, M and Stuart, RK and Ustun, C and Woolfrey, AE and Yared, JA and Alyea, EP and Kalaycio, ME and Popat, U and Sobecks, RM and Saber, W}, title = {Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia.}, journal = {Blood advances}, volume = {2}, number = {21}, pages = {2922-2936}, doi = {10.1182/bloodadvances.2018024844}, pmid = {30396912}, issn = {2473-9537}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.}, }
@article {pmid30395637, year = {2018}, author = {LaBranche, CC and McGuire, AT and Gray, MD and Behrens, S and Zhou, T and Sattentau, QJ and Peacock, J and Eaton, A and Greene, K and Gao, H and Tang, H and Perez, LG and Saunders, KO and Mascola, JR and Haynes, BF and Stamatatos, L and Montefiori, DC}, title = {HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies.}, journal = {PLoS pathogens}, volume = {14}, number = {11}, pages = {e1007431}, doi = {10.1371/journal.ppat.1007431}, pmid = {30395637}, issn = {1553-7374}, abstract = {Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naïve B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N-glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs.}, }
@article {pmid30395313, year = {2018}, author = {Shen, BW and Doyle, L and Bradley, P and Heiter, DF and Lunnen, KD and Wilson, GG and Stoddard, BL}, title = {Structure, subunit organization and behavior of the asymmetric Type IIT restriction endonuclease BbvCI.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gky1059}, pmid = {30395313}, issn = {1362-4962}, abstract = {BbvCI, a Type IIT restriction endonuclease, recognizes and cleaves the seven base pair sequence 5'-CCTCAGC-3', generating 3-base, 5'-overhangs. BbvCI is composed of two protein subunits, each containing one catalytic site. Either site can be inactivated by mutation resulting in enzyme variants that nick DNA in a strand-specific manner. Here we demonstrate that the holoenzyme is labile, with the R1 subunit dissociating at low pH. Crystallization of the R2 subunit under such conditions revealed an elongated dimer with the two catalytic sites located on opposite sides. Subsequent crystallization at physiological pH revealed a tetramer comprising two copies of each subunit, with a pair of deep clefts each containing two catalytic sites appropriately positioned and oriented for DNA cleavage. This domain organization was further validated with single-chain protein constructs in which the two enzyme subunits were tethered via peptide linkers of variable length. We were unable to crystallize a DNA-bound complex; however, structural similarity to previously crystallized restriction endonucleases facilitated creation of an energy-minimized model bound to DNA, and identification of candidate residues responsible for target recognition. Mutation of residues predicted to recognize the central C:G base pair resulted in an altered enzyme that recognizes and cleaves CCTNAGC (N = any base).}, }
@article {pmid30394566, year = {2018}, author = {Short, NJ and Jabbour, E and Albitar, M and de Lima, M and Gore, L and Jorgensen, J and Logan, AC and Park, J and Ravandi, F and Shah, B and Radich, J and Kantarjian, H}, title = {Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia: A consensus of North American experts.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.25338}, pmid = {30394566}, issn = {1096-8652}, support = {//PLATO (Physicians Learning and Teaching in Oncology) Foundation/ ; }, abstract = {Measurable residual disease (MRD) that persists after initial therapy is a powerful predictor of relapse and survival in acute lymphoblastic leukemia (ALL). However, the optimal use of this information to influence therapeutic decisions is controversial. Herein, we comprehensively review the role of MRD assessment in adults with ALL, including methods to quantify residual leukemia cells during remission, prognostic impact of MRD across ALL subtypes, and available therapeutic approaches to eradicate MRD. This review presents consensus statements and provides an evidence-based framework for practicing hematologists and oncologists to use MRD information to make rational treatment decisions in adult patients with ALL.}, }
@article {pmid30393007, year = {2018}, author = {Pugh, TJ and Fink, JM and Lu, X and Mathew, S and Murata-Collins, J and Willem, P and Fang, M and , }, title = {Assessing genome-wide copy number aberrations and copy-neutral loss-of-heterozygosity as best practice: An evidence-based review from the Cancer Genomics Consortium working group for plasma cell disorders.}, journal = {Cancer genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cancergen.2018.07.002}, pmid = {30393007}, issn = {2210-7762}, abstract = {BACKGROUND: Plasma cell neoplasms (PCNs) encompass a spectrum of disorders including monoclonal gammopathy of undetermined significance, smoldering myeloma, plasma cell myeloma, and plasma cell leukemia. Molecular subtypes have been defined by recurrent cytogenetic abnormalities and somatic mutations that are prognostic and predictive. Karyotype and fluorescence in situ hybridization (FISH) have historically been used to guide management; however, new technologies and markers raise the need to reassess current testing algorithms.
METHODS: We convened a panel of representatives from international clinical laboratories to capture current state-of-the-art testing from published reports and to put forward recommendations for cytogenomic testing of plasma cell neoplasms. We reviewed 65 papers applying FISH, chromosomal microarray (CMA), next-generation sequencing, and gene expression profiling for plasma cell neoplasm diagnosis and prognosis. We also performed a survey of our peers to capture current laboratory practice employed outside our working group.
RESULTS: Plasma cell enrichment is widely used prior to FISH testing, most commonly by magnetic bead selection. A variety of strategies for direct, short- and long-term cell culture are employed to ensure clonal representation for karyotyping. Testing of clinically-informative 1p/1q, del(13q) and del(17p) are common using karyotype, FISH and, increasingly, CMA testing. FISH for a variety of clinically-informative balanced IGH rearrangements is prevalent. Literature review found that CMA analysis can detect abnormalities in 85-100% of patients with PCNs; more specifically, in 5-53% (median 14%) of cases otherwise normal by FISH and cytogenetics. CMA results in plasma cell neoplasms are usually complex, with alteration counts ranging from 1 to 74 (median 10-20), primarily affecting loci not covered by FISH testing. Emerging biomarkers include structural alterations of MYC as well as somatic mutations of KRAS, NRAS, BRAF, and TP53. Together, these may be measured in a comprehensive manner by a combination of newer technologies including CMA and next-generation sequencing (NGS). Our survey suggests most laboratories have, or are soon to have, clinical CMA platforms, with a desire to move to NGS assays in the future.
CONCLUSION: We present an overview of current practices in plasma cell neoplasm testing as well as an algorithm for integrated FISH and CMA testing to guide treatment of this disease.}, }
@article {pmid30391142, year = {2018}, author = {Kuhlmann, AS and Haworth, KG and Barber-Axthelm, IM and Ironside, C and Giese, MA and Peterson, CW and Kiem, HP}, title = {Long-Term Persistence of Anti-HIV Broadly Neutralizing Antibody-Secreting Hematopoietic Cells in Humanized Mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2018.09.017}, pmid = {30391142}, issn = {1525-0024}, abstract = {Broadly neutralizing antibodies (bNAbs) are among the most promising strategies to achieve long-term control of HIV-1 in the absence of combination antiretroviral therapy. Passive administration of such antibodies in patients efficiently decreases HIV-1 viremia, but is limited by the serum half-life of the protein. Here, we investigated whether antibody-secreting hematopoietic cells could overcome this problem. We genetically modified human CD34+ hematopoietic stem and progenitor cells (HSPCs) to secrete bNAbs and transplanted them into immunodeficient mice. We found that the gene-modified cells engraft and stably secrete antibodies in the peripheral blood of the animals for the 9 months of the study. Antibodies were predominantly expressed by human HSPC-derived T- and B cells. Importantly, we found that secreted PGT128 was able to delay HIV-1 viremia in vivo and also prevent a decline in CD4+ cells. Gene-modified cells were maintained in bone marrow and were also detected in spleen, thymus, lymph nodes, and gut-associated lymphoid tissue. These data indicate that the bNAb secretion from HSPC-derived cells in mice is functional and can affect viral infection and CD4+ cell maintenance. This study paves the way for potential applications to other diseases requiring long-lasting protein or antibody delivery.}, }
@article {pmid30391013, year = {2018}, author = {Zhen, DB and Coveler, A and Zanon, S and Reni, M and Chiorean, EG}, title = {Biomarker-driven and molecularly targeted therapies for pancreatic adenocarcinoma.}, journal = {Seminars in oncology}, volume = {45}, number = {3}, pages = {107-115}, doi = {10.1053/j.seminoncol.2018.05.004}, pmid = {30391013}, issn = {1532-8708}, abstract = {Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.}, }
@article {pmid30390057, year = {2018}, author = {Iotchkova, V and Huang, J and Morris, JA and Jain, D and Barbieri, C and Walter, K and Min, JL and Chen, L and Astle, W and Cocca, M and Deelen, P and Elding, H and Farmaki, AE and Franklin, CS and Franberg, M and Gaunt, TR and Hofman, A and Jiang, T and Kleber, ME and Lachance, G and Luan, J and Malerba, G and Matchan, A and Mead, D and Memari, Y and Ntalla, I and Panoutsopoulou, K and Pazoki, R and Perry, JRB and Rivadeneira, F and Sabater-Lleal, M and Sennblad, B and Shin, SY and Southam, L and Traglia, M and van Dijk, F and van Leeuwen, EM and Zaza, G and Zhang, W and , and Amin, N and Butterworth, A and Chambers, JC and Dedoussis, G and Dehghan, A and Franco, OH and Franke, L and Frontini, M and Gambaro, G and Gasparini, P and Hamsten, A and Isaacs, A and Kooner, JS and Kooperberg, C and Langenberg, C and Marz, W and Scott, RA and Swertz, MA and Toniolo, D and Uitterlinden, AG and van Duijn, CM and Watkins, H and Zeggini, E and Maurano, MT and Timpson, NJ and Reiner, AP and Auer, PL and Soranzo, N}, title = {Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.}, journal = {Nature genetics}, volume = {50}, number = {12}, pages = {1752}, doi = {10.1038/s41588-018-0276-8}, pmid = {30390057}, issn = {1546-1718}, abstract = {In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.}, }
@article {pmid30388821, year = {2018}, author = {Riedel, RF and Jones, RL and Italiano, A and Bohac, C and Thompson, JC and Mueller, K and Khan, Z and Pollack, SM and Van Tine, BA}, title = {Systemic Anti-Cancer Therapy in Synovial Sarcoma: A Systematic Review.}, journal = {Cancers}, volume = {10}, number = {11}, pages = {}, doi = {10.3390/cancers10110417}, pmid = {30388821}, issn = {2072-6694}, abstract = {Synovial sarcoma (SS) is an aggressive malignancy which accounts for approximately 5⁻10% of all soft-tissue sarcomas. SS has pathologic and genomic characteristics that define it as a distinct subtype of soft tissue sarcoma (STS). STS subtypes continue to be recognized as distinct entities with specific characteristics, including differential chemo-sensitivity. The objective of this study was to conduct a descriptive review of current data on survival outcomes of systemic anti-cancer therapy specific to SS. A systematic literature review was conducted, using a custom search strategy to search EMBASE, Medline and CENTRAL for clinical trials and observational studies reporting overall survival (OS), progression-free survival (PFS) and/or response for cohorts of at least 50 SS patients. We identified 28 studies meeting these criteria, 25 of which were retrospective studies. Only three prospective studies were identified. Survival reports varied widely between studies based on the population, in particular on the disease stage, and reporting was heterogeneous in terms of the time points reported on. For patients with localized disease, reports of five-year PFS ranged from 26% to 80.7% and five-year OS from 40% to 90.7%, whereas five-year OS for patients with metastatic disease was very low at around 10%; and in one case, 0% was reported. Only four of the included publications reported outcomes by type of systemic anti-cancer therapy received. Our study draws attention to the fact that additional prospective studies to better define the most appropriate treatment for SS in all stages and lines of therapy are still needed.}, }
@article {pmid30388411, year = {2018}, author = {Blazquez, L and Emmett, W and Faraway, R and Pineda, JMB and Bajew, S and Gohr, A and Haberman, N and Sibley, CR and Bradley, RK and Irimia, M and Ule, J}, title = {Exon Junction Complex Shapes the Transcriptome by Repressing Recursive Splicing.}, journal = {Molecular cell}, volume = {72}, number = {3}, pages = {496-509.e9}, doi = {10.1016/j.molcel.2018.09.033}, pmid = {30388411}, issn = {1097-4164}, support = {//Wellcome Trust/United Kingdom ; }, abstract = {Recursive splicing (RS) starts by defining an "RS-exon," which is then spliced to the preceding exon, thus creating a recursive 5' splice site (RS-5ss). Previous studies focused on cryptic RS-exons, and now we find that the exon junction complex (EJC) represses RS of hundreds of annotated, mainly constitutive RS-exons. The core EJC factors, and the peripheral factors PNN and RNPS1, maintain RS-exon inclusion by repressing spliceosomal assembly on RS-5ss. The EJC also blocks 5ss located near exon-exon junctions, thus repressing inclusion of cryptic microexons. The prevalence of annotated RS-exons is high in deuterostomes, while the cryptic RS-exons are more prevalent in Drosophila, where EJC appears less capable of repressing RS. Notably, incomplete repression of RS also contributes to physiological alternative splicing of several human RS-exons. Finally, haploinsufficiency of the EJC factor Magoh in mice is associated with skipping of RS-exons in the brain, with relevance to the microcephaly phenotype and human diseases.}, }
@article {pmid30388399, year = {2018}, author = {Ligthart, S and Vaez, A and Võsa, U and Stathopoulou, MG and de Vries, PS and Prins, BP and Van der Most, PJ and Tanaka, T and Naderi, E and Rose, LM and Wu, Y and Karlsson, R and Barbalic, M and Lin, H and Pool, R and Zhu, G and Macé, A and Sidore, C and Trompet, S and Mangino, M and Sabater-Lleal, M and Kemp, JP and Abbasi, A and Kacprowski, T and Verweij, N and Smith, AV and Huang, T and Marzi, C and Feitosa, MF and Lohman, KK and Kleber, ME and Milaneschi, Y and Mueller, C and Huq, M and Vlachopoulou, E and Lyytikäinen, LP and Oldmeadow, C and Deelen, J and Perola, M and Zhao, JH and Feenstra, B and , and Amini, M and , and Lahti, J and Schraut, KE and Fornage, M and Suktitipat, B and Chen, WM and Li, X and Nutile, T and Malerba, G and Luan, J and Bak, T and Schork, N and Del Greco M, F and Thiering, E and Mahajan, A and Marioni, RE and Mihailov, E and Eriksson, J and Ozel, AB and Zhang, W and Nethander, M and Cheng, YC and Aslibekyan, S and Ang, W and Gandin, I and Yengo, L and Portas, L and Kooperberg, C and Hofer, E and Rajan, KB and Schurmann, C and den Hollander, W and Ahluwalia, TS and Zhao, J and Draisma, HHM and Ford, I and Timpson, N and Teumer, A and Huang, H and Wahl, S and Liu, Y and Huang, J and Uh, HW and Geller, F and Joshi, PK and Yanek, LR and Trabetti, E and Lehne, B and Vozzi, D and Verbanck, M and Biino, G and Saba, Y and Meulenbelt, I and O'Connell, JR and Laakso, M and Giulianini, F and Magnusson, PKE and Ballantyne, CM and Hottenga, JJ and Montgomery, GW and Rivadineira, F and Rueedi, R and Steri, M and Herzig, KH and Stott, DJ and Menni, C and Frånberg, M and St Pourcain, B and Felix, SB and Pers, TH and Bakker, SJL and Kraft, P and Peters, A and Vaidya, D and Delgado, G and Smit, JH and Großmann, V and Sinisalo, J and Seppälä, I and Williams, SR and Holliday, EG and Moed, M and Langenberg, C and Räikkönen, K and Ding, J and Campbell, H and Sale, MM and Chen, YI and James, AL and Ruggiero, D and Soranzo, N and Hartman, CA and Smith, EN and Berenson, GS and Fuchsberger, C and Hernandez, D and Tiesler, CMT and Giedraitis, V and Liewald, D and Fischer, K and Mellström, D and Larsson, A and Wang, Y and Scott, WR and Lorentzon, M and Beilby, J and Ryan, KA and Pennell, CE and Vuckovic, D and Balkau, B and Concas, MP and Schmidt, R and Mendes de Leon, CF and Bottinger, EP and Kloppenburg, M and Paternoster, L and Boehnke, M and Musk, AW and Willemsen, G and Evans, DM and Madden, PAF and Kähönen, M and Kutalik, Z and Zoledziewska, M and Karhunen, V and Kritchevsky, SB and Sattar, N and Lachance, G and Clarke, R and Harris, TB and Raitakari, OT and Attia, JR and van Heemst, D and Kajantie, E and Sorice, R and Gambaro, G and Scott, RA and Hicks, AA and Ferrucci, L and Standl, M and Lindgren, CM and Starr, JM and Karlsson, M and Lind, L and Li, JZ and Chambers, JC and Mori, TA and de Geus, EJCN and Heath, AC and Martin, NG and Auvinen, J and Buckley, BM and de Craen, AJM and Waldenberger, M and Strauch, K and Meitinger, T and Scott, RJ and McEvoy, M and Beekman, M and Bombieri, C and Ridker, PM and Mohlke, KL and Pedersen, NL and Morrison, AC and Boomsma, DI and Whitfield, JB and Strachan, DP and Hofman, A and Vollenweider, P and Cucca, F and Jarvelin, MR and Jukema, JW and Spector, TD and Hamsten, A and Zeller, T and Uitterlinden, AG and Nauck, M and Gudnason, V and Qi, L and Grallert, H and Borecki, IB and Rotter, JI and März, W and Wild, PS and Lokki, ML and Boyle, M and Salomaa, V and Melbye, M and Eriksson, JG and Wilson, JF and Penninx, BWJH and Becker, DM and Worrall, BB and Gibson, G and Krauss, RM and Ciullo, M and Zaza, G and Wareham, NJ and Oldehinkel, AJ and Palmer, LJ and Murray, SS and Pramstaller, PP and Bandinelli, S and Heinrich, J and Ingelsson, E and Deary, IJ and Mägi, R and Vandenput, L and van der Harst, P and Desch, KC and Kooner, JS and Ohlsson, C and Hayward, C and Lehtimäki, T and Shuldiner, AR and Arnett, DK and Beilin, LJ and Robino, A and Froguel, P and Pirastu, M and Jess, T and Koenig, W and Loos, RJF and Evans, DA and Schmidt, H and Smith, GD and Slagboom, PE and Eiriksdottir, G and Morris, AP and Psaty, BM and Tracy, RP and Nolte, IM and Boerwinkle, E and Visvikis-Siest, S and Reiner, AP and Gross, M and Bis, JC and Franke, L and Franco, OH and Benjamin, EJ and Chasman, DI and Dupuis, J and Snieder, H and Dehghan, A and Alizadeh, BZ}, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {American journal of human genetics}, volume = {103}, number = {5}, pages = {691-706}, doi = {10.1016/j.ajhg.2018.09.009}, pmid = {30388399}, issn = {1537-6605}, abstract = {C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.}, }
@article {pmid30388102, year = {2018}, author = {Liu, Y and He, Q and Sun, W}, title = {Association analysis using somatic mutations.}, journal = {PLoS genetics}, volume = {14}, number = {11}, pages = {e1007746}, doi = {10.1371/journal.pgen.1007746}, pmid = {30388102}, issn = {1553-7404}, abstract = {Somatic mutations drive the growth of tumor cells and are pivotal biomarkers for many cancer treatments. Genetic association analysis using somatic mutations is an effective approach to study the functional impact of somatic mutations. However, standard regression methods are not appropriate for somatic mutation association studies because somatic mutation calls often have non-ignorable false positive rate and/or false negative rate. While large scale association analysis using somatic mutations becomes feasible recently-thanks for the improvement of sequencing techniques and the reduction of sequencing cost-there is an urgent need for a new statistical method designed for somatic mutation association analysis. We propose such a method with computationally efficient software implementation: Somatic mutation Association test with Measurement Errors (SAME). SAME accounts for somatic mutation calling uncertainty using a likelihood based approach. It can be used to assess the associations between continuous/dichotomous outcomes and individual mutations or gene-level mutations. Through simulation studies across a wide range of realistic scenarios, we show that SAME can significantly improve statistical power than the naive generalized linear model that ignores mutation calling uncertainty. Finally, using the data collected from The Cancer Genome Atlas (TCGA) project, we apply SAME to study the associations between somatic mutations and gene expression in 12 cancer types, as well as the associations between somatic mutations and colon cancer subtype defined by DNA methylation data. SAME recovered some interesting findings that were missed by the generalized linear model. In addition, we demonstrated that mutation-level and gene-level analyses are often more appropriate for oncogene and tumor-suppressor gene, respectively.}, }
@article {pmid30387077, year = {2018}, author = {Gust, J and Taraseviciute, A and Turtle, CJ}, title = {Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies.}, journal = {CNS drugs}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40263-018-0582-9}, pmid = {30387077}, issn = {1179-1934}, abstract = {Neurotoxicity is an important and common complication of chimeric antigen receptor-T cell therapies. Acute neurologic signs and/or symptoms occur in a significant proportion of patients treated with CD19-directed chimeric antigen receptor-T cells for B-cell malignancies. Clinical manifestations include headache, confusion, delirium, language disturbance, seizures and rarely, acute cerebral edema. Neurotoxicity is associated with cytokine release syndrome, which occurs in the setting of in-vivo chimeric antigen receptor-T cell activation and proliferation. The mechanisms that lead to neurotoxicity remain unknown, but data from patients and animal models suggest there is compromise of the blood-brain barrier, associated with high levels of cytokines in the blood and cerebrospinal fluid, as well as endothelial activation. Corticosteroids, interleukin-6-targeted therapies, and supportive care are frequently used to manage patients with neurotoxicity, but high-quality evidence of their efficacy is lacking.}, }
@article {pmid30385821, year = {2018}, author = {Jones, GN and Rooney, C and Griffin, N and Roudier, M and Young, LA and Garcia-Trinidad, A and Hughes, GD and Whiteaker, JR and Wilson, Z and Odedra, R and Zhao, L and Ivey, RG and Howat, WJ and Harrington, EA and Barrett, JC and Ramos-Montoya, A and Lau, A and Paulovich, AG and Cadogan, EB and Pierce, AJ}, title = {pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.}, journal = {British journal of cancer}, volume = {119}, number = {10}, pages = {1233-1243}, doi = {10.1038/s41416-018-0286-4}, pmid = {30385821}, issn = {1532-1827}, abstract = {BACKGROUND: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage.
METHODS: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue.
RESULTS: We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors.
CONCLUSION: Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.}, }
@article {pmid30384135, year = {2018}, author = {Wallmann, T and Zhang, XM and Wallerius, M and Bolin, S and Joly, AL and Sobocki, C and Leiss, L and Jiang, Y and Bergh, J and Holland, EC and Enger, PØ and Andersson, J and Swartling, FJ and Miletic, H and Uhrbom, L and Harris, RA and Rolny, C}, title = {Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity.}, journal = {iScience}, volume = {9}, number = {}, pages = {71-83}, doi = {10.1016/j.isci.2018.10.011}, pmid = {30384135}, issn = {2589-0042}, abstract = {High-grade gliomas (HGGs) are the most aggressive and invasive primary brain tumors. The platelet-derived growth factor (PDGF) signaling pathway drives HGG progression, and enhanced expression of PDGF receptors (PDGFRs) is a well-established aberration in a subset of glioblastomas (GBMs). PDGFRA is expressed in glioma cells, whereas PDGFRB is mostly restricted to the glioma-associated stroma. Here we show that the spatial location of TAMMs correlates with the expansion of a subset of tumor cells that have acquired expression of PDGFRB in both mouse and human low-grade glioma and HCGs. Furthermore, M2-polarized microglia but not bone marrow (BM)-derived macrophages (BMDMs) induced PDGFRB expression in glioma cells and stimulated their migratory capacity. These findings illustrate a heterotypic cross-talk between microglia and glioma cells that may enhance the migratory and invasive capacity of the latter by inducing PDGFRB.}, }
@article {pmid30384037, year = {2018}, author = {Hagan, KA and Harrington, LB and Kim, J and Lindström, S and Camargo, CA and Grodstein, F and Kabrhel, C}, title = {Adiposity throughout the life course and risk of venous thromboembolism.}, journal = {Thrombosis research}, volume = {172}, number = {}, pages = {67-73}, doi = {10.1016/j.thromres.2018.10.024}, pmid = {30384037}, issn = {1879-2472}, support = {UM1 CA176726/CA/NCI NIH HHS/United States ; R01 HL116854/HL/NHLBI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; T32 HL098048/HL/NHLBI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 HL035464/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: Adult body mass index (BMI) is strongly associated with venous thromboembolism (VTE), however whether earlier-life adiposity or other measures of adult adiposity are associated with VTE risk remains largely unknown.
MATERIALS AND METHODS: We evaluated associations of childhood somatotype, BMI in early adulthood, adult adiposity, and change in weight since early adulthood with incident VTE risk over ≥20 years of follow-up among 205,935 participants from Nurses' Health Studies (NHS/NHS II) and Health Professionals Follow-Up Study (HPFS), ages 29-76 at baseline. We estimated multivariable-adjusted hazard ratios for VTE using Cox proportional hazards models.
RESULTS AND CONCLUSIONS: Somatotype in childhood and young adulthood BMI were not significantly associated with VTE risk, after accounting for adult BMI. Adult BMI was strongly associated with VTE in all three cohorts (e.g., multivariable-adjusted HRs comparing ≥35 kg/m2 vs. <22.5 kg/m2: NHS:3.03[95% CI: 2.58, 3.56], NHS II:3.82[95% CI: 3.24, 4.51], HPFS:2.81 [95% CI: 2.08, 3.80]; all p-trends < 0.01). Adult waist circumference was associated with greater VTE risk, even after adjusting for adult BMI (all p-trends < 0.01). Increasing weight gain from young adulthood was significantly associated with VTE after adjusting for current BMI among women (HR comparing gain ≥20 kg vs. no change: NHS:1.36[95% CI: 1.13, 1.65], NHS II:1.48[95% CI: 1.17, 1.87]) and not men (HPFS:1.20[95% CI: 0.97, 1.50]). These results indicate that BMI and adiposity are likely more important acutely than cumulatively over time in the etiology and prevention of VTE. Clinically, encouraging weight loss in individuals who are overweight or obese could help reduce VTE risk.}, }
@article {pmid30383589, year = {2018}, author = {Makanani, B and Balkus, JE and Jiao, Y and Noguchi, LM and Palanee-Phillips, T and Mbilizi, Y and Moodley, J and Kintu, K and Reddy, K and Kabwigu, S and Jeenariain, N and Harkoo, I and Mgodi, N and Piper, J and Rees, H and Scheckter, R and Beigi, R and Baeten, JM}, title = {Pregnancy and Infant Outcomes Among Women Using the Dapivirine Vaginal Ring in Early Pregnancy.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {79}, number = {5}, pages = {566-572}, doi = {10.1097/QAI.0000000000001861}, pmid = {30383589}, issn = {1944-7884}, support = {UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Monthly use of the dapivirine vaginal ring has been shown to be safe and effective for HIV-1 prevention in nonpregnant reproductive-aged women. The impact of dapivirine on pregnancy outcomes and infant is not known. We compared pregnancy incidence and outcomes by study arm among HIV-1-uninfected women who became pregnant while participating in MTN-020/ASPIRE.
METHODS: ASPIRE was a randomized, double-blind, placebo-controlled phase III safety and effectiveness study of the dapivirine ring for HIV-1 prevention. Sexually active women aged 18-45 years from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. Urine pregnancy tests were performed monthly, and, if positive, study product was withheld during pregnancy and breastfeeding. Pregnancy-related outcomes included the following: pregnancy incidence, pregnancy outcomes (live birth, preterm birth, pregnancy loss, and congenital anomalies), and infant growth.
RESULTS: Of 2629 women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm was observed (hazard ratio = 0.93; 95% confidence interval: 0.68 to 1.26). The distribution of pregnancy outcomes was similar by study arm, and no difference was noted in the frequency or pattern of congenital anomalies or infant growth parameters by study arm.
CONCLUSIONS: Dapivirine use in the periconception period does not seem to be associated with adverse effects on pregnancy or infant outcomes. Our findings provide support for additional safety studies of the dapivirine ring throughout pregnancy.}, }
@article {pmid30383394, year = {2018}, author = {Andeen, NK and Qu, X and Antic, T and Tykodi, SS and Fang, M and Tretiakova, MS}, title = {Clinical Utility of Chromosome Genomic Array Testing for Unclassified and Advanced-Stage Renal Cell Carcinomas.}, journal = {Archives of pathology & laboratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.5858/arpa.2018-0104-OA}, pmid = {30383394}, issn = {1543-2165}, abstract = {CONTEXT.—: Cytogenomic analysis provides a useful adjunct to traditional pathology in the categorization of renal cell carcinomas (RCCs), particularly in morphologically ambiguous cases, but it has disadvantages, including cost.
OBJECTIVE.—: To define the clinical scenarios in which this technology has direct clinical applications.
DESIGN.—: DNA was isolated from paraffin-embedded tissue from 40 selected cases of RCC. Chromosome genomic array testing was performed using the OncoScan.
RESULTS.—: Of 23 cases of unclassified renal tumors, 19 (83%) were reclassified with incorporation of cytogenetic and histologic features, including 10 as clear cell RCC, 2 as collecting duct carcinoma, 2 as papillary RCC, and 1 as novel TFEB-amplified tumor lacking TFEB translocation. Of 5 tumors with "hybrid" oncocytic features, 3 were reclassified as an eosinophilic variant of chromophobe RCC and 1 as oncocytoma. Appropriate staging in 2 patients was determined by identifying distinct, nonshared cytogenetic profiles. Of 11 cases of metastatic clear cell RCC, 7 (63%) had cytogenetic features associated with a poor prognosis.
CONCLUSIONS.—: We identified 5 scenarios in which chromosome genomic array testing has direct clinical utility: (1) to investigate unclassified RCCs, (2) to understand tumors with "hybrid" features and "collision" tumors, (3) to determine appropriate staging in questions of bilateral tumors and/or metastases, (4) to identify chromosomal aberrations in metastatic clear cell RCCs associated with a worse prognosis, and (5) to identify new entities. This has practical value in our institution, where a molecular profile diagnostically separating morphologically difficult to classify clear cell, papillary, chromophobe, and unclassified RCC influences treatment recommendations and clinical trial eligibility.}, }
@article {pmid30383234, year = {2018}, author = {Ramchandani, MS and Jing, L and Russell, RM and Tran, T and Laing, KJ and Magaret, AS and Selke, S and Cheng, A and Huang, ML and Xie, H and Strachan, E and Greninger, AL and Roychoudhury, P and Jerome, KR and Wald, A and Koelle, DM}, title = {Viral genetics modulate orolabial HSV-1 shedding in humans.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiy631}, pmid = {30383234}, issn = {1537-6613}, abstract = {Background: Orolabial herpes simplex virus type 1 (HSV-1) infection has wide severity spectrum in immunocompetent persons. To study the role of viral genotype and host immunity, we characterized oral HSV-1 shedding rates, host cellular response and genotyped viral strains in mono- (MZ) and dizygotic (DZ) twins.
Methods: 29 MZ and 22 DZ HSV-1 seropositive twin pairs were evaluated for oral HSV-1 shedding for 60 days. HSV-1 strains from twins were genotyped as identical or different. CD4 T-cell responses to HSV-1 proteins were studied.
Results: The median oral HSV shedding rate was 9% (mean 10.2%). A positive correlation between shedding rates within all twin pairs was observed, and in MZ and DZ twins. In twins with sufficient HSV-1 DNA to genotype, 15 had the same and 14 had different strains. Viral shedding rates were correlated for those with the same but not different strains. The median number of HSV-1 ORFs recognized per person was 16. The CD4 T-cell response agreement to different HSV-1 ORFs was greater between MZ twins, than between unrelated persons (p=0.002).
Conclusion: Viral strain characteristics likely contribute to oral HSV-1 shedding rates.}, }
@article {pmid30382603, year = {2018}, author = {Lupo, PJ and Brown, AL and Arroyo, VM and Kamdar, KY and Belmont, JW and Scheurer, ME and Leisenring, WM and Gramatges, MM and Okcu, MF and Yasui, Y and Oeffinger, KC and Robison, LL and Armstrong, GT and Bhatia, S}, title = {DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.}, journal = {Genes, chromosomes & cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/gcc.22701}, pmid = {30382603}, issn = {1098-2264}, abstract = {Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study (CCSS): 48 obese (BMI ≥30.0 kg/m2) and 48 normal weight (BMI = 18.5-24.9 kg/m2). The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. The false discovery rate (FDR) was used to account for multiple testing. In exploratory analyses, we also tested for interaction between cranial radiotherapy (CRT) status and selected CpG sites to evaluate differences by CRT exposure. Thirty-nine loci were associated (FDR <0.05) with obesity among survivors who only received chemotherapy (n = 49), including ABCG1 cg06500161. No loci were significantly associated with obesity among CRT-exposed survivors (n = 47). There was evidence (P-value <0.05) of interaction between CRT and methylation at six of the 39 methylation sites. Our results suggest that previously identified BMI-DNA methylation loci are associated with obesity in pediatric ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT. Given the obesogenic characteristics of ALL therapy, this study adds to the growing evidence of that the mechanisms underlying obesity in ALL survivors differ based on treatment exposures and may inform future intervention strategies among these individuals. This article is protected by copyright. All rights reserved.}, }
@article {pmid30382189, year = {2018}, author = {Jia, Y and Gu, D and Wan, J and Yu, B and Zhang, X and Chiorean, EG and Wang, Y and Xie, J}, title = {The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer.}, journal = {Oncogene}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41388-018-0553-0}, pmid = {30382189}, issn = {1476-5594}, support = {R01 CA155086/CA/NCI NIH HHS/United States ; }, abstract = {Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.}, }
@article {pmid30381458, year = {2018}, author = {Sarhan, J and Liu, BC and Muendlein, HI and Li, P and Nilson, R and Tang, AY and Rongvaux, A and Bunnell, SC and Shao, F and Green, DR and Poltorak, A}, title = {Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, number = {46}, pages = {E10888-E10897}, doi = {10.1073/pnas.1809548115}, pmid = {30381458}, issn = {1091-6490}, support = {R21 AI135369/AI/NIAID NIH HHS/United States ; T32 AI007077/AI/NIAID NIH HHS/United States ; }, abstract = {Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8-mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. We found that the Yersinia-driven IL-1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations are required to provide signal 1 and signal 2 for IL-1α/β release. Furthermore, we found that human macrophages are resistant to YopJ-mediated pyroptosis, with dampened IL-1β production. Our results uncover a form of caspase-8-mediated pyroptosis and suggest a hypothesis for the increased sensitivity of humans to Yersinia infection compared with the rodent reservoir.}, }
@article {pmid30381415, year = {2018}, author = {Schiffer, JT and Schiffer, CA}, title = {To what extent can mathematical modeling inform the design of clinical trials? The example of safe dose reduction of tyrosine kinase inhibitors in responding patients with chronic myeloid leukemia.}, journal = {Haematologica}, volume = {103}, number = {11}, pages = {1756-1757}, doi = {10.3324/haematol.2018.201897}, pmid = {30381415}, issn = {1592-8721}, }
@article {pmid30381375, year = {2018}, author = {Tsai, JJ and Velardi, E and Shono, Y and Argyropoulos, KV and Holland, AM and Smith, OM and Yim, NL and Rao, UK and Kreines, FM and Lieberman, SR and Young, LF and Lazrak, A and Youssef, S and Fu, YY and Liu, C and Lezcano, C and Murphy, GF and Na, IK and Jenq, RR and Hanash, AM and Dudakov, JA and van den Brink, MRM}, title = {Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood-2017-10-812941}, pmid = {30381375}, issn = {1528-0020}, abstract = {Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor well known for its role in regulating the cellular redox pathway. While there is mounting evidence suggesting a critical role of Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role of Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2-/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2-/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2-/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings not only characterized a previously unrecognized role of Nrf2 in T-cell function, but also revealed a novel therapeutic target to improve the outcomes of allo-HCT.}, }
@article {pmid30381298, 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 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 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 Parameswaran, V 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 Confer, DL and Shaw, BE}, title = {Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at 1-year compared to unrelated donors.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.200121}, pmid = {30381298}, issn = {1592-8721}, abstract = {Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation related toxicities we conducted a prospective observational trial of 11,942 related and unrelated age 18-60. Bone marrow was collected at 37 transplant and 78 National Marrow Donor Program centers and peripheral blood stem cells were collected at 42 transplant and 87 unrelated donor centers in North America. Ascertainment of medical comorbidities occurred prior to donation and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for marrow collection in related and unrelated donors, however, related stem cell donors had increased risk of moderate (OR 1.42, p<0.001) and severe pain (OR 8.91, p<0.001) and toxicities (OR 1.84, p<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56 p=0.021) and non-recovery from pain (OR 1.42 p=0.001) at 1 year. RD with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43, p<0.001) and non-recovery from toxicities (OR 3.71, p<0.001) at 1 year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43, p<0.001) and non-recovery from toxicities (OR 3.71, p<0.001) at 1 year. Related donors reporting grade ≥2 pain had significant decreases in HR-QoL at 1 month and 1 year post-donation (p=0.004). Conclusion: related peripheral blood stem cell donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at 1 year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Clinicaltrials.gov NCT00948636.}, }
@article {pmid30380125, year = {2018}, author = {Choi, YH and Lakhal-Chaieb, L and Kröl, A and Yu, B and Buchanan, D and Ahnen, D and Le Marchand, L and Newcomb, PA and Win, AK and Jenkins, M and Lindor, NM and Briollais, L}, title = {Risks of Colorectal Cancer and Cancer-Related Mortality in Familial Colorectal Cancer Type X and Lynch Syndrome Families.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djy159}, pmid = {30380125}, issn = {1460-2105}, support = {U24 CA074783/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U24 CA074806/CA/NCI NIH HHS/United States ; U24 CA097735/CA/NCI NIH HHS/United States ; UM1 CA167551/CA/NCI NIH HHS/United States ; U24 CA074799/CA/NCI NIH HHS/United States ; U24 CA074800/CA/NCI NIH HHS/United States ; }, abstract = {Background: The risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families.
Methods: In this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes).
Results: We found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively.
Conclusions: Individuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.}, }
@article {pmid30379922, year = {2018}, author = {Chun, KA and Kocarnik, JM and Hardikar, SS and Robinson, JR and Berndt, SI and Chan, AT and Figueiredo, JC and Lindor, NM and Song, M and Schoen, RE and Hayes, RB and Potter, JD and Nassir, R and Bézieau, S and Le Marchand, L and Slattery, ML and White, E and Peters, U and Newcomb, PA}, title = {Leptin gene variants and colorectal cancer risk: Sex-specific associations.}, journal = {PloS one}, volume = {13}, number = {10}, pages = {e0206519}, doi = {10.1371/journal.pone.0206519}, pmid = {30379922}, issn = {1932-6203}, abstract = {BACKGROUND: High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk.
METHODS: We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance.
RESULTS: Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men.
CONCLUSIONS: Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.}, }
@article {pmid30377365, year = {2018}, author = {Brent, R and Boucheron, L}, title = {Deep learning to predict microscope images.}, journal = {Nature methods}, volume = {15}, number = {11}, pages = {868-870}, doi = {10.1038/s41592-018-0194-9}, pmid = {30377365}, issn = {1548-7105}, support = {R21 CA223901/CA/NCI NIH HHS/United States ; }, }
@article {pmid30377258, year = {2018}, author = {Rooney, MR and Lutsey, PL and Bhatti, P and Prizment, A}, title = {Urinary 2,5-dicholorophenol and 2,4-dichlorophenol concentrations and prevalent disease among adults in the National Health and Nutrition Examination Survey (NHANES).}, journal = {Occupational and environmental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1136/oemed-2018-105278}, pmid = {30377258}, issn = {1470-7926}, support = {T32 HL007779/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: To test cross-sectional associations between urinary concentrations of 2,5-dichlorophenol (2,5-DCP) and 2,4-dichlorophenol (2,4-DCP) with the prevalence of cardiovascular disease (CVD), cancer, lung disease, thyroid problems and liver conditions.
METHODS: Logistic regression was used to evaluate associations of urinary concentrations of 2,5-DCP and 2,4-DCP with prevalence of various medical conditions among 3617 National Health and Nutrition Examination Survey participants from 2007-2008 and 2009-2010. ORs and 95% CIs for each disease were estimated. All regression models were adjusted for urinary creatinine.
RESULTS: We observed a monotonically increasing association between quartiles of 2,5-DCP and prevalence of CVD. After adjustment for sociodemographic and lifestyle characteristics, participants with the highest versus lowest quartile of urinary 2,5-DCP had an OR=1.84 (95% CI 1.26 to 2.70) (p linear trend=0.006). The association was similar with further adjustment for established clinical CVD risk factors. Higher 2,5-DCP was also associated with prevalence of all cancers combined (ORQ4 vs Q1=1.50 (95% CI 1.00 to 2.26); p trend=0.05) and, in exploratory analyses, with gynaecological cancers (ORQ4 vs Q1=4.15 (95% CI 1.51 to 11.40; p trend=0.01)). No associations were detected between 2,5-DCP and lung diseases, thyroid problems or liver conditions, nor between 2,4-DCP and prevalent disease.
CONCLUSION: In this nationally representative study, higher urinary 2,5-DCP concentrations were associated with greater prevalence of CVD and all cancers combined. Further examination may be warranted to assess whether chronic exposure to 2,5-DCP is associated with incidence of adverse health outcomes.}, }
@article {pmid30377209, year = {2018}, author = {Gramatges, MM and Morton, LM and Yasui, Y and Arnold, MA and Neglia, JP and Leisenring, WM and Machiela, MJ and Dagnall, CL and Chanock, SJ and Armstrong, GT and Robison, LL and Bhatia, S and Lupo, PJ}, title = {Telomere length-associated genetic variants and the risk of thyroid cancer in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS).}, journal = {Cancer epidemiology, biomarkers & 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-18-0972}, pmid = {30377209}, issn = {1538-7755}, support = {L40 CA153043/CA/NCI NIH HHS/United States ; R01 CA194473/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Given the inverse relationship previously described between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length and thyroid SMN among survivors.
METHODS: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the hazard ratio for thyroid SMN among 5,324 genotyped survivors.
RESULTS: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically-estimated leukocyte telomere length and risk for thyroid SMN was identified.
CONCLUSIONS: Our results suggest that variation in common SNPs influencing leukocyte telomere length is not strongly associated with risk for thyroid SMN in survivors of childhood cancer.
IMPACT: The previously-observed inverse relationship between leukocyte telomere length and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms, and warrants further study.}, }
@article {pmid30377203, year = {2018}, author = {Barnard, ME and Hecht, JL and Rice, MS and Gupta, M and Harris, HR and Eliassen, AH and Rosner, BA and Terry, KL and Tworoger, SS}, title = {Antiinflammatory Drug Use and Ovarian Cancer Risk by COX1/COX2 Expression and Infiltration of Tumor-Associated Macrophages.}, journal = {Cancer epidemiology, biomarkers & 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-18-0346}, pmid = {30377203}, issn = {1538-7755}, abstract = {Background: NSAID use may affect ovarian cancer risk via prostaglandin synthesis and tumor-associated macrophage (TAM) infiltration. We evaluated if associations between aspirin or non-aspirin NSAID use and ovarian cancer risk differed by tumor expression of prostaglandin-related (COX1, COX2) and TAM-related (CD68, CD163) markers.Methods: We evaluated cases and matched controls from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (NECC). Cases with IHC data on COX1 and COX2 (n = 532) or CD68 and CD163 (n = 530) were included. We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate OR for NSAID use and ovarian cancer risk by marker level.Results: Recent aspirin use had a nonsignificant inverse association and recent non-aspirin NSAID use had no association with ovarian cancer risk. NSAID use was not differentially associated with ovarian cancer by COX1 or COX2 expression. However, recent aspirin use was associated with lower ovarian cancer risk for high [OR 0.54; 95% confidence interval (CI), 0.37-0.78], but not low (OR 1.50; 95% CI, 0.97-2.31), CD163 density (Pheterogeneity < 0.001). Similar results were observed for aspirin duration and tablets and for recent non-aspirin NSAID use. Results were not clearly different by macrophage density defined by the less specific macrophage marker, CD68.Conclusions: NSAID use was inversely associated with risk of ovarian cancer with high density CD163, a marker for M2-type, immunosuppressive macrophages. However, the relationship did not differ by prostaglandin synthesis markers.Impact: Future research should explore prostaglandin-independent mechanisms for the association between NSAID use and ovarian cancer risk, including immune mechanisms. Cancer Epidemiol Biomarkers Prev; 1-9. ©2018 AACR.}, }
@article {pmid30377088, year = {2018}, author = {Kanagal-Shamanna, R and Hodge, JC and Tucker, T and Shetty, S and Yenamandra, A and Dixon-McIver, A and Bryke, C and Huxley, E and Lennon, PA and Raca, G and Xu, X and Jeffries, S and Quintero-Rivera, F and Greipp, PT and Slovak, ML and Iqbal, MA and Fang, M}, title = {Assessing copy number aberrations and copy neutral loss of heterozygosity across the genome as best practice: An evidence based review of clinical utility from the cancer genomics consortium (CGC) working group for myelodysplastic syndrome, myelodysplastic/myeloproliferative and myeloproliferative neoplasms.}, journal = {Cancer genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cancergen.2018.07.003}, pmid = {30377088}, issn = {2210-7762}, abstract = {Multiple studies have demonstrated the utility of chromosomal microarray (CMA) testing to identify clinically significant copy number alterations (CNAs) and copy-neutral loss-of-heterozygosity (CN-LOH) in myeloid malignancies. However, guidelines for integrating CMA as a standard practice for diagnostic evaluation, assessment of prognosis and predicting treatment response are still lacking. CMA has not been recommended for clinical work-up of myeloid malignancies by the WHO 2016 or the NCCN 2017 guidelines but is a suggested test by the European LeukaemiaNet 2013 for the diagnosis of primary myelodysplastic syndrome (MDS). The Cancer Genomics Consortium (CGC) Working Group for Myeloid Neoplasms systematically reviewed peer-reviewed literature to determine the power of CMA in (1) improving diagnostic yield, (2) refining risk stratification, and (3) providing additional genomic information to guide therapy. In this manuscript, we summarize the evidence base for the clinical utility of array testing in the workup of MDS, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and myeloproliferative neoplasms (MPN). This review provides a list of recurrent CNAs and CN-LOH noted in this disease spectrum and describes the clinical significance of the aberrations and how they complement gene mutation findings by sequencing. Furthermore, for new or suspected diagnosis of MDS or MPN, we present suggestions for integrating genomic testing methods (CMA and mutation testing by next generation sequencing) into the current standard-of-care clinical laboratory testing (karyotype, FISH, morphology, and flow).}, }
@article {pmid30374464, year = {2018}, author = {Dai, JY and Wang, X and Buas, MF and Zhang, C and Ma, J and Wei, B and Li, Y and Zhao, B and Hyun, TS and Chen, X and Loeb, KR and Odze, R and Yao, L and Sun, X and Self, S and Vaughan, TL and Guo, Y}, title = {Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations.}, journal = {Communications biology}, volume = {1}, number = {}, pages = {174}, doi = {10.1038/s42003-018-0182-8}, pmid = {30374464}, issn = {2399-3642}, support = {K05 CA124911/CA/NCI NIH HHS/United States ; P01 CA053996/CA/NCI NIH HHS/United States ; R01 CA136725/CA/NCI NIH HHS/United States ; R21 CA197502/CA/NCI NIH HHS/United States ; R01 HL114901/HL/NHLBI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; }, abstract = {While the incidence of esophageal adenocarcinoma (EAC) has risen drastically in Western countries over the last 40 years, a similar trend has not been observed for EAC in China. Here, we analyzed mutational spectrum, copy number alterations, and structural variants from whole-genome sequencing of 10 Chinese EAC tumor samples and their matched normal samples, and compared them to previously reported EAC tumor specimens from Western countries. The mutational burden in Chinese EAC was significantly lower than that found in EAC from Western countries. The hallmark A>C mutational signature observed at high frequency in EAC from Western countries, which has been linked to acid reflux, is completely absent in Chinese samples. Furthermore, none of the Chinese samples showed evidence of chromothripsis and genome doubling that are often found in EAC from Western countries. In summary, Chinese EAC tumor samples had distinct genomic profiles and signatures, suggesting that EAC in Chinese individuals may arise from a different etiological pathway.}, }
@article {pmid30371813, year = {2018}, author = {Yu, B and Davidson, NE}, title = {Gonadotropin-Releasing Hormone (GnRH) Agonists for Fertility Preservation: Is POEMS the Final Verse?.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djy188}, pmid = {30371813}, issn = {1460-2105}, support = {K08 CA222385/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; }, }
@article {pmid30371803, year = {2018}, author = {Graham, JB and Swarts, JL and Thomas, S and Voss, KM and Sekine, A and Green, R and Ireton, RC and Gale, M and Lund, JM}, title = {Immune correlates of protection from West Nile virus neuroinvasion and disease.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiy623}, pmid = {30371803}, issn = {1537-6613}, abstract = {Background: A challenge to the design of improved therapeutics and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection.
Methods: We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion, neuroinvasion with disease, and lines that remained virus- and disease-free.
Results: Our data reveal that protection from neuroinvasion and disease is multifactorial, and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T-cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8 T-cells in the brain correlated with protection from disease.
Conclusions: These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited pre-infection at baseline provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.}, }
@article {pmid30371800, year = {2018}, author = {Moore, HCF and Unger, JM and Phillips, KA and Boyle, F and Hitre, E and Moseley, A and Porter, DJ and Francis, PA and Goldstein, LJ and Gomez, HL and Vallejos, CS and Partridge, AH and Dakhil, SR and Garcia, AA and Gralow, JR and Lombard, JM and Forbes, JF and Martino, S and Barlow, WE and Fabian, CJ and Minasian, LM and Meyskens, FL and Gelber, RD and Hortobagyi, GN and Albain, KS}, title = {Final Analysis of the Prevention of Early Menopause Study (POEMS)/SWOG Intergroup S0230.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djy185}, pmid = {30371800}, issn = {1460-2105}, abstract = {Premature menopause is a serious long-term side effect of chemotherapy. We evaluated long-term pregnancy and disease-related outcomes for patients in S0230/POEMS, a study in premenopausal women with stage I-IIIA estrogen receptor-negative, progesterone receptor-negative breast cancer to be treated with cyclophosphamide-containing chemotherapy. Women were randomly assigned to standard chemotherapy with or without goserelin, a gonadotropin-releasing hormone agonist, and were stratified by age and chemotherapy regimen. All statistical tests were two-sided. Of 257 patients, 218 were eligible and evaluable (105 in the chemotherapy + goserelin arm and 113 in the chemotherapy arm). More patients in the chemotherapy + goserelin arm reported at least one pregnancy vs the chemotherapy arm (5-year cumulative incidence = 23.1%, 95% confidence interval [CI] = 15.3% to 31.9%; and 12.2%, 95% CI = 6.8% to 19.2%, respectively; odds ratio = 2.34; 95% CI = 1.07 to 5.11; P = .03). Randomization to goserelin + chemotherapy was associated with a nonstatistically significant improvement in disease-free survival (hazard ratio [HR] = 0.55; 95% CI = 0.27 to 1.10; P = .09) and overall survival (HR = 0.45; 95% CI = 0.19 to 1.04; P = .06). In this long-term analysis of POEMS/S0230, we found continued evidence that patients randomly assigned to receive goserelin + chemotherapy were not only more likely to avoid premature menopause, but were also more likely to become pregnant without adverse effect on disease-related outcomes.}, }
@article {pmid30368908, year = {2018}, author = {Grinde, KE and Qi, Q and Thornton, TA and Liu, S and Shadyab, AH and Chan, KHK and Reiner, AP and Sofer, T}, title = {Generalizing polygenic risk scores from Europeans to Hispanics/Latinos.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/gepi.22166}, pmid = {30368908}, issn = {1098-2272}, support = {HHSN268201300001I/N01-HC-65233//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201300005C//National Heart, Lung, and Blood Institute (NHLBI)/ ; AM03 and MOD03//National Heart, Lung, and Blood Institute (NHLBI)/ ; HL120393-03S1//National Heart, Lung, and Blood Institute (NHLBI)/ ; 1R35HL135818 HHSN268201100046C//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201100001C//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201100002C//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201100003C//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201100004C//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSC271201100004C//National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201300004I/N01-HC-65234//University of Miami/ ; HHSN268201300002I/N01-HC-65235//Albert Einstein College of Medicine/ ; HHSN268201300003I/N01-HC-65236//University of Illinois at Chicago/ ; //Northwestern University/ ; HHSN268201300005I/N01-HC-65237//San Diego State University/ ; //National Institute on Minority Health and Health Disparities/ ; //National Institute on Deafness and Other Communication Disorders/ ; //National Institute of Dental and Craniofacial Research/ ; //National Institute of Diabetes and Digestive and Kidney Diseases/ ; //National Institute of Neurological Disorders and Stroke/ ; //NIH Institution-Office of Dietary Supplements/ ; HG006292//National Human Genome Research Institute/ ; HL129132//National Human Genome Research Institute/ ; R01HG005827//National Human Genome Research Institute/ ; //U.S. Department of Health and Human Services/ ; DGE-1256082//National Science Foundation/ ; }, abstract = {Polygenic risk scores (PRSs) are weighted sums of risk allele counts of single-nucleotide polymorphisms (SNPs) associated with a disease or trait. PRSs are typically constructed based on published results from Genome-Wide Association Studies (GWASs), and the majority of which has been performed in large populations of European ancestry (EA) individuals. Although many genotype-trait associations have generalized across populations, the optimal choice of SNPs and weights for PRSs may differ between populations due to different linkage disequilibrium (LD) and allele frequency patterns. We compare various approaches for PRS construction, using GWAS results from both large EA studies and a smaller study in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL, n = 12 , 803). We consider multiple approaches for selecting SNPs and for computing SNP weights. We study the performance of the resulting PRSs in an independent study of Hispanics/Latinos from the Women's Health Initiative (WHI, n = 3 , 582). We support our investigation with simulation studies of potential genetic architectures in a single locus. We observed that selecting variants based on EA GWASs generally performs well, except for blood pressure trait. However, the use of EA GWASs for weight estimation was suboptimal. Using non-EA GWAS results to estimate weights improved results.}, }
@article {pmid30368771, year = {2018}, author = {Bhatt, NS and Brazauskas, R and Tecca, HR and Carreras, J and Burns, LJ and Phelan, R and Salit, RB and Syrjala, KL and Talano, JM and Shaw, BE}, title = {Post-transplantation employment status of adult survivors of childhood allogeneic hematopoietic cell transplant: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR).}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31781}, pmid = {30368771}, issn = {1097-0142}, support = {//Karyopharm Therapeutics/ ; //Sunesis Pharmaceuticals, Inc./ ; //Mediware/ ; //Sanofi Genzyme/ ; //St. Baldrick's Foundation/ ; //MesoScale Diagnostics, Inc./ ; //bluebird bio, Inc./ ; //Patient-Centered Outcomes Research Institute/ ; //Cerus Corporation/ ; //Mesoblast/ ; 4U10HL069294//National Heart, Lung, and Blood Institute/ ; //Swedish Orphan Biovitrum, Inc./ ; //Immucor/ ; //HistoGenetics/ ; //Millennium/ ; U24 CA076518/CA/NCI NIH HHS/United States ; //Actinium Pharmaceuticals/ ; //Neovii Biotech NA, Inc./ ; //Jazz Pharmaceuticals/ ; //Angiocrine Bioscience, Inc./ ; N00014-17-1-2388//Office of Naval Research/ ; //Amneal Biosciences/ ; //Amgen/ ; //Novartis Pharmaceuticals Corporation/ ; //Medical College of Wisconsin/ ; //Juno Therapeutics/ ; //Kite Pharma, Inc./ ; //Merck/ ; //Be The Match Foundation/ ; //Incyte Corporation/ ; //Pharmacyclics, LLC/ ; //MedImmune/ ; 5U24CA076518//National Cancer Institute/ ; 4U10HL069294//National Cancer Institute/ ; //Gilead Sciences/ ; //Anonymous donation to the Medical College of Wisconsin/ ; //Medac, GmbH/ ; //Astellas Pharma US/ ; //Seattle Genetics/ ; //Celgene/ ; //Shire/ ; 5U24CA076518//National Heart, Lung, and Blood Institute/ ; //Chimerix, Inc./ ; //University of Minnesota/ ; //National Marrow Donor Program/ ; 5U24CA076518//National Institute of Allergy and Infectious Diseases/ ; //Miltenyi Biotec/ ; //PIRCHE AG/ ; //Pfizer/ ; //Otsuka Pharmaceutical/ ; //Fred Hutchinson Cancer Research Center/ ; //Gamida Cell Ltd./ ; HHSH250201200016C//Health Resources and Services Administration/ ; //Bristol Myers Squibb Oncology/ ; //Atara Biotherapeutics, Inc./ ; //Telomere Diagnostics, Inc./ ; //Janssen Scientific Affairs, LLC/ ; //the Takeda Oncology Co./ ; N0014-17-1-2850//Office of Naval Research/ ; //Spectrum Pharmaceuticals/ ; }, abstract = {BACKGROUND: Data are scarce regarding employment outcomes of survivors of childhood allogeneic hematopoietic cell transplantation (alloHCT) and the factors that affect their employment status.
METHODS: By using the Center for International Blood and Marrow Transplant Research database, the authors studied employment outcomes of ≥1-year survivors of childhood alloHCT who were age ≥18 years at their most recent assessment (year of transplantation, 1985-2010). Employment status was assessed at their attained ages (ages 18-22, 23-27, and 28-32 years) and according to transplantation center (TC) location (United States or International). A multivariable analysis assessing the factors that affected employed status (full-time/part-time work or student) was performed.
RESULTS: Unemployment rates among 2844 survivors were persistently high at all attained ages (United States TCs: ages 18-22 [14%], 23-27 [15%], and 28-32 [13%] years; International TCs: ages 18-22 [56%], 23-27 [53%], and 28-32 [68%] years). The factors associated a with higher likelihood of employment included: older age at alloHCT (ages 5-9-years: hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.65-2.6; ages 10-14 years: HR, 4.43; 95% CI, 3.58-5.47; ages 15-18-years: HR, 7.13; 95% CI, 5.72-8.88), myeloablative conditioning without total body irradiation (TBI) (HR, 1.56; 95% CI, 1.38-1.77), reduced-intensity conditioning with TBI (HR, 1.47; 95% CI, 1.19-1.8) or without TBI (HR, 2.51; 95% CI, 2.15-2.92), and US-based TC (HR, 1.84; 95% CI, 1.62-2.08).
CONCLUSIONS: Young adult survivors of childhood alloHCT have high unemployment rates at all studied attained ages after HCT. Future efforts should be directed toward understanding the causes of unemployment their and relation to quality of life using patient-reported outcome measures.}, }
@article {pmid30368015, year = {2018}, author = {Barkley, AS and Kuo, CH and Leary, SES and Ojemann, JG and Susarla, SM}, title = {Unusual Radiographic Presentation of Intracranial Mature Teratoma and Resection via a Supraorbital Approach.}, journal = {World neurosurgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.wneu.2018.10.089}, pmid = {30368015}, issn = {1878-8769}, abstract = {BACKGROUND: Primary intracranial teratomas account for <1% of intracranial masses during childhood after infancy. When supratentorial, they commonly occur in the pineal and suprasellar regions demonstrating multilocularity, areas of fat as well as calcifications and increasing enhancement correlating with decreased maturity. However, the presence of a teratoma as a mobile fat lesion within a large unilocular suprasellar cyst is rarely documented in this patient population.
CASE DESCRIPTION: We present the first pediatric case of a suprasellar mature teratoma presenting as a mobile fat suppressing lesion within a large unilocular suprasellar cyst and describe a supraorbital approach with adjunctive use of the endoscope for resection. We also provide a literature review of other cases presenting with similar radiographic findings.
CONCLUSIONS: Mature teratomas may manifest atypically as unilocular cystic lesions with a central mobile fatty component and are treated by gross total surgical resection. The supraorbital approach with adjunctive use of an endoscope can provide adequate exposure for resection with optimal cosmetic outcome.}, }
@article {pmid30367972, year = {2018}, author = {Issaka, RB and Avila, P and Whitaker, E and Bent, S and Somsouk, M}, title = {Population health interventions to improve colorectal cancer screening by fecal immunochemical tests: A systematic review.}, journal = {Preventive medicine}, volume = {118}, number = {}, pages = {113-121}, doi = {10.1016/j.ypmed.2018.10.021}, pmid = {30367972}, issn = {1096-0260}, support = {L32 MD012892/MD/NIMHD NIH HHS/United States ; T32 DK007007/DK/NIDDK NIH HHS/United States ; }, abstract = {Despite clear evidence that colorectal cancer (CRC) screening reduces mortality, screening, including fecal immunochemical tests (FIT), is underutilized. We conducted a systematic review to determine the evidence of efficacy of interventions to improve FIT completion that could be scaled and utilized in population health management. We systematically searched publication databases for studies evaluating provider- or system-level interventions to improve CRC screening by FIT between 1 January 1996 and 13 December 2017 without language restrictions. Twenty articles describing 25 studies were included, 23 were randomized controlled trials with 1 quasi-experimental and 1 observational study. Ten studies discussed mailed FIT outreach, 4 pre-FIT patient reminders, 3 tailored patient messages, 2 post-FIT reminders, 2 paired FIT with influenza vaccinations, 2 provider alerts and 1 study each described the use of high-quality small media and patient financial incentives. Mailed FIT outreach was consistently effective with median improvement in CRC screening of 21.5% (interquartile range (IQR) 13.6%-29.0%). FIT paired with vaccinations led to a median 15.9% (IQR 15.6%-16.3%) improvement, while pre-FIT and post-FIT reminders demonstrated modest efficacy with median 4.1% (IQR 3.6%-6.7%) and 3.1% (IQR 2.9%-3.3%) improvement in CRC screening, respectively. More than half the studies were at high or unclear risk of bias; heterogeneous study designs and characteristics precluded meta-analysis. FIT-based CRC screening programs utilizing multilevel interventions (e.g. mailed FIT outreach, FIT paired with other preventative services, and provider alerts) have the potential to significantly increase screening participation. However, such programs must also follow-up patients with abnormal FIT results.}, }
@article {pmid30367401, year = {2018}, author = {Chiyaka, ET and Nghiem, VT and Zhang, L and Deshpande, A and Mullen, PD and Le, P}, title = {Cost-Effectiveness of Herpes Zoster Vaccination: A Systematic Review.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40273-018-0735-1}, pmid = {30367401}, issn = {1179-2027}, abstract = {BACKGROUND: Herpes zoster (HZ) is one of the most common diseases among adults. Its reactivation is characterized by a severe and painful complication. In addition to the existing herpes zoster vaccine (ZVL), the FDA approved a new adjuvanted subunit zoster vaccine (RZV) in 2017 for use in adults aged 50 years and older. Several studies have assessed the cost-effectiveness of ZVL, many of which were conducted before the long-term vaccine efficacy data was available in 2014.
OBJECTIVE: Our objectives were to (i) summarize and compare the cost-effectiveness analyses (CEAs) of ZVL conducted before and after 2014, (ii) summarize the CEAs of RZV, and (iii) critically assess the cost-effectiveness models and identify key parameters to consider for future CEAs of RZV.
METHODS: We searched PubMed and two other databases from inception to March 2018 for original cost-effectiveness, cost-utility, or cost-benefit analyses of HZ vaccines. Three investigators independently reviewed and assessed full-text articles after screening the titles and abstracts to determine eligibility. For all included studies, we assessed study quality using the Drummond and Jefferson's checklist and extracted study characteristics, model structure, vaccine characteristics, incidence of HZ and complications, incremental cost-effectiveness ratio, and sensitivity analyses. We summarized data by type of vaccine, year of publication, and funding sources.
RESULTS: Twenty-seven studies met eligibility criteria. All studies were from high-income countries and were of moderate-to-high or high quality. Twenty studies repeatedly used four cost-effectiveness models. The assumption on long-term efficacy of ZVL was not based on clinical trial data in > 50% of studies. Fifteen out of 25 studies concluded that ZVL was cost-effective compared with no vaccine at a vaccine price ranging between US$93 and US$236 per dose (2018 US$), 40% of which were published after 2014. All industry-funded studies favored the use of ZVL. The single study assessing RZV found it to be more effective and less costly than ZVL, and cost-effective compared with no vaccination. More studies conducted after 2014 included various efficacy endpoints for ZVL, adverse reactions, and productivity loss compared with those conducted before 2014.
CONCLUSIONS: A majority of studies of ZVL found it to be cost-effective compared with no vaccine using the authors' chosen willingness-to-pay thresholds. RZV was dominant in the single study comparing the two vaccines, but the finding needs to be confirmed with further studies in different settings. Future studies should assume vaccine efficacy in line with clinical data, account for more efficacy endpoints for ZVL, and include other HZ long-term complications, vaccine adverse reactions, and productivity loss.}, }
@article {pmid30366816, year = {2018}, author = {Moon, JY and Zolnik, CP and Wang, Z and Qiu, Y and Usyk, M and Wang, T and Kizer, JR and Landay, AL and Kurland, IJ and Anastos, K and Kaplan, RC and Burk, RD and Qi, Q}, title = {Gut microbiota and plasma metabolites associated with diabetes in women with, or at high risk for, HIV infection.}, journal = {EBioMedicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ebiom.2018.10.037}, pmid = {30366816}, issn = {2352-3964}, support = {K01 HL129892/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Gut microbiota alteration has been implicated in HIV infection and metabolic disorders. The relationship between gut microbiota and diabetes has rarely been studied in HIV-infected individuals, who have excess risk of metabolic disorders.
METHODS: Our study during 2015-2016 enrolled predominantly African Americans and Hispanics in the Women's Interagency HIV Study. We studied 28 women with long-standing HIV infection under antiretroviral therapy and 20 HIV-uninfected, but at high risk of infection, women (16 HIV+ and 6 HIV- with diabetes). Fecal samples were analyzed by sequencing prokaryotic16S rRNA gene. Plasma metabolomics profiling was performed by liquid chromatography-tandem mass spectrometry.
FINDINGS: No significant differences in bacterial α- or β-diversity were observed by diabetes or HIV serostatus (all P > .1). Relative abundances of four genera (Finegoldia, Anaerococcus, Sneathia, and Adlercreutzia) were lower in women with diabetes compared to those without diabetes (all P < .01). In women with diabetes, plasma levels of several metabolites in tryptophan catabolism (e,g., kynurenine/tryptophan ratio), branched-chain amino acid and proline metabolism pathways were higher, while glycerophospholipids were lower (all P < .05). Results were generally consistent between HIV-infected and HIV-uninfected women, and no significant modification effects by HIV serostatus were observed (all Pinteraction > 0.05). Anaerococcus, known to produce butyrate which is involved in anti-inflammation and glucose metabolism, showed an inverse correlation with kynurenine/tryptophan ratio (r = -0.38, P < .01).
INTERPRETATION: Among women with or at high risk for HIV infection, diabetes is associated with gut microbiota and plasma metabolite alteration, including depletion of butyrate-producing bacterial population along with higher tryptophan catabolism. FUND: NHLBI (K01HL129892, R01HL140976) and FMF.}, }
@article {pmid30364167, year = {2018}, author = {Langer, SL and Romano, JM and Todd, M and Strauman, TJ and Keefe, FJ and Syrjala, KL and Bricker, JB and Ghosh, N and Burns, JW and Bolger, N and Puleo, BK and Gralow, JR and Shankaran, V and Westbrook, K and Zafar, SY and Porter, LS}, title = {Links Between Communication and Relationship Satisfaction Among Patients With Cancer and Their Spouses: Results of a Fourteen-Day Smartphone-Based Ecological Momentary Assessment Study.}, journal = {Frontiers in psychology}, volume = {9}, number = {}, pages = {1843}, doi = {10.3389/fpsyg.2018.01843}, pmid = {30364167}, issn = {1664-1078}, support = {R01 CA201179/CA/NCI NIH HHS/United States ; }, abstract = {Cancer treatment poses significant challenges not just for those diagnosed with the disease but also for their intimate partners. Evidence suggests that couples' communication plays a major role in the adjustment of both individuals and in the quality of their relationship. Most descriptive studies linking communication to adjustment have relied on traditional questionnaire methodologies and cross-sectional designs, limiting external validity and discernment of temporal patterns. Using the systemic-transactional model of dyadic coping as a framework, we examined intra- and inter-personal associations between communication (both enacted and perceived) and relationship satisfaction (RS) among patients with stage II-IV breast or colorectal cancer and their spouses (N = 107 couples). Participants (mean age = 51, 64.5% female patients, and 37.4% female spouses) independently completed twice-daily ecological momentary assessments (EMA) via smartphone for 14 consecutive days. Items assessed RS and communication (expression of feelings, holding back from expression, support and criticism of partner, and parallel ratings of partner behavior). Linear mixed models employing an Actor Partner Interdependence Model were used to examine concurrent, time-lagged, and cross-lagged associations between communication and RS. Expressing one's feelings was unassociated with RS. Holding back from doing so, in contrast, was associated with lower RS for both patients and spouses in concurrent models. These effects were both intrapersonal and interpersonal, meaning that when individuals held back from expressing their feelings, they reported lower RS and so too did their partner. Giving and receiving support were associated with one's own higher RS for both patients and spouses in concurrent models, and for patients in lagged models. Conversely, criticizing one's partner and feeling criticized were maladaptive, associated with lower RS (own and in some cases, partner's). Cross-lagged analyses (evening RS to next-day afternoon communication) yielded virtually no effects, suggesting that communication may have a stronger influence on short-term RS than the reverse. Findings underscore the importance of responsive communication, more so than expression per se, in explaining both concurrent and later relationship adjustment. In addition, a focus on holding back from expressing feelings may enhance the understanding of RS for couples coping with cancer.}, }
@article {pmid30363022, year = {2018}, author = {Zueger, PM and Holmes, HM and Qato, DM and Pickard, AS and Calip, GS and Lee, TA}, title = {Use of Nonpalliative Medications Following Burdensome Health Care Transitions in Hospice Patients: A Matched Cohort Analysis.}, journal = {Medical care}, volume = {}, number = {}, pages = {}, doi = {10.1097/MLR.0000000000001008}, pmid = {30363022}, issn = {1537-1948}, abstract = {BACKGROUND: Limited benefit medications (LBMs), those medications with questionable benefit at the end of life, are often recommended for discontinuation in hospice patients. Transitions in care are associated with inappropriate prescribing in older and terminally ill populations.
OBJECTIVES: To evaluate the association between burdensome health care transitions and subsequent receipt of LBMs in older hospice patients.
METHODS: We conducted a matched cohort analysis of patients admitted to hospice between 2008 and 2013 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The prevalence of post-health care transition LBM use was assessed. Adjusted incidence rate ratios (IRRs) were estimated for the association between transitions and subsequent receipt of LBMs.
RESULTS: In total, 17.9% of 7064 hospice patients received at least 1 LBM following their first burdensome health care transition. Posttransition continuation of a medication class used before hospice admission was most common for antidementia medications (14.2%) and antihypertensives (11.2%). Transitions were associated with a 33% increase in the risk of receiving at least 1 LBM [IRR, 1.33; 95% confidence interval (CI), 1.25-1.42], increasing to 56% when evaluating only hospitalization transitions (IRR, 1.56; 95% CI, 1.39-1.76). Medication classes more likely to be dispensed after a transition included antihyperlipidemics (IRR, 1.38; 95% CI, 1.13-1.70), antihypertensives (IRR, 1.28; 95% CI, 1.16-1.40), and proton-pump inhibitors (IRR, 1.40; 95% CI, 1.20-1.63).
CONCLUSIONS: Burdensome health care transitions were associated with the receipt of nonpalliative medications in older hospice patients. Interventions aimed at improving provider communication and reducing fragmentation in care may help reduce unnecessary medication use in this vulnerable population.}, }
@article {pmid30362586, year = {2018}, author = {Mirzaei, HR and Jamali, A and Jafarzadeh, L and Masoumi, E and Alishah, K and Fallah Mehrjardi, K and Emami, SAH and Noorbakhsh, F and Till, BG and Hadjati, J}, title = {Construction and functional characterization of a fully human anti-CD19 chimeric antigen receptor (huCAR)-expressing primary human T cells.}, journal = {Journal of cellular physiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcp.27599}, pmid = {30362586}, issn = {1097-4652}, support = {942554//National Institute for Medical Research Development (NIMAD) of Iran/ ; 30381//Tehran University of Medical Sciences and Health Services/ ; }, abstract = {Although remarkable results have been attained by adoptively transferring T cells expressing fully murine and/or humanized anti-CD19 chimeric antigen receptors (CARs) to treat B cell malignancies, evidence of human anti-mouse immune responses against CARs provides a rationale for the development of less immunogenic CARs. By developing a fully human CAR (huCAR), these human anti-mouse immune responses are likely eliminated. This, perhaps, not only increases the persistence of anti-CD19 CAR T cells-thereby reducing the risk of tumor relapse-but also facilitates administration of multiple, temporally separated doses of CAR T cells to the same recipient. To these ends, we have designed and constructed a second-generation fully human anti-CD19 CAR (or huCAR19) containing a fully human single-chain variable fragment (ScFv) fused with a CD8a hinge, a 4-1BB transmembrane domain and intracellular T cell signaling domains of 4-1BB and CD3z. T cells expressing this CAR specifically recognized and lysed CD19+ target cells produced cytokines and proliferated in vitro. Moreover, cell volume data revealed that our huCAR construct cannot induce antigen-independent tonic signaling in the absence of cognate antigen. Considering our results, our anti-CD19 huCAR may overcome issues of transgene immunogenicity that plague trials utilizing CARs containing mouse-derived ScFvs. These results suggest that this huCAR19 be safely and effectively applied for adaptive T cell immunotherapy in clinical practice.}, }
@article {pmid30361702, year = {2018}, author = {Goddard, ET and Bozic, I and Riddell, SR and Ghajar, CM}, title = {Dormant tumour cells, their niches and the influence of immunity.}, journal = {Nature cell biology}, volume = {20}, number = {11}, pages = {1240-1249}, doi = {10.1038/s41556-018-0214-0}, pmid = {30361702}, issn = {1476-4679}, abstract = {Despite increased focus on the clinical relevance of dormant metastatic disease, our understanding of dormant niches, mechanisms underlying emergence from dormancy, and the immune system's role in this phenomenon, remains in its infancy. Here, we discuss key work that has shaped our current understanding of these topics. Because tumour dormancy provides a unique therapeutic window to prevent metastatic disease, we discuss on-going clinical trials and weigh the potential for immunotherapy to eradicate dormant disease.}, }
@article {pmid30361695, year = {2018}, author = {Ying, Z and Sandoval, M and Beronja, S}, title = {Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth.}, journal = {Nature cell biology}, volume = {20}, number = {11}, pages = {1256-1266}, doi = {10.1038/s41556-018-0218-9}, pmid = {30361695}, issn = {1476-4679}, abstract = {Oncogenic lesions are surprisingly common in morphologically and functionally normal human skin. However, the cellular and molecular mechanisms that suppress their cancer-driving potential to maintain tissue homeostasis are unknown. By employing assays for the direct and quantitative assessment of cell fate choices in vivo, we show that oncogenic activation of PI3K-AKT, the most commonly activated oncogenic pathway in cancer, promotes the differentiation and cell cycle exit of epidermal progenitors. As a result, oncogenic PI3K-AKT-activated epidermis exhibits a growth disadvantage even though its cells are more proliferative. We then sought to uncover the underlying mechanism behind oncogene-induced differentiation via a series of genetic screens in vivo. An AKT substrate, SH3RF1, is identified as a specific promoter of epidermal differentiation that has no effect on proliferation. Our study provides evidence for a direct, cell autonomous mechanism that can suppresses progenitor cell renewal and block clonal expansion of epidermal cells bearing a common and activating mutation in Pik3ca.}, }
@article {pmid30361514, year = {2018}, author = {Colonna, L and Peterson, CW and Schell, JB and Carlson, JM and Tkachev, V and Brown, M and Yu, A and Reddy, S and Obenza, WM and Nelson, V and Polacino, PS and Mack, H and Hu, SL and Zeleski, K and Hoffman, M and Olvera, J and Furlan, SN and Zheng, H and Taraseviciute, A and Hunt, DJ and Betz, K and Lane, JF and Vogel, K and Hotchkiss, CE and Moats, C and Baldessari, A and Murnane, RD and English, C and Astley, CA and Wangari, S and Agricola, B and Ahrens, J and Iwayama, N and May, A and Stensland, L and Huang, MW and Jerome, KR and Kiem, HP and Kean, LS}, title = {Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {4438}, doi = {10.1038/s41467-018-06736-7}, pmid = {30361514}, issn = {2041-1723}, support = {R01 HL095791/HL/NHLBI NIH HHS/United States ; UM1 AI126623//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI126617//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R33 AI116184/AI/NIAID NIH HHS/United States ; U19 AI096111/AI/NIAID NIH HHS/United States ; U19 AI051731/AI/NIAID NIH HHS/United States ; R01 HL116217/HL/NHLBI NIH HHS/United States ; UM1 AI126623/AI/NIAID NIH HHS/United States ; U19 HL129902/HL/NHLBI NIH HHS/United States ; U19 AI051731//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U19 AI096111//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI116184//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI126617/AI/NIAID NIH HHS/United States ; R21 AI116184/AI/NIAID NIH HHS/United States ; }, abstract = {Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.}, }
@article {pmid30361262, year = {2018}, author = {DiNardo, CD and Pratz, K and Pullarkat, V and Jonas, BA and Arellano, M and Becker, PS and Frankfurt, O and Konopleva, M and Wei, AH and Kantarjian, HM and Xu, T and Hong, WJ and Chyla, B and Potluri, J and Pollyea, DA and Letai, A}, title = {Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood-2018-08-868752}, pmid = {30361262}, issn = {1528-0020}, abstract = {Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. BCL-2 overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N=145) were ≥65 years with treatment-naive AML ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5; intravenously [IV]) or azacitidine (75 mg/m2, days 1-7; IV or subcutaneously). In the expansion, 400 mg or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR+CRi rate of 73% in the venetoclax 400-mg + HMA cohort. Patients with poor-risk cytogenetics and those ≥75 years had CR+CRi rates of 60% and 65%, respectively. The median duration of CR+CRi (all patients) was 11.3 months and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400 mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (https://clinicaltrials.gov/, NCT02203773).}, }
@article {pmid30359878, year = {2019}, author = {Soltys, DT and Pereira, CPM and Rowies, FT and Farfel, JM and Grinberg, LT and Suemoto, CK and Leite, REP and Rodriguez, RD and Ericson, NG and Bielas, JH and Souza-Pinto, NC}, title = {Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects.}, journal = {Neurobiology of aging}, volume = {73}, number = {}, pages = {161-170}, doi = {10.1016/j.neurobiolaging.2018.09.015}, pmid = {30359878}, issn = {1558-1497}, abstract = {Accumulation of oxidative mitochondrial DNA (mtDNA) damage and impaired base excision repair (BER) in brains have been associated with Alzheimer's disease (AD). However, it is still not clear how these affect mtDNA stability, as reported levels of mtDNA mutations in AD are conflicting. Thus, we investigated whether alterations in BER correlate with mtDNA instability in AD using postmortem brain samples from cognitively normal AD subjects and individuals who show neuropathological features of AD, but remained cognitively normal (high-pathology control). To date, no data on DNA repair and mtDNA stability are available for these individuals. BER activities, mtDNA mutations, and mtDNA copy number were measured in the nuclear and mitochondrial extracts. Significantly lower uracil DNA glycosylase activity was detected in nuclear and mitochondrial extracts from AD subjects, while apurinic/apyrimidinic endonuclease activity was similar in all groups. Although mtDNA mutation frequency was similar in all groups, mtDNA copy number was significantly decreased in the temporal cortex of AD brains but not of high-pathology control subjects. Our results show that lower mitochondrial uracil DNA glycosylase activity does not result in increased mutagenesis, but rather in depletion of mtDNA in early-affected brain regions during AD development.}, }
@article {pmid30358728, year = {2018}, author = {Chlebowski, RT and Cirillo, DJ and Eaton, CB and Stefanick, ML and Pettinger, M and Carbone, LD and Johnson, KC and Simon, MS and Woods, NF and Wactawski-Wende, J}, title = {Estrogen alone and joint symptoms in the Women's Health Initiative randomized trial.}, journal = {Menopause (New York, N.Y.)}, volume = {25}, number = {11}, pages = {1313-1320}, doi = {10.1097/GME.0000000000001235}, pmid = {30358728}, issn = {1530-0374}, abstract = {OBJECTIVE: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial.
METHODS: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms.
RESULTS: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling.
CONCLUSIONS: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.}, }
@article {pmid30358713, year = {2018}, author = {Brinton, LA and Brogan, DR and Coates, RJ and Swanson, CA and Potischman, N and Stanford, JL}, title = {Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy.}, journal = {Menopause (New York, N.Y.)}, volume = {25}, number = {11}, pages = {1195-1200}, doi = {10.1097/GME.0000000000001217}, pmid = {30358713}, issn = {1530-0374}, abstract = {OBJECTIVE: To assess effects on breast cancer risk of exposure to both oral contraceptives and menopausal hormones, an increasingly common exposure.
DESIGN: A case-control study of breast cancer among women under the age of 55 years in Atlanta, GA involving 1,031 cases and 919 population controls was conducted.
RESULTS: Ever use of oral contraceptives was associated with a relative risk of 1.1 (95% 0.9-1.4), whereas the relative risk for hormone replacement therapy was 0.9 (95% CI 0.7-1.2). Seventeen percent of the cases versus 19% of the population controls reported exposure to both agents, resulting in a relative risk of 1.0 (95% CI 0.7-1.4) relative to those unexposed to either preparation. Although there was little variation in risk associated with joint effects by either age or race, there were statistically nonsignificant elevations in risk for this exposure among women who had experienced a natural menopause (relative risk = 2.0, 95% CI 0.7-5.6), were relatively thin (relative risk = 1.5, 0.8-3.0), or who had a first degree relative with breast cancer (relative risk = 2.0, 0.6-7.0). When joint effects of longer term use of both agents were considered, subjects who reported use of oral contraceptives for 10 or more years and hormone replacement for 3 or more years had a relative risk of 3.2 (95% CI 1.4-7.4) compared with nonusers of either preparation.
CONCLUSIONS: Although our results must be cautiously interpreted given small numbers within subgroups, they raise concern and emphasize the need for further evaluation on breast cancer risk of the increasingly common exposure to both oral contraceptives and hormone replacement therapy.}, }
@article {pmid30358530, year = {2018}, author = {Andrews, SS and Brent, R and Balázsi, G}, title = {Transferring information without distortion.}, journal = {eLife}, volume = {7}, number = {}, pages = {}, doi = {10.7554/eLife.41894}, pmid = {30358530}, issn = {2050-084X}, mesh = {*Computational Biology ; *Signal Transduction ; }, abstract = {Despite employing diverse molecular mechanisms, many different cell signaling systems avoid losing information by transmitting it in a linear manner.}, }
@article {pmid30357256, year = {2018}, author = {, and Simonis, FD and Serpa Neto, A and Binnekade, JM and Braber, A and Bruin, KCM and Determann, RM and Goekoop, GJ and Heidt, J and Horn, J and Innemee, G and de Jonge, E and Juffermans, NP and Spronk, PE and Steuten, LM and Tuinman, PR and de Wilde, RBP and Vriends, M and Gama de Abreu, M and Pelosi, P and Schultz, MJ}, title = {Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial.}, journal = {JAMA}, volume = {320}, number = {18}, pages = {1872-1880}, doi = {10.1001/jama.2018.14280}, pmid = {30357256}, issn = {1538-3598}, mesh = {Aged ; Critical Illness/mortality/therapy ; Female ; Hospital Mortality ; Humans ; Intensive Care Units ; Male ; Middle Aged ; Outcome and Process Assessment (Health Care) ; Respiration, Artificial/adverse effects/*methods ; Respiratory Distress Syndrome, Adult ; Respiratory Insufficiency/physiopathology/*therapy ; *Tidal Volume ; Ventilator Weaning ; Ventilator-Induced Lung Injury ; }, abstract = {Importance: It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS).
Objective: To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy.
A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands.
Interventions: Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484).
Main Outcomes and Measures: The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax.
Results: In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, -0.27 [95% CI, -1.74 to 1.19]; P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [-1.09 to 1.89]; P = .58) and hospital (median, 14 vs 15 days; -0.60 [-3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55).
Conclusions and Relevance: In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy.
Trial Registration: ClinicalTrials.gov Identifier: NCT02153294.}, }
@article {pmid30355728, year = {2018}, author = {Cutler, S and Lee, LJ and Tsukiyama, T}, title = {Chromatin Remodeling Factors Isw2 and Ino80 Regulate Chromatin, Replication, and Copy Number of the Saccharomyces cerevisiae Ribosomal DNA Locus.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1534/genetics.118.301579}, pmid = {30355728}, issn = {1943-2631}, abstract = {In the budding yeast Saccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA Polymerases I and III, transcription of non-coding RNAs by RNA Polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors decreases the fraction of actively transcribed 35S ribosomal RNA genes and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.}, }
@article {pmid30355496, year = {2018}, author = {Wagh, K and Kreider, EF and Li, Y and Barbian, HJ and Learn, GH and Giorgi, E and Hraber, PT and Decker, TG and Smith, AG and Gondim, MV and Gillis, L and Wandzilak, J and Chuang, GY and Rawi, R and Cai, F and Pellegrino, P and Williams, I and Overbaugh, J and Gao, F and Kwong, PD and Haynes, BF and Shaw, GM and Borrow, P and Seaman, MS and Hahn, BH and Korber, B}, title = {Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth.}, journal = {Cell reports}, volume = {25}, number = {4}, pages = {893-908.e7}, doi = {10.1016/j.celrep.2018.09.087}, pmid = {30355496}, issn = {2211-1247}, abstract = {Densely arranged N-linked glycans shield the HIV-1 envelope (Env) trimer from antibody recognition. Strain-specific breaches in this shield (glycan holes) can be targets of vaccine-induced neutralizing antibodies that lack breadth. To understand the interplay between glycan holes and neutralization breadth in HIV-1 infection, we developed a sequence- and structure-based approach to identify glycan holes for individual Env sequences that are shielded in most M-group viruses. Applying this approach to 12 longitudinally followed individuals, we found that transmitted viruses with more intact glycan shields correlated with development of greater neutralization breadth. Within 2 years, glycan acquisition filled most glycan holes present at transmission, indicating escape from hole-targeting neutralizing antibodies. Glycan hole filling generally preceded the time to first detectable breadth, although time intervals varied across hosts. Thus, completely glycan-shielded viruses were associated with accelerated neutralization breadth development, suggesting that Env immunogens with intact glycan shields may be preferred components of AIDS vaccines.}, }
@article {pmid30354935, year = {2018}, author = {Shaik, F and Uldrick, TS and Esterhuizen, T and Mosam, A}, title = {Health-Related Quality of Life in Patients Treated With Antiretroviral Therapy Only Versus Chemotherapy and Antiretroviral Therapy for HIV-Associated Kaposi Sarcoma: A Randomized Control Trial.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-9}, doi = {10.1200/JGO.18.00105}, pmid = {30354935}, issn = {2378-9506}, abstract = {PURPOSE: In sub-Saharan Africa, Kaposi sarcoma (KS) is the most common HIV-associated cancer. KS causes substantial morbidity, and treatment goals should emphasize quality of life (QOL). Antiretroviral therapy (ART) is indicated, and early chemotherapy significantly improves tumor regression. The effect of ART alone or with chemotherapy on QOL in treatment-naïve South Africans with HIV-associated KS was assessed.
METHODS: KAART (Kaposi Sarcoma AIDS Anti-Retroviral Therapy) is a randomized, controlled, open-label trial of ART versus ART plus chemotherapy. Crossover between arms was allowed for patients with progressive disease. Eighty-nine percent of patients had advanced tumor burden. Within KAART, QOL measured by European Organization for Research and Treatment of Cancer-QLQ-C30 questionnaire evaluated functional and symptom domains and global QOL. Intragroup changes between baseline and month 12 (Wilcoxon rank sign test), changes between the arms (Mann-Whitney test), and the relationship between responses, determined by AIDS Clinical Trial Group criteria and QOL measures (Kruskal-Wallis test), were evaluated. P values < .01 were considered significant.
RESULTS: QOL information was available for 111 of 112 patients. Significant improvements over 12 months were seen in global health status and functional scales (emotional, cognitive, and social scales; not physical and role function). Most symptom scales (fatigue, pain, dyspnea, insomnia, appetite, diarrhea, and constipation) also showed significant improvement. There were no statistically significant changes between arms in intention-to-treat analysis. Patients showing a response to the tumor (complete or partial) reported significantly increased global QOL (P < .001), pain relief, and improved role functioning. Adherence, adverse events, HIV viral load, and CD4 count did not correlate with global QOL.
CONCLUSION: African patients with HIV-associated KS derive a significant benefit in QOL from ART and tumor regression.}, }
@article {pmid30353911, year = {2018}, author = {Kamineni, A and Tiro, JA and Beaber, EF and Silverberg, MJ and Wheeler, CM and Chao, CR and Chubak, J and Skinner, CS and Corley, DA and Kim, JJ and Balasubramanian, BA and Doria-Rose, VP and , }, title = {Cervical Cancer Screening Research in the PROSPR I Consortium: Rationale, Methods, and Baseline Findings from a U.S. Cohort.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.31940}, pmid = {30353911}, issn = {1097-0215}, support = {U54 CA164336/CA/NCI NIH HHS/United States ; }, abstract = {Little is known about the effect of evolving risk-based cervical cancer screening and management guidelines on United States (US) clinical practice and patient outcomes. We describe the National Cancer Institute's Population-based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium, methods, and baseline findings from its cervical sites: Kaiser Permanente Washington, Kaiser Permanente Northern California, Kaiser Permanente Southern California, Parkland Health & Hospital System/University of Texas Southwestern (Parkland-UTSW), and New Mexico HPV Pap Registry housed by University of New Mexico (UNM-NMHPVPR). Across these diverse healthcare settings, we collected data on human papillomavirus (HPV) vaccinations, screening tests/results, diagnostic and treatment procedures/results, and cancer diagnoses on nearly 4.7 million women aged 18-89 years from 2010 to 2014. We calculated baseline (2012 for UNM-NMHPVPR; 2010 for other sites) frequencies for sociodemographics, cervical cancer risk factors, and key screening process measures for each site's cohort. Healthcare delivery settings, cervical cancer screening strategy, Ethnic group/ethnicity, and insurance status varied among sites. The proportion of women receiving a Pap test during the baseline year was similar across sites (26.1-36.1%). Most high-risk HPV tests were performed either reflexively or as co-tests, and utilization pattern varied by site. Prevalence of colposcopy or biopsy was higher at Parkland-UTSW (3.6%) than other sites (1.3-1.4%). Incident cervical cancer was rare. HPV vaccination among age-eligible women not already immunized was modest across sites (0.1-7.2%). Cervical PROSPR I makes available high-quality, multilevel, longitudinal screening process data from a large and diverse cohort of women to evaluate and improve the effectiveness of US cervical cancer screening delivery. This article is protected by copyright. All rights reserved.}, }
@article {pmid30352968, year = {2018}, author = {Wang, Y and Savage, SA and Alsaggaf, R and Aubert, G and Dagnall, CL and Spellman, SR and Lee, SJ and Hicks, B and Jones, K and Katki, HA and Gadalla, SM}, title = {Telomere Length Calibration from qPCR Measurement: Limitations of Current Method.}, journal = {Cells}, volume = {7}, number = {11}, pages = {}, doi = {10.3390/cells7110183}, pmid = {30352968}, issn = {2073-4409}, support = {The Intramural Research Program of the Division of Cancer Epidemiology and Genetics//National Cancer Institute, National Institutes of Health/ ; 5U24CA076518//National Cancer Institute, National Heart, Lung and Blood Institute and National Institute of Allergy and Infectious Diseases/ ; 4U10HL069294//National Heart, Lung and Blood Institute and National Cancer Institute/ ; HHSH250201200018C//Health Resources and Services Administration (HRSA/DHHS)/ ; N00014-17-1-2388//The Office of Naval Research/ ; N0014-17-1-2850//The Office of Naval Research/ ; }, abstract = {Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). We developed a linear regression equation to predict TL from qPCR T/S using flow cytometry with fluorescence in situ hybridization (flow FISH) TL data from 181 healthy donors (age range = 19⁻53) from the National Marrow Donor Program (NMDP) biorepository. TL measurements by qPCR and flow FISH were modestly correlated (R² = 0.56, p < 0.0001). In Bland-Altman analyses, individuals with the shortest (≤10th percentile) or longest (≥90th) flow FISH TL had an over- or under-estimated qPCR TL (bias = 0.89 and -0.77 kb, respectively). Comparisons of calculated TL from the NMDP samples and 1810 age- and sex-matched individuals from the National Health and Nutrition Examination Survey showed significant differences (median = 7.1 versus 5.8 kb, respectively, p < 0.0001). Differences in annual TL attrition were also noted (31 versus 13 bp/year, respectively, p = 0.02). Our results demonstrate that TL calculated in kb from qPCR T/S may yield biased estimates for individuals with the shortest or longest TL, those often of high clinical interest. We also showed that calculated TL in kb from qPCR data are not comparable across populations and therefore are not necessarily useful.}, }
@article {pmid30352818, year = {2018}, author = {Adams, C and Richmond, RC and Santos Ferreira, DL and Spiller, W and Tan, VY and Zheng, J and Wurtz, P and Donovan, JL and Hamdy, FC and Neal, DE and Lane, JA and Davey Smith, G and Relton, CL and Eeles, RA and Henderson, BE and Haiman, CA and Kote-Jarai, Z and Schumacher, FR and Amin Al Olama, A and Benlloch, S and Muir, K and Berndt, SI and Conti, DV and Wiklund, F and Chanock, SJ and Gapstur, SM and Stevens, VL and Tangen, CM and Batra, J and Clements, JA and Grönberg, H and Pashayan, N and Schleutker, J and Albanes, D and Wolk, A and West, CML and Mucci, LA and Cancel-Tassin, G and Koutros, S and Sørensen, KD and Maehle, L and Travis, RC and Hamilton, R and Ingles, SA and Rosenstein, BS and Lu, YJ and Giles, GG and Kibel, AS and Vega, A 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 John, EM and Teixeira, MR and Neuhausen, SL and DeRuyck, K and Razack, A and Newcomb, LF and Lessel, D and Kaneva, RP and Usmani, N and Claessens, F and Townsend, P and Gago Dominguez, M and Roobol, MJ and Menegaux, F and Khaw, KT and Cannon-Albright, LA and Pandha, H and Thibodeau, SN and Martin, RM}, title = {Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.}, journal = {Cancer epidemiology, biomarkers & 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-18-0079}, pmid = {30352818}, issn = {1538-7755}, abstract = {BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).
MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.
RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.
CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.
IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.}, }
@article {pmid30351998, year = {2018}, author = {Walterhouse, DO and Barkauskas, DA and Hall, D and Ferrari, A and De Salvo, GL and Koscielniak, E and Stevens, MCG and Martelli, H and Seitz, G and Rodeberg, DA and Shnorhavorian, M and Dasgupta, R and Breneman, JC and Anderson, JR and Bergeron, C and Bisogno, G and Meyer, WH and Hawkins, DS and Minard-Colin, V}, title = {Demographic and Treatment Variables Influencing Outcome for Localized Paratesticular Rhabdomyosarcoma: Results From a Pooled Analysis of North American and European Cooperative Groups.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2018789388}, doi = {10.1200/JCO.2018.78.9388}, pmid = {30351998}, issn = {1527-7755}, abstract = {PURPOSE: Treatment recommendations for localized paratesticular rhabdomyosarcoma (PT RMS) differ in North America and Europe. We conducted a pooled analysis to identify demographic features and treatment choices that affect outcome.
PATIENTS AND METHODS: We retrospectively analyzed the effect of nine demographic variables and four treatment choices on event-free survival (EFS) and overall survival (OS) from 12 studies conducted by five cooperative groups.
RESULTS: Eight hundred forty-two patients with localized PT RMS who enrolled from 1988 to 2013 were included. Patients age ≥ 10 years were more likely than younger patients to have tumors that were > 5 cm, enlarged nodes (N1), or pathologically involved nodes (P ≤ .05 each). With a median follow-up of 7.5 years, Kaplan-Meier estimates for 5-year EFS and OS were 87.7% and 94.8%, respectively. Of demographic variables, cooperative group, era of enrollment, age category, tumor size, Intergroup Rhabdomyosarcoma Study group, and T stage affected EFS (P ≤ .05 each). Surgical assessment of regional nodes, which was performed in 23.5% of patients-usually in those age ≥ 10 years or with suspicious or N1 nodes-was the only treatment variable associated with EFS by univariable and multivariable analyses (P ≤ .05 each) in patients age ≥ 1 year. A variable selection procedure on a proportional hazards regression model selected era of enrollment, age, tumor size, and surgical assessment of regional nodes as significant (P ≤ .05 each) in the EFS model, and era of enrollment, age, tumor size, and histology (P ≤ .05 each) in the OS model.
CONCLUSION: Localized PT RMS has a favorable prognosis. Age ≥ 10 years at diagnosis and tumor size larger than 5 cm are unfavorable prognostic features. Surgical assessment of regional nodes is important in patients age ≥ 10 years and in those with N1 nodes as it affects EFS.}, }
@article {pmid30351457, year = {2018}, author = {Malempati, S and Weigel, BJ and Chi, YY and Tian, J and Anderson, JR and Parham, DM and Teot, LA and Rodeberg, DA and Yock, TI and Shulkin, BL and Spunt, SL and Meyer, WH and Hawkins, DS}, title = {The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31770}, pmid = {30351457}, issn = {1097-0142}, support = {//St. Baldrick's Foundation/ ; U10 CA098413/CA/NCI NIH HHS/United States ; U10CA180886//National Cancer Institute/ ; U10CA0981413//National Cancer Institute/ ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10CA180899//National Cancer Institute/ ; U10CA098543//National Cancer Institute/ ; }, abstract = {BACKGROUND: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone.
METHODS: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites.
RESULTS: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide.
CONCLUSIONS: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.}, }
@article {pmid30350734, year = {2018}, author = {Laetsch, TW and Hawkins, DS}, title = {Larotrectinib for the treatment of TRK fusion solid tumors.}, journal = {Expert review of anticancer therapy}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/14737140.2019.1538796}, pmid = {30350734}, issn = {1744-8328}, abstract = {INTRODUCTION: TRK fusions occur across a wide range of cancers in children and adults. These fusions drive constitutive expression and ligand-independent activation of the TRK kinase and are oncogenic. Larotrectinib is the first highly potent and selective small molecule ATP competitive inhibitor of all three TRK kinases to enter clinical development. Areas covered: This review covers the current preclinical and clinical evidence for TRK inhibitors for TRK fusion cancers, focusing on larotrectinib. Expert commentary: Larotrectinib has demonstrated a remarkable 75% centrally confirmed objective response rate in patients with TRK fusion cancers in phase 1 and phase 2 clinical trials with generally mild side effects. Responses appear independent of the patient's age, underlying histology, and specific fusion partner and are durable in many patients. Larotrectinib is likely to be the first FDA-approved histology-agnostic molecularly targeted therapy. The evolving role of molecular profiling of advanced cancers is discussed.}, }
@article {pmid30349086, year = {2018}, author = {Brabetz, S and Leary, SES and Gröbner, SN and Nakamoto, MW and Şeker-Cin, H and Girard, EJ and Cole, B and Strand, AD and Bloom, KL and Hovestadt, V and Mack, NL and Pakiam, F and Schwalm, B and Korshunov, A and Balasubramanian, GP and Northcott, PA and Pedro, KD and Dey, J and Hansen, S and Ditzler, S and Lichter, P and Chavez, L and Jones, DTW and Koster, J and Pfister, SM and Kool, M and Olson, JM}, title = {A biobank of patient-derived pediatric brain tumor models.}, journal = {Nature medicine}, volume = {24}, number = {11}, pages = {1752-1761}, doi = {10.1038/s41591-018-0207-3}, pmid = {30349086}, issn = {1546-170X}, abstract = {Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.}, }
@article {pmid30349062, year = {2018}, author = {Han, YJ and Boatman, SM and Zhang, J and Du, XC and Yeh, AC and Zheng, Y and Mueller, J and Olopade, OI}, title = {LncRNA BLAT1 is Upregulated in Basal-like Breast Cancer through Epigenetic Modifications.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {15572}, doi = {10.1038/s41598-018-33629-y}, pmid = {30349062}, issn = {2045-2322}, abstract = {Long-noncoding RNAs (lncRNAs) have been shown to participate in oncogenesis across a variety of cancers and may represent novel therapeutic targets. However, little is known about the role of lncRNAs in basal-like breast cancer (BLBC), the aggressive form of breast cancer with no molecularly defined therapeutic target. To examine whether altered lncRNA expression contributes to the aggressive phenotype characteristic of BLBC, we performed a comparative analysis of BLBC versus non-BLBC using microarray profiling and RNA sequencing of primary breast cancer. We identified RP11-19E11.1 as a significantly up-regulated lncRNA in BLBC tumors and named it Basal-Like breast cancer Associated Transcript 1 (BLAT1). Analysis of pan-cancer datasets showed the highest expression of BLAT1 in BLBC tumors compared to all other cancers. Depletion of BLAT1 in breast cancer cells led to significantly increased apoptosis, partly because of accumulation of DNA damage. Mechanistically, BLAT1 expression is regulated at the epigenetic level via DNA methylation at CpG islands in the promoter. Concordantly, patients harboring tumors with BLAT1 hypomethylation showed decreased overall survival. Our results suggest that increased expression of BLAT1 via CpG site hypomethylation may contribute to the aggressive phenotype of BLBC, raising a possibility of new biomarkers for prognosis of aggressive BLBC tumors.}, }
@article {pmid30348809, year = {2018}, author = {Spiciarich, DR and Oh, ST and Foley, A and Hughes, SB and Mauro, MJ and Abdel-Wahab, O and Press, RD and Viner, R and Thompson, SL and Chen, Q and Azadi, P and Bertozzi, CR and Maxson, JE}, title = {A novel germline variant in CSF3R reduces N-glycosylation and exerts potent oncogenic effects in leukemia.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-18-1638}, pmid = {30348809}, issn = {1538-7445}, support = {R00 CA190605/CA/NCI NIH HHS/United States ; R01 CA200423/CA/NCI NIH HHS/United States ; S10 OD018530/OD/NIH HHS/United States ; U01 CA207702/CA/NCI NIH HHS/United States ; }, abstract = {Mutations in the colony stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as AML. Here we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation.}, }
@article {pmid30348531, year = {2018}, author = {Harris, WP and Wong, KM and Saha, S and Dika, IE and Abou-Alfa, GK}, title = {Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers.}, journal = {Seminars in oncology}, volume = {45}, number = {3}, pages = {116-123}, doi = {10.1053/j.seminoncol.2018.03.002}, pmid = {30348531}, issn = {1532-8708}, abstract = {The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.}, }
@article {pmid30345065, year = {2018}, author = {Langer, SL and Soltero, EG and Beresford, SA and McGregor, BA and Albano, DL and Patrick, DL and Bowen, DJ}, title = {Socioeconomic status differences in food consumption following a laboratory-induced stressor.}, journal = {Health psychology open}, volume = {5}, number = {2}, pages = {2055102918804664}, doi = {10.1177/2055102918804664}, pmid = {30345065}, issn = {2055-1029}, support = {R01 DK079042/DK/NIDDK NIH HHS/United States ; }, abstract = {We examined food consumption in response to a laboratory-induced stressor (two challenging neuropsychological tasks) among non-Hispanic White women categorized as lower or higher in socioeconomic status based on education. The two socioeconomic status groups did not differ with respect to current hunger or baseline dietary habits. Perceived stress was measured pre- and post-challenge. Snacks were offered post-challenge; food consumption was measured by weighing snack bowls pre- and post-offering. Perceived stress increased pre- to post-challenge for both groups, but this effect was stronger for women lower in socioeconomic status. In addition, women lower versus higher in socioeconomic status consumed more food overall and more high-fat sweet food in particular (large effect sizes). These findings provide evidence of socioeconomic status differences in food consumption following an acute stressor.}, }
@article {pmid30344357, year = {2018}, author = {Dinh, V and Tung Ho, LS and Suchard, MA and Matsen, FA}, title = {Consistency and convergence rate of phylogenetic inference via regularization.}, journal = {Annals of statistics}, volume = {46}, number = {4}, pages = {1481-1512}, doi = {10.1214/17-AOS1592}, pmid = {30344357}, issn = {0090-5364}, support = {R01 AI107034/AI/NIAID NIH HHS/United States ; U54 GM111274/GM/NIGMS NIH HHS/United States ; }, abstract = {It is common in phylogenetics to have some, perhaps partial, information about the overall evolutionary tree of a group of organisms and wish to find an evolutionary tree of a specific gene for those organisms. There may not be enough information in the gene sequences alone to accurately reconstruct the correct "gene tree." Although the gene tree may deviate from the "species tree" due to a variety of genetic processes, in the absence of evidence to the contrary it is parsimonious to assume that they agree. A common statistical approach in these situations is to develop a likelihood penalty to incorporate such additional information. Recent studies using simulation and empirical data suggest that a likelihood penalty quantifying concordance with a species tree can significantly improve the accuracy of gene tree reconstruction compared to using sequence data alone. However, the consistency of such an approach has not yet been established, nor have convergence rates been bounded. Because phylogenetics is a non-standard inference problem, the standard theory does not apply. In this paper, we propose a penalized maximum likelihood estimator for gene tree reconstruction, where the penalty is the square of the Billera-Holmes-Vogtmann geodesic distance from the gene tree to the species tree. We prove that this method is consistent, and derive its convergence rate for estimating the discrete gene tree structure and continuous edge lengths (representing the amount of evolution that has occurred on that branch) simultaneously. We find that the regularized estimator is "adaptive fast converging," meaning that it can reconstruct all edges of length greater than any given threshold from gene sequences of polynomial length. Our method does not require the species tree to be known exactly; in fact, our asymptotic theory holds for any such guide tree.}, }
@article {pmid30344013, year = {2018}, author = {Xu, X and Bryke, C and Sukhanova, M and Huxley, E and Dash, DP and Dixon-Mciver, A and Fang, M and Griepp, PT and Hodge, JC and Iqbal, A and Jeffries, S and Kanagal-Shamanna, R and Quintero-Rivera, F and Shetty, S and Slovak, ML and Yenamandra, A and Lennon, PA and Raca, G}, title = {Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group.}, journal = {Cancer genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cancergen.2018.07.005}, pmid = {30344013}, issn = {2210-7762}, abstract = {Structural genomic abnormalities, including balanced chromosomal rearrangements, copy number gains and losses and copy-neutral loss-of-heterozygosity (CN-LOH) represent an important category of diagnostic, prognostic and therapeutic markers in acute myeloid leukemia (AML). Genome-wide evaluation for copy number abnormalities (CNAs) is at present performed by karyotype analysis which has low resolution and is unobtainable in a subset of cases. Furthermore, examination for possible CN-LOH in leukemia cells is at present not routinely performed in the clinical setting. Chromosomal microarray (CMA) analysis is a widely available assay for CNAs and CN-LOH in diagnostic laboratories, but there are currently no guidelines how to best incorporate this technology into clinical testing algorithms for neoplastic diseases including AML. The Cancer Genomics Consortium Working Group for Myeloid Neoplasms performed an extensive review of peer-reviewed publications focused on CMA analysis in AML. Here we summarize evidence regarding clinical utility of CMA analysis in AML extracted from published data, and provide recommendations for optimal utilization of CMA testing in the diagnostic workup. In addition, we provide a list of CNAs and CN-LOH regions which have documented clinical significance in diagnosis, prognosis and treatment decisions in AML.}, }
@article {pmid30343628, year = {2018}, author = {Carmona, JJ and Barfield, RT and Panni, T and Nwanaji-Enwerem, JC and Just, AC and Hutchinson, JN and Colicino, E and Karrasch, S and Wahl, S and Kunze, S and Jafari, N and Zheng, Y and Hou, L and DeMeo, DL and Litonjua, AA and Vokonas, PS and Peters, A and Lin, X and Schwartz, J and Schulz, H and Baccarelli, AA}, title = {Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts.}, journal = {Epigenetics}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/15592294.2018.1529849}, pmid = {30343628}, issn = {1559-2308}, abstract = {DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV1, FEF25-75%) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.}, }
@article {pmid30343422, year = {2018}, author = {Lipira, L and Williams, EC and Huh, D and Kemp, CG and Nevin, PE and Greene, P and Unger, JM and Heagerty, P and French, AL and Cohn, SE and Turan, JM and Mugavero, MJ and Simoni, JM and Andrasik, MP and Rao, D}, title = {HIV-Related Stigma and Viral Suppression Among African-American Women: Exploring the Mediating Roles of Depression and ART Nonadherence.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10461-018-2301-4}, pmid = {30343422}, issn = {1573-3254}, support = {R01-MH98675//National Institute of Mental Health/ ; T32 HS013853-13//Agency for Healthcare Research and Quality/ ; CDA 12-276//Health Services Research and Development/ ; }, abstract = {We used baseline data from a sample of African-American women living with HIV who were recruited to participate in a stigma-reduction intervention in Chicago and Birmingham (2013-2015) to (1) evaluate the relationship between HIV-related stigma and viral suppression, and (2) assess the role of depression and nonadherence to antiretroviral therapy (ART) as mediators. Data from women were included in this secondary analysis if they were on ART, had viral load data collected within 8-weeks of study entry and had complete covariate data. We used logistic regression to estimate the total effect of HIV-related stigma (14-item Stigma Scale for Chronic Illness) on viral suppression (< 200 copies/mL), and serial mediation analysis to estimate indirect effects mediated by depressive symptoms (8-item Patient Health Questionnaire) and ART nonadherence (number of days with missed doses). Among 100 women who met study inclusion criteria, 95% reported some level of HIV-related stigma. In adjusted models, higher levels of HIV-related stigma were associated with lower odds of being virally suppressed (AOR = 0.93, 95% CI = 0.89-0.98). In mediation analysis, indirect effects through depression and ART nonadherence were not significant. Findings suggest that HIV-related stigma is common among African-American women living with HIV, and those who experience higher levels of stigma are less likely to be virally suppressed. However, the mechanisms remain unclear.}, }
@article {pmid30340143, year = {2018}, author = {Heffner, JL and Mull, KE and Watson, NL and McClure, JB and Bricker, JB}, title = {Smokers with bipolar disorder, other affective disorders, and no mental health conditions: Comparison of baseline characteristics and success at quitting in a large 12-month behavioral intervention randomized trial.}, journal = {Drug and alcohol dependence}, volume = {193}, number = {}, pages = {35-41}, doi = {10.1016/j.drugalcdep.2018.08.034}, pmid = {30340143}, issn = {1879-0046}, support = {R01 CA166646/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The extent to which smokers with bipolar disorder (BD) differ from other smokers on cessation-related characteristics and outcomes is unknown and could improve knowledge of treatment needs for this group. These analyses compared smokers with BD versus smokers with other affective disorders (ADs; anxiety and unipolar depression) and smokers with no mental health conditions (MHCs).
METHOD: Participants (n = 2570) were a subsample of those enrolled in a smoking cessation trial comparing two web-delivered intervention approaches: acceptance and commitment therapy (ACT) and cognitive behavioral therapy. Those included in this analysis self-reported having BD (n = 221), other ADs (n = 783) or no major MHCs (n = 1566). Surveys assessed baseline characteristics and self-reported abstinence at 3, 6, and 12-months post-randomization. Treatment utilization was tracked via page views.
RESULTS: Smokers with BD were distinct from both AD and no MHC smokers on the majority of baseline characteristics. At 12-months, quit rates were lower for smokers with BD (20%) than no MHCs (29%; p = 0.01), but no different than other ADs (20%; p = .467). Interactions between treatment assignment and diagnostic group were non-significant for cessation outcome. The number of logins was higher for smokers with BD than AD in the ACT arm only (p = .001), but this finding was not replicated across other utilization indicators.
CONCLUSIONS: Smokers with BD and other ADs had similar long-term quit rates despite numerous differences in baseline characteristics. Despite being lower than for smokers without MHCs, long-term quit rates from web-based treatment are promising for smokers with BD as well as other ADs.}, }
@article {pmid30337342, year = {2018}, author = {Mariotto, AB and Zou, Z and Zhang, F and Howlader, N and Kurian, AW and Etzioni, R}, title = {Can We Use Survival Data from Cancer Registries to Learn about Disease Recurrence? The Case of Breast Cancer.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {27}, number = {11}, pages = {1332-1341}, doi = {10.1158/1055-9965.EPI-17-1129}, pmid = {30337342}, issn = {1538-7755}, abstract = {Background: Population-representative risks of metastatic recurrence are not generally available because cancer registries do not collect data on recurrence. This article presents a novel method that estimates the risk of recurrence using cancer registry disease-specific survival.Methods: The method is based on an illness-death process coupled with a mixture cure model for net cancer survival. The risk of recurrence is inferred from the estimated survival among the noncured fraction and published data on survival after recurrence. We apply the method to disease-specific survival curves from female breast cancer cases without a prior cancer diagnosis and with complete stage and hormone receptor (HR) status in Surveillance, Epidemiology and End Results registries (1992-2013).Results: The risk of recurrence is higher for women diagnosed with breast cancer at older age, earlier period, more advanced stage, and HR-negative tumors. For women diagnosed at ages 60-74 in 2000-2013, the projected percent recurring within 5 years is 2.5%, 9.6%, and 34.5% for stages I, II, and III HR-positive, and 6.5%, 20.2%, and 48.5% for stages I, II, and III HR-negative tumors. Although HR-positive cases have lower risk of recurrence soon after diagnosis, their risk persists longer than for HR-negative cases. Results show a high degree of robustness to model assumptions.Conclusions: The results show that it is possible to extract information about the risk of recurrence using disease-specific survival, and the methods can in principle be extended to other cancer sites.Impact: This study provides the first population-based summaries of the risk of breast cancer recurrence in U.S. women. Cancer Epidemiol Biomarkers Prev; 27(11); 1332-41. ©2018 AACR.}, }
@article {pmid30336937, year = {2018}, author = {Looney, MR and Headley, MB}, title = {Live imaging of the pulmonary immune environment.}, journal = {Cellular immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cellimm.2018.09.007}, pmid = {30336937}, issn = {1090-2163}, support = {R01 AI125445/AI/NIAID NIH HHS/United States ; R01 HL107386/HL/NHLBI NIH HHS/United States ; }, abstract = {The lung represents a unique immune environment. The primary function of the lung is to enable gas exchange by facilitating the transfer of oxygen into and carbon dioxide out of the blood. However, as a direct byproduct of this process the lung is also constantly exposed to particles, allergens, and pathogens alongside air itself. Due to this, the pulmonary immune system exists in a fine balance between quiescence and inflammation, deviations from which can lead to a failure in respiratory function. A rich history exists attempting to define the critical features of lung immunity, and most recently advances in intravital microscopy have enabled the visualization of intercellular immune dynamics in both steady-state and a variety of disease conditions. In this review, we will summarize a variety of approaches to intravital lung imaging as well as how its application has advanced our understanding of normal lung function as well as disease states such as pulmonary metastasis, asthma, and lung injury.}, }
@article {pmid30336778, year = {2018}, author = {Sun, K and Zhang, Q and Pastore-Piontti, A and Chinazzi, M and Mistry, D and Dean, NE and Rojas, DP and Merler, S and Poletti, P and Rossi, L and Halloran, ME and Longini, IM and Vespignani, A}, title = {Quantifying the risk of local Zika virus transmission in the contiguous US during the 2015-2016 ZIKV epidemic.}, journal = {BMC medicine}, volume = {16}, number = {1}, pages = {195}, doi = {10.1186/s12916-018-1185-5}, pmid = {30336778}, issn = {1741-7015}, support = {U54 GM111274/GM/NIGMS NIH HHS/United States ; U54GM111274//National Institutes of Health/ ; R01 AI102939-05//National Institutes of Health/ ; }, abstract = {BACKGROUND: Local mosquito-borne Zika virus (ZIKV) transmission has been reported in two counties in the contiguous United States (US), prompting the issuance of travel, prevention, and testing guidance across the contiguous US. Large uncertainty, however, surrounds the quantification of the actual risk of ZIKV introduction and autochthonous transmission across different areas of the US.
METHODS: We present a framework for the projection of ZIKV autochthonous transmission in the contiguous US during the 2015-2016 epidemic using a data-driven stochastic and spatial epidemic model accounting for seasonal, environmental, and detailed population data. The model generates an ensemble of travel-related case counts and simulates their potential to have triggered local transmission at the individual level in the 2015-2016 ZIKV epidemic.
RESULTS: We estimate the risk of ZIKV introduction and local transmission at the county level and at the 0.025° × 0.025° cell level across the contiguous US. We provide a risk measure based on the probability of observing local transmission in a specific location during a ZIKV epidemic modeled after the epidemic observed during the years 2015-2016. The high spatial and temporal resolution of the model allows us to generate statistical estimates of the number of ZIKV introductions leading to local transmission in each location. We find that the risk was spatially heterogeneously distributed and concentrated in a few specific areas that account for less than 1% of the contiguous US population. Locations in Texas and Florida that have actually experienced local ZIKV transmission were among the places at highest risk according to our results. We also provide an analysis of the key determinants for local transmission and identify the key introduction routes and their contributions to ZIKV transmission in the contiguous US.
CONCLUSIONS: This framework provides quantitative risk estimates, fully captures the stochasticity of ZIKV introduction events, and is not biased by the under-ascertainment of cases due to asymptomatic cases. It provides general information on key risk determinants and data with potential uses in defining public health recommendations and guidance about ZIKV risk in the US.}, }
@article {pmid30336747, year = {2018}, author = {Cranston, RD and Carballo-Diéguez, A and Gundacker, H and Richardson, BA and Giguere, R and Dolezal, C and Siegel, A and KunjaraNaAyudhya, RP and Gomez, K and Piper, JM and Lama, JR and McGowan, I and , }, title = {Prevalence and determinants of anal human papillomavirus infection in men who have sex with men and transgender women.}, journal = {International journal of STD & AIDS}, volume = {}, number = {}, pages = {956462418797864}, doi = {10.1177/0956462418797864}, pmid = {30336747}, issn = {1758-1052}, abstract = {Human papillomavirus (HPV) prevalence varies by population. This study investigated anal HPV type detection risk by country in a population of men who have sex with men (MSM) and transgender women (TW) at risk of HIV. Sexually active HIV-1-uninfected MSM and TW were enrolled at eight sites: four in the United States (US), two in Thailand, one in Peru, and one in South Africa. Baseline anal HPV swabs were collected, and DNA typing was performed. One hundred and ninety-five participants, 76 (42%) from the US, had a mean age of 30.9 years (range 18-64). In 182 participants with results available, anal HPV infection was common with 169 (93%) with ≥1 type, 132 (73%) with ≥1 nine-valent vaccine types, and 66 (36%) with HPV 16. Participants in the US had a higher prevalence of HPV 16 (56%, p = 0.004) and HPV 6 (69%, p < 0.001) compared to the other regions. Stimulant drug use was significantly associated with HPV 6 detection. Anal HPV is highly prevalent in this population of MSM and TW sampled from four countries, with HPV 16 the most commonly detected type. The nine-valent HPV vaccine has the potential to provide significant protection if given prior to exposure.}, }
@article {pmid30335787, year = {2018}, author = {Li, Y and Hamlin, DK and Chyan, MK and Wong, R and Dorman, EF and Emery, RC and Woodle, DR and Manger, RL and Nartea, M and Kenoyer, AL and Orozco, JJ and Green, DJ and Press, OW and Storb, R and Sandmaier, BM and Wilbur, DS}, title = {cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies.}, journal = {PloS one}, volume = {13}, number = {10}, pages = {e0205135}, doi = {10.1371/journal.pone.0205135}, pmid = {30335787}, issn = {1932-6203}, support = {P01 HL122173/HL/NHLBI NIH HHS/United States ; R33 AI116225/AI/NIAID NIH HHS/United States ; R01 CA205248/CA/NCI NIH HHS/United States ; R21 AI116225/AI/NIAID NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; }, abstract = {The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(211At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, 211At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of 211At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [211At]NaAt, and (5) 211At-BC8-B10. The 211At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [211At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the 211At using a "wet chemistry" method. The clinical product, 211At-BC8-B10, was prepared by reacting [211At]NaAt with BC8-B10 in NH4OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the 211At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the 211At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive 211At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver 211At-BC8-B10 to a patient. These cGMP preparations provided 0.80-1.28 Gbq (21.5-34.5 mCi) of 211At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level <0.50 EU/mL. Cell binding was retained by the 211At-BC8-B10. 211At-BC8-B10 in ascorbic acid solution demonstrated a radiochemical stability of >95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of 211At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using 211At-BC8-B10 (NCT03128034).}, }
@article {pmid30335223, year = {2018}, author = {Galvin, A and Weglarz, M and Folz-Donahue, K and Handley, M and Baum, M and Mazzola, M and Litwa, H and Scadden, DT and Silberstein, L}, title = {Cell Cycle Analysis of Hematopoietic Stem and Progenitor Cells by Multicolor Flow Cytometry.}, journal = {Current protocols in cytometry}, volume = {}, number = {}, pages = {e50}, doi = {10.1002/cpcy.50}, pmid = {30335223}, issn = {1934-9300}, support = {//Fred Hutchinson Cancer Research Center/ ; //Leukemia and Lymphoma Society/ ; //Fred Hutch Career Development Fund/ ; R01CA194596//National Cancer Institute/ ; }, abstract = {Maintenance of hematopoietic stem cell (HSC) quiescence is critical for self-renewal and differentiation into mature lineages. Therefore, the ability to reliably detect abnormal HSC cycling is essential for experiments that seek to investigate abnormalities of HSC function. The ability to reproducibly evaluate cell cycle status in a rare cell subset requires careful optimization of multiple parameters during cell preparation and sample processing. Here, we describe a method where data acquisition parameters and fluorochrome combination for long-term HSC staining have been specifically designed for concurrent use with DAPI and Ki-67 antibodies. © 2018 by John Wiley & Sons, Inc.}, }
@article {pmid30334814, year = {2018}, author = {Sharp, A and Coleman, I and Yuan, W and Sprenger, C and Dolling, D and Nava Rodrigues, D and Russo, JW and Figueiredo, I and Bertan, C and Seed, G and Riisnaes, R and Uo, T and Neeb, A and Welti, J and Morrissey, C and Carreira, S and Luo, J and Nelson, PS and Balk, SP and True, LD and de Bono, JS and Plymate, SR}, title = {Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI122819}, pmid = {30334814}, issn = {1558-8238}, abstract = {BACKGROUND: Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue.
METHODS: Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full-length androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined.
RESULTS: We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of AR-V7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100% vs. 54%, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy).
CONCLUSION: This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm its clinical significance of AR-V7.
FUNDING: Work at the University of Washington and in the Plymate and Nelson laboratories is supported by the Department of Defense Prostate Cancer Research Program (W81XWH-14-2-0183, W81XWH-12-PCRP-TIA, W81XWH-15-1-0430, and W81XWH-13-2-0070), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the Institute for Prostate Cancer Research, the Veterans Affairs Research Program, the NIH/National Cancer Institute (P01CA163227), and the Prostate Cancer Foundation. Work in the de Bono laboratory was supported by funding from the Movember Foundation/Prostate Cancer UK (CEO13-2-002), the US Department of Defense (W81XWH-13-2-0093), the Prostate Cancer Foundation (20131017 and 20131017-1), Stand Up To Cancer (SU2C-AACR-DT0712), Cancer Research UK (CRM108X-A25144), and the UK Department of Health through an Experimental Cancer Medicine Centre grant (ECMC-CRM064X).}, }
@article {pmid30334600, year = {2018}, author = {Wheeler, DP and Lucas, J and Wilton, L and Nelson, LE and Hucks-Ortiz, C and Watson, CC and Hutchinson, C and Mayer, KH and Kuo, I and Magnus, M and Beauchamp, G and Shoptaw, S and Emel, LM and Chen, YQ and Hightow-Weidman, L and Fields, SD}, title = {Building effective multilevel HIV prevention partnerships with Black men who have sex with men: experience from HPTN 073, a pre-exposure prophylaxis study in three US cities.}, journal = {Journal of the International AIDS Society}, volume = {21 Suppl 7}, number = {}, pages = {e25180}, doi = {10.1002/jia2.25180}, pmid = {30334600}, issn = {1758-2652}, support = {UM1AI068613//National Institutes of Health/ ; UM1AI068617//National Institutes of Health/ ; //U.S. Department of Health and Human Services/ ; P30 AI117970/AI/NIAID NIH HHS/United States ; //National Institute on Drug Abuse and the National Institute of Mental Health/ ; //National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068619//National Institutes of Health/ ; }, }
@article {pmid30334182, year = {2018}, author = {Crandall, CJ and Larson, J and LaCroix, A and Cauley, JA and LeBoff, MS and Li, W and LeBlanc, ES and Edwards, BJ and Manson, JE and Ensrud, K}, title = {Predicting Fracture Risk in Younger Postmenopausal Women: Comparison of the Garvan and FRAX Risk Calculators in the Women's Health Initiative Study.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11606-018-4696-z}, pmid = {30334182}, issn = {1525-1497}, abstract = {BACKGROUND: Guidelines recommend fracture risk assessment in postmenopausal women aged 50-64, but the optimal method is unknown.
OBJECTIVES: To compare discrimination and calibration of the Fracture Risk Assessment Tool (FRAX) and Garvan fracture risk calculator for predicting fractures in postmenopausal women aged 50-64 at baseline.
DESIGN: Prospective observational study.
PARTICIPANTS: Sixty-three thousand seven hundred twenty-three postmenopausal women aged 50-64 years participating in the Women's Health Initiative Observational Study and Clinical Trials.
MAIN MEASURES: Incident hip fractures and major osteoporotic fractures (MOF) during 10-year follow-up. Calculated FRAX- and Garvan-predicted hip fracture and MOF fracture probabilities.
KEY RESULTS: The observed 10-year hip fracture probability was 0.3% for women aged 50-54 years (n = 14,768), 0.6% for women aged 55-59 years (n = 22,442), and 1.1% for women aged 60-64 years (n = 25,513). At sensitivity thresholds ≥ 80%, specificity of both tools for detecting incident hip fracture during 10 years of follow-up was low: Garvan 30.6% (95% confidence interval [CI] 30.3-31.0%) and FRAX 43.1% (95% CI 42.7-43.5%). At maximal area under the receiver operating characteristic curve (AUC(c), 0.58 for Garvan, 0.65 for FRAX), sensitivity was 16.0% (95% CI 12.7-19.4%) for Garvan and 59.2% (95% CI 54.7-63.7%) for FRAX. At AUC(c) values, sensitivity was lower in African American and Hispanic women than among white women and lower in women aged 50-54 than those 60-64 years old. Observed hip fracture probabilities were similar to FRAX-predicted probabilities but greater than Garvan-predicted probabilities. At AUC(c) values (0.56 for both tools), sensitivity for identifying MOF was also low (range 26.7-46.8%). At AUC(c) values (0.55 for both tools), sensitivity for identifying any clinical fracture ranged from 18.1 to 34.0%.
CONCLUSIONS: In postmenopausal women aged 50-64 years, the FRAX and Garvan fracture risk calculator discriminate poorly between women who do and do not experience fracture during 10-year follow-up. There is no useful threshold for either tool.}, }
@article {pmid30334014, year = {2017}, author = {Twardowski, PW and Tangen, CM and Wu, X and Plets, MR and Plimack, ER and Agarwal, N and Vogelzang, NJ and Wang, J and Tao, S and Thompson, IM and Lara, P}, title = {Parallel (Randomized) Phase II Evaluation of Tivantinib (ARQ197) and Tivantinib in Combination with Erlotinib in Papillary Renal Cell Carcinoma: SWOG S1107.}, journal = {Kidney cancer}, volume = {1}, number = {2}, pages = {123-132}, doi = {10.3233/KCA-170018}, pmid = {30334014}, issn = {2468-4570}, abstract = {Background: Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC.
Methods: Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2). Target max accrual was 70 patients (35 per arm) with interim analysis planned after enrollment of 20 patients per arm.
Results: Six % of patients had type 1 pRCC, 42% had type 2, and 52% had no subtype assigned. The study was closed after the first stage when both arms yielded RR of 0%. Median progression free survival (PFS) was 2.0 and 3.9 months, and OS was 10.3 and 11.3 months in Arms 1 and 2 respectively. Treatment was well tolerated. Exome of tumor tissue from 16 patients were successfully sequenced using Agilent SureSelect probes. Only 1 of 16 samples harbored MET mutation. Other mutations associated primarily with type 2 pRCC were noted and included CDKN2A, PBRM1, SETD2, KDM6A, FAT1 and NF2.
Conclusions: Tivantinib - either alone or in combination with erlotinib has no clinical activity in patients with advanced pRCC. The S1107 cohort had a low proportion of patients with MET alterations. MET remains a reasonable therapeutic target in pRCC, but selection of patient subsets exhibiting MET activation may be required to better benefit from therapy with MET inhibitors.}, }
@article {pmid30333177, year = {2018}, author = {Lo, M and Zhu, J and Hansen, SG and Carroll, T and Farr Zuend, C and Nöel-Romas, L and Ma, ZM and Fritts, L and Huang, ML and Sun, S and Huang, Y and Koelle, D and Picker, LJ and Burgener, A and Corey, L and Miller, CJ}, title = {Acute infection and subsequent subclinical reactivation of herpes simplex virus-2 after vaginal inoculation of rhesus macaques.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {}, doi = {10.1128/JVI.01574-18}, pmid = {30333177}, issn = {1098-5514}, support = {R01 AI111780/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes simplex virus-2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study the host/HSV-2 interactions an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333 and/or G); total dose 1x107 pfu HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA was consistently shed in vaginal swabs for the first 7-14 days after each inoculation. Proteins associated with wound healing, innate immunity and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. Histologic evidence of acute herpesvirus pathology including: acantholysis in the squamous epithelium, ballooning degeneration of, and intranuclear inclusion bodies, in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (102-103 DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals albeit antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women, but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation.Importance Herpes simplex virus-2 (HSV-2) infects nearly 500 million persons globally with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus-1 (HIV-1) acquisition and this risk does not decline with the use of anti-herpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents require an animal model. We found that HSV-2 can infect RMs after vaginal inoculation, establish latency in the nervous system and spontaneously reactivate which mimics some of the key features of HSV-2 infection in women. Studying HSV-2 infected RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation.}, }
@article {pmid30333104, year = {2018}, author = {Lai, HT and de Oliveira Otto, MC and Lemaitre, RN and McKnight, B and Song, X and King, IB and Chaves, PH and Odden, MC and Newman, AB and Siscovick, DS and Mozaffarian, D}, title = {Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study.}, journal = {BMJ (Clinical research ed.)}, volume = {363}, number = {}, pages = {k4067}, doi = {10.1136/bmj.k4067}, pmid = {30333104}, issn = {1756-1833}, abstract = {OBJECTIVE: To determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing.
DESIGN: Prospective cohort study.
SETTING: Four communities in the United States (Cardiovascular Health Study) from 1992 to 2015.
PARTICIPANTS: 2622 adults with a mean (SD) age of 74.4 (4.8) and with successful healthy ageing at baseline in 1992-93.
EXPOSURE: Cumulative levels of plasma phospholipid n3-PUFAs were measured using gas chromatography in 1992-93, 1998-99, and 2005-06, expressed as percentage of total fatty acids, including α-linolenic acid from plants and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid from seafoood.
MAIN OUTCOME MEASURE: Healthy ageing defined as survival without chronic diseases (ie, cardiovascular disease, cancer, lung disease, and severe chronic kidney disease), the absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Events were centrally adjudicated or determined from medical records and diagnostic tests.
RESULTS: Higher levels of long chain n3-PUFAs were associated with an 18% lower risk (95% confidence interval 7% to 28%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15% (6% to 23%) and 16% (6% to 25%), respectively. α-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95% confidence interval 0.83 to 1.02).
CONCLUSIONS: In older adults, a higher cumulative level of serially measured circulating n3-PUFAs from seafood (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid), eicosapentaenoic acid, and docosapentaenoic acid (but not docosahexaenoic acid from seafood or α-linolenic acid from plants) was associated with a higher likelihood of healthy ageing. These findings support guidelines for increased dietary consumption of n3-PUFAs in older adults.}, }
@article {pmid30332400, year = {2018}, author = {Dhar, A and Davidsen, K and Matsen, FA and Minin, VN}, title = {Predicting B cell receptor substitution profiles using public repertoire data.}, journal = {PLoS computational biology}, volume = {14}, number = {10}, pages = {e1006388}, doi = {10.1371/journal.pcbi.1006388}, pmid = {30332400}, issn = {1553-7358}, support = {R01 AI120961/AI/NIAID NIH HHS/United States ; }, abstract = {B cells develop high affinity receptors during the course of affinity maturation, a cyclic process of mutation and selection. At the end of affinity maturation, a number of cells sharing the same ancestor (i.e. in the same "clonal family") are released from the germinal center; their amino acid frequency profile reflects the allowed and disallowed substitutions at each position. These clonal-family-specific frequency profiles, called "substitution profiles", are useful for studying the course of affinity maturation as well as for antibody engineering purposes. However, most often only a single sequence is recovered from each clonal family in a sequencing experiment, making it impossible to construct a clonal-family-specific substitution profile. Given the public release of many high-quality large B cell receptor datasets, one may ask whether it is possible to use such data in a prediction model for clonal-family-specific substitution profiles. In this paper, we present the method "Substitution Profiles Using Related Families" (SPURF), a penalized tensor regression framework that integrates information from a rich assemblage of datasets to predict the clonal-family-specific substitution profile for any single input sequence. Using this framework, we show that substitution profiles from similar clonal families can be leveraged together with simulated substitution profiles and germline gene sequence information to improve prediction. We fit this model on a large public dataset and validate the robustness of our approach on two external datasets. Furthermore, we provide a command-line tool in an open-source software package (https://github.com/krdav/SPURF) implementing these ideas and providing easy prediction using our pre-fit models.}, }
@article {pmid30332335, year = {2018}, author = {Hwang, EI and Kool, M and Burger, PC and Capper, D and Chavez, L and Brabetz, S and Williams-Hughes, C and Billups, C and Heier, L and Jaju, A and Michalski, J and Li, Y and Leary, S and Zhou, T and von Deimling, A and Jones, DTW and Fouladi, M and Pollack, IF and Gajjar, A and Packer, RJ and Pfister, SM and Olson, JM}, title = {Extensive Molecular and Clinical Heterogeneity in Patients With Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children's Oncology Group Randomized ACNS0332 Trial.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2017764720}, doi = {10.1200/JCO.2017.76.4720}, pmid = {30332335}, issn = {1527-7755}, support = {U10 CA180899/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Children with histologically diagnosed high-risk medulloblastoma, supratentorial primitive neuroectodermal tumor of the CNS (CNS-PNET), and pineoblastoma (PBL) have had poor survival despite intensive treatment. We included these patients in this Children's Oncology Group trial. Molecular profiling later revealed tumor heterogeneity that was not detectable at protocol inception. Enrollment of patients with CNS-PNET/PBL was subsequently discontinued, and outcomes for this part of the study are reported here.
PATIENTS AND METHODS: In this phase III, four-arm prospective trial, consenting children age 3-22 years with newly diagnosed CNS-PNET were randomly assigned (1:1) to receive carboplatin during radiation and/or adjuvant isotretinoin after standard intensive therapy. Primary outcome measure was event-free survival (EFS) in the intent-to-treat population. Molecular tumor classification was retrospectively completed using DNA methylation profiling.
RESULTS: Eighty-five participants with institutionally diagnosed CNS-PNETs/PBLs were enrolled. Of 60 patients with sufficient tissue, 31 were nonpineal in location, of which 22 (71%) represented tumors that were not intended for trial inclusion, including 18 high-grade gliomas (HGGs), two atypical teratoid rhabdoid tumors, and two ependymomas. Outcomes across tumor types were strikingly different. Patients with supratentorial embryonal tumors/PBLs exhibited 5-year EFS and overall survival of 62.8% (95% CI, 43.4% to 82.2%) and 78.5% (95% CI, 62.2% to 94.8%), respectively, whereas patients with molecularly classified HGG had EFS and overall survival of 5.6% (95% CI, 0% to 13.0%) and 12.0% (95% CI, 0% to 24.7%), respectively. Neither carboplatin, nor isotretinoin significantly altered outcomes for all patients. Survival for patients with HGG was similar to that of historic studies that avoid craniospinal irradiation and intensive chemotherapy.
CONCLUSION: For patients with CNS-PNET/PBL, prognosis is considerably better than previously assumed when molecularly confirmed HGGs are removed. Identification of molecular HGGs may spare affected children from unhelpful intensive treatment. This trial highlights the challenges of a histology-based diagnosis for pediatric brain tumors and indicates that molecular profiling should become a standard component of initial diagnosis.}, }
@article {pmid30329038, year = {2018}, author = {Papanicolaou, GA and Silveira, FP and Langston, AA and Pereira, MR and Avery, RK and Uknis, M and Wijatyk, A and Wu, J and Boeckh, M and Marty, FM and Villano, S}, title = {Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy706}, pmid = {30329038}, issn = {1537-6591}, abstract = {Background: Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.
Methods: Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).
Results: From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.
Conclusions: Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.
Clinical Trials Registration: NCT01611974.}, }
@article {pmid30328165, year = {2018}, author = {Estey, EH}, title = {Acute myeloid leukemia: 2019 update on risk-stratification and management.}, journal = {American journal of hematology}, volume = {93}, number = {10}, pages = {1267-1291}, doi = {10.1002/ajh.25214}, pmid = {30328165}, issn = {1096-8652}, abstract = {Outcome in patients with acute myeloid leukemia (AML) ranges from death within a few days of beginning treatment (treatment related mortality, TRM) to likely cure. The major reason patients are not cured is resistance to treatment, often manifested as relapse from remission, rather than, even in older patients, TRM, whose incidence is decreasing. Knowledge of the pre-treatment mutation status of various genes has improved our ability to assign initial treatment and, of particular importance, knowledge of whether patients ostensibly in remission have measurable residual disease should influence subsequent management. Several new drugs have been approved by the FDA and we discuss their role in treatment.}, }
@article {pmid30325864, year = {2018}, author = {Maitra, A and Sharma, A and Brand, RE and Van Den Eeden, SK and Fisher, WE and Hart, PA and Hughes, SJ and Mather, KJ and Pandol, SJ and Park, WG and Feng, Z and Serrano, J and Rinaudo, JAS and Srivastava, S and Chari, ST and , }, title = {A Prospective Study to Establish a New-Onset Diabetes Cohort: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.}, journal = {Pancreas}, volume = {47}, number = {10}, pages = {1244-1248}, doi = {10.1097/MPA.0000000000001169}, pmid = {30325864}, issn = {1536-4828}, abstract = {The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.}, }
@article {pmid30325862, year = {2018}, author = {Yadav, D and Park, WG and Fogel, EL and Li, L and Chari, ST and Feng, Z and Fisher, WE and Forsmark, CE and Jeon, CY and Habtezion, A and Hart, PA and Hughes, SJ and Othman, MO and Rinaudo, JAS and Pandol, SJ and Tirkes, T and Serrano, J and Srivastava, S and Van Den Eeden, SK and Whitcomb, DC and Topazian, M and Conwell, DL and , }, title = {PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies: Rationale and Study Design for PROCEED From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.}, journal = {Pancreas}, volume = {47}, number = {10}, pages = {1229-1238}, doi = {10.1097/MPA.0000000000001170}, pmid = {30325862}, issn = {1536-4828}, abstract = {Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP-controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.}, }
@article {pmid30325415, year = {2018}, author = {Ryser, MD and Gulati, R and Eisenberg, MC and Shen, Y and Hwang, ES and Etzioni, RB}, title = {Identification of the Fraction of Indolent Tumors and Associated Overdiagnosis in Breast Cancer Screening Trials.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwy214}, pmid = {30325415}, issn = {1476-6256}, support = {U01 CA157224/CA/NCI NIH HHS/United States ; }, abstract = {It is generally accepted that some screen-detected breast cancers are overdiagnosed and would not progress to symptomatic cancer if left untreated. However, precise estimates of the fraction of non-progressive cancers remain elusive. In recognition of the weaknesses of overdiagnosis estimation methods based on excess incidence, there is a need for model-based approaches that accommodate non-progressive lesions. Here, we present an in-depth analysis of a generalized breast cancer natural history model that allows for a mixture of progressive and indolent lesions. We provide a formal proof of global structural identifiability of the model and use simulation to identify conditions that allow for parameter estimates that are sufficiently precise and practically actionable. We show that clinical follow-up after the last screen can play a critical role in ensuring adequately precise identification of the fraction of indolent cancers in a stop-screen trial design, and we demonstrate that model misspecification can lead to substantially biased mean sojourn time estimates. Finally, we illustrate our findings on the example of the Canadian National Breast Screening Study-2 and show that the fraction of indolent cancers is not precisely identifiable. Our findings provide the foundation for extended models that account for both in situ and invasive lesions.}, }
@article {pmid30325190, year = {2018}, author = {Panattoni, L and Chan, A and Yang, Y and Olson, C and Tai-Seale, M}, title = {Nudging physicians and patients with autopend clinical decision support to improve diabetes management.}, journal = {The American journal of managed care}, volume = {24}, number = {10}, pages = {479-483}, pmid = {30325190}, issn = {1936-2692}, abstract = {OBJECTIVES: To determine the impact on routine glycated hemoglobin (A1C) laboratory test completion of incorporating an autopend laboratory order functionality into clinical decision support, which (1) routed provider alerts to a separate electronic folder, (2) automatically populated preauthorization forms, and (3) linked the timing and content of electronic patient health maintenance topic (HMT) reminders to the provider authorization.
STUDY DESIGN: Observational pre-post study from November 2011 (1 year before autopend) through June 2014 (1.5 years after).
METHODS: The study included HMT reminders concerning an A1C test for patients with type 1 or type 2 diabetes (N = 15,630 HMT reminders; 8792 patients) in a large multispecialty ambulatory healthcare system. A Cox proportional hazard model, adjusted for patient and provider demographics, estimated the likelihood of laboratory test completion based on 3 HMT reminder characteristics: preautopend versus postautopend period, read versus unread, and the patient's time to reading.
RESULTS: In the postautopend period, the median time for patients to read reminders decreased (1 vs 3 days; P <.001) and the median time to complete laboratory tests decreased (40 vs 48 days; P <.001). Comparing preautopend HMT reminders with a similar time to reading, the likelihood of A1C laboratory test completion increased after autopend by between 21.1% (hazard ratio [HR], 1.211; P = .050), when time to reading was 57 days, and 33.9% (HR, 1.339; P = .003), when time to reading was 0 days. This result included 68% of the reminders. There was no statistical difference in A1C laboratory test completion for unread reminders in the preautopend versus postautopend period.
CONCLUSIONS: Automated patient-centered decision support can improve guideline-concordant monitoring of A1C among patients with diabetes, particularly among patients who read reminders in a timely fashion.}, }
@article {pmid30325055, year = {2018}, author = {Connelly-Smith, L and Tanhehco, YC and Chhibber, V and Delaney, M and Eichbaum, Q and Fernandez, C and Joshi, S and Schwartz, J and Linenberger, M}, title = {Choosing Wisely for apheresis.}, journal = {Journal of clinical apheresis}, volume = {33}, number = {5}, pages = {576-579}, doi = {10.1002/jca.21643}, pmid = {30325055}, issn = {1098-1101}, mesh = {Blood Component Removal/*methods ; *Health Planning Guidelines ; Humans ; Practice Guidelines as Topic/standards ; Societies, Medical ; }, abstract = {The Choosing Wisely campaign has stimulated clinicians to think about the appropriateness of various tests and procedures, compelling physicians to make smarter, safer and more effective choices for high quality patient care and to reduce healthcare cost. The American Society for Apheresis (ASFA) strives to advance apheresis medicine through education, evidence-based practice, research and advocacy. To complement these shared missions, ASFA created a working group, consisting of representatives from the various ASFA committees, to produce recommendations for apheresis medicine that reflect the Choosing Wisely guiding principles. A diverse group of ASFA physician and allied health members reviewed, rated and ranked 9 original draft proposals. Additional revisions and refinements were made prior to external review and adoption of five final recommendations by the ASFA Board of Directors. The ASFA Choosing Wisely recommendations encourage apheresis practitioners, patients and donors to discuss and prioritize best clinical practices that avoid harm and waste while optimizing clinical benefit.}, }
@article {pmid30324461, year = {2018}, author = {Peterson, LM and Kurland, BF and Schubert, EK and Link, JM and Gadi, VK and Specht, JM and Eary, JF and Porter, P and Shankar, LK and Mankoff, DA and Linden, HM}, title = {Correction to: a Phase 2 Study of 16α-[18F]-Fluoro-17β-Estradiol Positron Emission Tomography (FES-PET) as a Marker of Hormone Sensitivity in Metastatic Breast Cancer (MBC).}, journal = {Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11307-018-1287-7}, pmid = {30324461}, issn = {1860-2002}, abstract = {Two data points from Table 1. (continued) were published in error. The corrected data in Table 1. (continued) are shown, in italic, below.}, }
@article {pmid30323809, year = {2018}, author = {Vander Heiden, JA and Marquez, S and Marthandan, N and Bukhari, SAC and Busse, CE and Corrie, B and Hershberg, U and Kleinstein, SH and Matsen Iv, FA and Ralph, DK and Rosenfeld, AM and Schramm, CA and , and Christley, S and Laserson, U}, title = {AIRR Community Standardized Representations for Annotated Immune Repertoires.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2206}, doi = {10.3389/fimmu.2018.02206}, pmid = {30323809}, issn = {1664-3224}, support = {P01 AI106697/AI/NIAID NIH HHS/United States ; R01 AI097403/AI/NIAID NIH HHS/United States ; R01 AI104739/AI/NIAID NIH HHS/United States ; R01 GM113246/GM/NIGMS NIH HHS/United States ; }, abstract = {Increased interest in the immune system's involvement in pathophysiological phenomena coupled with decreased DNA sequencing costs have led to an explosion of antibody and T cell receptor sequencing data collectively termed "adaptive immune receptor repertoire sequencing" (AIRR-seq or Rep-Seq). The AIRR Community has been actively working to standardize protocols, metadata, formats, APIs, and other guidelines to promote open and reproducible studies of the immune repertoire. In this paper, we describe the work of the AIRR Community's Data Representation Working Group to develop standardized data representations for storing and sharing annotated antibody and T cell receptor data. Our file format emphasizes ease-of-use, accessibility, scalability to large data sets, and a commitment to open and transparent science. It is composed of a tab-delimited format with a specific schema. Several popular repertoire analysis tools and data repositories already utilize this AIRR-seq data format. We hope that others will follow suit in the interest of promoting interoperable standards.}, }
@article {pmid30323087, year = {2018}, author = {Kalemkerian, GP and Loo, BW and Akerley, W and Attia, A and Bassetti, M and Boumber, Y and Decker, R and Dobelbower, MC and Dowlati, A and Downey, RJ and Florsheim, C and Ganti, AKP and Grecula, JC and Gubens, MA and Hann, CL and Hayman, JA and Heist, RS and Koczywas, M and Merritt, RE and Mohindra, N and Molina, J and Moran, CA and Morgensztern, D and Pokharel, S and Portnoy, DC and Rhodes, D and Rusthoven, C and Santana-Davila, R and Williams, CC and Hoffmann, KG and Hughes, M}, title = {NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {16}, number = {10}, pages = {1171-1182}, doi = {10.6004/jnccn.2018.0079}, pmid = {30323087}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."}, }
@article {pmid30322915, year = {2018}, author = {Fei, DL and Zhen, T and Durham, B and Ferrarone, J and Zhang, T and Garrett, L and Yoshimi, A and Abdel-Wahab, O and Bradley, RK and Liu, P and Varmus, H}, title = {Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, number = {44}, pages = {E10437-E10446}, doi = {10.1073/pnas.1812669115}, pmid = {30322915}, issn = {1091-6490}, abstract = {Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of U2af1(S34F), the murine version of the most common mutant allele of U2AF1 encountered in human cancers. Cre-mediated recombination in murine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, low-grade dysplasias, and impaired transplantability, but without lifespan shortening or leukemia development. In an attempt to identify U2af1(S34F)-cooperating changes that promote leukemogenesis, we combined U2af1(S34F) with Runx1 deficiency in mice and further treated the mice with a mutagen, N-ethyl-N-nitrosourea (ENU). Overall, 3 of 16 ENU-treated compound transgenic mice developed AML. However, AML did not arise in mice with other genotypes or without ENU treatment. Sequencing DNA from the three AMLs revealed somatic mutations homologous to those considered to be drivers of human AML, including predicted loss- or gain-of-function mutations in Tet2, Gata2, Idh1, and Ikzf1 However, the engineered U2af1(S34F) missense mutation reverted to WT in two of the three AML cases, implying that U2af1(S34F) is dispensable, or even selected against, once leukemia is established.}, }
@article {pmid30321633, year = {2018}, author = {Petersdorf, EW and O'hUigin, C}, title = {The MHC in the Era of Next-Generation Sequencing: Implications for Bridging Structure with Function.}, journal = {Human immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.humimm.2018.10.002}, pmid = {30321633}, issn = {1879-1166}, support = {R01 CA100019/CA/NCI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; }, abstract = {The MHC continues to have the most disease-associations compared to other regions of the human genome, even in the genome-wide association study (GWAS) and single nucleotide polymorphism (SNP) era. Analysis of non-coding variation and their impact on the level of expression of HLA allotypes has shed new light on the potential mechanisms underlying HLA disease associations and alloreactivity in transplantation. Next-generation sequencing (NGS) technology has the capability of delineating the phase of variants in the HLA antigen-recognition site (ARS) with non-coding regulatory polymorphisms. These relationships are critical for understanding the qualitative and quantitative implications of HLA gene diversity. This article summarizes current understanding of non-coding region variation of HLA loci, the consequences of regulatory variation on HLA expression, the role for evolution in shaping lineage-specific expression, and the impact of HLA expression on disease susceptibility and transplantation outcomes. A role for phased sequencing methods for the MHC, and perspectives for future directions in basic and applied immunogenetic studies of the MHC are presented.}, }
@article {pmid30317583, year = {2018}, author = {Mirzaei, HR and Mirzaei, H and Namdar, A and Rahmati, M and Till, BG and Hadjati, J}, title = {Predictive and therapeutic biomarkers in chimeric antigen receptor T-cell therapy: A clinical perspective.}, journal = {Journal of cellular physiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcp.27519}, pmid = {30317583}, issn = {1097-4652}, support = {30381//Tehran University of Medical Sciences and Health Services/ ; 942554//National Institute for Medical Research Development (NIMAD) of Iran/ ; }, abstract = {The adoptive transfer of genetically engineered T cells modified to express a chimeric antigen receptor (CAR) has shown remarkable activity and induces long-term remissions in patients with advanced hematologic malignancies. To date, little is known about predictive indicators of therapeutic efficacy or serious toxicity after CAR T-cell therapy in clinical practice. Biomarkers are not only potentially able to inform physicians and researchers of immunotherapy targets in particular but could also be used to monitor the effectiveness of treatments and to predict incidence of side effects in some circumstances. Identification of new biomarkers can therefore not only contribute to the development of new therapeutic and prognostic strategies for CAR T-cell therapy for cancer but also help to generate improved clinical practices for early recognition and minimization of adverse effects while preserving the antitumor activity of the CAR T cells. Herein, we will consider a variety of predictive and therapeutic biomarkers in CAR T-cell therapy and the state of current understanding of their clinical utility. The incorporation of biomarker studies in CAR T-cell clinical trials and practice will help to realize the potential clinical benefit of biomarker-guided therapy.}, }
@article {pmid30315943, year = {2018}, author = {Doney, K and McMillen, K and Buono, L and Deeg, HJ and Gooley, T}, title = {Impact of Body Mass Index on Outcomes of Hematopoietic Stem Cell Transplantation in Adults.}, 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.2018.10.006}, pmid = {30315943}, issn = {1523-6536}, abstract = {This retrospective analysis of 2503 adult (age ≥20 years) allogeneic hematopoietic cell transplantation (HCT) recipients assessed the effect of body mass index (BMI) on transplantation outcomes. The median patient age was 51.7 years. Patients with both nonmalignant and malignant diagnoses were included. Patients received either a myeloablative (52%) or a reduced-intensity (48%) conditioning regimen. Donors were either related (42%) or unrelated (58%). Cord blood recipients were excluded. Granulocyte colony-stimulating factor-mobilized peripheral blood cells were the stem cell source in 86% of transplantations. Graft-versus-host disease prophylaxis included at least 2 immunosuppressive agents, 1 of which was a calcineurin inhibitor. Patient groups were categorized as underweight, normal weight, overweight, obese, or very obese based on BMI. Endpoints included day +100 mortality, overall mortality, nonrelapse mortality (NRM), and relapse. Changes in nutritional status, based on laboratory parameters, were also examined. Underweight patients had significantly lower early and overall survival and greater NRM. Very obese patients had increased NRM, which was associated with the intensity of conditioning regimen. With long-term follow-up, increasing NRM was associated with both underweight and obese patients compared with normal-weight individuals. Changes in serum protein and albumin levels did not correlate with BMI. Although enteral nutrition is now recommended for some undernourished patients, the efficacy of enteral or parenteral nutrition has not been well studied. For obese patients, there are no guidelines regarding weight loss before transplantation, and acute weight loss in the pretransplantation period may be detrimental.}, }
@article {pmid30315942, year = {2018}, author = {Künkele, A and Brown, C and Beebe, A and Mgebroff, S and Johnson, AJ and Taraseviciute, A and Rolczynski, LS and Chang, CA and Finney, OC and Park, JR and Jensen, MC}, title = {Manufacture of Chimeric Antigen Receptor T Cells from Mobilized Cyropreserved Peripheral Blood Stem Cell Units Depends on Monocyte Depletion.}, 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.2018.10.004}, pmid = {30315942}, issn = {1523-6536}, abstract = {Cytotoxic chemotherapy and radiation can render lymphocyte repertoires qualitatively and quantitatively defective. Thus, heavily treated patients are often poor candidates for the manufacture of autologous chimeric antigen receptor (CAR)-T cell products. In the United States and Europe, children with high-risk neuroblastoma undergo apheresis early in the course of treatment to collect peripheral blood stem cells (PBSCs) for cryopreservation in preparation for high-dose chemotherapy followed by autologous stem cell rescue. Here, we investigate whether these cryopreserved chemotherapy and granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs can serve as starting material for CAR-T cell manufacturing. We evaluated T cell precursor subsets in cryopreserved PBSC units from 8 patients with neuroblastoma using fluorescent activated cell sorting-based analysis. Every cryopreserved unit collected early in treatment contained both CD4 and CD8 precursors with significant numbers of naïve and central memory precursors. Significant numbers of Ki67+/PD1+ T cells were detected, presumably the result of chemotherapy-induced lymphopenia and subsequent homeostatic proliferation. Cryopreserved PBSC units containing 56 to 112 × 106 T cells were amenable to immunomagnetic selection, CD3 × 28 bead activation, lentiviral transduction, and cytokine-driven expansion, provided that CD14 monocytes were depleted before the initiation of cultures. Second- and third-generation CD171 CAR+ CD4 and CD8 effector cells derived from cryopreserved units displayed antineuroblastoma lytic potency and cytokine secretion comparable to those derived from a healthy donor and mediated in vivo antitumor regression in NSG mice. We conclude that cryopreserved PBSCs procured via standard methods during early treatment can serve as an alternative starting source for CAR-T cell manufacturing, extending the options for heavily treated patients.}, }
@article {pmid30315940, year = {2018}, author = {Denzen, EM and Preussler, JM and Murphy, EA and Baker, KS and Burns, LJ and Foster, J and Idossa, L and Moore, HK and Payton, TJ and Haven, D and Jahagirdar, B and Kamani, N and Rizzo, JD and Salazar, L and Schatz, BA and Syrjala, KL and Wingard, JR and Majhail, NS}, title = {Tailoring a Survivorship Care Plan: Patient and Provider Preferences for Recipients of 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.2018.10.005}, pmid = {30315940}, issn = {1523-6536}, support = {R01 CA215134/CA/NCI NIH HHS/United States ; }, abstract = {This study aimed to develop a survivorship care plan (SCP) that can be individualized to facilitate long-term follow-up care of hematopoietic cell transplantation (HCT) survivors. A sample SCP was developed that included 2 documents: a treatment summary and preventive care recommendations that combined data on treatment exposures routinely submitted by HCT centers to the Center for International Blood and Marrow Transplant Research (CIBMTR) with long-term follow-up guidelines. Focus groups were conducted by phone to characterize the critical patient-centered elements of the SCP. Focus group eligibility criteria included (1) adult patients >1 year post-HCT and their caregivers (3 groups; n = 22), (2) HCT physicians and advanced practice providers (APPs) (2 groups; n = 14), (3) HCT nurses and social workers (4 groups; n = 17), and (4) community health care professionals (3 groups; n = 24). Transcripts were analyzed for saturation of key themes using NVivo 10 software. Patients and caregivers suggested combining the treatment summary and care guidelines into a single document. They also requested sections on sexual and emotional health and the immune system. Providers wanted the treatment summary to focus only on what they absolutely must know. Themes were similar across healthcare professionals, although screening for psychosocial issues was emphasized more by the nurses and social workers. All preferred to receive the SCP electronically; however, hardcopy was considered necessary for some patients. All felt that the SCP would facilitate appropriate post-HCT care. This study highlights the need for an SCP instrument to facilitate HCT survivorship care. Furthermore, it demonstrates the feasibility and value of engaging HCT recipients, caregivers, and providers in developing an SCP. Their feedback was incorporated into a final SCP that was subsequently tested in a randomized trial.}, }
@article {pmid30315234, year = {2018}, author = {Othus, M and Sekeres, MA and Nand, S and Garcia-Manero, G and Appelbaum, FR and Erba, HP and Estey, E}, title = {Relative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-018-0275-x}, pmid = {30315234}, issn = {1476-5551}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; CA180888//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA180819//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Here we quantify and compare the absolute and relative overall survival (OS) benefits conveyed by complete remission (CR) in AML and high-risk MDS, and by CR with incomplete count recovery (CRi) in AML and by hematologic improvement (HI) in MDS, following treatment with 7 + 3 versus azacytidine. We compared patients receiving 7 + 3 in SWOG studies S0106 (n = 301) and S1203 (n = 261) enrolling adults ≤ 60 years, with patients receiving azacytidine therapies in S0703 (n = 133 AML patients ≥ 60) and S1117 (n = 277 MDS patients ≥ 18). Absolute survival benefit was evaluated with 1-year, 3-year, and median OS; relative benefit was evaluated with univariate and covariate-adjusted hazard ratios. CR conveyed a relative survival advantage in multivariable analysis, with a similar relative effect of CR across studies. CR also conferred an absolute survival benefit, but with a smaller magnitude of absolute benefit in the azacytidine trials. In AML, OS was similar for CRi and failure to achieve CR/CRi. In MDS, CR conferred a survival advantage versus HI and HI versus failure. The relative survival benefit of CR was similar regardless of initial therapy for AML or high-risk MDS. With both therapies, CR has a beneficial effect on survival compared with CRi or HI.}, }
@article {pmid30315233, year = {2018}, author = {Othus, M and Estey, EH and Garcia-Manero, G and Wood, BL and Stirewalt, DL and Godwin, JE and Weick, JK and Anderson, JE and Appelbaum, FR and Erba, HP and Walter, RB}, title = {Second cycle remission achievement with 7+3 and survival in adults with newly diagnosed acute myeloid leukemia: analysis of recent SWOG trials.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-018-0274-y}, pmid = {30315233}, issn = {1476-5551}, support = {CA180888//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA180819//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid30310789, year = {2018}, author = {Greenbaum, AM and Green, DJ and Holmberg, LA and Gooley, T and Till, BG and Budde, LE and Rasmussen, H and Press, OW and Gopal, AK}, title = {Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma.}, journal = {Blood research}, volume = {53}, number = {3}, pages = {223-226}, doi = {10.5045/br.2018.53.3.223}, pmid = {30310789}, issn = {2287-979X}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA076287/CA/NCI NIH HHS/United States ; P01 CA044991/CA/NCI NIH HHS/United States ; R01 CA138720/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; K24 CA184039/CA/NCI NIH HHS/United States ; K08 CA151682/CA/NCI NIH HHS/United States ; }, abstract = {Background: Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may adversely affect stem cell collection. Here we describe the lymphoma subset of a prospective, non-randomized phase II study of bendamustine, etoposide, and dexamethasone (BED) as a mobilization agent for lymphoid malignancies.
Methods: This subset analysis includes diffuse large B-cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m2 IV d 1, 2), etoposide (200 mg/m2 IV d 1-3), and dexamethasone (40 mg PO d 1-4) followed by filgrastim (10 mcg/kg/d sc. through collection).
Results: We successfully collected stem cells from all patients, with a median of 7.9×106/kg of body weight (range, 4.4 to 17.3×106/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non-hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5).
Conclusion: For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective.}, }
@article {pmid30310236, year = {2018}, author = {Laird, DW and Lampe, PD}, title = {Therapeutic strategies targeting connexins.}, journal = {Nature reviews. Drug discovery}, volume = {}, number = {}, pages = {}, doi = {10.1038/nrd.2018.138}, pmid = {30310236}, issn = {1474-1784}, support = {R01 GM055632/GM/NIGMS NIH HHS/United States ; }, abstract = {The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges.}, }
@article {pmid30309244, year = {2018}, author = {Han, CJ and Jarrett, ME and Cain, KC and Jun, S and Heitkemper, MM}, title = {Association of Fatigue With TPH2 Genetic Polymorphisms in Women With Irritable Bowel Syndrome.}, journal = {Biological research for nursing}, volume = {}, number = {}, pages = {1099800418806055}, doi = {10.1177/1099800418806055}, pmid = {30309244}, issn = {1552-4175}, abstract = {Fatigue is the most common extraintestinal symptom in women with irritable bowel syndrome (IBS). Genetic polymorphisms of monoamines are associated with fatigue in many chronic diseases. In this pilot exploratory study, the primary aim was to determine whether genetic polymorphisms of tryptophan hydroxylase (TPH1/TPH2), serotonin reuptake transporter (SERT), or catechol-O-methyltransferase (COMT) are associated with fatigue in women with IBS. Additionally, analysis explored whether these genetic associations with fatigue would be present when controlling for abdominal pain, psychological distress, feeling stressed, and sleepiness during the day. Secondary analysis of two randomized controlled trial baseline data sets in Caucasian women with IBS (N = 185) was conducted. Participants kept a daily diary with one dimension (i.e., severity) for each of the 26 symptoms, including fatigue, for 28 days prior to randomization. DNA samples were tested for single-nucleotide polymorphisms (SNPs) of TPH1 (four SNPs) /TPH2 (one SNP), SERT (one SNP), and COMT (one SNP). Analysis of covariance was used to examine associations of percentage of diary days with moderate to very severe symptoms with genetic polymorphisms. Only one SNP, TPH2 rs4570625, was significantly associated with fatigue (p = .005). T-allele (low functional) carriers of TPH2 (i.e., G/T or T/T genotypes) reported a greater percentage of days with moderate to very severe fatigue than G/G homozygotes (p = .001). Reduced synthesis of tryptophan in the central nervous system may contribute to reports of fatigue in women with IBS. Understanding genetic risk factors for fatigue may elucidate preemptive strategies to reduce fatigue in individuals with IBS.}, }
@article {pmid30308327, year = {2018}, author = {Amonoo, HL and Barclay, ME and El-Jawahri, A and Traeger, LN and Lee, SJ and Huffman, JC}, title = {Positive Psychological Constructs and Health Outcomes in Hematopoietic Stem Cell Transplantation Patients: A Systematic Review.}, 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.2018.09.030}, pmid = {30308327}, issn = {1523-6536}, abstract = {Positive psychological constructs (eg, optimism, positive affect) have been independently associated with superior health outcomes across many medical populations. However, there has been little synthesis of the literature examining these associations among patients with hematologic malignancies receiving hematopoietic stem cell transplantation (HSCT). To address this gap we completed a systematic review, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, of studies examining relationships between positive psychological constructs and health-related outcomes (eg, psychiatric symptoms, function, health-related quality of life [HRQoL], or treatment compliance) after HSCT. Eighteen eligible studies (N = 4201; 47% women; mean age, 47.1) were identified. Optimism (n = 12 studies) was the most frequently studied positive construct and HRQoL (examined in n = 11 studies) the most common outcome. All 17 studies with quantitative analyses found a significant (P < .05) association between a positive psychological construct and a health outcome; most but not all controlled for 1 or more relevant covariates. Among patients with hematologic malignancies who receive HSCT, positive psychological constructs appear to be associated with improved HRQoL and other health outcomes. Further work is warranted to more comprehensively understand the independent effects of positive psychological constructs on a variety of health outcomes and to develop interventions to promote well-being that are adapted to the needs of this population.}, }
@article {pmid30307805, year = {2018}, author = {Ddungu, H and Krantz, EM and Phipps, W and Naluzze, S and Orem, J and Kiwanuka, N and Wald, A and Kajja, I}, title = {Survey to Assess Knowledge and Reported Practices Regarding Blood Transfusion Among Cancer Physicians in Uganda.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-12}, doi = {10.1200/JGO.18.00143}, pmid = {30307805}, issn = {2378-9506}, abstract = {PURPOSE: Optimal decision making regarding blood transfusion for patients with cancer requires appropriate knowledge of transfusion medicine among physicians. We assessed blood transfusion knowledge, attitudes, and reported practices among physicians working at Uganda Cancer Institute (UCI).
MATERIALS AND METHODS: A cross-sectional self-administered survey of UCI physicians on their knowledge, attitudes, and practices regarding blood transfusion was conducted from June to September 2014. In consultation with transfusion medicine experts, 30 questions were developed, including 10 questions for each of the following three domains: knowledge, attitudes, and practices. For the knowledge domain, we created a knowledge score equal to the number of questions correctly answered out of 10.
RESULTS: Of 31 physicians approached, 90% participated. The mean knowledge score was 5.3 (median, 5.5), and 32% correctly answered at least seven of 10 questions. Almost all (96%) understood the importance of proper patient identification before transfusion and indicated identification error as the most common cause of fatal transfusion reactions. More than 60% of physicians acknowledged they lacked knowledge and needed training in transfusion medicine. Most physicians reported sometimes changing their mind about whether to provide a patient with a transfusion on the basis of opinion of colleagues and sometimes administering unnecessary transfusions because of influence from others.
CONCLUSION: Although UCI physicians have some basic knowledge in transfusion, most reported gaps in their knowledge, and all expressed a need for additional education in the basics of blood transfusion. Transfusion training and evidence-based guidelines are needed to reduce inappropriate transfusions and improve patient care. Greater understanding of peer influence in transfusion decision making is required.}, }
@article {pmid30307607, year = {2018}, author = {Deeg, HJ}, title = {More than one angle to target aplastic anemia?.}, journal = {Cancer}, volume = {124}, number = {21}, pages = {4165-4167}, doi = {10.1002/cncr.31656}, pmid = {30307607}, issn = {1097-0142}, }
@article {pmid30307499, year = {2018}, author = {Polfus, LM and Raffield, LM and Wheeler, MM and Tracy, RP and Lange, LA and Lettre, G and Miller, A and Correa, A and Bowler, RP and Bis, JC and Salimi, S and Jenny, NS and Pankratz, N and Wang, B and Preuss, MH and Zhou, L and Moscati, A and Nadkarni, GN and Loos, RJF and Zhong, X and Li, B and Johnsen, JM and Nickerson, DA and Reiner, AP and Auer, PL and Precision Medicine Consortium, NTF}, title = {Whole genome sequence association with E-selectin levels reveals Loss-of-function variant in African Americans.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddy360}, pmid = {30307499}, issn = {1460-2083}, abstract = {E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p.Glu274Lys, p=9.02 x 10-24) with higher soluble E-selectin levels. This variant is considerably more common in populations of African-ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women's Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an EMR-based phenome-wide association scan of over 9,000 African Americans.}, }
@article {pmid30306600, year = {2018}, author = {Gabriel, EE and Sachs, MC and Daniels, MJ and Halloran, ME}, title = {Optimizing and evaluating biomarker combinations as trial-level general surrogates.}, journal = {Statistics in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/sim.7996}, pmid = {30306600}, issn = {1097-0258}, support = {2016-01267//Vetenskapsrådet/ ; 2017-01898//Vetenskapsrådet/ ; R01CA183854//National Institutes of Health/ ; R37AI032042//National Institutes of Health/ ; GM112327//National Institutes of Health/ ; AI108441//National Institutes of Health/ ; }, abstract = {We extend the method proposed in a recent work by the Authors for trial-level general surrogate evaluation to allow combinations of biomarkers and provide a procedure for finding the "best" combination of biomarkers based on the absolute prediction error summary of surrogate quality. We use a nonparametric Bayesian model that allows us to select an optimal subset of biomarkers without having to consider a large number of explicit model specifications for that subset. This dramatically reduces the number of model comparisons needed. Given the model's flexibility, complex nonlinear relationships can be fit when enough data are available. We evaluate the operating characteristics of our proposed method in simulations designed to be similar to our motivating example. We use our method to compare and evaluate combinations of biomarkers as trial-level general surrogates for the pentavalent rotavirus vaccine RotaTeq™ (RV5) (Merck & Co, Inc, Kenilworth, New Jersey, USA), finding that the same single biomarker identified in our previously published analysis is likely the optimal subset.}, }
@article {pmid30306429, year = {2018}, author = {Panattoni, L and Lieu, TA and Jayasekera, J and O'Neill, S and Mandelblatt, JS and Etzioni, R and Phelps, CE and Ramsey, SD}, title = {The impact of gene expression profile testing on confidence in chemotherapy decisions and prognostic expectations.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10549-018-4988-3}, pmid = {30306429}, issn = {1573-7217}, support = {U01 CA152958/CA/NCI NIH HHS/United States ; U01 CA152958//National Cancer Institute/ ; R01 CA105274/CA/NCI NIH HHS/United States ; UC2 CA148471//National Cancer Institute/ ; ASPO-17-001//American Society of Preventive Oncology/ ; UO1 CA183081//National Cancer Institute/ ; ACS IRG 92-152-20//American Cancer Society/ ; U01 CA183081/CA/NCI NIH HHS/United States ; R35CA197289//National Cancer Institute/ ; R35 CA197289/CA/NCI NIH HHS/United States ; R01 CA105274//National Cancer Institute/ ; }, abstract = {PURPOSE: Little is known about whether gene expression profile (GEP) testing and specific recurrence scores (e.g., medium risk) improve women's confidence in their chemotherapy decision or perceived recurrence risk. We evaluate the relationship between these outcomes and GEP testing.
METHODS: We surveyed women eligible for GEP testing (stage I or II, Gr1-2, ER+, HER2-) identified through the Surveillance, Epidemiology, and End Results (SEER) Registry of Washington or Kaiser Permanente Northern California from 2012 to 2016, approximately 0-4 years from diagnosis (N = 904, RR = 45.4%). Confidence in chemotherapy was measured as confident (Very, completely) versus Not Confident (Somewhat, A little, Not At All); perceived risk recurrence was recorded numerically (0-100%). Women reported their GEP test receipt (Yes, No, Unknown) and risk recurrence score (High, Intermediate, Low, Unknown). In our analytic sample (N = 833), we propensity score weighted the three test receipt cohorts and used propensity weighted multivariable regressions to examine associations between the outcomes and the three test receipt cohorts, with receipt stratified by score.
RESULTS: 29.5% reported an unknown GEP test receipt; 86% being confident. Compared to no test receipt, an intermediate score (aOR 0.34; 95% CI 0.20-0.58), unknown score (aOR 0.09; 95% CI 0.05-0.18), and unknown test receipt (aOR 0.37; 95% CI 0.24-0.57) were less likely to report confidence. Most women greatly overestimated their recurrence risk regardless of their test receipt or score.
CONCLUSIONS: GEP testing was not associated with greater confidence in chemotherapy decisions. Better communication about GEP testing and the implications for recurrence risk may improve women's decisional confidence.}, }
@article {pmid30305637, year = {2018}, author = {McMaster, ML and Berndt, SI and Zhang, J and Slager, SL and Li, SA and Vajdic, CM and Smedby, KE and Yan, H and Birmann, BM and Brown, EE and Smith, A and Kleinstern, G and Fansler, MM and Mayr, C and Zhu, B and Chung, CC and Park, JH and Burdette, L and Hicks, BD and Hutchinson, A and Teras, LR and Adami, HO and Bracci, PM and McKay, J and Monnereau, A and Link, BK and Vermeulen, RCH and Ansell, SM and Maria, A and Diver, WR and Melbye, M and Ojesina, AI and Kraft, P and Boffetta, P and Clavel, J and Giovannucci, E and Besson, CM and Canzian, F and Travis, RC and Vineis, P and Weiderpass, E and Montalvan, R and Wang, Z and Yeager, M and Becker, N and Benavente, Y and Brennan, P and Foretova, L and Maynadie, M and Nieters, A and de Sanjose, S and Staines, A and Conde, L and Riby, J and Glimelius, B and Hjalgrim, H and Pradhan, N and Feldman, AL and Novak, AJ and Lawrence, C and Bassig, BA and Lan, Q and Zheng, T and North, KE and Tinker, LF and Cozen, W and Severson, RK and Hofmann, JN and Zhang, Y and Jackson, RD and Morton, LM and Purdue, MP and Chatterjee, N and Offit, K and Cerhan, JR and Chanock, SJ and Rothman, N and Vijai, J and Goldin, LR and Skibola, CF and Caporaso, NE}, title = {Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {4182}, doi = {10.1038/s41467-018-06541-2}, pmid = {30305637}, issn = {2041-1723}, support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; P50 CA097274/CA/NCI NIH HHS/United States ; }, abstract = {Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10-54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.}, }
@article {pmid30305383, year = {2018}, author = {Dalmat, RR and Makhsous, N and Pepper, GG and Magaret, A and Jerome, KR and Wald, A and Greninger, AL}, title = {Limited Marginal Utility of Deep Sequencing for HIV Drug Resistance Testing in the Age of Integrase Inhibitors.}, journal = {Journal of clinical microbiology}, volume = {56}, number = {12}, pages = {}, doi = {10.1128/JCM.01443-18}, pmid = {30305383}, issn = {1098-660X}, abstract = {HIV drug resistance genotyping is a critical tool in the clinical management of HIV infections. Although resistance genotyping has traditionally been conducted using Sanger sequencing, next-generation sequencing (NGS) is emerging as a powerful tool due to its ability to detect low-frequency alleles. However, the clinical value added from NGS approaches to antiviral resistance testing remains to be demonstrated. We compared the variant detection capacity of NGS versus Sanger sequencing methods for resistance genotyping in 144 drug resistance tests (105 protease-reverse transcriptase tests and 39 integrase tests) submitted to our clinical virology laboratory over a four-month period in 2016 for Sanger-based HIV drug resistance testing. NGS detected all true high-frequency drug resistance mutations (>20% frequency) found by Sanger sequencing, with greater accuracy in one instance of a Sanger-detected false positive. Freely available online NGS variant callers HyDRA and PASeq were superior to Sanger methods for interpretations of allele linkage and automated variant calling. NGS additionally detected low-frequency mutations (1 to 20% frequency) associated with higher levels of drug resistance in 30/105 (29%) protease-reverse transcriptase tests and 4/39 (10%) integrase tests. In clinical follow-up of 69 individuals for a median of 674 days, we did not find a difference in rates of virological failure between individuals with and without low-frequency mutations, although rates of virological failure were higher for individuals with drug-relevant low-frequency mutations. However, all 27 individuals who experienced virological failure reported poor adherence to their drug regimen during the preceding follow-up time, and all 19 who subsequently improved their adherence achieved viral suppression at later time points, consistent with a lack of clinical resistance. In conclusion, in a population with low antiviral resistance emergence, NGS methods detected numerous instances of minor alleles that did not result in subsequent bona fide virological failure due to antiviral resistance.}, }
@article {pmid30304993, year = {2018}, author = {Hohl, SD and Ceballos, R and Scott, MA and Thompson, B}, title = {Developing a Culturally Informed Survey Instrument to Assess Biomedical Research Participation Among Latinos on the U.S.-Mexico Border.}, journal = {Qualitative health research}, volume = {}, number = {}, pages = {1049732318801364}, doi = {10.1177/1049732318801364}, pmid = {30304993}, issn = {1049-7323}, abstract = {Racial/ethnic minorities, rural populations, and those with low socioeconomic status income are underrepresented in research in the United States (U.S.). Assessing preferences for recruitment, participation, and the role of beliefs about biomedical research in specific and unique underserved communities represents a potentially critical step in reducing barriers to biomedical research participation. We developed a culturally informed survey to measure factors related to participation, knowledge, expectations, and barriers to biomedical research participation among Latinos living in a U.S. border community. We employed a multidisciplinary team approach to a sequential, three-phase qualitative study that included interviews (n = 35), focus groups (n =24), and "think-aloud" cognitive interviews (n = 5). Our study demonstrates the value of applying multiple qualitative approaches to inform a culturally relevant quantitative survey incorporating words and constructs relevant to the population of interest. The study contributes to qualitative method research paradigms by developing a research protocol that integrates the expertise and perspectives of researchers and community members from multiple disciplines and institutions.}, }
@article {pmid30304938, year = {2018}, author = {Chi, NC and Han, S and Barani, E and Parker Oliver, D and Washington, KT and Lewis, FM and Walker, A and Demiris, G}, title = {Development and Preliminary Evaluation of a Pain Management Manual for Hospice Providers to Support and Educate Family Caregivers.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {1049909118804984}, doi = {10.1177/1049909118804984}, pmid = {30304938}, issn = {1938-2715}, abstract = {BACKGROUND: Family caregivers encounter many barriers to managing patients' pain in the home hospice setting. However, there are limited clinically applicable resources for hospice providers to help family caregivers identify and address these barriers.
AIM: To develop a pain management manual for hospice providers to support family caregivers and conduct a preliminary providers' evaluation of the manual.
DESIGN AND PARTICIPANTS: A pain management manual was developed and structured into 3 parts: (1) 5 common pain management case scenarios based on a secondary data analysis of a hospice clinical trial; (2) a list of suggested assessment questions and strategies for each case scenario was developed based on a caregiver framework; and (3) pain educational material was included from established clinical guidelines. The manual was vetted by 5 experts and then was evaluated by interviewing 25 hospice providers. Interview data were analyzed using thematic analysis.
RESULTS: The hospice providers found that the manual could potentially serve as a reference in their practice and be a source for their continuing education. They suggested enhancing the clarity of the case scenarios and adding additional strategies to the manual. Moreover, they suggested expanding the paper-based version and developing a web-based platform to deliver the content would maximize its utility.
CONCLUSIONS: The manual has the potential to be integrated into routine hospice care to improve the quality of pain management.}, }
@article {pmid30302281, year = {2018}, author = {Van Hoeven, N and Wiley, S and Gage, E and Fiore-Gartland, A and Granger, B and Gray, S and Fox, C and Clements, DE and Parks, DE and Winram, S and Stinchcomb, DT and Reed, SG and Coler, RN}, title = {A combination of TLR-4 agonist and saponin adjuvants increases antibody diversity and protective efficacy of a recombinant West Nile Virus antigen.}, journal = {NPJ vaccines}, volume = {3}, number = {}, pages = {39}, doi = {10.1038/s41541-018-0077-1}, pmid = {30302281}, issn = {2059-0105}, abstract = {Members of the Flaviviridae family are the leading causes of mosquito-borne viral disease worldwide. While dengue virus is the most prevalent, the recent Zika virus outbreak in the Americas triggered a WHO public health emergency, and yellow fever and West Nile viruses (WNV) continue to cause regional epidemics. Given the sporadic nature of flaviviral epidemics both temporally and geographically, there is an urgent need for vaccines that can rapidly provide effective immunity. Protection from flaviviral infection is correlated with antibodies to the viral envelope (E) protein, which encodes receptor binding and fusion functions. TLR agonist adjuvants represent a promising tool to enhance the protective capacity of flavivirus vaccines through dose and dosage reduction and broadening of antiviral antibody responses. This study investigates the ability to improve the immunogenicity and protective capacity of a promising clinical-stage WNV recombinant E-protein vaccine (WN-80E) using a novel combination adjuvant, which contains a potent TLR-4 agonist and the saponin QS21 in a liposomal formulation (SLA-LSQ). Here, we show that, in combination with WN-80E, optimized SLA-LSQ is capable of inducing long-lasting immune responses in preclinical models that provide sterilizing protection from WNV challenge, reducing viral titers following WNV challenge to undetectable levels in Syrian hamsters. We have investigated potential mechanisms of action by examining the antibody repertoire generated post-immunization. SLA-LSQ induced a more diverse antibody response to WNV recombinant E-protein antigen than less protective adjuvants. Collectively, these studies identify an adjuvant formulation that enhances the protective capacity of recombinant flavivirus vaccines.}, }
@article {pmid30300420, year = {2018}, author = {Khan, AI and Levin, A and Chao, DL and DeRoeck, D and Dimitrov, DT and Khan, JAM and Islam, MS and Ali, M and Islam, MT and Sarker, AR and Clemens, JD and Qadri, F}, title = {The impact and cost-effectiveness of controlling cholera through the use of oral cholera vaccines in urban Bangladesh: A disease modeling and economic analysis.}, journal = {PLoS neglected tropical diseases}, volume = {12}, number = {10}, pages = {e0006652}, doi = {10.1371/journal.pntd.0006652}, pmid = {30300420}, issn = {1935-2735}, abstract = {BACKGROUND: Cholera remains an important public health problem in major cities in Bangladesh, especially in slum areas. In response to growing interest among local policymakers to control this disease, this study estimated the impact and cost-effectiveness of preventive cholera vaccination over a ten-year period in a high-risk slum population in Dhaka to inform decisions about the use of oral cholera vaccines as a key tool in reducing cholera risk in such populations.
Assuming use of a two-dose killed whole-cell oral cholera vaccine to be produced locally, the number of cholera cases and deaths averted was estimated for three target group options (1-4 year olds, 1-14 year olds, and all persons 1+), using cholera incidence data from Dhaka, estimates of vaccination coverage rates from the literature, and a dynamic model of cholera transmission based on data from Matlab, which incorporates herd effects. Local estimates of vaccination costs minus savings in treatment costs, were used to obtain incremental cost-effectiveness ratios for one- and ten-dose vial sizes. Vaccinating 1-14 year olds every three years, combined with annual routine vaccination of children, would be the most cost-effective strategy, reducing incidence in this population by 45% (assuming 10% annual migration), and costing was $823 (2015 USD) for single dose vials and $591 (2015 USD) for ten-dose vials per disability-adjusted life year (DALY) averted. Vaccinating all ages one year and above would reduce incidence by >90%, but would be 50% less cost-effective ($894-1,234/DALY averted). Limiting vaccination to 1-4 year olds would be the least cost-effective strategy (preventing only 7% of cases and costing $1,276-$1,731/DALY averted), due to the limited herd effects of vaccinating this small population and the lower vaccine efficacy in this age group.
CONCLUSIONS/SIGNIFICANCE: Providing cholera vaccine to slum populations in Dhaka through periodic vaccination campaigns would significantly reduce cholera incidence and inequities, and be especially cost-effective if all 1-14 year olds are targeted.}, }
@article {pmid30300141, year = {2018}, author = {Vuckovic, S and Minnie, SA and Smith, D and Gartlan, KH and Watkins, TS and Markey, KA and Mukhopadhyay, P and Guillerey, C and Kuns, RD and Locke, KR and Pritchard, AL and Johansson, PA and Varelias, A and Zhang, P and Huntington, ND and Waddell, N and Chesi, M and Miles, JJ and Smyth, MJ and Hill, GR}, title = {Bone marrow transplantation generates T cell-dependent control of myeloma in mice.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI98888}, pmid = {30300141}, issn = {1558-8238}, abstract = {Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk*MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.}, }
@article {pmid30299481, year = {2018}, author = {Sundermann, AJ and Clancy, CJ and Pasculle, AW and Liu, G and Cumbie, RB and Driscoll, E and Ayres, A and Donahue, L and Pergam, SA and Abbo, L and Andes, DR and Chandrasekar, P and Galdys, AL and Hanson, KE and Marr, KA and Mayer, J and Mehta, S and Morris, MI and Perfect, J and Revankar, SG and Smith, B and Swaminathan, S and Thompson, GR and Varghese, M and Vazquez, J and Whimbey, E and Wingard, JR and Nguyen, MH}, title = {How Clean Is the Linen at My Hospital? The Mucorales on Unclean Linen Discovery Study of Large United States Transplant and Cancer Centers.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy669}, pmid = {30299481}, issn = {1537-6591}, abstract = {Mucormycosis outbreaks have been linked to contaminated linen. We performed fungal cultures on freshly-laundered linens at 15 transplant and cancer hospitals. At 33% of hospitals, the linens were visibly unclean. At 20%, Mucorales were recovered from >10% of linens. Studies are needed to understand the clinical significance of our findings.}, }
@article {pmid30297967, year = {2018}, author = {Weiss, CV and Roop, JI and Hackley, RK and Chuong, JN and Grigoriev, IV and Arkin, AP and Skerker, JM and Brem, RB}, title = {Genetic dissection of interspecific differences in yeast thermotolerance.}, journal = {Nature genetics}, volume = {50}, number = {11}, pages = {1501-1504}, doi = {10.1038/s41588-018-0243-4}, pmid = {30297967}, issn = {1546-1718}, abstract = {Some of the most unique and compelling survival strategies in the natural world are fixed in isolated species1. To date, molecular insight into these ancient adaptations has been limited, as classic experimental genetics has focused on interfertile individuals in populations2. Here we use a new mapping approach, which screens mutants in a sterile interspecific hybrid, to identify eight housekeeping genes that underlie the growth advantage of Saccharomyces cerevisiae over its distant relative Saccharomyces paradoxus at high temperature. Pro-thermotolerance alleles at these mapped loci were required for the adaptive trait in S. cerevisiae and sufficient for its partial reconstruction in S. paradoxus. The emerging picture is one in which S. cerevisiae improved the heat resistance of multiple components of the fundamental growth machinery in response to selective pressure. Our study lays the groundwork for the mapping of genotype to phenotype in clades of sister species across Eukarya.}, }
@article {pmid30297124, year = {2018}, author = {Mugo, NR and Eckert, L and Magaret, AS and Cheng, A and Mwaniki, L and Ngure, K and Celum, C and Baeten, JM and Galloway, DA and Wamalwa, D and Wald, A}, title = {Quadrivalent HPV vaccine in HIV-1-infected early adolescent girls and boys in Kenya: Month 7 and 12 post vaccine immunogenicity and correlation with immune status.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2018.09.059}, pmid = {30297124}, issn = {1873-2518}, abstract = {INTRODUCTION: In sub-Saharan Africa, a generation of HIV-1-infected children is approaching the age of sexual debut and becoming at risk for HPV infection and its sequelae. We assessed safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in HIV-1-infected adolescents.
METHODS: In an open-label trial among Kenyan, HIV-1-infected adolescents aged 9-14 years, we administered the qHPV vaccine at 0, 2 and 6 months and measured antibody titers to HPV-16, 18, 6 and 11 at month 7 and 12 post-vaccination. Measures of immunogenic response from HIV-1-negative historical cohorts from Africa and HIV-1 positive adolescent cohorts from the USA were used for comparison.
RESULTS: We enrolled 100 girls and 80 boys with a median age of 12 years and median baseline CD4 cell count of 684 (IQR 478, 935) cells/µL. One hundred and fifty four (86%) were receiving antiretroviral therapy for a median of 4.5 (IQR 2.3, 6.3) years; 110 (71%) had <400 copies of plasma HIV-1 RNA/mL. Of 189 enrolled children, 179 received all three doses. Two hundred and eighty five (64%) of 445 adverse events were injection site reactions; none were greater than grade 2. Of 6 Serious Adverse Events (SAEs), none were considered vaccine related. Seroconversion to HPV-18, 16, 11, 6 at month 7 occurred in 93.3%, 98.3%, 97.2% and 99.6% of vaccine recipients; similar rates have been reported in historical controls. The mean log10 HPV antibody titer measured at month 7 increased with each log10 increase in CD4 by 1.4 (95% CI: 1.1-1.7) for HPV-18; 1.2 (0.9-1.4) for HPV-16; 1.1 (0.8-1.3) for HPV-11; 0.7 (0.5-1.0) for HPV-6 (all p < 0.0001).
CONCLUSION: Almost all Kenyan HIV-1-infected adolescents mounted an immune response comparable to other immunized populations. HPV antibody titers were higher in those with preserved CD4 cell counts. Longer term-follow up will determine sustainability of the immune response. ClinicalTrials.gov number, NCT00557245.}, }
@article {pmid30296479, year = {2018}, author = {Khera, N and Hamilton, BK and Pidala, JA and Wood, WA and Wu, V and Voutsinas, J and Onstad, L and Alousi, AM and Broady, R and Chen, GL and Arora, M and Cutler, C and Flowers, ME and Ganetsky, A and Jagasia, M and McCarthy, PL and Sarantopoulos, S and Abel, GA and Majhail, NS and Lee, SJ}, title = {Employment, Insurance, and Financial Experiences of Patients with Chronic Graft-versus-Host Disease in North America.}, 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.2018.09.040}, pmid = {30296479}, issn = {1523-6536}, support = {R01 CA118953/CA/NCI NIH HHS/United States ; }, abstract = {Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56 years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group.}, }
@article {pmid30296434, year = {2018}, author = {Butt, J and Varga, MG and Blot, WJ and Teras, L and Visvanathan, K and Le Marchand, L and Haiman, C and Chen, Y and Bao, Y and Sesso, HD and Wassertheil-Smoller, S and Ho, GYF and Tinker, LE and Peek, RM and Potter, JD and Cover, TL and Hendrix, LH and Huang, LC and Hyslop, T and Um, C and Grodstein, F and Song, M and Zeleniuch-Jacquotte, A and Berndt, S and Hildesheim, A and Waterboer, T and Pawlita, M and Epplein, M}, title = {Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2018.09.054}, pmid = {30296434}, issn = {1528-0012}, support = {R01 CA077955/CA/NCI NIH HHS/United States ; R01 CA092447/CA/NCI NIH HHS/United States ; R01 CA190428/CA/NCI NIH HHS/United States ; K99 CA215314/CA/NCI NIH HHS/United States ; R01 AI039657/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States.
METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression.
RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007).
CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.}, }
@article {pmid30294925, year = {2018}, author = {Adimadhyam, S and Schumock, GT and Calip, GS and Smith Marsh, DE and Layden, BT and Lee, TA}, title = {Increased risk of mycotic infections associated with sodium-glucose co-transporter 2 inhibitors: a prescription sequence symmetry analysis.}, journal = {British journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bcp.13782}, pmid = {30294925}, issn = {1365-2125}, abstract = {AIMS: To determine the risk of mycotic infections associated with the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in a real-world setting.
METHODS: We conducted a prescription sequence symmetry analysis using data from Truven Health MarketScan (2009-2015). We selected continuously enrolled patients newly initiating both an SGLT2i and an antifungal between 1 April 2013 and 31 December 2015 within time periods of 30, 60, 90, 180 or 365 days of each other. Adjusted sequence ratios (ASR) were calculated for each time period as the ratio of patients initiating SGLT2i first over those initiating an antifungal first adjusted for time trends in prescribing. Analyses were stratified by sex and type of SGLT2i.
RESULTS: There were 23 276 patients who newly initiated both SGLT2i and an antifungal in our study period. These patients were further classified into those initiating the two drugs within 365 (n = 17 504), 180 (n = 11 873), 90 (n = 7697), 60 (n = 5856) or 30 (n = 3650) days of each other. Increased risks of mycotic infections were present across all time periods, with the strongest effect observed in the 90-day interval [ASR 1.53 (confidence interval, CI 1.43-1.60)]. Findings differed by sex [90-day ASR females: 1.65 (CI 1.56-1.74); males 1.25 (CI 1.14-1.36)] and by SGLT2i [90-day ASR canagliflozin 1.57 (CI 1.49-1.66); non-canagliflozin 1.42 (CI 1.31-1.55)].
CONCLUSION: Initiation of SGLT2i was associated with an increased risk for mycotic infections. Findings from this commercially insured population in the real world are consistent with evidence available from clinical trials.}, }
@article {pmid30294882, year = {2019}, author = {Smith, AW and Keegan, T and Hamilton, A and Lynch, C and Wu, XC and Schwartz, SM and Kato, I and Cress, R and Harlan, L and , }, title = {Understanding care and outcomes in adolescents and young adult with Cancer: A review of the AYA HOPE study.}, journal = {Pediatric blood & cancer}, volume = {66}, number = {1}, pages = {e27486}, doi = {10.1002/pbc.27486}, pmid = {30294882}, issn = {1545-5017}, support = {N01PC-2010-00029//National Cancer Institute/ ; N01PC-2010-00028//National Cancer Institute/ ; N01PC-2010-00030//National Cancer Institute/ ; N01PC-2010-00032//National Cancer Institute/ ; N01PC-2010-00034//National Cancer Institute/ ; N01PC-2010-00035//National Cancer Institute/ ; N01PC-2010-00140//National Cancer Institute/ ; }, abstract = {Historically, adolescents and young adults (AYA) diagnosed with cancer have been an understudied population, and their unique care experiences, needs, and outcomes were not well understood. Thus, 10 years ago, the National Cancer Institute supported the fielding of the Adolescent and Young Adult Health Outcomes and Patient Experiences (AYA HOPE) study to address this gap. We recruited individuals diagnosed at ages 15 to 39 with germ cell, Hodgkin and non-Hodgkin lymphoma, acute lymphoblastic leukemia, and sarcoma from Surveillance, Epidemiology, and End Results cancer registries into the first multicenter population-based study of medical care, physical, and mental health outcomes for AYAs with cancer in the United States. This review of the 17 published manuscripts showed low awareness of clinical trials and substantial impact of cancer on financial burden, education and work, relationships and family planning, and physical and mental health. It highlights the feasibility of a longitudinal population-based study and key lessons learned for research on AYAs with cancer in and beyond the United States.}, }
@article {pmid30294816, year = {2018}, author = {Chlebowski, RT and Luo, J and Anderson, GL and Barrington, W and Reding, K and Simon, MS and Manson, JE and Rohan, TE and Wactawski-Wende, J and Lane, D and Strickler, H and Mosaver-Rahmani, Y and Freudenheim, JL and Saquib, N and Stefanick, ML}, title = {Weight loss and breast cancer incidence in postmenopausal women.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31687}, pmid = {30294816}, issn = {1097-0142}, support = {30210-01//American Institute for Cancer Research/ ; 24152//National Heart, Lung, and Blood Institute/ ; 32100-2//National Heart, Lung, and Blood Institute/ ; 32105-6//National Heart, Lung, and Blood Institute/ ; 32108-9//National Heart, Lung, and Blood Institute/ ; 32111-13//National Heart, Lung, and Blood Institute/ ; 32115//National Heart, Lung, and Blood Institute/ ; 32118-32119//National Heart, Lung, and Blood Institute/ ; 32122//National Heart, Lung, and Blood Institute/ ; 42107-26//National Heart, Lung, and Blood Institute/ ; 42129-32//National Heart, Lung, and Blood Institute/ ; 44221//National Heart, Lung, and Blood Institute/ ; N01WH22110//National Heart, Lung, and Blood Institute/ ; }, abstract = {BACKGROUND: Although obesity is an established risk factor for postmenopausal breast cancer, the results of weight loss and breast cancer studies are inconsistent. Therefore, we evaluated associations between weight change and breast cancer risk in postmenopausal women in the Women's Health Initiative Observational Study.
METHODS: Postmenopausal women (n = 61,335) who had no prior breast cancer and a normal mammogram had body weight and height measured and body mass index (BMI) calculated at baseline and year 3. Weight change at year 3 was categorized as stable (<5%), loss (≥5%), or gain (≥5%) with further assessment of weight loss intentionality by self-report. Multivariable Cox proportional hazard regression models were used to evaluate relationships between weight change and subsequent breast cancer incidence.
RESULTS: During a mean follow-up of 11.4 years with 3061 incident breast cancers, women with weight loss (n = 8175) had a significantly lower risk of breast cancer compared with women whose weight remained stable (n = 41,139) (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.78-0.98; P = .02) with no interaction by BMI. Adjustment for mammography did not alter findings (HR, 0.88; 95% CI, 0.78-0.99) with no significant difference by weight loss intentionality. Weight gain (≥5%) (n = 12,021) was not associated with breast cancer risk (HR, 1.02; 95% CI, 0.93-1.11) but was associated with higher triple-negative breast cancer incidence (HR, 1.54; 95% CI, 1.16-2.05).
CONCLUSIONS: Postmenopausal women who lose weight have lower breast cancer risk than those with stable weight. These findings suggest that postmenopausal women who lose weight may reduce their breast cancer risk.}, }
@article {pmid30293490, year = {2018}, author = {Hanscom, B and Hughes, JP and Williamson, BD and Donnell, D}, title = {Adaptive non-inferiority margins under observable non-constancy.}, journal = {Statistical methods in medical research}, volume = {}, number = {}, pages = {962280218801134}, doi = {10.1177/0962280218801134}, pmid = {30293490}, issn = {1477-0334}, abstract = {A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the 'constancy' assumption. If the constancy assumption fails, decisions based on the chosen non-inferiority margin may be incorrect, and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. When there are strong, observable predictors of constancy, such as dosing and adherence to the active-control product, we can specify conditions where the constancy assumption will likely fail. We propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population characteristics. We describe a pre-specified method, using baseline characteristics or post-baseline predictors in the active-control arm, to adapt the non-inferiority margin at the end of the study if constancy is violated. Adaptive margins can help adjust for constancy violations that will inevitably occur in real clinical trials, while maintaining pre-specified levels of Type I error and power.}, }
@article {pmid30293246, year = {2018}, author = {Stewart, BT and Anderson, BO}, title = {Outpatient surgical care in sub-Saharan Africa: Learning points for low- and high-income settings.}, journal = {Journal of surgical oncology}, volume = {118}, number = {6}, pages = {859-860}, doi = {10.1002/jso.25212}, pmid = {30293246}, issn = {1096-9098}, }
@article {pmid30292744, year = {2018}, author = {Marty, FM and Winston, DJ and Chemaly, RF and Mullane, KM and Shore, TB and Papanicolaou, GA and Chittick, G and Brundage, TM and Wilson, C and Morrison, ME and Foster, SA and Nichols, WG and Boeckh, MJ and , }, title = {A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in 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.2018.09.038}, pmid = {30292744}, issn = {1523-6536}, abstract = {Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.}, }
@article {pmid30291839, year = {2018}, author = {Doll, KM and Khor, S and Odem-Davis, K and He, H and Wolff, EM and Flum, DR and Ramsey, SD and Goff, BA}, title = {Role of bleeding recognition and evaluation in Black-White disparities in endometrial cancer.}, journal = {American journal of obstetrics and gynecology}, volume = {219}, number = {6}, pages = {593.e1-593.e14}, doi = {10.1016/j.ajog.2018.09.040}, pmid = {30291839}, issn = {1097-6868}, abstract = {BACKGROUND: Advanced stage at diagnosis is an independent, unexplained contributor to racial disparity in endometrial cancer.
OBJECTIVE: We sought to investigate whether, prior to diagnosis, provider recognition of the cardinal symptom of endometrial cancer, postmenopausal bleeding, differs by patient race.
STUDY DESIGN: Black and White women diagnosed with endometrial cancer (2001 through 2011) from Surveillance, Epidemiology, and End Results-Medicare who had at least 2 years of claims prior to diagnosis were identified. Bleeding diagnoses along with procedures done prior to diagnosis were captured via claims data. Multinomial logistic regression was used to evaluate the association of race with diagnostic workup and multivariate models built to determine the association of appropriate diagnostic procedures with stage at diagnosis.
RESULTS: In all, 4354 White and 537 Black women diagnosed with endometrial cancer were included. Compared to White women, Black women were less likely to have guideline-concordant care: postmenopausal bleeding and appropriate diagnostic evaluation (70% vs 79%, P < .001), with adjusted relative risk ratios of 1.12-1.73 for different nonguideline-concordant pathways: bleeding without diagnostic procedures, alternative bleeding descriptions, and neither bleeding nor procedures. These pathways were associated with higher odds of advanced stage at diagnosis (adjusted odds ratio, 1.90-2.88).
CONCLUSION: The lack of recognition and evaluation of postmenopausal bleeding is associated with advanced stage at diagnosis in endometrial cancer. Older Black women are at highest risk for the most aggressive histology types, yet they are less likely to have guideline-concordant evaluation of vaginal bleeding. Efforts aimed at improving recognition-among patients and providers-of postmenopausal bleeding in Black women could substantially reduce disparities in endometrial cancer.}, }
@article {pmid30291811, year = {2018}, author = {Ullrich, CK and Dussel, V and Orellana, L and Kang, TI and Rosenberg, AR and Feudtner, C and Wolfe, J}, title = {Self-reported fatigue in children with advanced cancer: Results of the PediQUEST study.}, journal = {Cancer}, volume = {124}, number = {18}, pages = {3776-3783}, doi = {10.1002/cncr.31639}, pmid = {30291811}, issn = {1097-0142}, support = {K07 CA096746/CA/NCI NIH HHS/United States ; 1K07 CA096746-01//National Institutes of Health/National Cancer Institute/ ; 1K23 HL107452//National Institutes of Health/National Heart, Lung, and Blood Institute/ ; //American Cancer Society Pilot and Exploratory Project Award in Palliative Care of Cancer Patients and Their Families/ ; K23 HL107452/HL/NHLBI NIH HHS/United States ; //Charles H. Hood Foundation Child Health Research Award/ ; }, abstract = {BACKGROUND: Pediatric cancer-related fatigue is prevalent and significantly impairs health-related quality of life, yet its patterns and correlates are poorly understood. The objectives of this study were to describe fatigue as prospectively reported by children with advanced cancer and to identify the factors associated with fatigue and associated distress.
METHODS: Children (age ≥2 years) with advanced cancer (N = 104) or their parents at 3 academic hospitals reported symptoms at most weekly over 9 months using the computer-based Pediatric Quality of Life Evaluation of Symptoms Technology (PediQUEST) system. PediQUEST administered a modified version of the Memorial Symptom Assessment Scale (PQ-MSAS) as part of a randomized controlled trial. Clinical information was abstracted from medical records. Primary outcomes were: 1) fatigue prevalence (yes/no response to PQ-MSAS fatigue item) and 2) fatigue distress (composite score of severity, frequency, and bother). Multivariable models were constructed to identify factors independently associated with fatigue prevalence and scores reflecting fatigue distress (ie, burden).
RESULTS: Of 920 reports, 46% (n = 425) noted fatigue. When reported, fatigue was of high frequency in 41% of respondents (n = 174), severity in 25%of respondents (n = 107), and bother in 34%of respondents (n = 143). Most reports (84%; n = 358) were associated with scores indicating fatigue distress. In multivariable analyses, fatigue was associated with older age, lower hemoglobin, and distress from particular symptoms (anorexia, nausea, sleep disturbance, sadness, and irritability). In contrast, fatigue distress was associated with distress from nausea, cough, and pain.
CONCLUSIONS: Fatigue is common among children with advanced cancer and is often highly distressing. Interventions focused on uncontrolled symptoms may ease fatigue distress in children with advanced cancer.}, }
@article {pmid30291334, year = {2018}, author = {Humbert, O and Laszlo, GS and Sichel, S and Ironside, C and Haworth, KG and Bates, OM and Beddoe, ME and Carrillo, RR and Kiem, HP and Walter, RB}, title = {Engineering resistance to CD33-targeted immunotherapy in normal hematopoiesis by CRISPR/Cas9-deletion of CD33 exon 2.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-018-0277-8}, pmid = {30291334}, issn = {1476-5551}, support = {6489-16//Leukemia and Lymphoma Society (LLS)/ ; }, }
@article {pmid30291306, year = {2018}, author = {Chung, SH and Hughes, G and Koffman, B and Turtle, CJ and Maloney, DG and Acharya, UH}, title = {Not so crystal clear: observations from a case of crystalline arthritis with cytokine release syndrome (CRS) after chimeric antigen receptor (CAR)-T cell therapy.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-018-0357-4}, pmid = {30291306}, issn = {1476-5365}, }
@article {pmid30291105, year = {2018}, author = {Luebeck, GE and Hazelton, WD and Curtius, K and Maden, SK and Yu, M and Carter, KT and Burke, W and Lampe, PD and Li, CI and Ulrich, CM and Newcomb, PA and Westerhoff, M and Kaz, AM and Luo, Y and Inadomi, JM and Grady, WM}, title = {Implications of epigenetic drift in colorectal neoplasia.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-18-1682}, pmid = {30291105}, issn = {1538-7445}, support = {U01 CA182940/CA/NCI NIH HHS/United States ; U01 CA199336/CA/NCI NIH HHS/United States ; }, abstract = {Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here we identify and validate 781 CpG-islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced (~3-4 fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were broadly consistent with modeled adenoma-carcinoma sojourn time distributions from colorectal cancer (CRC) incidence data. These results support the hypothesis that, beginning with the founder premalignant cell, cancer precursors frequently sojourn for decades before turning into cancer, implying that the founder cell typically arises early in life. At least 77-89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplastic progression, while only 55% of the variance was explained for proximal tumors. However, gene-CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of CRC. Methylomic drift advanced in colorectal neoplasia consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in CRC. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing CRC incidence.}, }
@article {pmid30289980, year = {2018}, author = {El-Jawahri, A and LeBlanc, TW and Burns, LJ and Denzen, E and Meyer, C and Mau, LW and Roeland, EJ and Wood, WA and Petersdorf, E}, title = {What Do Transplant Physicians Think About Palliative Care? A National Survey Study.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31709}, pmid = {30289980}, issn = {1097-0142}, support = {AI069197, CA162194, CA100019, and CA218185//National Institutes of Health/ ; R01 CA231838/CA/NCI NIH HHS/United States ; L30 CA209031/CA/NCI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; K12 CA087723/CA/NCI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; K12 Program//National Cancer Institute/ ; }, abstract = {BACKGROUND: Despite its established benefits, palliative care (PC) is rarely utilized for hematopoietic stem cell transplant (HSCT) patients. We sought to examine transplant physicians' perceptions of PC.
METHODS: We conducted a cross-sectional survey of transplant physicians recruited from the American-Society-for-Blood-and-Marrow-Transplantation. Using a 28-item questionnaire adapted from prior studies, we examined physicians' access to PC services, and perceptions of PC. We computed a composite score of physicians' attitudes about PC (mean = 16.9, SD = 3.37) and explored predictors of attitudes using a linear mixed model.
RESULTS: 277/1005 (28%) of eligible physicians completed the questionnaire. The majority (76%) stated that they trust PC clinicians to care for their patients, but 40% felt that PC clinicians do not have enough understanding to counsel HSCT patients about their treatments. Most endorsed that when patients hear the term PC, they feel scared (82%) and anxious (76%). Nearly half (46%) reported that the service name 'palliative care' is a barrier to utilization. Female sex (β = 0.85, P = .024), having <10 years of clinical practice (β = 1.39, P = .004), and perceived quality of PC services (β = 0.60, P < .001) were all associated with a more positive attitude towards PC. Physicians with a higher sense of ownership over their patients' PC issues (β = -0.36, P < .001) were more likely to have a negative attitude towards PC.
CONCLUSIONS: The majority of transplant physicians trust PC, but have substantial concerns about PC clinicians' knowledge about HSCT and patients' perception of the term 'palliative care'. Interventions are needed to promote collaboration, improve perceptions, and enhance integration of PC for HSCT recipients.}, }
@article {pmid30289813, year = {2019}, author = {Stoner, MCD and Nguyen, N and Kilburn, K and Gómez-Olivé, FX and Edwards, JK and Selin, A and Hughes, JP and Agyei, Y and Macphail, C and Kahn, K and Pettifor, A}, title = {Age-disparate partnerships and incident HIV infection in adolescent girls and young women in rural South Africa.}, journal = {AIDS (London, England)}, volume = {33}, number = {1}, pages = {83-91}, doi = {10.1097/QAD.0000000000002037}, pmid = {30289813}, issn = {1473-5571}, support = {R01 MH110186/MH/NIMH NIH HHS/United States ; R01 MH087118/MH/NIMH NIH HHS/United States ; T32 MH019139/MH/NIMH NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; R24 HD050924/HD/NICHD NIH HHS/United States ; P2C HD050924/HD/NICHD NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {OBJECTIVE: Adolescent girls and young women (AGYW) have a much higher risk of HIV infection than young men of the same age. One hypothesis for this disparity is AGYW are more likely to be in sexual partnerships with older men with HIV; however, evidence has been inconclusive.
DESIGN: We used longitudinal data from a randomized trial in South Africa (HPTN 068) to determined whether partner age difference is associated with incident HIV infection in AGYW.
METHODS: Age difference was examined continuously and dichotomously (≥5 years). We examined inverse probability of exposure weighted survival curves and calculated time-specific risk differences and risk ratios over 5.5 years of follow-up. We also used a marginal structural Cox model to estimate hazard ratios over the entire study period.
RESULTS: Risk of HIV was higher in AGYW with an age-disparate partnership versus not and the risk difference was largest at later time points. At 5.5 years, AGYW with an age-disparate partnership had a 12.6% (95% confidence interval 1.9-23.3) higher risk than AGYW with no age-disparate partnerships. The weighted hazard ratio was 1.91 (95% confidence interval 1.33-2.74), an association that remained after weighting for either transactional or condomless sex, and after examining continuous age-differences.
CONCLUSION: Age-disparate partnerships increased risk of HIV infection, even after accounting for transactional sex and condomless sex. The relationship between age-disparate partnerships and HIV infection may be explained by increased exposure to infection from men in a higher HIV prevalence pool rather than differences in sexual behaviour within these partnerships.}, }
@article {pmid30289810, year = {2018}, author = {Ford, ES and Magaret, AS and Spak, CW and Selke, S and Kuntz, S and Corey, L and Wald, A}, title = {Increase in HSV shedding at initiation of antiretroviral therapy and decrease in shedding over time on antiretroviral therapy in HIV and HSV-2 infected persons.}, journal = {AIDS (London, England)}, volume = {32}, number = {17}, pages = {2525-2531}, doi = {10.1097/QAD.0000000000002002}, pmid = {30289810}, issn = {1473-5571}, abstract = {OBJECTIVES: HIV-infected persons with chronic herpesvirus infections may experience paradoxical worsening after initiation of antiretroviral therapy (ART), but the impact of longer term ART is unclear. We evaluated the relationships between genital herpes simplex virus (HSV) shedding and ART initiation and time on therapy in HIV and HSV-2-infected persons.
DESIGN: Prospective observational study.
METHODS: Rates of HSV shedding in 45 HIV and HSV-2-infected persons on or off ART were prospectively followed over up to three, noncontiguous, 60-day periods, during which participants performed daily genital swabs for HSV detection by real-time HSV DNA PCR and reported symptoms. Initiation or discontinuation of ART was at the discretion of participants' healthcare providers.
RESULTS: In all, 6425 daily genital swabs were obtained from 45 persons (38 men and seven women) during 105 swabbing sessions. During the three sessions, 67, 74, and 92% of persons were on ART. HSV was detected on 26.5% of days in men and 22.3% of days in women. The overall rates of genital HSV shedding were 19.4% of days in persons not on ART, 30.2% in persons within 90 days of ART initiation, and 23.3% in persons on ART for longer than 90 days. After initiation of ART, HSV shedding decreased by 2% per month, or 23% per year (RR 0.98/month on ART; P = 0.0003 in adjusted analysis). This finding was consistent after including consideration of HIV viral load and CD4 cell count.
CONCLUSIONS: HSV shedding increased significantly shortly after ART initiation, but decreased with time on prolonged ART.}, }
@article {pmid30289485, year = {2018}, author = {Chen, BA and Zhang, J and Gundacker, HM and Hendrix, CW and Hoesley, CJ and Salata, RA and Dezzutti, CS and van der Straten, A and Hall, WB and Jacobson, CE and Johnson, S and McGowan, I and Nel, AM and Soto-Torres, L and Marzinke, MA and , }, title = {Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy654}, pmid = {30289485}, issn = {1537-6591}, abstract = {Background: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women.
Methods: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report.
Results: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR.
Conclusions: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women.
Clinical Trials Registration: ClinicalTrials.gov identifier: NCT02010593.}, }
@article {pmid30289444, year = {2018}, author = {Liu, AY and Zhang, J and Anderson, PL and Wagner, T and Pan, Z and Peda, M and Gomez, K and Beamer, M and Jacobson, C and Strizki, J and Dezzutti, CS and Piper, JM and , }, title = {Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy652}, pmid = {30289444}, issn = {1537-6591}, abstract = {Background: Vaginal rings (VRs) are a promising approach for sustained delivery of antiretroviral (ARV) medication to prevent human immunodeficiency virus (HIV) infection in women. Combination ARV VRs could increase efficacy.
Methods: MTN-028, a phase 1 trial in 19 HIV-uninfected women, evaluated 2 VRs containing vicriviroc (VCV) and MK-2048. Participants were randomized 2:1 to a low-dose (VCV, 91 mg; MK-2048, 10 mg) or original-dose (VCV, 182 mg; MK-2048, 30 mg) ring used for 28 days. Safety was assessed by documenting adverse events (AEs). Drug concentrations were evaluated in plasma, cervicovaginal fluid (CVF), and cervical tissue samples.
Results: All AEs reported were grade 1 or 2, with no statistically significant differences in related genitourinary AEs or grade ≥2 AEs observed between arms (P = >.99). VCV/MK-2048 concentrations rose rapidly, with higher plasma area under the concentration-time curve (AUC) in the original-dose arm (geometric mean ratio, 3.29 for VCV and 1.49 for MK-2048) and similar AUCs across arms for CVF samples. Cervical tissue concentrations were higher in the original-dose arm (geometric mean ratio, 7.94 for VCV and 6.45 for MK-2048), with greater drug released based on residual drug levels. Plasma and CVF concentrations for both drugs fell rapidly after ring removal.
Conclusions: In this first study evaluating 2 doses of a combination VCV/MK-2048 VR, both rings were found to be safe and well tolerated. VCV and MK-2048 were detectable in plasma, CVF, and cervical tissue samples, and drug release and plasma drug exposure were higher for the original-dose than for the low-dose ring.}, }
@article {pmid30289435, year = {2018}, author = {Hoesley, CJ and Chen, BA and Anderson, PL and Dezzutti, CS and Strizki, J and Sprinkle, C and Heard, F and Bauermeister, J and Hall, W and Jacobson, C and Berthiaume, J and Mayo, A and Gundacker, H and Richardson-Harman, N and Piper, J and , }, title = {Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy653}, pmid = {30289435}, issn = {1537-6591}, abstract = {Background: Vaginal rings (VR) containing antiretroviral (ARV) drugs can be utilized for prevention of human immunodeficiency virus (HIV) with potential for improved adherence compared to daily pills. Combination ARV VRs could improve efficacy.
Methods: MTN-027, a single-blind, randomized, placebo-controlled trial in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo used continuously for 28 days. Safety was assessed by recording adverse events. Drug concentrations were quantified in plasma, vaginal fluid, cervical tissue, and rectal fluid. Cervical tissue was utilized for ex vivo HIV inhibition analysis.
Results: There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable.
Conclusions: VCV and/or MK-2048 containing VRs were safe and acceptable. Both VCV and MK-2048 were quantifiable in all matrixes tested with peak compartmental drug concentrations similar for single and combination drug VRs. Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships.}, }
@article {pmid30287390, year = {2018}, author = {Norkin, M and Shaw, BE and Brazauskas, R and Tecca, HR and Leather, HL and Gea-Banacloche, J and T Kamble, R and DeFilipp, Z and Jacobsohn, DA and Ringden, O and Inamoto, Y and A Kasow, K and Buchbinder, D and Shaw, P and Hematti, P and Schears, R and Badawy, SM and Lazarus, HM and Bhatt, N and Horn, B and Chhabra, S and M Page, K and Hamilton, B and Hildebrandt, GC and Yared, JA and Agrawal, V and M Beitinjaneh, A and Majhail, N and Kindwall-Keller, T and Olsson, RF and Schoemans, H and Gale, RP and Ganguly, S and A Ahmed, I and Schouten, HC and L Liesveld, J and Khera, N and Steinberg, A and Shah, AJ and Solh, M and Marks, DI and Rybka, W and Aljurf, M and Dietz, AC and Gergis, U and George, B and Seo, S and Flowers, MED and Battiwalla, M and Savani, BN and Riches, ML and Wingard, JR}, title = {Characteristics of Late Fatal Infections after 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.2018.09.031}, pmid = {30287390}, issn = {1523-6536}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.}, }
@article {pmid30287277, year = {2018}, author = {Yu, EY and Gillessen, S and Mottet, N}, title = {What Do the Guidelines Say for Metastatic Prostate Cancer Starting Androgen Deprivation Therapy? National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology recommendations.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2018.09.015}, pmid = {30287277}, issn = {2405-4569}, abstract = {Clinical trial data forms the foundation of how we treat men with metastatic prostate cancer who are initiating therapy. However, clinical trial data does not answer everything; hence, good clinical practice, pragmatism, and occasionally extrapolation drives how we manage these patients. Fortunately, multiple international guideline committees meet regularly and offer clinical guidance. In this mini-review, we focus on the United States National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology (EAU) recommendations for the initial treatment of metastatic prostate cancer.}, }
@article {pmid30285852, year = {2018}, author = {Giraldo, NA and Nguyen, P and Engle, EL and Kaunitz, GJ and Cottrell, TR and Berry, S and Green, B and Soni, A and Cuda, JD and Stein, JE and Sunshine, JC and Succaria, F and Xu, H and Ogurtsova, A and Danilova, L and Church, CD and Miller, NJ and Fling, S and Lundgren, L and Ramchurren, N and Yearley, JH and Lipson, EJ and Cheever, M and Anders, RA and Nghiem, PT and Topalian, SL and Taube, JM}, title = {Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.}, journal = {Journal for immunotherapy of cancer}, volume = {6}, number = {1}, pages = {99}, doi = {10.1186/s40425-018-0404-0}, pmid = {30285852}, issn = {2051-1426}, support = {P30 CA006973//Sidney Kimmel Comprehensive Cancer Center/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA142779//National Cancer Institute/ ; T32 CA193145/CA/NCI NIH HHS/United States ; UM1 CA154967//National Institutes of Health/ ; K24 CA139052/CA/NCI NIH HHS/United States ; UM1 CA154967/CA/NCI NIH HHS/United States ; K24 CA139052//National Cancer Institute/ ; IH/NCI Cancer Center Support Grant P30 CA015704//National Institutes of Health/ ; T32 CA193145//National Institutes of Health/ ; SU2C-AACR-DT1012//Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant/ ; R01 CA142779/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified.
METHODS: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1.
RESULTS: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1.
CONCLUSIONS: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.}, }
@article {pmid30283148, year = {2018}, author = {Pahnke, S and Egeland, T and Halter, J and Hägglund, H and Shaw, BE and Woolfrey, AE and Szer, J and , }, title = {Current use of biosimilar G-CSF for haematopoietic stem cell mobilisation.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-018-0350-y}, pmid = {30283148}, issn = {1476-5365}, abstract = {Despite biosimilars of the granulocyte-colony stimulating factor (G-CSF) filgrastim being approved by the European Medicines Agency since 2008, there is still some debate regarding their use in related and unrelated healthy haematopoietic stem cell donors. We present a review of published experiences using biosimilar filgrastim for healthy donor mobilisation as well as the results of a survey by the World Marrow Donor Association (WMDA) of its current use by register-associated transplant and collection centres for both related and unrelated donors. A total of 1287 healthy donors and volunteers are included in the reviewed studies. The pharmacokinetics and pharmacodynamics studies show a high degree of similarity to the reference product Neupogen. Mobilisation of CD34 + cells as well as reported adverse events are also found to be comparable, although there is still a lack of long-term follow up for both Neupogen and filgrastim biosimilars. No evidence is found of a higher risk of filgrastim antibody formation using filgrastim biosimilars. Based on this increased experience, the WMDA therefore recommend that Stem Cell Donor Registries can use filgrastim biosimilars for the mobilisation of peripheral blood progenitor cells in healthy donors, provided that they are approved by national and/or regional agencies.}, }
@article {pmid30282788, year = {2018}, author = {Cook, L and Starr, K and Boonyaratanakornkit, J and Hayden, R and Sam, SS and Caliendo, AM}, title = {Does Size Matter? Comparison of Extraction Yields for Different-Sized DNA Fragments by Seven Different Routine and Four New Circulating Cell-Free Extraction Methods.}, journal = {Journal of clinical microbiology}, volume = {56}, number = {12}, pages = {}, doi = {10.1128/JCM.01061-18}, pmid = {30282788}, issn = {1098-660X}, abstract = {An element essential for PCR detection of microbial agents in many sample types is the extraction step, designed to purify nucleic acids. Despite the importance of this step, yields have not been extensively compared across methods to determine whether the method used contributes to quantitative differences and the lack of commutability seen with existing clinical methods. This may in part explain why plasma and blood viral load assays have proven difficult to standardize. Also, studies have identified small DNA fragments of <200 bp in plasma (cell-free DNA [cfDNA]), which may include significant quantities of viral DNA. Our study evaluated extraction yields for 11 commercially available extraction methods, including 4 new methods designed to isolate cfDNA. Solutions of DNA fragments with sizes ranging from 50 to 1,500 bp were extracted, and then the eluates were tested by droplet digital PCR to determine the DNA fragment yield for each method. The results demonstrated a wide range of extraction yields across the variety of methods/instruments used, with the 50- and 100-bp fragment sizes showing especially inconsistent quantitative results and poor yields of less than 20%. Slightly higher, more consistent yields were seen with 2 of the 4 circulating cell-free extraction kits. These results demonstrate a significant need for further evaluation of nucleic acid yields across the variety of extraction platforms and highlight the poor extraction yields of small DNA fragments by existing methods. Further work is necessary to determine the impact of this inconsistency across instruments and the relevance of the low yields for smaller DNA fragments in clinical virology testing.}, }
@article {pmid30282661, year = {2018}, author = {Nakamura, M and Dominguez, ANM and Decker, JR and Hull, AJ and Verboon, JM and Parkhurst, SM}, title = {Into the breach: how cells cope with wounds.}, journal = {Open biology}, volume = {8}, number = {10}, pages = {}, doi = {10.1098/rsob.180135}, pmid = {30282661}, issn = {2046-2441}, support = {R01 GM111635/GM/NIGMS NIH HHS/United States ; }, abstract = {Repair of wounds to individual cells is crucial for organisms to survive daily physiological or environmental stresses, as well as pathogen assaults, which disrupt the plasma membrane. Sensing wounds, resealing membranes, closing wounds and remodelling plasma membrane/cortical cytoskeleton are four major steps that are essential to return cells to their pre-wounded states. This process relies on dynamic changes of the membrane/cytoskeleton that are indispensable for carrying out the repairs within tens of minutes. Studies from different cell wound repair models over the last two decades have revealed that the molecular mechanisms of single cell wound repair are very diverse and dependent on wound type, size, and/or species. Interestingly, different repair models have been shown to use similar proteins to achieve the same end result, albeit sometimes by distinctive mechanisms. Recent studies using cutting edge microscopy and molecular techniques are shedding new light on the molecular mechanisms during cellular wound repair. Here, we describe what is currently known about the mechanisms underlying this repair process. In addition, we discuss how the study of cellular wound repair-a powerful and inducible model-can contribute to our understanding of other fundamental biological processes such as cytokinesis, cell migration, cancer metastasis and human diseases.}, }
@article {pmid30282622, year = {2018}, author = {Mngadi, KT and Maharaj, B and Duki, Y and Grove, D and Andriesen, J}, title = {Using Mobile Technology (pMOTAR) to Assess Reactogenicity: Protocol for a Pilot Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {7}, number = {10}, pages = {e175}, doi = {10.2196/resprot.9396}, pmid = {30282622}, issn = {1929-0748}, abstract = {BACKGROUND: Accurate safety monitoring in HIV vaccine trials is vital to eventual licensure and consequent uptake of products. Current practice in preventive vaccine trials, under the HIV Vaccine Trials Network (HVTN), is to capture related side effects in a hardcopy tool. The reconciliation of this tool, 2 weeks after vaccination at the safety visit, is time consuming, laborious, and fraught with error. Unstructured Supplementary Service Data (USSD), commonly used to purchase airtime, has been suggested for collection of safety data in vaccine trials. With saturated access to mobile phones in South Africa, this cheap, accessible tool may improve accuracy and completeness of collected data and prove feasible and acceptable over the hardcopy tool.
OBJECTIVE: The objective of our study is to develop and implement a USSD tool for real-time safety data collection that is feasible and acceptable to participants and staff, allowing for a comparison with the hardcopy tool in terms of completeness and accuracy.
METHODS: This feasibility study is being conducted at a single study site, the Centre for the AIDS Programme of Research in South Africa eThekwini Clinical Research site, in South Africa. The feasibility study is nested within a parent phase 1/2a preventive HIV vaccine trial (HVTN 108) as an open-label, randomized controlled trial, open to all consenting parent trial participants. Participants are randomly assigned in a 1:1 ratio to the hardcopy or USSD tool, with data collection targeted to the third and fourth injection time points in the parent trial. Online feasibility and acceptability surveys will be completed by staff and participants at the safety visit. We will itemize and compare error rates between the hardcopy tool and the USSD printout and associated source documentation. We hypothesize that the USSD tool will be shown to be feasible and acceptable to staff and participants and to have superior quality and completion rates to the hardcopy tool.
RESULTS: The study has received regulatory approval. We have designed and developed the USSD tool to include all the data fields required for reactogenicity reporting. Online feasibility and accessibility surveys in both English and isiZulu have been successfully installed on a tablet. Data collection is complete, but analysis is pending.
CONCLUSIONS: Several HIV preventive vaccine trials are active in Southern Africa, making tools to improve efficiencies and minimize error necessary. Our results will help to determine whether the USSD tool can be used in future vaccine studies and can eventually be rolled out.
TRIAL REGISTRATION: ClincalTrials.gov NCT02915016; https://clinicaltrials.gov/ct2/show/NCT02915016 (Archived by WebCite at http://www.webcitation.org/71h0cztDM).
REGISTERED REPORT IDENTIFIER: RR1-10.2196/9396.}, }
@article {pmid30281145, year = {2018}, author = {Jeter, JM and Bowles, TL and Curiel-Lewandrowski, C and Swetter, SM and Filipp, FV and Abdel-Malek, ZA and Geskin, LJ and Brewer, JD and Arbiser, JL and Gershenwald, JE and Chu, EY and Kirkwood, JM and Box, NF and Funchain, P and Fisher, DE and Kendra, KL and Marghoob, AA and Chen, SC and Ming, ME and Albertini, MR and Vetto, JT and Margolin, KA and Pagoto, SL and Hay, JL and Grossman, D and Ellis, DL and Kashani-Sabet, M and Mangold, AR and Markovic, SN and Nelson, KC and Powers, JG and Robinson, JK and Sahni, D and Sekulic, A and Sondak, VK and Wei, ML and Zager, JS and Dellavalle, RP and Thompson, JA and Weinstock, MA and Leachman, SA and Cassidy, PB}, title = {Chemoprevention agents for melanoma: a path forward into phase 3 clinical trials.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.31719}, pmid = {30281145}, issn = {1097-0142}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, abstract = {Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.}, }
@article {pmid30281109, year = {2018}, author = {Neuhouser, ML}, title = {90th Anniversary Commentary: Vitamin D Is Critical for Human Nutrition, but Research Is Still Needed to Identify Optimal Blood Concentrations and Intake Levels for Human Health.}, journal = {The Journal of nutrition}, volume = {148}, number = {10}, pages = {1686-1687}, doi = {10.1093/jn/nxy122}, pmid = {30281109}, issn = {1541-6100}, }
@article {pmid30280289, year = {2018}, author = {Appelbaum, JS and Milano, F}, title = {Hematopoietic Stem Cell Transplantation in the Era of Engineered Cell Therapy.}, journal = {Current hematologic malignancy reports}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11899-018-0476-4}, pmid = {30280289}, issn = {1558-822X}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19+ B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients.
RECENT FINDINGS: Within the past 2 years, results from larger trials and increased follow-up of patients treated with CD19 CAR-T cell therapy suggest that some may achieve durable remission without transplant. The balance of efficacy and toxicity for CAR-T cell therapy and alloHCT vary by disease type, disease status at the time of treatment, patient characteristics, and the specific therapy employed. There are early signals that subsequent transplantation of patients who have achieved remission with CAR-T may be a potentially viable (though expensive) strategy.}, }
@article {pmid30279968, year = {2018}, author = {MacLeod, JA and Gao, Y and Hall, C and Muller, WJ and Gujral, TS and Greer, PA}, title = {Genetic disruption of calpain-1 and calpain-2 attenuates tumorigenesis in mouse models of HER2+ breast cancer and sensitizes cancer cells to doxorubicin and lapatinib.}, journal = {Oncotarget}, volume = {9}, number = {70}, pages = {33382-33395}, doi = {10.18632/oncotarget.26078}, pmid = {30279968}, issn = {1949-2553}, abstract = {Calpains are a family of calcium activated cysteine proteases which participate in a wide range of cellular functions including migration, invasion, autophagy, programmed cell death, and gene expression. Calpain-1 and calpain-2 isoforms are ubiquitously expressed heterodimers composed of isoform specific catalytic subunits coupled with an obligate common regulatory subunit encoded by capns1. Here, we report that conditional deletion of capns1 disrupted calpain-1 and calpain-2 expression and activity, and this was associated with delayed tumorigenesis and altered signaling in a transgenic mouse model of spontaneous HER2+ breast cancer and effectively blocked tumorigenesis in an orthotopic engraftment model. Furthermore, capns1 knockout in a tumor derived cell line correlated with enhanced sensitivity to the chemotherapeutic doxorubicin and the HER2/EGFR tyrosine kinase inhibitor lapatinib. Collectively, these results indicate pro-tumorigenic roles for calpains-1/2 in HER2+ breast cancer and provide evidence that calpain-1/2 inhibitors could have anti-tumor effects if used either alone or in combination with chemotherapeutics and targeted agents.}, }
@article {pmid30279575, year = {2018}, author = {Pingel, J and Wang, T and Hagenlocher, Y and Hernández-Frederick, CJ and Nagler, A and Haagenson, MD and Fleischhauer, K and Hsu, KC and Verneris, MR and Lee, SJ and Mohty, M and Polge, E and Spellman, SR and Schmidt, AH and van Rood, JJ}, title = {The effect of NIMA matching in adult unrelated mismatched hematopoietic stem cell transplantation - a joint study of the Acute Leukemia Working Party of the EBMT and the CIBMTR.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-018-0345-8}, pmid = {30279575}, issn = {1476-5365}, support = {5U24CA076518//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; 4U10HL069294//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSH250201200016C//U.S. Department of Health & Human Services | Health Resources and Services Administration (HRSA)/ ; N00014-17-1-2388//DOD | Office of Naval Research (ONR)/ ; N0014-17-1-2850//DOD | Office of Naval Research (ONR)/ ; }, abstract = {Hematological malignancies can be cured by unrelated donor allogeneic HSCT and outcomes are optimized by high-resolution HLA matching at HLA-A, -B, -C, -DRB1 and -DQB1 (10/10 match). If a 10/10 match is unavailable, 9/10 matches may be suitable. Fetal exposure to non-inherited maternal antigens (NIMA) may impart lifelong NIMA tolerance modulating the immune response, as shown in adult haploidentical transplantation. In cord blood transplantation, NIMA matching lowered rates of aGvHD and TRM; in haploidentical transplantation, sibling donors with non-shared maternal antigens showed less grade II-IV aGvHD. This retrospective analysis examined if 9/10 matched unrelated donor HSCT benefits from NIMA matching. DKMS contacted 1,735 donors and obtained 733 (42%) maternal samples. NIMA-matched and -mismatched cases with a minimum follow-up of 1 year were compared by univariate and multivariate analyses adjusted for co-variates for OS, DFS, relapse, TRM and a/cGvHD. The study population (N = 445) comprised 31 NIMA-matched and 414 NIMA-mismatched cases. No significant differences between NIMA-matched and NIMA-mismatched groups were found for any outcomes with similar OS and TRM rates within both groups. This study provides the proof of principle that NIMA matching is possible in the unrelated donor HSCT setting; larger studies may be able to provide significant results.}, }
@article {pmid30279573, year = {2018}, author = {Sorror, ML and Gooley, TA and Maclean, KH and Hubbard, J and Marcondes, MA and Torok-Storb, BJ and Tewari, M}, title = {Pre-transplant expressions of microRNAs, comorbidities, and post-transplant mortality.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-018-0352-9}, pmid = {30279573}, issn = {1476-5365}, support = {HL088021//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R00 HL088021/HL/NHLBI NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; RSG-13-084-01-CPHPS//American Cancer Society (American Cancer Society, Inc.)/ ; U01 HL099993/HL/NHLBI NIH HHS/United States ; HL099993//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; K99 HL088021/HL/NHLBI NIH HHS/United States ; CE-1304-7451//Patient-Centered Outcomes Research Institute (PCORI)/ ; }, abstract = {We analyzed micro-RNAs (miRs) as possible diagnostic biomarkers for relevant comorbidities prior to and prognostic biomarkers for mortality following hematopoietic cell transplantation (HCT). A randomly selected group of patients (n = 36) were divided into low-risk (HCT-comorbidity index [HCT-CI] score of 0 and survived HCT) and high-risk (HCT-CI scores ≥ 4 and deceased after HCT) groups. There were 654 miRs tested and 19 met the pre-specified significance level of p < 0.1. In subsequent models, only eight miRs maintained statistical significance in regression models after adjusting for baseline demographic factors; miRs-374b and -454 were underexpressed, whereas miRs-142-3p, -191, -424, -590-3p, -29c, and -15b were overexpressed among high-risk patients relative to low-risk patients. Areas under the curve for these eight miRs ranged between 0.74 and 0.81, suggesting strong predictive capacity. Consideration of miRs may improve risk assessment of mortality and should be further explored in larger future prospective studies.}, }
@article {pmid30279201, year = {2018}, author = {Newcomb, PA}, title = {Realistic (and Still Idealistic) about Cancer Prevention.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {27}, number = {10}, pages = {1234-1235}, doi = {10.1158/1055-9965.EPI-18-0555}, pmid = {30279201}, issn = {1538-7755}, }
@article {pmid30277825, year = {2018}, author = {Flowers, CR and Ramsey, SD}, title = {What Can Cost-Effectiveness Analysis Tell Us About Chimeric Antigen Receptor T-Cell Therapy for Relapsed Acute Lymphoblastic Leukemia?.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2018793570}, doi = {10.1200/JCO.2018.79.3570}, pmid = {30277825}, issn = {1527-7755}, }
@article {pmid30277649, year = {2018}, author = {Commenges, D and Alkhassim, C and Gottardo, R and Hejblum, B and Thiébaut, R}, title = {cytometree: A binary tree algorithm for automatic gating in cytometry analysis.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {93}, number = {11}, pages = {1132-1140}, doi = {10.1002/cyto.a.23601}, pmid = {30277649}, issn = {1552-4930}, support = {ANR-10-LABX-77//Agence Nationale de la Recherche/ ; 681032//European Union's Horizon 2020 research and innovation programme/ ; //European HIV Alliance/ ; }, abstract = {Flow cytometry is a powerful technology that allows the high-throughput quantification of dozens of surface and intracellular proteins at the single-cell level. It has become the most widely used technology for immunophenotyping of cells over the past three decades. Due to the increasing complexity of cytometry experiments (more cells and more markers), traditional manual flow cytometry data analysis has become untenable due to its subjectivity and time-consuming nature. We present a new unsupervised algorithm called "cytometree" to perform automated population identification (aka gating) in flow cytometry. cytometree is based on the construction of a binary tree, the nodes of which are subpopulations of cells. At each node, the marker distributions are modeled by mixtures of normal distributions. Node splitting is done according to a model selection procedure based on a normalized difference of Akaike information criteria between two competing models. Post-processing of the tree structure and derived populations allows us to complete the annotation of the populations. The algorithm is shown to perform better than the state-of-the-art unsupervised algorithms previously proposed on panels introduced by the Flow Cytometry: Critical Assessment of Population Identification Methods project. The algorithm is also applied to a T-cell panel proposed by the Human Immunology Project Consortium (HIPC) program; it also outperforms the best unsupervised open-source available algorithm while requiring the shortest computation time. © 2018 International Society for Advancement of Cytometry.}, }
@article {pmid30277112, year = {2018}, author = {Buckley, SA and Percival, ME and Othus, M and Halpern, AB and Huebner, EM and Becker, PS and Shaw, C and Shadman, M and Walter, RB and Estey, EH}, title = {A comparison of patients with acute myeloid leukemia and high-risk myelodysplastic syndrome treated on versus off study.}, journal = {Leukemia & lymphoma}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/10428194.2018.1516036}, pmid = {30277112}, issn = {1029-2403}, abstract = {Patients with newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS, ≥10% blasts) often receive intensive chemotherapy at diagnosis and relapse. We retrospectively identified 365 patients and categorized the reasons for receiving treatment off study (medical, logistical, or unclear). The pretreatment characteristics of the on and off study groups were similar. Rates of the complete remission (CR) without measurable residual disease were significantly higher for ND patients treated on versus off study (61% versus 35%), but CR rates and survival were low for all RR patients regardless of study assignment. The subset of ND patients treated off study for medical reasons had significantly decreased overall survival and relapse-free survival. Standard, stringent study eligibility criteria may delineate a population of ND, but not RR, patients with improved outcomes with intensive induction chemotherapy.}, }
@article {pmid30273912, year = {2018}, author = {Bello, T and Gujral, TS}, title = {KInhibition: A Kinase Inhibitor Selection Portal.}, journal = {iScience}, volume = {8}, number = {}, pages = {49-53}, doi = {10.1016/j.isci.2018.09.009}, pmid = {30273912}, issn = {2589-0042}, support = {K22 CA201229/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; }, abstract = {Protein kinases constitute a large class of signaling molecules frequently targeted in research and clinical uses. However, kinase inhibitors are notoriously non-specific, making it difficult to select an appropriate inhibitor for a given kinase. Available data from large-scale kinase inhibitor screens are often difficult to query. Here, we present KInhibition (https://kinhibition.fredhutch.org), an online portal that allows users to search publicly available datasets to find selective inhibitors for a chosen kinase or group of kinases. Compounds are sorted by a KInhibition Selectivity Score, calculated based on compounds' activity against the selected kinase(s) versus activity against all other kinases for which that compound has been profiled. The current version allows users to query four datasets, with a framework that can easily accommodate additional datasets. KInhibition represents a powerful platform through which researchers from broad areas of biology, chemistry, and pharmacology can easily interrogate large datasets to help guide their selection of kinase inhibitors.}, }
@article {pmid30272836, year = {2018}, author = {Greenlee, H and Lew, DL and Hershman, DL and Newman, VA and Hansen, L and Hartman, SJ and Korner, J and Shi, Z and Sardo Molmenti, CL and Sayegh, A and Fehrenbacher, L and Lo, S and Klemp, J and Rinn, K and Robertson, JM and Unger, J and Gralow, J and Albain, K and Krouse, R and Fabian, C}, title = {Phase II Feasibility Study of a Weight Loss Intervention in Female Breast and Colorectal Cancer Survivors (SWOG S1008).}, journal = {Obesity (Silver Spring, Md.)}, volume = {26}, number = {10}, pages = {1539-1549}, doi = {10.1002/oby.22269}, pmid = {30272836}, issn = {1930-739X}, support = {U10CA46282//National Cancer Institute/ ; R21 CA155973/CA/NCI NIH HHS/United States ; UG1CA189974//National Cancer Institute/ ; R21CA155973//National Cancer Institute/ ; UG1 CA189974/CA/NCI NIH HHS/United States ; //National Institutes of Health/ ; U10CA12644//National Cancer Institute/ ; UG1CA189972//National Cancer Institute/ ; UG1CA189821//National Cancer Institute/ ; U10CA13612//National Cancer Institute/ ; UG1CA189960//National Cancer Institute/ ; UG1CA189808//National Cancer Institute/ ; //Curves International/ ; UG1CA190002//National Cancer Institute/ ; UG1CA189953//National Cancer Institute/ ; }, abstract = {OBJECTIVE: This study aimed to test the feasibility of a 12-month weight loss intervention using telephone-based counseling plus community-situated physical activity (PA) in female breast cancer (BC) and colorectal cancer (CRC) survivors.
METHODS: This multisite cooperative group study enrolled sedentary, female, postmenopausal BC and CRC survivors with BMI ≥ 25 kg/m2 to receive 12-month fitness center memberships and telephone counseling encouraging 150 min/wk of PA and a 500-kcal/ddecrease in energy intake. Feasibility criteria included accrual, adherence, and retention. Target weight loss was ≥ 5%.
RESULTS: Among 25 BC survivors, median baseline BMI was 37.2 (range: 27.7-54.6), accrual occurred in 10 months, 60% and 28% met diet and exercise goals, 80% provided 12-month measures, and average weight loss was 7.6% (95% CI: -3.9%, 19.2%). Among 23 CRC survivors, median BMI was 31.8 (range: 26.4-48.7), accrual occurred in 24 months, 61% and 17% met diet and exercise goals, 87% provided measures, and average weight loss was 2.5% (95% CI: -8.2%, 13.3%).
CONCLUSIONS: It is feasible to recruit and retain BC survivors in a cooperative group diet and PA weight loss trial. BC survivors achieved clinically meaningful weight loss but did not meet a priori adherence goals. In CRC survivors, recruitment was more difficult, and the intervention was less effective.}, }
@article {pmid30270489, year = {2019}, author = {Rosenberg, AR and Bradford, MC and Barton, KS and Etsekson, N and McCauley, E and Curtis, JR and Wolfe, J and Baker, KS and Yi-Frazier, JP}, title = {Hope and benefit finding: Results from the PRISM randomized controlled trial.}, journal = {Pediatric blood & cancer}, volume = {66}, number = {1}, pages = {e27485}, doi = {10.1002/pbc.27485}, pmid = {30270489}, issn = {1545-5017}, support = {KL2 TR000421/TR/NCATS NIH HHS/United States ; KL2TR000421//National Center for Advancing Translational Sciences/ ; //CureSearch for Children's Cancer/ ; }, abstract = {BACKGROUND: Adolescents and young adults (AYAs) with cancer are at risk for poor psychosocial outcomes, perhaps because they have not acquired skills to navigate the adversities of illness. In a recent phase II randomized controlled trial (RCT), the "Promoting Resilience in Stress Management" (PRISM) intervention was associated with improved patient-reported resilience, quality of life, and distress. In this planned analysis of secondary aims, we hypothesized PRISM would also improve targeted coping skills of hopeful thinking, benefit finding, and goal setting.
METHODS: We conducted this parallel RCT at Seattle Children's Hospital from January 2015 to October 2016. English-speaking AYAs (12-25 years old) with cancer were randomized one-to-one to PRISM or usual care (UC). PRISM teaches stress-management, goal-setting, cognitive-reframing, and meaning-making skills in four sessions delivered in-person every other week. Participants completed surveys at enrollment and 6 months later. Mixed effects linear regression models evaluated associations between PRISM and benefit finding (Benefit-Finding Scale for Children), hopeful thinking (Hope Scale), and an exploratory outcome of goal setting (queried with open-ended items about participant's goals, measured qualitatively by three blinded reviewers).
RESULTS: Of N = 92 AYAs (48 PRISM, 44 UC), 73% were 12-17 years old, 43% female, and 62% diagnosed with leukemia or lymphoma. PRISM was associated with improved benefit finding and hope with moderate-to-large effect sizes-benefit finding: +3.1 points, 95% CI 0.0, 6.2, d = 0.4, and P = 0.05; and hope: +3.6 points, 95% CI 0.7, 6.4, d = 0.6, and P = 0.01. We did not detect changes in goal setting (-0.5 points, 95% CI -1.2, 0.3, d = -0.3, P = 0.23).
CONCLUSIONS: PRISM was associated with improvements in benefit finding and hopeful thinking, two adaptive coping skills which may mitigate long-term psychosocial risk.}, }
@article {pmid30270197, year = {2018}, author = {Saffore, CD and Ko, NY and Holmes, HM and Patel, PR and Sweiss, K and Adimadhyam, S and Chiu, BC and Calip, GS}, title = {Treatment of older patients with diffuse large B-cell lymphoma and mild cognitive impairment or dementia.}, journal = {Journal of geriatric oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jgo.2018.09.002}, pmid = {30270197}, issn = {1879-4076}, }
@article {pmid30269386, year = {2018}, author = {Hino, K and Simó, S and Cooper, JA}, title = {Comparative Analysis of cul5 and rbx2 Expression in the Developing and Adult Murine Brain and Their Essentiality During Mouse Embryogenesis.}, journal = {Developmental dynamics : an official publication of the American Association of Anatomists}, volume = {247}, number = {11}, pages = {1227-1236}, doi = {10.1002/dvdy.24675}, pmid = {30269386}, issn = {1097-0177}, abstract = {BACKGROUND: The E3 Cullin 5-RING ubiquitin ligase (CRL5) is a multiprotein complex that has recently been highlighted as a major regulator of central nervous system development. Cullin 5 (Cul5) and the RING finger protein Rbx2 are two CRL5 core components required for CRL5 function in the brain, but their full expression patterns and developmental functions have not been described in detail.
RESULTS: Using a gene-trap mouse model for Cul5 and a knock-in-knockout mouse model for Rbx2, we show that lack of Cul5, but not Rbx2, disrupts blastocyst formation. However, Rbx2 is required for embryo survival at later embryonic stages. We also show that cul5 is expressed in the embryo proper as early as E7.5 and its expression is mostly restricted to the central nervous system and limbs at later time points. Finally, we show that rbx2 and cul5 are co-expressed in most areas of the brain during development and in the adult.
CONCLUSIONS: Our results show that Cul5, but not Rbx2, is required during early embryogenesis and suggests that Cul5 has Rbx2-independent functions in early development. In the brain, Cul5 and Rbx2 are expressed in a similar fashion, allowing the nucleation of an active CRL5 complex. Developmental Dynamics 247:1227-1236, 2018. © 2018 Wiley Periodicals, Inc.}, }
@article {pmid30268698, year = {2018}, author = {Blumenthal, GM and Bunn, PA and Chaft, JE and McCoach, CE and Perez, EA and Scagliotti, GV and Carbone, DP and Aerts, HJWL and Aisner, DL and Bergh, J and Berry, DA and Jarkowski, A and Botwood, N and Cross, DAE and Diehn, M and Drezner, NL and Doebele, RC and Blakely, CM and Eberhardt, WEE and Felip, E and Gianni, L and Keller, SP and Leavey, PJ and Malik, S and Pignatti, F and Prowell, TM and Redman, MW and Rizvi, NA and Rosell, R and Rusch, V and de Ruysscher, D and Schwartz, LH and Sridhara, R and Stahel, RA and Swisher, S and Taube, JM and Travis, WD and Keegan, P and Wiens, JR and Wistuba, II and Wynes, MW and Hirsch, FR and Kris, MG}, title = {Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {13}, number = {12}, pages = {1818-1831}, doi = {10.1016/j.jtho.2018.09.017}, pmid = {30268698}, issn = {1556-1380}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.}, }
@article {pmid30267214, year = {2018}, author = {Rosenthal, EA and Shirts, BH and Amendola, LM and Horike-Pyne, M and Robertson, PD and Hisama, FM and Bennett, RL and Dorschner, MO and Nickerson, DA and Stanaway, IB and Nassir, R and Vickers, KT and Li, C and Grady, WM and Peters, U and Jarvik, GP and , }, title = {Rare loss of function variants in candidate genes and risk of colorectal cancer.}, journal = {Human genetics}, volume = {137}, number = {10}, pages = {795-806}, doi = {10.1007/s00439-018-1938-4}, pmid = {30267214}, issn = {1432-1203}, support = {UO1 HG006507//National Human Genome Research Institute/ ; UO1 HG007307//National Human Genome Research Institute/ ; 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/ ; HHSN268201100046C//National Heart, Lung, and Blood Institute/ ; 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/ ; HHSN271201100004C//National Heart, Lung, and Blood Institute/ ; RC2 HL-103010//National Heart, Lung, and Blood Institute/ ; RC2 HL-102923//National Heart, Lung, and Blood Institute/ ; RC2 HL-102924//National Heart, Lung, and Blood Institute/ ; RC2 HL-102925//National Heart, Lung, and Blood Institute/ ; RC2 HL-102926//National Heart, Lung, and Blood Institute/ ; X01-HG006196//National Institutes of Health/ ; UO1152756//National Institutes of Health/ ; 2P30CA015704-40//National Cancer Institute/ ; RO1CA194663//National Cancer Institute/ ; RO1CA189184//National Cancer Institute/ ; U01 HG007307/HG/NHGRI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; BRCA2 Protein/*genetics ; Colorectal Neoplasms/*genetics ; Deoxyribonuclease (Pyrimidine Dimer)/*genetics ; Fanconi Anemia Complementation Group Proteins/*genetics ; Female ; *Genetic Loci ; *Genetic Variation ; Humans ; Male ; Middle Aged ; RNA Helicases/*genetics ; Risk Factors ; }, abstract = {Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.}, }
@article {pmid30267200, year = {2018}, author = {Tzeng, A and Diaz-Montero, CM and Rayman, PA and Kim, JS and Pavicic, PG and Finke, JH and Barata, PC and Lamenza, M and Devonshire, S and Schach, K and Emamekhoo, H and Ernstoff, MS and Hoimes, CJ and Rini, BI and Garcia, JA and Gilligan, TD and Ornstein, MC and Grivas, P}, title = {Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.}, journal = {Targeted oncology}, volume = {13}, number = {5}, pages = {599-609}, doi = {10.1007/s11523-018-0595-9}, pmid = {30267200}, issn = {1776-260X}, abstract = {BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.
OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).
PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.
RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Guérin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.
CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.}, }
@article {pmid30262560, year = {2018}, author = {Maffini, E and Storer, BE and Sandmaier, BM and Bruno, B and Sahebi, F and Shizuru, JA and Chauncey, TR and Hari, P and Lange, T and Pulsipher, MA and McSweeney, PA and Holmberg, L and Becker, PS and Green, DJ and Mielcarek, M and Maloney, DG and Storb, R}, title = {Long term follow-up of tandem autologous-allogeneic hematopoietic cell transplantation for multiple myeloma.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.200253}, pmid = {30262560}, issn = {1592-8721}, abstract = {We previously reported initial results in 102 multiple myeloma patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow-up of 8.3 (range 1.0-8.1) years. Donors included human leucocyte antigen identical siblings (n= 179) and HLA-matched unrelated donors (n= 65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) days after allogeneic transplantation. Five-year rates of overall survival and progression-free survival were 54% and 31%, respectively. Ten-year overall survival and progression-free survival were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at 5 years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter overall survival and progression-free survival. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease by flow cytometry experienced a significantly lower relapse rate as compared with minimal residual disease-positive patients (P = 0.03). Our study showed that the graft-vs-myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered with ClinicalTrials.gov and include NCT00075478, NCT00005799, NCT01251575, NCT00078858, NCT00105001, NCT00027820, NCT00089011, NCT00003196, NCT00006251, NCT00793572, NCT00054353, NCT00014235, NCT00003954, NCT00003954.}, }
@article {pmid30262484, year = {2018}, author = {Ahmad, K and Henikoff, S}, title = {No strand left behind.}, journal = {Science (New York, N.Y.)}, volume = {361}, number = {6409}, pages = {1311-1312}, doi = {10.1126/science.aav0871}, pmid = {30262484}, issn = {1095-9203}, mesh = {*DNA Replication ; *Histones ; }, }
@article {pmid30261694, year = {2018}, author = {Ledsgaard, L and Jenkins, TP and Davidsen, K and Krause, KE and Martos-Esteban, A and Engmark, M and Rørdam Andersen, M and Lund, O and Laustsen, AH}, title = {Antibody Cross-Reactivity in Antivenom Research.}, journal = {Toxins}, volume = {10}, number = {10}, pages = {}, doi = {10.3390/toxins10100393}, pmid = {30261694}, issn = {2072-6651}, abstract = {Antivenom cross-reactivity has been investigated for decades to determine which antivenoms can be used to treat snakebite envenomings from different snake species. Traditionally, the methods used for analyzing cross-reactivity have been immunodiffusion, immunoblotting, enzyme-linked immunosorbent assay (ELISA), enzymatic assays, and in vivo neutralization studies. In recent years, new methods for determination of cross-reactivity have emerged, including surface plasmon resonance, antivenomics, and high-density peptide microarray technology. Antivenomics involves a top-down assessment of the toxin-binding capacities of antivenoms, whereas high-density peptide microarray technology may be harnessed to provide in-depth knowledge on which toxin epitopes are recognized by antivenoms. This review provides an overview of both the classical and new methods used to investigate antivenom cross-reactivity, the advantages and disadvantages of each method, and examples of studies using the methods. A special focus is given to antivenomics and high-density peptide microarray technology as these high-throughput methods have recently been introduced in this field and may enable more detailed assessments of antivenom cross-reactivity.}, }
@article {pmid30254314, year = {2018}, author = {Ferreiro-Iglesias, A and Lesseur, C and McKay, J and Hung, RJ and Han, Y and Zong, X and Christiani, D and Johansson, M and Xiao, X and Li, Y and Qian, DC and Ji, X and Liu, G and Caporaso, N and Scelo, G and Zaridze, D and Mukeriya, A and Kontic, M and Ognjanovic, S and Lissowska, J and Szołkowska, M and Swiatkowska, B and Janout, V and Holcatova, I and Bolca, C and Savic, M and Ognjanovic, M and Bojesen, SE and Wu, X and Albanes, D and Aldrich, MC and Tardon, A and Fernandez-Somoano, A and Fernandez-Tardon, G and Le Marchand, L and Rennert, G and Chen, C and Doherty, J and Goodman, G and Bickeböller, H and Wichmann, HE and Risch, A and Rosenberger, A and Shen, H and Dai, J and Field, JK and Davies, M and Woll, P and Teare, MD and Kiemeney, LA and van der Heijden, EHFM and Yuan, JM and Hong, YC and Haugen, A and Zienolddiny, S and Lam, S and Tsao, MS and Johansson, M and Grankvist, K and Schabath, MB and Andrew, A and Duell, E and Melander, O and Brunnström, H and Lazarus, P and Arnold, S and Slone, S and Byun, J and Kamal, A and Zhu, D and Landi, MT and Amos, CI and Brennan, P}, title = {Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {3927}, doi = {10.1038/s41467-018-05890-2}, pmid = {30254314}, issn = {2041-1723}, support = {P20 CA090578/CA/NCI NIH HHS/United States ; U19 CA148127/CA/NCI NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; R01 CA092824/CA/NCI NIH HHS/United States ; UM1 CA164973/CA/NCI NIH HHS/United States ; P01 CA068384/CA/NCI NIH HHS/United States ; R01 DE013158/DE/NIDCR NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; P20 RR018787/RR/NCRR NIH HHS/United States ; S10 RR025141/RR/NCRR NIH HHS/United States ; R01 CA074386/CA/NCI NIH HHS/United States ; K07 CA172294/CA/NCI NIH HHS/United States ; P50 CA119997/CA/NCI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; R01 ES025460/ES/NIEHS NIH HHS/United States ; P50 CA090578/CA/NCI NIH HHS/United States ; U01 CA063464/CA/NCI NIH HHS/United States ; U01 HG004798/HG/NHGRI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R01 CA111703/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; }, abstract = {Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.}, }
@article {pmid30254255, year = {2018}, author = {Plascak, JJ and Griffith, WC and Workman, T and Smith, MN and Vigoren, E and Faustman, EM and Thompson, B}, title = {Evaluation of the relationship between residential orchard density and dimethyl organophosphate pesticide residues in house dust.}, journal = {Journal of exposure science & environmental epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41370-018-0074-5}, pmid = {30254255}, issn = {1559-064X}, support = {P01 ES009601/ES/NIEHS NIH HHS/United States ; R25 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {Reducing residential pesticide exposure requires identification of exposure pathways. Compared to the agriculture worker 'take-home' and residential use pathways, evidence of the 'drift' pathway to pesticide exposure has been inconsistent. Questionnaire data from individuals (n = 99) and dust samples (n = 418) from households across three growing seasons in 2011 were from the For Healthy Kids!
STUDY: Summed dimethyl organophosphate pesticide (OP) (Azinphos-Methyl, Phosmet, and Malathion) concentrations were quantified from house dust samples. Spatially-weighted orchard densities surrounding households were calculated based on various distances from homes. Regression models tested associations between orchard density, residential pesticide use, agriculture worker residents, and summed dimethyl OP house dust concentrations. Estimated relationships between orchard density and dimethyl OP in house dust were mixed: a 5% increase in orchard density resulted in 0.3 and 0.5% decreases in dimethyl OP house dust concentrations when considering land-cover 750 m or 1250 m away from households, respectively, but null associations with land-cover 60 m or 200 m away. Dimethyl OP house dust concentrations were 400% higher within homes where at least two residents were agriculture workers. Despite inconclusive evidence for the drift pathway due to potential for bias, relationships between number of agriculture workers and dimethyl OP house dust concentration underscores the take-home pathway.}, }
@article {pmid30254071, year = {2018}, author = {Grieshober, L and Graw, S and Barnett, MJ and Thornquist, MD and Goodman, GE and Chen, C and Koestler, DC and Marsit, CJ and Doherty, JA}, title = {Methylation-derived Neutrophil-to-Lymphocyte Ratio and Lung Cancer Risk in Heavy Smokers.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {11}, number = {11}, pages = {727-734}, doi = {10.1158/1940-6207.CAPR-18-0111}, pmid = {30254071}, issn = {1940-6215}, support = {U01 CA063673/CA/NCI NIH HHS/United States ; P30 CA168524/CA/NCI NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; R01 CA151989/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; R01 CA111703/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, abstract = {The neutrophil-to-lymphocyte ratio (NLR) is a biomarker that indicates systemic inflammation and can be estimated using array-based DNA methylation data as methylation-derived NLR (mdNLR). We assessed the relationship between prediagnosis mdNLR and lung cancer risk in a nested case-control study in the β-Carotene and Retinol Efficacy Trial (CARET) of individuals at high risk for lung cancer due to heavy smoking or substantial occupational asbestos exposure. We matched 319 incident lung cancer cases to controls based on age at blood draw, smoking, sex, race, asbestos, enrollment year, and time at risk. We computed mdNLR using the ratio of predicted granulocyte and lymphocyte proportions derived from DNA methylation signatures in whole blood collected prior to diagnosis (median 4.4 years in cases). Mean mdNLR was higher in cases than controls (2.06 vs. 1.86, P = 0.03). Conditional logistic regression models adjusted for potential confounders revealed a 21% increased risk of lung cancer per unit increase in mdNLR [OR 1.21; 95% confidence interval (CI) 1.01-1.45]. A 30% increased risk of non-small cell lung cancer (NSCLC) was observed for each unit increase in mdNLR (n = 240 pairs; OR 1.30, 95% CI, 1.03-1.63), and there was no statistically significant association between mdNLR and small-cell lung cancer risk. The mdNLR-NSCLC association was most pronounced in those with asbestos exposure (n = 42 male pairs; OR 3.39; 95% CI, 1.32-8.67). A better understanding of the role of mdNLR in lung cancer etiology may improve prevention and detection of lung cancer. Cancer Prev Res; 11(11); 727-34. ©2018 AACR.}, }
@article {pmid30253794, year = {2018}, author = {Wagner, MJ and Ricciotti, RW and Mantilla, J and Loggers, ET and Pollack, SM and Cranmer, LD}, title = {Response to PD1 inhibition in conventional chondrosarcoma.}, journal = {Journal for immunotherapy of cancer}, volume = {6}, number = {1}, pages = {94}, doi = {10.1186/s40425-018-0413-z}, pmid = {30253794}, issn = {2051-1426}, support = {11305//ASCO-Conquer Cancer Foundation/ ; 17-4-37-WAGN//QuadW Foundation-AACR Fellowship for Clinical/Translational Sarcoma Research/ ; }, abstract = {BACKGROUND: Chondrosarcoma is one of the most common malignant bone tumors in adults. Conventional chondrosarcoma represents around 85% of all chondrosarcomas and is notoriously difficult to treat with chemotherapy.
CASE PRESENTATION: We describe a 67-year-old man with metastatic conventional chondrosarcoma who was treated with nivolumab. Treatment was discontinued after restaging showed increased tumor burden, which later proved to be pseudoprogression. The patient restarted nivolumab and continues to have a near complete response.
CONCLUSION: Conventional chondrosarcoma may be sensitive to checkpoint inhibitors. Further, this case demonstrates clearly the phenomenon of pseudo-progression in this disease, a factor that must be considered in the design of clinical trials and clinical care. This case supports additional study of immunomodulatory agents in this deadly disease.}, }
@article {pmid30250229, year = {2018}, author = {Paulson, KG and Voillet, V and McAfee, MS and Hunter, DS and Wagener, FD and Perdicchio, M and Valente, WJ and Koelle, SJ and Church, CD and Vandeven, N and Thomas, H and Colunga, AG and Iyer, JG and Yee, C and Kulikauskas, R and Koelle, DM and Pierce, RH and Bielas, JH and Greenberg, PD and Bhatia, S and Gottardo, R and Nghiem, P and Chapuis, AG}, title = {Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {3868}, doi = {10.1038/s41467-018-06300-3}, pmid = {30250229}, issn = {2041-1723}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; K24 CA139052/CA/NCI NIH HHS/United States ; K08 CA169485/CA/NCI NIH HHS/United States ; R01 CA176841/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.}, }
@article {pmid30248472, year = {2018}, author = {Williams, LA and Richardson, M and Kehm, RD and McLaughlin, CC and Mueller, BA and Chow, EJ and Spector, LG}, title = {The association between sex and most childhood cancers is not mediated by birthweight.}, journal = {Cancer epidemiology}, volume = {57}, number = {}, pages = {7-12}, doi = {10.1016/j.canep.2018.09.002}, pmid = {30248472}, issn = {1877-783X}, support = {T32 CA099936/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator.
METHODS: Cases (n = 12,632) and controls (n = 64,439) (ages 0-14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970-2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer.
RESULTS: A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02-1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08-1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22-1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40-7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18-1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26-1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40-2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19-1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26-0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25-0.50).
CONCLUSION: Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk.}, }
@article {pmid30247974, year = {2018}, author = {Zick, SM and Czuhajewski, C and Fouladbakhsh, JM and Greenlee, H and Harris, RE and Henry, NL and Jolly, S and Khabir, T and Perlmutter, J and Remington, T and Snyder, D and Spratke, L and Zebrack, B and Zettell, E and Benn, R}, title = {Integrative Oncology Scholars Program: A Model for Integrative Oncology Education.}, journal = {Journal of alternative and complementary medicine (New York, N.Y.)}, volume = {24}, number = {9-10}, pages = {1018-1022}, doi = {10.1089/acm.2018.0184}, pmid = {30247974}, issn = {1557-7708}, mesh = {Complementary Therapies/*education ; Health Personnel ; Humans ; Integrative Medicine/*education ; *Integrative Oncology ; United States ; }, abstract = {OBJECTIVES: Oncology providers are often confronted by patients who use complementary or alternative therapies, but have limited knowledge or confidence on how to advise patients on appropriate use. Despite this, there are few opportunities for oncology providers to learn about complementary or alternative therapies, while at the same time there is a high demand for integrative oncology (IO) training. To address a gap in IO educational opportunities, and particularly for nonphysicians, we created the Integrative Oncology Scholars (IOS) Program. The program's goal is to train 100 IO leaders and facilitate partnerships between them and complementary practitioners.
DESIGN: Four iterations of a year-long National Cancer Institute-funded educational program that combines in-person team-based learning and eLearning to teach the evidence, application, and philosophy supporting IO.
SETTINGS: In-person sessions take place at the University of Michigan, and eLearning is implemented using a Canvas website (Instructure, Inc., Salt Lake City, UT).
SUBJECTS: Nurses, social workers, physician assistants, psychologists, physicians, pharmacists, and physical/occupational therapists with active oncology practices. Educational intervention: Four cohorts of 25 oncology providers per year will learn the evidence base for complementary and alternative approaches to a wide number of oncology topics, including symptom control, dietary supplements commonly used by cancer patients, diet, and the utility of specific integrative approaches for common oncology side-effects such as fatigue.
OUTCOME MEASURES: A mixed methods approach will be used to evaluate overall IOS Program progress and individual scholar's impact on IO research, education, and clinical endeavors.
RESULTS: The first cohort of 25 IOS has been recruited and their education will begin in Summer 2018. Scholars come from 13 states and represent 23 different healthcare systems.
CONCLUSIONS: The IOS Program has the potential to increase the number of trained IO providers, educators, and researchers in the United States.}, }
@article {pmid30247601, year = {2018}, author = {Gilbert, PB and Luedtke, AR}, title = {Statistical Learning Methods to Determine Immune Correlates of Herpes Zoster in Vaccine Efficacy Trials.}, journal = {The Journal of infectious diseases}, volume = {218}, number = {suppl_2}, pages = {S99-S101}, doi = {10.1093/infdis/jiy421}, pmid = {30247601}, issn = {1537-6613}, abstract = {Using Super Learner, a machine learning statistical method, we assessed varicella zoster virus-specific glycoprotein-based enzyme-linked immunosorbent assay (gpELISA) antibody titer as an individual-level signature of herpes zoster (HZ) risk in the Zostavax Efficacy and Safety Trial. Gender and pre- and postvaccination gpELISA titers had moderate ability to predict whether a 50-59 year old experienced HZ over 1-2 years of follow-up, with equal classification accuracy (cross-validated area under the receiver operator curve = 0.65) for vaccine and placebo recipients. Previous analyses suggested that fold-rise gpELISA titer is a statistical correlate of protection and supported the hypothesis that it is not a mechanistic correlate of protection. Our results also support this hypothesis.}, }
@article {pmid30247598, year = {2018}, author = {Laing, KJ and Ouwendijk, WJD and Koelle, DM and Verjans, GMGM}, title = {Immunobiology of Varicella-Zoster Virus Infection.}, journal = {The Journal of infectious diseases}, volume = {218}, number = {suppl_2}, pages = {S68-S74}, doi = {10.1093/infdis/jiy403}, pmid = {30247598}, issn = {1537-6613}, abstract = {Varicella-zoster virus (VZV) causes clinically significant illness during acute and recurrent infection accompanied by robust innate and acquired immune responses. Innate immune cells in skin and ganglion secrete type I interferon (IFN-I) and proinflammatory cytokines to control VZV. Varicella-zoster virus subverts pattern recognition receptor sensing to modulate antigen presentation and IFN-I production. During primary infection, VZV hijacks T cells to disseminate to the skin and establishes latency in ganglia. Durable T- and B-cell memory formed within a few weeks of infection is boosted by reactivation or re-exposure. Antigen-specific T cells are recruited and potentially retained in VZV-infected skin to counteract reactivation. In latently VZV-infected ganglia, however, virus-specific T cells have not been recovered, suggesting that local innate immune responses control VZV latency. Antibodies prevent primary VZV infection, whereas T cells are fundamental to resolving disease, limiting severity, and preventing reactivation. In this study, we review current knowledge on the interactions between VZV and the human immune system.}, }
@article {pmid30244104, year = {2018}, author = {Ito, R and Inamoto, Y and Inoue, Y and Ito, A and Tanaka, T and Fuji, S and Okinaka, K and Kurosawa, S and Kim, SW and Yamashita, T and Fukuda, T}, title = {Characterization of Late Acute and Chronic Graft-Versus-Host Disease according to the 2014 National Institutes of Health Consensus Criteria in Japanese Patients.}, 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.2018.09.014}, pmid = {30244104}, issn = {1523-6536}, abstract = {To characterize the incidences and outcomes of late acute (LA) and chronic graft-versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences.}, }
@article {pmid30242112, year = {2018}, author = {Russo, JW and Gao, C and Bhasin, SS and Voznesensky, OS and Calagua, C and Arai, S and Nelson, PS and Montgomery, B and Mostaghel, EA and Corey, E and Taplin, ME and Ye, H and Bhasin, M and Balk, SP}, title = {Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer.}, journal = {Cancer research}, volume = {78}, number = {22}, pages = {6354-6362}, doi = {10.1158/0008-5472.CAN-18-0687}, pmid = {30242112}, issn = {1538-7445}, support = {P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA090381/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; }, abstract = {The standard treatment for metastatic prostate cancer, androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP prostate cancer xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR-targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide-resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was dipeptidyl peptidase 4 (DPP4), which encodes a membrane-anchored protein that cleaves dipeptides from multiple growth factors, resulting in their increased degradation. DPP4 mRNA and protein were also decreased in clinical CRPC cases, and inhibition of DPP4 with sitagliptin enhanced the growth of prostate cancer xenografts following castration. Significantly, DPP4 inhibitors are frequently used to treat type 2 diabetes as they increase insulin secretion. Together, these results implicate DPP4 as an AR-regulated tumor suppressor gene whose loss enhances growth factor activity and suggest that treatment with DPP4 inhibitors may accelerate emergence of resistance to ADT.Significance: These findings identify DPP4 as an AR-stimulated tumor suppressor gene that is downregulated during progression to castration-resistant prostate cancer, warning that treatment with DPP4 inhibitors, commonly used to treat type 2 diabetes, may accelerate prostate cancer progression following androgen deprivation therapy. Cancer Res; 78(22); 6354-62. ©2018 AACR.}, }
@article {pmid30241258, year = {2018}, author = {Phipps, W and Kansiime, R and Stevenson, P and Orem, J and Casper, C and Morrow, RA}, title = {Peer Mentoring at the Uganda Cancer Institute: A Novel Model for Career Development of Clinician-Scientists in Resource-Limited Settings.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-11}, doi = {10.1200/JGO.17.00134}, pmid = {30241258}, issn = {2378-9506}, support = {D43 CA153720/CA/NCI NIH HHS/United States ; D43 TW009759/TW/FIC NIH HHS/United States ; U54 CA190146/CA/NCI NIH HHS/United States ; }, abstract = {Cancer centers are beginning to emerge in low- and middle-income countries despite having relatively few oncologists and specialists in related fields. Uganda, like many countries in sub-Saharan Africa, has a cadre of highly motivated clinician-scientists-in-training who are committed to developing the capacity for cancer care and research. However, potential local mentors for these trainees are burdened with uniquely high demands on their time for clinical care, teaching, institutional development, advocacy, and research. Facilitated peer mentoring helps to fill skills and confidence gaps and teaches mentoring skills so that trainees can learn to support one another and regularly access a more senior facilitator/role model. With an added consultant component, programs can engage limited senior faculty time to address specific training needs and to introduce junior investigators to advisors and even potential dyadic mentors. Two years after its inception, our facilitated peer mentoring career development program at the Uganda Cancer Institute in Kampala is successfully developing a new generation of researchers who, in turn, are now providing role models and mentors from within their group. This program provides a practical model for building the next generation of clinical scientists in developing countries.}, }
@article {pmid30241255, year = {2018}, author = {Elzembely, MM and Park, JR and Riad, KF and Sayed, HA and Pinto, N and Carpenter, PA and Baker, KS and El-Haddad, A}, title = {Acute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-12}, doi = {10.1200/JGO.17.00118}, pmid = {30241255}, issn = {2378-9506}, abstract = {PURPOSE: High-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States.
PATIENTS AND METHODS: We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015).
RESULTS: Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy.
CONCLUSION: Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.}, }
@article {pmid30241187, year = {2018}, author = {Hortobagyi, GN and Pyle, D and Cazap, EL and El Saghir, NS and Shulman, LN and Lyman, GH and Schnipper, LE and Adebamowo, CA and Gandara, DR and Vose, J and Wong, SL and Yu, P}, title = {American Society of Clinical Oncology's Global Oncology Leadership Task Force: Findings and Actions.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-8}, doi = {10.1200/JGO.17.00060}, pmid = {30241187}, issn = {2378-9506}, abstract = {In response to rising cancer incidence and mortality rates in low- and middle-income countries and the increasingly global profile of ASCO's membership, the ASCO Board of Directors appointed the Global Oncology Leadership Task Force (Task Force) to provide recommendations on ASCO's engagement in global oncology. To accomplish its work, the Task Force convened meetings of global oncology experts, conducted focus group discussions with member groups, did site visits to South America and India, and met regularly to analyze the findings and develop recommendations. Task Force findings included global concerns, such as access to care, and specific concerns of middle- and low-resource settings. The need to strengthen health systems and the importance of alliances with a range of international cancer stakeholders were emphasized. Task Force recommendations to the ASCO Board of Directors were based on a three-part global oncology strategy of professional development, improvement of access to quality care, and acceleration of global oncology research. Specific areas of focus within each of these strategic pillars are provided along with an update on areas of ASCO activity as these recommendations are implemented.}, }
@article {pmid30241166, year = {2018}, author = {Scheel, JR and Molina, Y and Anderson, BO and Patrick, DL and Nakigudde, G and Gralow, JR and Lehman, CD and Thompson, B}, title = {Breast Cancer Beliefs as Potential Targets for Breast Cancer Awareness Efforts to Decrease Late-Stage Presentation in Uganda.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-9}, doi = {10.1200/JGO.2016.008748}, pmid = {30241166}, issn = {2378-9506}, support = {R25 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: To assess breast cancer beliefs in Uganda and determine whether these beliefs are associated with factors potentially related to nonparticipation in early detection.
METHODS: A survey with open- and close-ended items was conducted in a community sample of Ugandan women to assess their beliefs about breast cancer. Linear regression was used to ascertain associations between breast cancer beliefs and demographic factors potentially associated with early detection, including socioeconomic factors, health care access, prior breast cancer knowledge, and personal detection practices.
RESULTS: Of the 401 Ugandan women surveyed, most had less than a primary school education and received medical care at community health centers. Most women either believed in or were unsure about cultural explanatory models for developing breast cancer (> 82%), and the majority listed these beliefs as the most important causes of breast cancer (69%). By comparison, ≤ 45% of women believed in scientific explanatory risks for developing breast cancer. Although most believed that regular screening and early detection would find breast cancer when it is easy to treat (88% and 80%, respectively), they simultaneously held fatalistic attitudes toward their own detection efforts, including belief or uncertainty that a cure is impossible once they could self-detect a lump (54%). Individual beliefs were largely independent of demographic factors.
CONCLUSION: Misconceptions about breast cancer risks and benefits of early detection are widespread in Uganda and must be addressed in future breast cancer awareness efforts. Until screening programs exist, most breast cancer will be self-detected. Unless addressed by future awareness efforts, the high frequency of fatalistic attitudes held by women toward their own detection efforts will continue to be deleterious to breast cancer early detection in sub-Saharan countries like Uganda.}, }
@article {pmid30241147, year = {2018}, author = {Menon, MP and Coghill, A and Mutyaba, IO and Phipps, WT and Okuku, FM and Harlan, JM and Orem, J and Casper, C}, title = {Association Between HIV Infection and Cancer Stage at Presentation at the Uganda Cancer Institute.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-9}, doi = {10.1200/JGO.17.00005}, pmid = {30241147}, issn = {2378-9506}, support = {D43 TW009759/TW/FIC NIH HHS/United States ; K12 HL087165/HL/NHLBI NIH HHS/United States ; K23 CA150931/CA/NCI NIH HHS/United States ; U54 CA190146/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: The HIV epidemic has contributed to the increasing incidence of cancer in sub-Saharan Africa, where most patients with cancer present at an advanced stage. However, improved access to HIV care and treatment centers in sub-Saharan Africa may facilitate earlier diagnosis of cancer among patients who are HIV positive. To test this hypothesis, we characterized the stage of cancer and evaluated the factors associated with advanced stage at presentation among patients in Uganda.
METHODS: We conducted a retrospective analysis of adult patients with any of four specific cancers who presented for care in Kampala, Uganda, between 2003 and 2010. Demographic, clinical, and laboratory data were abstracted from the medical record, together with the outcome measure of advanced stage of disease (clinical stage III or IV). We identified measures for inclusion in a multivariate logistic regression model.
RESULTS: We analyzed 731 patients with both AIDS-defining cancers (cervical [43.1%], and non-Hodgkin lymphoma [18.3%]), and non-AIDS-defining cancers (breast [30.0%] and Hodgkin lymphoma [8.6%]). Nearly 80% of all patients presented at an advanced stage and 37% had HIV infection. More than 90% of patients were symptomatic and the median duration of symptoms before presentation was 5 months. In the multivariate model, HIV-positive patients were less likely to present at an advanced stage as were patients with higher hemoglobin and fewer symptoms.
CONCLUSION: Patients with limited access to primary care may present with advanced cancer because of a delay in diagnosis. However, patients with HIV now have better access to clinical care. Use of this growing infrastructure to increase cancer screening and referral is promising and deserves continued support, because the prognosis of HIV-positive patients with advanced cancer is characterized by poor survival globally.}, }
@article {pmid30241140, year = {2018}, author = {Zujewski, JA and Dvaladze, AL and Ilbawi, A and Anderson, BO and Luciani, S and Stevens, L and Torode, J}, title = {Knowledge Summaries for Comprehensive Breast Cancer Control.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-7}, doi = {10.1200/JGO.17.00141}, pmid = {30241140}, issn = {2378-9506}, abstract = {Breast cancer is the most common cancer in women worldwide, affecting > 1.6 million women each year, projected to increase to 2.2 million cases annually by 2025. A disproportionate number of the > 500,000 women who die as a result of breast cancer each year reside in low-resource settings. Breast cancer control is an important component of cancer control planning and women's health programs, and tools are needed across the care continuum to reduce the cancer burden, especially in low-resource settings. Cancer control planning is complex and multifaceted. Evidence shows that outcomes are improved when prevention, early diagnosis, treatment, and palliation are integrated and synchronously developed within a country/region's health plan. The Knowledge Summaries for Comprehensive Breast Cancer Control are the product of a multiyear collaboration led by the Union for International Cancer Control, Breast Health Global Initiative, Pan American Health Organization, and Center for Global Health of the US National Cancer Institute. Fourteen knowledge summaries distilled from evidence-based, resource-stratified guidelines, and aligned with WHO guidance on breast cancer control, build a framework for resource prioritization pathways and delivery systems for breast cancer control at four levels of available resources: basic, limited, enhanced, and maximal. Each summary contains relevant content to inform breast cancer policy, clinical care, and advocacy, aiding in the development and implementation of policies and programs. These tools provide a common platform for stakeholders, including policymakers, administrators, clinicians, and advocates to engage in decision making appropriate to their local setting. The goal is to facilitate evidence-based policy actions and urgently advance implementation of an integrated approach to reduce breast cancer mortality and improve quality of life.}, }
@article {pmid30241139, year = {2018}, author = {Bender Ignacio, R and Ghadrshenas, M and Low, D and Orem, J and Casper, C and Phipps, W}, title = {HIV Status and Associated Clinical Characteristics Among Adult Patients With Cancer at the Uganda Cancer Institute.}, journal = {Journal of global oncology}, volume = {}, number = {4}, pages = {1-10}, doi = {10.1200/JGO.17.00112}, pmid = {30241139}, issn = {2378-9506}, support = {D43 TW009759/TW/FIC NIH HHS/United States ; K23 CA150931/CA/NCI NIH HHS/United States ; U54 CA190146/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: HIV increases cancer incidence and mortality. In Uganda, the HIV epidemic has led to an elevated incidence of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Limited information exists about how frequently HIV infection complicates the presentation and manifestations of cancer in sub-Saharan Africa.
METHODS: We abstracted medical records from patients with cancer who were age 18 years or older who registered at the Uganda Cancer Institute from June through September 2015 to determine the burden of HIV. We used χ2 tests and generalized linear models to evaluate factors associated with HIV positivity. A sensitivity analysis estimated HIV prevalence in those untested.
RESULTS: Among 1,137 patients with cancer, 23% were HIV infected, 48% were HIV negative, and 29% had no recorded HIV status. Of those with recorded HIV status, 32% were HIV positive. Forty-two percent (149 of 361 patients) with ADCs were documented as HIV infected (51% of those with documented status) compared with 14% (108 of 776 patients) of those with NADCs (21% of those with documented status). In multivariable analysis, HIV infection was associated with ADC diagnosis (adjusted prevalence ratio [aPR] compared with NADC, 2.2; 95% CI, 1.5 to 3.0), younger age (aPR, 0.9 per decade increase; 95% CI, 0.8 to 1.0), and worse performance status scores (aPR, 1.2 per point ECOG increase; 95% CI, 1.0 to 1.5). When sensitivity analysis accounted for undocumented HIV status, the expected prevalence of HIV infection was 29% (range, 23% to 32%), and almost one fourth of expected HIV cases were undiagnosed or unrecorded.
CONCLUSION: The prevalence of HIV infection among Ugandan patients with cancer is substantially higher than in the general population. Patients with cancer and HIV tend to be younger and have poorer performance status. Greater awareness of the dual burden of cancer and HIV in Uganda and universal testing of patients with cancer may improve outcomes of HIV-associated malignancies.}, }
@article {pmid30240678, year = {2018}, author = {Romine, PE and Eaton, KD and Paulson, KG and Hadi, R and Paauw, DS}, title = {Sarcoidosis presenting as isolated anasarca and hypercalcemia.}, journal = {The American journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.amjmed.2018.09.009}, pmid = {30240678}, issn = {1555-7162}, }
@article {pmid30239866, year = {2018}, author = {Yun, HY and Lampe, JW and Tinker, LF and Neuhouser, ML and Beresford, SAA and Niles, KR and Mossavar-Rahmani, Y and Snetselaar, LG and Van Horn, L and Prentice, RL and O'Brien, DM}, title = {Serum Nitrogen and Carbon Stable Isotope Ratios Meet Biomarker Criteria for Fish and Animal Protein Intake in a Controlled Feeding Study of a Women's Health Initiative Cohort.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/jn/nxy168}, pmid = {30239866}, issn = {1541-6100}, support = {R01 CA119171/CA/NCI NIH HHS/United States ; R01 DK109946/DK/NIDDK NIH HHS/United States ; R21 CA182674/CA/NCI NIH HHS/United States ; }, abstract = {Background: Natural abundance stable isotope ratios are candidate biomarkers of dietary intake that have not been evaluated in a controlled feeding study in a US population.
Objectives: Our goals were to evaluate dietary associations with serum carbon (CIR), nitrogen (NIR), and sulfur (SIR) isotope ratios in postmenopausal women, and to evaluate whether statistical models of dietary intake that include multiple isotopes and participant characteristics meet criteria for biomarker evaluation.
Methods: Postmenopausal women from the Women's Health Initiative (n = 153) were provided a 2-wk controlled diet that approximated each individual's habitual food intake. Dietary intakes of animal protein, fish/seafood, red meat, poultry, egg, dairy, total sugars, added sugars, sugar-sweetened beverages (SSBs), and corn products were characterized during the feeding period with the use of the Nutrition Data System for Research (NDS-R). The CIR, NIR, and SIR were measured in sera collected from fasting women at the beginning and the end of the feeding period. Linear models based on stable isotope ratios and participant characteristics predicted dietary intake. The criterion used for biomarker evaluation was R2 ≥ 0.36, based on the study's power to detect true associations with R2 ≥ 0.50.
Results: The NIR was associated with fish/seafood intake and met the criterion for biomarker evaluation (R2 = 0.40). The CIR was moderately associated with intakes of red meat and eggs, but not to the criterion for biomarker evaluation, and was not associated with intake of sugars (total, added, or SSB). A model of animal protein intake based on the NIR, CIR, and participant characteristics met the criterion for biomarker evaluation (R2 = 0.40). Otherwise, multiple isotopes did not improve models of intake, and improvements from including participant characteristics were modest.
Conclusion: Serum stable isotope ratios can, with participant characteristics, meet biomarker criteria as measures of fish/seafood and animal protein intake in a sample of postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.}, }
@article {pmid30239739, year = {2018}, author = {Kaluza, J and Harris, HR and Linden, A and Wolk, A}, title = {Long-term consumption of fruits and vegetables and risk of chronic obstructive pulmonary disease: a prospective cohort study of women.}, journal = {International journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ije/dyy178}, pmid = {30239739}, issn = {1464-3685}, abstract = {Background: Fruits and vegetables, due to high antioxidant capacity, may protect the lung from oxidative damage caused by tobacco smoke and potentially prevent chronic obstructive pulmonary disease (COPD). Only one study based on baseline diet has examined fruit and vegetable consumption in relation to risk of COPD, and no previous studies have examined long-term diet.
Methods: We investigated whether long-term fruit and vegetable consumption was associated with COPD incidence among 34 739 women (age 48-83 years) in the population-based prospective Swedish Mammography Cohort. Fruit and vegetable consumption was assessed twice (1987, 1997) with a self-administered questionnaire. Cases of COPD were identified by linkage to the Swedish health register. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: During follow-up from 2002 to 2014, 1512 women were diagnosed with COPD. Long-term fruit was associated with lower risk of COPD; women in the highest vs lowest quintile of consumption (≥2.5 vs <0.8 servings/day) had a 37% lower risk of COPD (95% CI: 25-48%; P-trend < 0.0001). No association was observed with long-term vegetable intake. Current and ex-smokers with low long-term consumption of fruits (<1 serving/day) in comparison to never smokers with high consumption (≥3 servings/day) had a 38-fold (HR: 38.1; 95% CI: 20.2-71.7) and 13-fold (HR: 12.5, 95% CI: 6.5-24.1) higher risk of COPD, respectively. However, no significant interaction between smoking status and fruit intake in relation to COPD incidence was observed (P-interaction = 0.95).
Conclusions: In this prospective cohort of middle-age and older women, long-term consumption of fruits but not vegetables was inversely associated with COPD incidence.}, }
@article {pmid30239426, year = {2018}, author = {Palanee-Phillips, T and Roberts, ST and Reddy, K and Govender, V and Naidoo, L and Siva, S and Gafoor, Z and Pather, A and Matovu, F and Hlahla, K and Makanani, B and Nair, G and Schwartz, K and Torjesen, K and Brown, E and Soto-Torres, L and Baeten, J and Montgomery, ET}, title = {Impact of Partner-Related Social Harms on Women's Adherence to the Dapivirine Vaginal Ring During a Phase III Trial.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {79}, number = {5}, pages = {580-589}, doi = {10.1097/QAI.0000000000001866}, pmid = {30239426}, issn = {1944-7884}, support = {UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1 AI106707/AI/NIAID NIH HHS/United States ; UM1 AI069518/AI/NIAID NIH HHS/United States ; UM1 AI069463/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Long-acting female-initiated methods such as the dapivirine ring may give women greater agency in HIV-1 prevention. However, social harms, defined as nonmedical adverse consequences of study participation or dapivirine ring use, may reduce product adherence and consequently HIV-1 protection.
METHODS: We assessed whether experiencing social harms from male partners was associated with lower adherence to the dapivirine ring in the MTN-020/ASPIRE trial. Reports of social harms were solicited quarterly. Low adherence was defined by plasma dapivirine levels ≤95 pg/mL or residual dapivirine levels in returned rings >23.5 mg.
RESULTS: Among 2629 women enrolled in ASPIRE, 85 (3.2%) reported 87 social harms during a median follow-up of 1.6 years. Women were significantly more likely to have low adherence, measured by plasma dapivirine levels, at visits with a social harm in the past month than at visits where no social harm was reported (adjusted risk ratio 2.53, 95% confidence interval: 1.37 to 4.66, P = 0.003). There was no association for social harms reported ≥1 month prior, suggesting an acute, short-term effect. Women were significantly more likely to not return a ring at visits with a social harm reported (adjusted risk ratio 24.70, 95% confidence interval: 18.57 to 32.85, P < 0.001). In rings that were returned, social harms were not associated with residual dapivirine levels.
CONCLUSIONS: Although social harms were uncommon (<5% of women with >1 year of use), participants reporting social harms by male partners had lower adherence to the dapivirine ring. Strategies to mitigate nonadherence to product use related to social harms should be evaluated in future studies of female-controlled HIV-1 prevention options.}, }
@article {pmid30237265, year = {2018}, author = {Gandelman, JS and Byrne, MT and Mistry, AM and Polikowsky, HG and Diggins, KE and Chen, H and Lee, SJ and Arora, M and Cutler, C and Flowers, M and Pidala, J and Irish, JM and Jagasia, MH}, title = {Machine learning reveals chronic graft-versus-host disease phenotypes and stratifies survival after stem cell transplant for hematologic malignancies.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2018.193441}, pmid = {30237265}, issn = {1592-8721}, abstract = {The application of machine learning in medicine has been productive in multiple fields, and has not previously been applied to analyze the complexity of chronic graft-versus-host disease organ involvement. Chronic graft-versus-host disease is classified by an overall composite score of mild, moderate or severe, which may overlook clinically relevant patterns in organ involvement. Here we applied a novel computational approach to chronic graft-versus-host disease with the goal of identifying phenotypic groups based on the subcomponents of the National Institutes of Health (NIH) Consensus Criteria. Computational analysis revealed 7 distinct patient groups with contrasting clinical risks. The high-risk group had an inferior overall survival compared to the low-risk group (HR 2.24 [95% CI 1.36-3.68]), and was independent of severity as measured by the NIH criteria. To test clinical applicability, knowledge was translated into a simplified clinical prognostic decision tree. Groups identified by the decision tree also stratified outcomes and closely matched those from the original analysis. Patients in the high and intermediate-risk decision tree groups had significantly shorter overall survival than those in the low-risk group (HR 2.79 [1.58-4.91] and HR 1.78 [1.06-3.01], respectively). Machine learning and other computational analyses may better reveal biomarkers and stratify risk than the current approach based on cumulative severity. This approach could now be explored in other disease models with complex clinical phenotypes. External validation must be completed prior to clinical application. Ultimately, this approach has the potential to reveal distinct pathophysiological mechanisms that may underlie clusters. Clinicaltrials.gov identifier: NCT00637689.}, }
@article {pmid30235319, year = {2018}, author = {Lohavanichbutr, P and Zhang, Y and Wang, P and Gu, H and Nagana Gowda, GA and Djukovic, D and Buas, MF and Raftery, D and Chen, C}, title = {Salivary metabolite profiling distinguishes patients with oral cavity squamous cell carcinoma from normal controls.}, journal = {PloS one}, volume = {13}, number = {9}, pages = {e0204249}, doi = {10.1371/journal.pone.0204249}, pmid = {30235319}, issn = {1932-6203}, abstract = {Oral cavity squamous cell carcinoma (OCC) and oropharyngeal squamous cell carcinoma (OPC) are among the most common cancers worldwide and are associated with high mortality and morbidity. The purpose of this study is to identify potential biomarkers to distinguish OCC/OPC from normal controls and to distinguish OCC patients with and without nodal metastasis. We tested saliva samples from 101 OCC, 58 OPC, and 35 normal controls using four analytical platforms (NMR, targeted aqueous by LC-MS/MS, global aqueous and global lipidomics by LC-Q-TOF). Samples from OCC and normal controls were divided into discovery and validation sets. Using linear regression adjusting for age, sex, race and experimental batches, we found the levels of two metabolites (glycine and proline) to be significantly different between OCC and controls (FDR < 0.1 for both discovery and validation sets) but did not find any appreciable differences in metabolite levels between OPC and controls or between OCC with and without nodal metastasis. Four metabolites, including glycine, proline, citrulline, and ornithine were associated with early stage OCC in both discovery and validation sets. Further study is warranted to confirm these results in the development of salivary metabolites as diagnostic markers.}, }
@article {pmid30235286, year = {2018}, author = {Elizaga, ML and Li, SS and Kochar, NK and Wilson, GJ and Allen, MA and Tieu, HVN and Frank, I and Sobieszczyk, ME and Cohen, KW and Sanchez, B and Latham, TE and Clarke, DK and Egan, MA and Eldridge, JH and Hannaman, D and Xu, R and Ota-Setlik, A and McElrath, MJ and Hay, CM and , }, title = {Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial.}, journal = {PloS one}, volume = {13}, number = {9}, pages = {e0202753}, doi = {10.1371/journal.pone.0202753}, pmid = {30235286}, issn = {1932-6203}, support = {UM1 AI069511/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant.
METHODS: In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 μg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 μg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 ⊆ 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months.
RESULTS: The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination.
CONCLUSIONS: HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated.
TRIAL REGISTRATION: Clinical Trials.gov NCT01578889.}, }
@article {pmid30235108, year = {2018}, author = {Steuten, L and Mewes, J and Lepage-Nefkens, I and Vrijhoef, H}, title = {Is Procalcitonin Biomarker-Guided Antibiotic Therapy a Cost-Effective Approach to Reduce Antibiotic Resistant and Clostridium difficile Infections in Hospitalized Patients?.}, journal = {Omics : a journal of integrative biology}, volume = {22}, number = {9}, pages = {616-625}, doi = {10.1089/omi.2018.0040}, pmid = {30235108}, issn = {1557-8100}, abstract = {Antibiotics (AB) can reduce morbidity and mortality in the treatment of patients with sepsis and chronic obstructive pulmonary disease (COPD) exacerbations. Yet, AB overuse or misuse increases antibiotic resistance (ABR) and Clostridium difficile infections (CDI). This study projected the expected impact of a procalcitonin (PCT) biomarker testing strategy on incremental ABR cases and CDI, and costs of care in a population of patients hospitalized with suspected sepsis or a COPD exacerbation, in three European countries: the United Kingdom, Germany, and the Netherlands. Based on a systematic literature search and a decision model, we analyzed the number of ABR and CDI cases avoided and the incremental healthcare costs per patient from a societal perspective over the time horizon of a hospital stay. In the sepsis population, the PCT-guided antibiotic prescription strategy was projected to reduce the number of ABR cases with circa 6%, the number of CDI cases with 21%, and societal costs with circa €1300 per patient. In the COPD population, the number of ABR and CDI cases is reduced with circa 50%, and societal cost savings ranged €1701, €2473, and €2435 per patient in Germany, the Netherlands, and the United Kingdom, respectively. Model outcomes were most sensitive to the impact of the PCT-guided strategy on the number of intensive care unit days and general hospital ward days. Taken together, a PCT biomarker-guided antibiotic management strategy is likely to reduce the number of ABR and CDI cases and generate cost savings in a population of patients hospitalized with suspected sepsis or with a COPD exacerbation.}, }
@article {pmid30234197, year = {2018}, author = {Finak, G and Mayer, B and Fulp, W and Obrecht, P and Sato, A and Chung, E and Holman, D and Gottardo, R}, title = {DataPackageR: Reproducible data preprocessing, standardization and sharing using R/Bioconductor for collaborative data analysis.}, journal = {Gates open research}, volume = {2}, number = {}, pages = {31}, doi = {10.12688/gatesopenres.12832.2}, pmid = {30234197}, issn = {2572-4754}, abstract = {A central tenet of reproducible research is that scientific results are published along with the underlying data and software code necessary to reproduce and verify the findings. A host of tools and software have been released that facilitate such work-flows and scientific journals have increasingly demanded that code and primary data be made available with publications. There has been little practical advice on implementing reproducible research work-flows for large 'omics' or systems biology data sets used by teams of analysts working in collaboration. In such instances it is important to ensure all analysts use the same version of a data set for their analyses. Yet, instantiating relational databases and standard operating procedures can be unwieldy, with high "startup" costs and poor adherence to procedures when they deviate substantially from an analyst's usual work-flow. Ideally a reproducible research work-flow should fit naturally into an individual's existing work-flow, with minimal disruption. Here, we provide an overview of how we have leveraged popular open source tools, including Bioconductor, Rmarkdown, git version control, R, and specifically R's package system combined with a new tool DataPackageR, to implement a lightweight reproducible research work-flow for preprocessing large data sets, suitable for sharing among small-to-medium sized teams of computational scientists. Our primary contribution is the DataPackageR tool, which decouples time-consuming data processing from data analysis while leaving a traceable record of how raw data is processed into analysis-ready data sets. The software ensures packaged data objects are properly documented and performs checksum verification of these along with basic package version management, and importantly, leaves a record of data processing code in the form of package vignettes. Our group has implemented this work-flow to manage, analyze and report on pre-clinical immunological trial data from multi-center, multi-assay studies for the past three years.}, }
@article {pmid30234027, year = {2018}, author = {Wang, Z and Zolnik, CP and Qiu, Y and Usyk, M and Wang, T and Strickler, HD and Isasi, CR and Kaplan, RC and Kurland, IJ and Qi, Q and Burk, RD}, title = {Comparison of Fecal Collection Methods for Microbiome and Metabolomics Studies.}, journal = {Frontiers in cellular and infection microbiology}, volume = {8}, number = {}, pages = {301}, doi = {10.3389/fcimb.2018.00301}, pmid = {30234027}, issn = {2235-2988}, support = {K01 HL129892/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; }, abstract = {Background: Integrated microbiome and metabolomics analyses hold the potential to reveal interactions between host and microbiota in relation to disease risks. However, there are few studies evaluating how field methods influence fecal microbiome characterization and metabolomics profiling. Methods: Five fecal collection methods [immediate freezing at -20°C without preservative, OMNIgene GUT, 95% ethanol, RNAlater, and Flinders Technology Associates (FTA) cards] were used to collect 40 fecal samples from eight healthy volunteers. We performed gut microbiota 16S rRNA sequencing, untargeted metabolomics profiling, and targeted metabolomics focusing on short chained fatty acids (SCFAs). Metrics included α-diversity and β-diversity as well as distributions of predominant phyla. To evaluate the concordance with the "gold standard" immediate freezing, the intraclass correlation coefficients (ICCs) for alternate fecal collection systems were calculated. Correlations between SCFAs and gut microbiota were also examined. Results: The FTA cards had the highest ICCs compared to the immediate freezing method for α-diversity indices (ICCs = 0.96, 0.96, 0.76 for Shannon index, Simpson's Index, Chao-1 Index, respectively), followed by OMNIgene GUT, RNAlater, and 95% ethanol. High ICCs (all >0.88) were observed for all methods for the β-diversity metric. For untargeted metabolomics, in comparison to immediate freezing which detected 621 metabolites at ≥75% detectability level, 95% ethanol showed the largest overlapping set of metabolites (n = 430; 69.2%), followed by FTA cards (n = 330; 53.1%) and OMNIgene GUT (n = 213; 34.3%). Both OMNIgene GUT (ICCs = 0.82, 0.93, 0.64) and FTA cards (ICCs = 0.87, 0.85, 0.54) had acceptable ICCs for the top three predominant SCFAs (butyric acid, propionic acid and acetic acid). Nominally significant correlations between bacterial genera and SCFAs (P < 0.05) were observed in fecal samples collected by different methods. Of note, a high correlation between the genus Blautia (known butyrate producer) and butyric acid was observed for both immediate freezing (r = 0.83) and FTA cards (r = 0.74). Conclusions: Four alternative fecal collection methods are generally comparable with immediate freezing, but there are differences in certain measures of the gut microbiome and fecal metabolome across methods. Choice of method depends on the research interests, simplicity of fecal collection procedures and ease of transportation to the lab, especially for large epidemiological studies.}, }
@article {pmid30233257, year = {2018}, author = {Wagner, MJ and Cranmer, LD and Loggers, ET and Pollack, SM}, title = {Propranolol for the treatment of vascular sarcomas.}, journal = {Journal of experimental pharmacology}, volume = {10}, number = {}, pages = {51-58}, doi = {10.2147/JEP.S146211}, pmid = {30233257}, issn = {1179-1454}, abstract = {Vascular sarcomas are abnormal proliferations of endothelial cells. They range from benign hemangioma to aggressive angiosarcoma, and are characterized by dysregulated angiogenic signaling. Propranolol is a β-adrenergic receptor inhibitor that has demonstrated clinical efficacy in benign infantile hemangioma, and is now being used experimentally for more aggressive vascular sarcomas and other cancers. In this review, we discuss the use of propranolol in targeting these receptors in vascular tumors and other cancers.}, }
@article {pmid30232414, year = {2018}, author = {Woolfrey, A and Wang, T and Lee, SJ and Haagenson, MD and Chen, G and Fleischhauer, K and Horan, J and Hsu, K and Verneris, M and Spellman, SR and Fernandez-Vina, M}, title = {Donor-specific anti-HLA antibodies in unrelated hematopoietic cell transplantation for non-malignant disorders.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-018-0334-y}, pmid = {30232414}, issn = {1476-5365}, support = {5U10HL069294//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U24 CA076518/CA/NCI NIH HHS/United States ; HHSH250201200016C//U.S. Department of Health & Human Services | Health Resources and Services Administration (HRSA)/ ; N00014-15-1-0848//DOD | Office of Naval Research (ONR)/ ; 5U24-CA076518//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N00014-16-1-2020//DOD | Office of Naval Research (ONR)/ ; }, }
@article {pmid30231576, year = {2018}, author = {Wen, FT and Bell, SM and Bedford, T and Cobey, S}, title = {Estimating Vaccine-Driven Selection in Seasonal Influenza.}, journal = {Viruses}, volume = {10}, number = {9}, pages = {}, doi = {10.3390/v10090509}, pmid = {30231576}, issn = {1999-4915}, support = {DP2 AI117921/AI/NIAID NIH HHS/United States ; T32 GM007281/GM/NIGMS NIH HHS/United States ; DP2AI117921/NH/NIH HHS/United States ; DGE-1256082//National Science Foundation/International ; T32GM007281/NH/NIH HHS/United States ; R35GM119774/NH/NIH HHS/United States ; U19AI117891/NH/NIH HHS/United States ; }, mesh = {Algorithms ; Antigenic Variation ; Humans ; Immunogenicity, Vaccine ; Incidence ; Influenza A Virus, H3N2 Subtype/immunology ; Influenza A virus/classification/*immunology ; Influenza Vaccines/*immunology ; Influenza, Human/*immunology/prevention & control/*virology ; Models, Statistical ; *Seasons ; Selection, Genetic/*immunology ; Vaccination ; Vaccination Coverage ; }, abstract = {Vaccination could be an evolutionary pressure on seasonal influenza if vaccines reduce the transmission rates of some ("targeted") strains more than others. In theory, more vaccinated populations should have a lower prevalence of targeted strains compared to less vaccinated populations. We tested for vaccine-induced selection in influenza by comparing strain frequencies between more and less vaccinated human populations. We defined strains in three ways: first as influenza types and subtypes, next as lineages of type B, and finally as clades of influenza A/H3N2. We detected spatial differences partially consistent with vaccine use in the frequencies of subtypes and types and between the lineages of influenza B, suggesting that vaccines do not select strongly among all these phylogenetic groups at regional scales. We did detect a significantly greater frequency of an H3N2 clade with known vaccine escape mutations in more vaccinated countries during the 2014⁻2015 season, which is consistent with vaccine-driven selection within the H3N2 subtype. Overall, we find more support for vaccine-driven selection when large differences in vaccine effectiveness suggest a strong effect size. Variation in surveillance practices across countries could obscure signals of selection, especially when strain-specific differences in vaccine effectiveness are small. Further examination of the influenza vaccine's evolutionary effects would benefit from improvements in epidemiological surveillance and reporting.}, }
@article {pmid30231388, year = {2018}, author = {Hahn, AW and Higano, CS and Taplin, ME and Ryan, CJ and Agarwal, N}, title = {Metastatic Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and Treatment.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {}, number = {38}, pages = {363-371}, doi = {10.1200/EDBK_200967}, pmid = {30231388}, issn = {1548-8756}, mesh = {Clinical Trials as Topic ; Combined Modality Therapy ; Disease Management ; Humans ; Male ; Neoplasm Metastasis ; Neoplasm Staging ; Patient Selection ; Prostatic Neoplasms/*diagnosis/mortality/*therapy ; Treatment Outcome ; }, abstract = {The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has rapidly evolved over the past 5 years. Although androgen-deprivation therapy (ADT) is still the backbone of treatment, the addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and become standard of care. With multiple treatment options available for patients with mCSPC, treatment selection to optimize patient outcomes has become increasingly difficult. Here, we review the clinical trials involving ADT plus docetaxel or abiraterone and provide clinicians with guidelines for treatment. Although surgery and/or radiation are standard of care for localized, intermediate- and high-risk prostate cancer, these treatments are not routinely used as part of initial treatment plans for patients with de novo mCSPC. Recent clinical data are challenging that dogma, and we review the literature on the addition of surgery and radiation to systemic therapy for mCSPC. Finally, the standard of care for oligometastatic prostate cancer (a subset of mCSPC with limited metastases) has not been established compared with that for some other cancers. We discuss the recent studies on metastasis-directed therapy for treatment of oligometastatic prostate cancer.}, }
@article {pmid30231356, year = {2018}, author = {Dietrich, B and Siefker-Radtke, AO and Srinivas, S and Yu, EY}, title = {Systemic Therapy for Advanced Urothelial Carcinoma: Current Standards and Treatment Considerations.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {}, number = {38}, pages = {342-353}, doi = {10.1200/EDBK_201193}, pmid = {30231356}, issn = {1548-8756}, mesh = {Combined Modality Therapy/methods ; Disease Management ; Humans ; Immunotherapy ; Molecular Targeted Therapy ; Neoplasm Metastasis ; Neoplasm Staging ; Retreatment ; Standard of Care ; Treatment Outcome ; Urologic Neoplasms/*pathology/*therapy ; }, abstract = {Urothelial carcinoma is the sixth most common malignancy in the United States. Although most are diagnosed with non-muscle-invasive malignancy, many patients will develop recurrent disease within 5 years, with 10% to 20% developing advanced muscle-invasive or more distant incurable disease. For such patients, clinical outcomes have remained suboptimal, although recent therapeutic advances have brought new hope to the field. Here, we discuss the main systemic treatment options available for the treatment of patients with advanced disease. This review begins with traditional chemotherapy, which remains a first-line treatment option for many patients. The second section focuses on the evolving landscape of immunotherapy, specifically on approved checkpoint inhibitors and future challenges. Last, we address advances in targeted treatments, including angiogenesis and fibroblast growth factor receptor (FGFR) inhibitors as well as antibody-drug conjugates. As the number of available treatment options continues to expand, ongoing trials to investigate the best sequence and combination strategies to incorporate these drugs into clinical practice will help delineate the future.}, }
@article {pmid30231352, year = {2018}, author = {Katz, D and Palmerini, E and Pollack, SM}, title = {More Than 50 Subtypes of Soft Tissue Sarcoma: Paving the Path for Histology-Driven Treatments.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {}, number = {38}, pages = {925-938}, doi = {10.1200/EDBK_205423}, pmid = {30231352}, issn = {1548-8756}, mesh = {Biomarkers ; Biopsy ; Clinical Decision-Making ; Clinical Trials as Topic ; Combined Modality Therapy/methods ; Disease Management ; Drug Resistance, Neoplasm ; Humans ; Immunotherapy ; Molecular Targeted Therapy ; Neoplasm Grading ; Sarcoma/*diagnosis/etiology/pathology/*therapy ; Treatment Outcome ; }, abstract = {Sarcomas are a diverse group of cancers with mesenchymal origin. Although sarcomas comprise less than 1% of cancers, there are more than 50 different subtypes that are quite different from one another in terms of both their biology and clinical behavior. Historically, the need for adequate patient numbers in clinical trials has pushed sarcoma researchers to lump these very different malignancies together and treat the patients using a "one-size-fits-all" approach. However, with improvements in our scientific understanding, we are finally ready for a histology-tailored therapeutic approach to these complex diseases. In this review, we discuss key advances in our understanding of the biology underlying selected sarcoma subtypes and how targeting these subtypes is relevant therapeutically with respect to both molecularly targeted agents as well as immunotherapy.}, }
@article {pmid30231342, year = {2018}, author = {Dienstmann, R and Salazar, R and Tabernero, J}, title = {Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {}, number = {38}, pages = {231-238}, doi = {10.1200/EDBK_200929}, pmid = {30231342}, issn = {1548-8756}, mesh = {*Biomarkers, Tumor ; Clinical Decision-Making ; Colorectal Neoplasms/*diagnosis/*genetics/therapy ; Humans ; Mutation ; Neoplasm Metastasis ; Neoplasm Staging ; Oncogenes ; }, abstract = {Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to epidermal growth factor receptor monoclonal antibodies have been described, with substantial overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment-refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers reflect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, whereas tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratified development of novel immunotherapy combinations. Here, we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.}, }
@article {pmid30230531, year = {2018}, author = {Rosenberg, AR and Bradford, MC and McCauley, E and Curtis, JR and Wolfe, J and Baker, KS and Yi-Frazier, JP}, title = {Promoting resilience in adolescents and young adults with cancer: Results from the PRISM randomized controlled trial.}, journal = {Cancer}, volume = {124}, number = {19}, pages = {3909-3917}, doi = {10.1002/cncr.31666}, pmid = {30230531}, issn = {1097-0142}, support = {K12 CA088084/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Adolescents and young adults (AYAs) with cancer are at risk for poor psychosocial outcomes. This study aimed to determine whether a novel intervention targeting resilience resources would improve patient-reported resilience, quality of life, and psychological distress.
METHODS: In this parallel, phase 2 randomized controlled trial, English-speaking AYAs (12-25 years old) with cancer were randomized to the Promoting Resilience in Stress Management (PRISM) intervention or usual care (UC). PRISM is a brief, skills-based intervention targeting stress management, goal setting, cognitive reframing, and meaning making. Participants completed surveys at enrollment and 6 months. Mixed effects regression models evaluated associations between PRISM and the primary outcome (10-item Connor-Davidson Resilience Scale scores) and secondary outcomes (generic and cancer-related quality of life [Pediatric Quality of Life modules], psychological distress [Kessler-6], and anxiety/depression [Hospital Anxiety and Depression]) at 6 months.
RESULTS: Ninety-two AYAs were enrolled, were randomized, and completed baseline surveys (48 in the PRISM group and 44 in the UC group); 73% were 12 to 17 years old, and 62% had leukemia or lymphoma. Attrition was primarily due to medical complications and/or death; 36 PRISM participants and 38 UC participants completed 6-month surveys. PRISM was associated with improved resilience (+3.0 points; 95% confidence interval [CI], 0.5-5.4; P = .02) and cancer-specific quality of life (+9.6; 95% CI, 2.6-16.7; P = .01) and reduced psychological distress (-2.1; 95% CI, -4.1 to -0.2; P = .03) but not generic quality of life (+7.2; 95% CI, -0.8 to 15.2; P = .08). Although anxiety was similar between the groups, 2 PRISM participants (6%) and 8 UC participants (21%) met the criteria for depression at 6 months (odds ratio, 0.09; 95% CI, 0.01-1.09; P = .06).
CONCLUSIONS: PRISM was associated with improved psychosocial outcomes in comparison with UC, suggesting that brief, skills-based interventions for AYAs may provide a benefit.}, }
@article {pmid30226143, year = {2018}, author = {Hennessey, MJ and Ellis, EM and Delorey, MJ and Panella, AJ and Kosoy, OI and Kirking, HL and Appiah, GD and Qin, J and Basile, AJ and Feldstein, LR and Biggerstaff, BJ and Lanciotti, RS and Fischer, M and Staples, JE}, title = {Seroprevalence and Symptomatic Attack Rate of Chikungunya Virus Infection, United States Virgin Islands, 2014-2015.}, journal = {The American journal of tropical medicine and hygiene}, volume = {99}, number = {5}, pages = {1321-1326}, doi = {10.4269/ajtmh.18-0437}, pmid = {30226143}, issn = {1476-1645}, abstract = {When introduced into a naïve population, chikungunya virus generally spreads rapidly, causing large outbreaks of fever and severe polyarthralgia. We randomly selected households in the U.S. Virgin Islands (USVI) to estimate seroprevalence and symptomatic attack rate for chikungunya virus infection at approximately 1 year following the introduction of the virus. Eligible household members were administered a questionnaire and tested for chikungunya virus antibodies. Estimated proportions were calibrated to age and gender of the population. We enrolled 509 participants. The weighted infection rate was 31% (95% confidence interval [CI]: 26-36%). Among those with evidence of chikungunya virus infection, 72% (95% CI: 65-80%) reported symptomatic illness and 31% (95% CI: 23-38%) reported joint pain at least once per week approximately 1 year following the introduction of the virus to USVI. Comparing rates from infected and noninfected study participants, 70% (95% CI: 62-79%) of fever and polyarthralgia and 23% (95% CI: 9-37%) of continuing joint pain in patients infected with chikungunya virus were due to their infection. Overall, an estimated 43% (95% CI: 33-52%) of the febrile illness and polyarthralgia in the USVI population during the outbreak was attributable to chikungunya virus and only 12% (95% CI: 7-17%) of longer term joint pains were attributed to chikungunya virus. Although the rates of infection, symptomatic disease, and longer term joint symptoms identified in USVI are similar to other outbreaks of the disease, a lower proportion of acute fever and joint pain was found to be attributable to chikungunya virus.}, }
@article {pmid30224943, year = {2018}, author = {Randolph, TW and Zhao, S and Copeland, W and Hullar, M and Shojaie, A}, title = {KERNEL-PENALIZED REGRESSION FOR ANALYSIS OF MICROBIOME DATA.}, journal = {The annals of applied statistics}, volume = {12}, number = {1}, pages = {540-566}, doi = {10.1214/17-AOAS1102}, pmid = {30224943}, issn = {1932-6157}, support = {K01 HL124050/HL/NHLBI NIH HHS/United States ; P01 CA168530/CA/NCI NIH HHS/United States ; R01 GM114029/GM/NIGMS NIH HHS/United States ; U01 CA162077/CA/NCI NIH HHS/United States ; }, abstract = {The analysis of human microbiome data is often based on dimension-reduced graphical displays and clusterings derived from vectors of microbial abundances in each sample. Common to these ordination methods is the use of biologically motivated definitions of similarity. Principal coordinate analysis, in particular, is often performed using ecologically defined distances, allowing analyses to incorporate context-dependent, non-Euclidean structure. In this paper, we go beyond dimension-reduced ordination methods and describe a framework of high-dimensional regression models that extends these distance-based methods. In particular, we use kernel-based methods to show how to incorporate a variety of extrinsic information, such as phylogeny, into penalized regression models that estimate taxonspecific associations with a phenotype or clinical outcome. Further, we show how this regression framework can be used to address the compositional nature of multivariate predictors comprised of relative abundances; that is, vectors whose entries sum to a constant. We illustrate this approach with several simulations using data from two recent studies on gut and vaginal microbiomes. We conclude with an application to our own data, where we also incorporate a significance test for the estimated coefficients that represent associations between microbial abundance and a percent fat.}, }
@article {pmid30224545, year = {2018}, author = {Bianchi-Frias, D and Damodarasamy, M and Hernandez, SA and Gil da Costa, RM and Vakar-Lopez, F and Coleman, IM and Reed, MJ and Nelson, PS}, title = {The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells.}, journal = {Molecular cancer research : MCR}, volume = {}, number = {}, pages = {}, doi = {10.1158/1541-7786.MCR-18-0522}, pmid = {30224545}, issn = {1557-3125}, abstract = {The incidence of prostate cancer is directly linked to age, but age-associated changes that facilitate prostate cancer development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on prostate cancer behavior. Prostate cancer cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared with young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. Tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis, or angiogenesis. However, analysis of tumor-infiltrating immune cells by IHC and RNA sequencing (RNA-seq) revealed elevated numbers of macrophages in prostates from aged mice, which are quickly polarized towards a phenotype resembling protumorigenic tumor-associated macrophages upon tumor cell engraftment. Older patients with prostate cancer (>60 years old) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset displayed higher expression of macrophage markers (CD163 and VSIG4) which associated with higher rates of biochemical relapse. Remodeling of the collagenous extracellular matrix (ECM) was associated with prostate cancer growth and invasion in the aged microenvironment. Moreover, the collagen matrix extracted from aged mice enhanced the invasiveness and proliferation of prostate cancer cells in vitro Together, these results demonstrate that the aged prostatic microenvironment can regulate the growth and metastasis of malignant prostate cells, highlighting the role of resident macrophages and their polarization towards a protumorigenic phenotype, along with remodeling of the ECM.Implications: These findings demonstrate the importance of age-associated tumor microenvironment alterations in regulating key aspects of prostate cancer progression. Mol Cancer Res; 1-11. ©2018 AACR.}, }
@article {pmid30222731, year = {2018}, author = {Phillips, AM and Ponomarenko, AI and Chen, K and Ashenberg, O and Miao, J and McHugh, SM and Butty, VL and Whittaker, CA and Moore, CL and Bloom, JD and Lin, YS and Shoulders, MD}, title = {Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones.}, journal = {PLoS biology}, volume = {16}, number = {9}, pages = {e3000008}, doi = {10.1371/journal.pbio.3000008}, pmid = {30222731}, issn = {1545-7885}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; R01 GM102198/GM/NIGMS NIH HHS/United States ; }, abstract = {The threat of viral pandemics demands a comprehensive understanding of evolution at the host-pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition-mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.}, }
@article {pmid30222470, year = {2018}, author = {Samples, LS and Graf, SA}, title = {On the front line: first choice pharmacotherapeutics for chronic lymphocytic leukemia.}, journal = {Expert opinion on pharmacotherapy}, volume = {19}, number = {15}, pages = {1675-1684}, doi = {10.1080/14656566.2018.1524874}, pmid = {30222470}, issn = {1744-7666}, abstract = {INTRODUCTION: Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with a highly variable clinical course. Frontline treatments include cytotoxic chemotherapies, immunotherapies, and small molecule inhibitors. Clinical and molecular factors guide treatment initiation and selection. Over the last decade, refinement of CLL risk stratification tools and growth of the arsenal of effective therapeutics have profoundly improved outcomes. These advances have concurrently increased the complexity of managing the early phases of treatment. Areas covered: This review describes the factors considered in the determination of first-line treatment of CLL. Areas of emphasis include assessment of patient fitness, disease classification and risk stratification, and the mechanisms, efficacy, and toxicities associated with available pharmacotherapeutics. Expert opinion: Multiple different treatments may be appropriate for a specific clinical scenario, and selection among them requires discussion of relative risks and benefits. Advances in frontline CLL treatment will continue to shift the treatment paradigm toward prioritizing quality of life alongside survival, limiting treatment and toxicity, and the development of biologically rational synergistic drug combinations and sequences.}, }
@article {pmid30220614, year = {2018}, author = {Radtke, S and Humbert, O and Kiem, HP}, title = {Sorting Out the Best: Enriching Hematopoietic Stem Cells for Gene Therapy and Editing.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {26}, number = {10}, pages = {2328-2329}, doi = {10.1016/j.ymthe.2018.08.025}, pmid = {30220614}, issn = {1525-0024}, }
@article {pmid30219700, year = {2018}, author = {Gandelman, JS and Zic, J and Dewan, AK and Lee, SJ and Flowers, M and Cutler, C and Pidala, J and Chen, H and Jagasia, MH and Tkaczyk, ER}, title = {The Anatomic Distribution of Skin Involvement in Patients with Incident Chronic 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.2018.09.007}, pmid = {30219700}, issn = {1523-6536}, abstract = {Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (n = 71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (n = 4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (n = 14; 8%) and lower extremities (n = 14; 8%). More than one-half of patients with erythema (n = 107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (n = 16; 30.2%).}, }
@article {pmid30219040, year = {2018}, author = {Retèl, VP and Steuten, LMG and Geukes Foppen, MH and Mewes, JC and Lindenberg, MA and Haanen, JBAG and van Harten, WH}, title = {Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.}, journal = {BMC cancer}, volume = {18}, number = {1}, pages = {895}, doi = {10.1186/s12885-018-4788-5}, pmid = {30219040}, issn = {1471-2407}, mesh = {Antibodies, Monoclonal/administration & dosage/economics ; *Cost-Benefit Analysis ; Denmark/epidemiology ; Disease-Free Survival ; Female ; Humans ; Immunotherapy/*economics ; Ipilimumab/administration & dosage/economics ; Lymphocytes, Tumor-Infiltrating/*immunology/transplantation ; Male ; Melanoma/*drug therapy/economics/pathology ; Models, Economic ; Netherlands/epidemiology ; Quality-Adjusted Life Years ; }, abstract = {BACKGROUND: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed.
METHODS: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed.
RESULTS: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M.
CONCLUSIONS: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.}, }
@article {pmid30218543, year = {2018}, author = {Zhan, X and Xue, L and Zheng, H and Plantinga, A and Wu, MC and Schaid, DJ and Zhao, N and Chen, J}, title = {A small-sample kernel association test for correlated data with application to microbiome association studies.}, journal = {Genetic epidemiology}, volume = {42}, number = {8}, pages = {772-782}, doi = {10.1002/gepi.22160}, pmid = {30218543}, issn = {1098-2272}, support = {GM065450/NH/NIH HHS/United States ; }, abstract = {Recent research has highlighted the importance of the human microbiome in many human disease and health conditions. Most current microbiome association analyses focus on unrelated samples; such methods are not appropriate for analysis of data collected from more advanced study designs such as longitudinal and pedigree studies, where outcomes can be correlated. Ignoring such correlations can sometimes lead to suboptimal results or even possibly biased conclusions. Thus, new methods to handle correlated outcome data in microbiome association studies are needed. In this paper, we propose the correlated sequence kernel association test (CSKAT) to address such correlations using the linear mixed model. Specifically, random effects are used to account for the outcome correlations and a variance component test is used to examine the microbiome effect. Compared to existing genetic association tests for longitudinal and family samples, we implement a correction procedure to better calibrate the null distribution of the score test statistic to accommodate the small sample size nature of data collected from a typical microbiome study. Comprehensive simulation studies are conducted to demonstrate the validity and efficiency of our method, and we show that CSKAT achieves a higher power than existing methods while correctly controlling the Type I error rate. We also apply our method to a microbiome data set collected from a UK twin study to illustrate its potential usefulness. A free implementation of our method in R software is available at https://github.com/jchen1981/SSKAT.}, }
@article {pmid30218318, year = {2018}, author = {Mensch, BS and Richardson, BA and Husnik, M and Brown, ER and Kiweewa, FM and Mayo, AJ and Baeten, JM and Palanee-Phillips, T and van der Straten, A and , }, title = {Vaginal Ring Use in a Phase 3 Microbicide Trial: A Comparison of Objective Measures and Self-reports of Non-adherence in ASPIRE.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10461-018-2261-8}, pmid = {30218318}, issn = {1573-3254}, support = {U01 AI068633/AI/NIAID NIH HHS/United States ; 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 = {This analysis compares self-reports of product use with objective measures of non-adherence-quarterly plasma dapivirine levels and monthly residual dapivirine (DPV) levels in used rings-in MTN-020/ASPIRE, a phase 3 trial of a monthly DPV vaginal ring among women aged 18-45 years in Malawi, South Africa, Uganda and Zimbabwe. For participants on active product (N = 1211) we assessed self-reported monthly non-adherence, as measured by (1) whether the ring was ever out, and out for ≥ 12 h in the previous month and, (2) by a self-rating scale assessing ability to keep the vaginal ring inserted, and compared the self-reports to two biomarkers of non-use separately and as a composite measure. For this analysis, a plasma DPV value ≤ 95 pg/ml and residual ring ≥ 23.5 mg were used to classify non-adherence (i.e. the ring never being in the vagina the previous month). Compared to self-reports, non-adherence was found to be substantially higher for the composite measure as well as its two components, an indication that ring removal was likely underreported in the trial. The discrepancy between the self-report measure of ring outage and the composite indicator was greater for those aged 18-21 than for those older, evidence that younger women are more likely to underreport non-adherence. Despite underreporting of non-adherence, self-reports of the ring never being out were significant in predicting the composite objective measure. Furthermore, the association between the self-rating scale and the objective measure was in the expected direction and significant, although 11% of those 18-21 and 7% of those 22+ who rated their ability to keep the ring inserted as good, very good or excellent in the 4 weeks prior to exit were considered non-adherent according to the objective measure. This analysis indicates that while self-reports are significantly associated with objective measures of adherence in the ASPIRE trial, they were inflated-more so by those younger-and therefore may have limited utility identifying those who have challenges using products as directed. ClinicalTrials.gov number NCT01617096.}, }
@article {pmid30217891, year = {2018}, author = {Fowler, KR and Hyppa, RW and Cromie, GA and Smith, GR}, title = {Physical basis for long-distance communication along meiotic chromosomes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, number = {40}, pages = {E9333-E9342}, doi = {10.1073/pnas.1801920115}, pmid = {30217891}, issn = {1091-6490}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM031693/GM/NIGMS NIH HHS/United States ; R01 GM032194/GM/NIGMS NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; }, mesh = {Chromosomes, Fungal/genetics/*metabolism ; *DNA Breaks, Double-Stranded ; *Meiosis ; Nuclear Proteins/genetics/*metabolism ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; }, abstract = {Viable gamete formation requires segregation of homologous chromosomes connected, in most species, by cross-overs. DNA double-strand break (DSB) formation and the resulting cross-overs are regulated at multiple levels to prevent overabundance along chromosomes. Meiotic cells coordinate these events between distant sites, but the physical basis of long-distance chromosomal communication has been unknown. We show that DSB hotspots up to ∼200 kb (∼35 cM) apart form clusters via hotspot-binding proteins Rec25 and Rec27 in fission yeast. Clustering coincides with hotspot competition and interference over similar distances. Without Tel1 (an ATM tumor-suppressor homolog), DSB and crossover interference become negative, reflecting coordinated action along a chromosome. These results indicate that DSB hotspots within a limited chromosomal region and bound by their protein determinants form a clustered structure that, via Tel1, allows only one DSB per region. Such a "roulette" process within clusters explains the observed pattern of crossover interference in fission yeast. Key structural and regulatory components of clusters are phylogenetically conserved, suggesting conservation of this vital regulation. Based on these observations, we propose a model and discuss variations in which clustering and competition between DSB sites leads to DSB interference and in turn produces crossover interference.}, }
@article {pmid30217764, year = {2018}, author = {Almassi, N and Gao, T and Lee, B and Stein, RJ and Haber, GP and Ornstein, MC and Rini, BI and Gilligan, TD and Garcia, JA and Stephenson, AJ and Grivas, P}, title = {Impact of Neoadjuvant Chemotherapy on Pathologic Response in Patients With Upper Tract Urothelial Carcinoma Undergoing Extirpative Surgery.}, journal = {Clinical genitourinary cancer}, volume = {16}, number = {6}, pages = {e1237-e1242}, doi = {10.1016/j.clgc.2018.08.003}, pmid = {30217764}, issn = {1938-0682}, abstract = {BACKGROUND: Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.
PATIENTS AND METHODS: A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR.
RESULTS: Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P < .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR.
CONCLUSIONS: Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.}, }
@article {pmid30216123, year = {2018}, author = {Madenci, AL and Weil, BR and Liu, Q and Murphy, AJ and Gibson, TM and Yasui, Y and Leisenring, WM and Howell, RM and Tinkle, CL and Nekhlyudov, L and Diller, LR and Armstrong, GT and Oeffinger, KC and Weldon, CB}, title = {Long-Term Risk of Venous Thromboembolism in Survivors of Childhood Cancer: 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 = {JCO2018784595}, doi = {10.1200/JCO.2018.78.4595}, pmid = {30216123}, issn = {1527-7755}, abstract = {Purpose To estimate the incidence of late-occurring venous thromboembolism (VTE) among survivors of childhood cancer and to identify risk factors for VTE to facilitate diagnosis and prevention. Methods The Childhood Cancer Survivor Study is a multi-institutional cohort of 24,355 5-year childhood cancer survivors (diagnosed between 1970 and 1999; median age at last follow-up, 28.7 years [range, 5.6 to 58.9 years]; median follow-up since diagnosis, 21.3 years [range, 5.0 to 39.2 years]) and 5,051 sibling participants. The primary end point was self-reported late (≥ 5 years after cancer diagnosis) VTE. Rate ratios (RRs) were estimated with multivariable piecewise exponential models. Results Late VTE incidence among survivors and siblings was 1.1 and 0.5 events per 1,000 person-years, respectively (RR, 2.2; 95% CI, 1.7 to 2.8), with 2.5 excess events per 100 survivors over 35 years. Among survivors, risk factors for VTE were female sex (RR, 1.3; 95% CI, 1.1 to 1.6), cisplatin (reference none; 1 to 199 mg/m2: RR, 3.0 [95% CI, 1.4 to 6.5]; 200 to 399 mg/m2: RR, 1.9 [95% CI, 1.0 to 3.6]; ≥ 400 mg/m2: RR, 2.0 [95% CI, 1.2 to 3.3]), l-asparaginase (RR, 1.3; 95% CI, 1.0 to 1.7), obesity or underweight (reference body mass index [BMI] 18.5 to 24.9 kg/m2; BMI ≥ 30.0 kg/m2: RR, 1.6 [95% CI, 1.2 to 2.0]; BMI < 18.5 kg/m2: RR, 2.4 [95% CI, 1.7 to 3.4]), and late cancer recurrence or subsequent malignant neoplasm (RR, 4.6; 95% CI, 3.6 to 5.8). Among lower-extremity osteosarcoma survivors, limb salvage (reference amputation; RR, 3.1; 95% CI, 1.2 to 7.5) and cisplatin 200 to 399 or ≥ 400 mg/m2 (reference none; RR, 4.0 [95% CI, 1.1 to 14.6] and 2.9 [95% CI, 1.1 to 8.0], respectively) were independently associated with late VTE. VTE was associated with increased risk for nonexternal cause late mortality (RR, 1.9; 95% CI, 1.6 to 2.3). Conclusion Childhood cancer survivors are at increased risk for VTE across their lifespan and a diagnosis of VTE increases mortality risk. Interventions that target potentially modifiable comorbidities, such as obesity, warrant consideration, with prophylaxis for high-risk survivors, including those treated with cisplatin and limb-sparing approaches.}, }
@article {pmid30215677, year = {2018}, author = {Long, GV and Tykodi, SS and Schneider, JG and Garbe, C and Gravis, G and Rashford, M and Agrawal, S and Grigoryeva, E and Bello, A and Roy, A and Rollin, L and Zhao, X}, title = {Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/annonc/mdy408}, pmid = {30215677}, issn = {1569-8041}, abstract = {Background: A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in the United States, Canada, and European Union as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure-response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen.
Patients and methods: Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials.
Results: Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grade 3-4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified.
Conclusions: The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care.
Clinical trial numbers: NCT01721772, NCT01668784, NCT01673867, NCT01642004.}, }
@article {pmid30215267, year = {2018}, author = {Eisenberg, AL and Patel, EU and Packman, ZR and Fernandez, RE and Piwowar-Manning, E and Hamilton, EL and MacPhail, C and Hughes, J and Pettifor, A and Kallas, EG and Busch, MP and Murphy, G and Quinn, TC and Eshleman, SH and Laeyendecker, O}, title = {Dried Blood Spots Stored at Room Temperature Should Not Be Used for HIV Incidence Testing.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/AID.2018.0138}, pmid = {30215267}, issn = {1931-8405}, support = {UM1 AI068613/AI/NIAID NIH HHS/United States ; }, abstract = {The limiting antigen (LAg)-avidity assay is a serologic assay used for cross-sectional HIV incidence testing. We compared the results obtained with the LAg-avidity assay using dried blood spot (DBS) samples stored at room temperature (18°C-25°C) or stored frozen at -80°C with results obtained from matched plasma samples. Matched DBS and plasma samples (306 paired samples) were collected in the HIV Prevention Trials Network (HPTN) 068 trial in South Africa (2012-2014). The DBS were stored at room temperature before testing. Matched DBS and plasma samples (100 paired samples) from the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA) were collected in 2016 and were stored at -80°C. All DBS testing was performed in 2017. Differences in normalized optical density (ODn) were compared between matched DBS and plasma samples. For DBS samples stored at room temperature (HPTN 068), the average difference in ODn values for plasma versus DBS was 1.49 (95% confidence intervals [CI]: 1.36-1.62). In contrast, when DBS samples were stored at -80°C (CEPHIA), the average difference in ODn values for plasma versus DBS was -0.22 (95% CI: -0.32 to -0.13). DBS samples stored at room temperature should not be used for cross-sectional HIV incidence testing with the LAg-avidity assay.}, }
@article {pmid30214939, year = {2018}, author = {Gast, CE and Silk, AD and Zarour, L and Riegler, L and Burkhart, JG and Gustafson, KT and Parappilly, MS and Roh-Johnson, M and Goodman, JR and Olson, B and Schmidt, M and Swain, JR and Davies, PS and Shasthri, V and Iizuka, S and Flynn, P and Watson, S and Korkola, J and Courtneidge, SA and Fischer, JM and Jaboin, J and Billingsley, KG and Lopez, CD and Burchard, J and Gray, J and Coussens, LM and Sheppard, BC and Wong, MH}, title = {Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival.}, journal = {Science advances}, volume = {4}, number = {9}, pages = {eaat7828}, doi = {10.1126/sciadv.aat7828}, pmid = {30214939}, issn = {2375-2548}, support = {R01 CA118235/CA/NCI NIH HHS/United States ; T32 HL007781/HL/NHLBI NIH HHS/United States ; R21 CA172334/CA/NCI NIH HHS/United States ; K99 CA190836/CA/NCI NIH HHS/United States ; T32 CA106195/CA/NCI NIH HHS/United States ; S10 RR023432/RR/NCRR NIH HHS/United States ; U54 CA112970/CA/NCI NIH HHS/United States ; R00 CA190836/CA/NCI NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; R15 GM071388/GM/NIGMS NIH HHS/United States ; P30 CA069533/CA/NCI NIH HHS/United States ; }, abstract = {High lethality rates associated with metastatic cancer highlight an urgent medical need for improved understanding of biologic mechanisms driving metastatic spread and identification of biomarkers predicting late-stage progression. Numerous neoplastic cell intrinsic and extrinsic mechanisms fuel tumor progression; however, mechanisms driving heterogeneity of neoplastic cells in solid tumors remain obscure. Increased mutational rates of neoplastic cells in stressed environments are implicated but cannot explain all aspects of tumor heterogeneity. We present evidence that fusion of neoplastic cells with leukocytes (for example, macrophages) contributes to tumor heterogeneity, resulting in cells exhibiting increased metastatic behavior. Fusion hybrids (cells harboring hematopoietic and epithelial properties) are readily detectible in cell culture and tumor-bearing mice. Further, hybrids enumerated in peripheral blood of human cancer patients correlate with disease stage and predict overall survival. This unique population of neoplastic cells provides a novel biomarker for tumor staging, as well as a potential therapeutic target for intervention.}, }
@article {pmid30211723, year = {2018}, author = {Cook, M and Baker, K and Redman, M and Lachance, K and Nguyen, MH and Parvathaneni, U and Bhatia, S and Nghiem, P and Tseng, YD}, title = {Differential Outcomes Among Immunosuppressed Patients With Merkel Cell Carcinoma: Impact of Immunosuppression Type on Cancer-specific and Overall Survival.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000000482}, pmid = {30211723}, issn = {1537-453X}, abstract = {OBJECTIVES: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with higher incidence among whites, elderly, and immunosuppressed patients. Although immunosuppressed MCC patients are at higher risk of recurrence and MCC-related death, it is unknown whether immunosuppression type is associated with differential outcomes.
MATERIALS AND METHODS: We retrospectively evaluated 89 nonmetastatic MCC patients with a diagnosis of chronic immunosuppression. Immunosuppression was categorized as chronic lymphocytic leukemia (31% of cohort), other hematologic malignancies (18%), solid organ transplant (21%), autoimmune disease (21%), and human immunodeficiency virus acquired deficiency syndrome (8%). Progression-free survival (PFS) and MCC-specific survival (MSS) were estimated with the cumulative incidence function. Overall survival (OS) was estimated by the Kaplan-Meier method.
RESULTS: With a median follow-up of 52 months, 53 deaths occurred (42 from MCC, 7 unknown, and 4 non-MCC). Two-year PFS, MSS, and OS were 30%, 55%, and 52%, respectively. Human immunodeficiency virus/acquired deficiency syndrome and solid organ transplant patients were diagnosed with MCC at a younger age (median 55 and 59 y, respectively) and with more advanced stage disease compared with other immunosuppressed subgroups. PFS did not significantly differ among the 5 immunosuppression subgroups (P=0.30), but significant differences were observed in MSS and OS (both P=0.01). Controlling for potential confounders for OS, including age and stage, immunosuppression type was still significantly associated with risk of death (P=0.01).
CONCLUSIONS: Among immunosuppressed MCC patients, recurrent MCC is the major cause of mortality. The risk of death from MCC differs among immunosuppression types, suggesting important biological differences in host-tumor immune interactions.}, }
@article {pmid30211249, year = {2018}, author = {Cornetta, K and Duffy, L and Feldman, SA and Mackall, CL and Davila, ML and Curran, KJ and Junghans, RP and Tang, JY and Kochenderfer, JN and O'Cearbhaill, R and Archer, G and Kiem, HP and Shah, NN and Delbrook, C and Kaplan, R and Brentjens, RJ and Rivière, I and Sadelain, M and Rosenberg, SA}, title = {Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience.}, journal = {Molecular therapy. Methods & clinical development}, volume = {10}, number = {}, pages = {371-378}, doi = {10.1016/j.omtm.2018.08.006}, pmid = {30211249}, issn = {2329-0501}, support = {P50 CA190991/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 CA190174/CA/NCI NIH HHS/United States ; P40 HL116242/HL/NHLBI NIH HHS/United States ; R01 CA114218/CA/NCI NIH HHS/United States ; R01 CA177476/CA/NCI NIH HHS/United States ; }, abstract = {Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1 month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.}, }
@article {pmid30209831, year = {2018}, author = {Kaluza, J and Håkansson, N and Harris, HR and Orsini, N and Michaëlsson, K and Wolk, A}, title = {Influence of anti-inflammatory diet and smoking on mortality and survival in men and women: two prospective cohort studies.}, journal = {Journal of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/joim.12823}, pmid = {30209831}, issn = {1365-2796}, support = {FORTE 2015-00778//Swedish Research Council for Health, Working Life and Welfare/ ; FR 2016/0004//Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning/ ; VR 2017-00644//Swedish Research Council/ ; //Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER)/ ; }, abstract = {BACKGROUND: The associations between an anti-inflammatory diet and both all-cause and cause-specific mortality have been studied previously; however, the influence of an anti-inflammatory diet on survival time has not been investigated. Moreover, the potential modification of these associations by smoking status remains unclear.
OBJECTIVE: The aims of this study were to examine the associations between an anti-inflammatory diet index (AIDI) and all-cause and cause-specific mortality, to determine the association between the AIDI and differences in survival time and to assess effect modification by smoking status.
METHODS: The study population included 68 273 Swedish men and women (aged 45-83 years) at baseline. The anti-inflammatory potential of the diet was estimated using the validated AIDI, which includes 11 potential anti-inflammatory and five potential pro-inflammatory foods. Cox proportional hazards and Laplace regression were used to estimate hazard ratios and differences in survival time.
RESULTS: During 16 years of follow-up (1 057 959 person-years), 16 088 deaths [5980 due to cardiovascular disease (CVD) and 5252 due to cancer] were recorded. Participants in the highest versus lowest quartile of the AIDI had lower risks of all-cause (18% reduction, 95% CI: 14-22%), CVD (20%, 95% CI: 14-26%) and cancer (13%, 95% CI: 5-20%) mortality. The strongest inverse associations between the highest and lowest quartiles of AIDI and risk of mortality were observed in current smokers: 31%, 36% and 22% lower risks of all-cause, CVD and cancer mortality, respectively. The difference in survival time between current smokers in the lowest AIDI quartile and never smokers in the highest quartile was 4.6 years.
CONCLUSION: Adherence to a diet with high anti-inflammatory potential may reduce all-cause, CVD and cancer mortality and prolong survival time especially amongst smokers.}, }
@article {pmid30209824, year = {2018}, author = {Wang, L and Huang, Y}, title = {Evaluating classification performance of biomarkers in two-phase case-control studies.}, journal = {Statistics in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/sim.7966}, pmid = {30209824}, issn = {1097-0258}, support = {R01 GM106177/GM/NIGMS NIH HHS/United States ; R01 GM106177-01//National Institutes of General Medical Sciences (NIGMS)/ ; }, abstract = {Biomarkers are playing an increasingly important role in disease screening, early detection, and risk prediction. The two-phase case-control sampling study design is widely used for the evaluation of candidate biomarkers. The sampling probabilities for cases and controls in the second phase can often depend on other covariates (sampling strata). This biased sampling can lead to invalid inference on a biomarker's classification accuracy if not properly accounted for. In this paper, we adopt the idea of inverse probability weighting and develop inverse probability weighting-based estimators for various measures of a biomarker's classification performance, including the points on the receiver operating characteristics (ROCs) curve, the area under the ROC curve (area under the curve), and the partial area under the curve. In particular, we consider classification accuracy estimators using sampling weights estimated conditionally on sampling strata and further improve their efficiency through the use of estimated weights that additionally take into account the auxiliary variables available from the phase-one cohort. We develop asymptotic properties of the proposed estimators and provide analytical variance for making inference. Extensive simulation studies demonstrate excellent performance of the proposed weighted estimators, while the traditional empirical estimator can be severely biased. We also investigate the advantages in efficiency gain for estimating various classification accuracy estimators through the use of auxiliary variables in addition to sampling strata and apply the proposed method to examples from a renal artery stenosis study and a prostate cancer study.}, }
@article {pmid30209393, year = {2018}, author = {Dou, J and Vorobieva, AA and Sheffler, W and Doyle, LA and Park, H and Bick, MJ and Mao, B and Foight, GW and Lee, MY and Gagnon, LA and Carter, L and Sankaran, B and Ovchinnikov, S and Marcos, E and Huang, PS and Vaughan, JC and Stoddard, BL and Baker, D}, title = {De novo design of a fluorescence-activating β-barrel.}, journal = {Nature}, volume = {561}, number = {7724}, pages = {485-491}, doi = {10.1038/s41586-018-0509-0}, pmid = {30209393}, issn = {1476-4687}, support = {R01 GM115545/GM/NIGMS NIH HHS/United States ; }, abstract = {The regular arrangements of β-strands around a central axis in β-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with β-barrels. Here we show that accurate de novo design of β-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of β-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli, yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures.}, }
@article {pmid30209392, year = {2018}, author = {Alexander, TB and Gu, Z and Iacobucci, I and Dickerson, K and Choi, JK and Xu, B and Payne-Turner, D and Yoshihara, H and Loh, ML and Horan, J and Buldini, B and Basso, G and Elitzur, S and de Haas, V and Zwaan, CM and Yeoh, A and Reinhardt, D and Tomizawa, D and Kiyokawa, N and Lammens, T and De Moerloose, B and Catchpoole, D and Hori, H and Moorman, A and Moore, AS and Hrusak, O and Meshinchi, S and Orgel, E and Devidas, M and Borowitz, M and Wood, B and Heerema, NA and Carrol, A and Yang, YL and Smith, MA and Davidsen, TM and Hermida, LC and Gesuwan, P and Marra, MA and Ma, Y and Mungall, AJ and Moore, RA and Jones, SJM and Valentine, M and Janke, LJ and Rubnitz, JE and Pui, CH and Ding, L and Liu, Y and Zhang, J and Nichols, KE and Downing, JR and Cao, X and Shi, L and Pounds, S and Newman, S and Pei, D and Guidry Auvil, JM and Gerhard, DS and Hunger, SP and Inaba, H and Mullighan, CG}, title = {The genetic basis and cell of origin of mixed phenotype acute leukaemia.}, journal = {Nature}, volume = {562}, number = {7727}, pages = {373-379}, doi = {10.1038/s41586-018-0436-0}, pmid = {30209392}, issn = {1476-4687}, support = {R35 CA197695/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; U24 CA114766/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, abstract = {Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.}, }
@article {pmid30208068, year = {2018}, author = {Talarico, S and Leverich, CK and Wei, B and Ma, J and Cao, X and Guo, Y and Han, G and Yao, L and Self, S and Zhao, Y and Salama, NR}, title = {Increased H. pylori stool shedding and EPIYA-D cagA alleles are associated with gastric cancer in an East Asian hospital.}, journal = {PloS one}, volume = {13}, number = {9}, pages = {e0202925}, doi = {10.1371/journal.pone.0202925}, pmid = {30208068}, issn = {1932-6203}, abstract = {BACKGROUND: Helicobacter pylori infection increases risk for gastric cancer. Geographic variation in gastric cancer risk has been attributed to variation in carriage and type of the H. pylori oncogene cagA. Colonization density may also influence disease and cagA has been associated with higher shedding in stool. However, the relationship between H. pylori load in the stool and in the stomach is not clear.
METHODS: To investigate possible differences in H. pylori load in the stomach and shedding in stool, H. pylori load and cagA genotype were assessed using droplet digital PCR assays on gastric mucosa and stool samples from 49 urea breath test-positive individuals, including 25 gastric cancer and 24 non-cancer subjects at Henan Cancer Hospital, Henan, China.
RESULTS: Quantitation of H. pylori DNA indicated similar gastric loads among cancer and non-cancer cases, but the gastric cancer group had a median H. pylori load in the stool that was six times higher than that of the non-cancer subjects. While the cagA gene was uniformly present among study subjects, only 70% had the East Asian cagA allele, which was significantly associated with gastric cancer (Fisher's Exact Test, p = 0.03).
CONCLUSION: H. pylori persists in a subset of gastric cancer cases and thus may contribute to cancer progression. In this East Asian population with a high prevalence of the cagA gene, the East Asian allele could still provide a marker for gastric cancer risk.
IMPACT: This study contributes to our understanding of H. pylori dynamics in the context of pathological changes.}, }
@article {pmid30206306, year = {2018}, author = {Klupsch, K and Baeriswyl, V and Scholz, R and Dannenberg, J and Santimaria, R and Senn, D and Kage, E and Zumsteg, A and Attinger-Toller, I and von der Bey, U and König-Friedrich, S and Dupuy, F and Lembke, W and Albani, C and Wendelspiess, S and Dinkel, L and Saro, D and Hepler, RW and Laszlo, GS and Gudgeon, CJ and Bertschinger, J and Brack, S and Walter, RB}, title = {COVA4231, a potent CD3/CD33 bispecific FynomAb with IgG-like pharmacokinetics for the treatment of acute myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-018-0249-z}, pmid = {30206306}, issn = {1476-5551}, support = {Scholar in Clinical Research//Leukemia and Lymphoma Society (LLS)/ ; }, }
@article {pmid30206059, year = {2018}, author = {Fu, BC and Randolph, TW and Lim, U and Monroe, KR and Cheng, I and Wilkens, LR and Le Marchand, L and Lampe, JW and Hullar, MAJ}, title = {Temporal variability and stability of the fecal microbiome: the Multiethnic Cohort Study.}, journal = {Cancer epidemiology, biomarkers & 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-18-0348}, pmid = {30206059}, issn = {1538-7755}, abstract = {BACKGROUND: Measurement reliability and biological stability need to be considered when developing sampling protocols for population-based fecal microbiome studies.
METHODS: Stool samples were collected biannually over a two-year period and sequenced for the V1-V3 region of the 16S rRNA gene in 50 participants from the Multiethnic Cohort Study. We evaluated the temporal stability of the fecal microbiome on a community level with permutational multivariate analysis of variance (PERMANOVA), as well as on taxa and diversity measures with intraclass correlation coefficients.
RESULTS: Inter-individual differences were the predominant source of fecal microbiome variation, and variation within individual was driven more by changing abundances than the complete loss or introduction of taxa. Phyla and diversity measures were reliable over the two years. Most genera were stable over time, although those with low abundances tended to be more dynamic. Reliability was lower among participants who used antibiotics, with the greatest difference seen in samples taken within one month of reported use.
CONCLUSIONS: The fecal microbiome as a whole is stable over a two-year period, although certain taxa may exhibit more temporal variability.
IMPACT: When designing large epidemiologic studies, a single sample is sufficient to capture the majority of the variation in the fecal microbiome from 16S rRNA gene sequencing, while multiple samples may be needed for rare or less abundant taxa.}, }
@article {pmid30204247, year = {2018}, author = {DuBois, SG and Laetsch, TW and Federman, N and Turpin, BK and Albert, CM and Nagasubramanian, R and Anderson, ME and Davis, JL and Qamoos, HE and Reynolds, ME and Cruickshank, S and Cox, MC and Hawkins, DS and Mascarenhas, L and Pappo, AS}, title = {The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas.}, journal = {Cancer}, volume = {124}, number = {21}, pages = {4241-4247}, doi = {10.1002/cncr.31701}, pmid = {30204247}, issn = {1097-0142}, support = {Center of Excellence Award//Alex's Lemonade Stand Foundation for Childhood Cancer/ ; UL1TR001881//National Center for Advancing Translational Sciences/ ; //Loxo Oncology Inc/ ; //Alex's Lemonade Stand Foundation Center of Excellence Award/ ; //Loxo Oncology/ ; UL1 TR001881/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection.
METHODS: A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively.
RESULTS: A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues.
CONCLUSIONS: Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.}, }
@article {pmid30203582, year = {2018}, author = {Waskito, LA and Salama, NR and Yamaoka, Y}, title = {Pathogenesis of Helicobacter pylori infection.}, journal = {Helicobacter}, volume = {23 Suppl 1}, number = {}, pages = {e12516}, doi = {10.1111/hel.12516}, pmid = {30203582}, issn = {1523-5378}, support = {R01 AI054423//US National Institutes of Health/ ; 16H05191//Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan/ ; }, abstract = {In this review, we highlight progress in the last year in characterizing known virulence factors like flagella and the Cag type IV secretion system with sophisticated structural and biochemical approaches to yield new insight on the assembly and functions of these critical virulence determinants. Several aspects of Helicobacter pylori physiology were newly explored this year and evaluated for their functions during stomach colonization, including a fascinating role for the essential protease HtrA in allowing access of H. pylori to the basolateral side of the gastric epithelium through cleavage of the tight junction protein E-cadherin to facilitate CagA delivery. Molecular biology tools standard in model bacteria, including regulated gene expression during animal infection and fluorescent reporter gene fusions, were newly applied to H. pylori to explore functions for urease beyond initial colonization and establish high salt consumption as a mediator of gene expression changes. New sequencing technologies enabled validation of long postulated roles for DNA methylation in regulating H. pylori gene expression. On the cell biology side, elegant work using lineage tracing in the murine model and organoid primary cell culture systems has provided new insights into how H. pylori manipulates gastric tissue functions, locally and at a distance, to promote its survival in the stomach and induce pathologic changes. Finally, new work has bolstered the case for genomic variation as an important mechanism to generate phenotypic diversity during changing environmental conditions in the context of diet manipulation in animal infection models and during human experimental infection after vaccination.}, }
@article {pmid30202945, year = {2018}, author = {Armstrong, AJ and Lin, P and Higano, CS and Sternberg, CN and Sonpavde, G and Tombal, B and Templeton, AJ and Fizazi, K and Phung, D and Wong, EK and Krivoshik, A and Beer, TM}, title = {Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/annonc/mdy406}, pmid = {30202945}, issn = {1569-8041}, abstract = {Background: Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide.
Patients and methods: Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2:1 into training (n=1159) and testing (n=550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set.
Results: Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups.
Conclusions: Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design.
Trial registration: ClinicalTrials.gov: NCT01212991.}, }
@article {pmid30202933, year = {2018}, author = {Chambers, LC and Srinivasan, S and Lukehart, SA and Ocbamichael, N and Morgan, JL and Lowens, MS and Fredricks, DN and Golden, MR and Manhart, LE}, title = {Primary Syphilis in the Male Urethra - A Case Report.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciy771}, pmid = {30202933}, issn = {1537-6591}, abstract = {A man with nongonococcal urethritis had negative syphilis serology. We documented urethral Treponema pallidum infection using broad-range bacterial polymerase-chain-reaction and sequencing, targeted polymerase-chain-reaction, and immunofluorescence microscopy. The patient subsequently seroconverted for syphilis; symptoms resolved with penicillin. Early syphilis may present as urethritis. Urethral T. pallidum shedding can occur before seroconversion.}, }
@article {pmid30202659, year = {2018}, author = {Bloom, JD}, title = {Estimating the frequency of multiplets in single-cell RNA sequencing from cell-mixing experiments.}, journal = {PeerJ}, volume = {6}, number = {}, pages = {e5578}, doi = {10.7717/peerj.5578}, pmid = {30202659}, issn = {2167-8359}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; R01 GM102198/GM/NIGMS NIH HHS/United States ; }, abstract = {In single-cell RNA-sequencing, it is important to know the frequency at which the sequenced transcriptomes actually derive from multiple cells. A common method to estimate this multiplet frequency is to mix two different types of cells (e.g., human and mouse), and then determine how often the transcriptomes contain transcripts from both cell types. When the two cell types are mixed in equal proportion, the calculation of the multiplet frequency from the frequency of mixed transcriptomes is straightforward. But surprisingly, there are no published descriptions of how to calculate the multiplet frequency in the general case when the cell types are mixed unequally. Here, I derive equations to analytically calculate the multiplet frequency from the numbers of observed pure and mixed transcriptomes when two cell types are mixed in arbitrary proportions, under the assumption that the loading of cells into droplets or wells is Poisson.}, }
@article {pmid30201817, year = {2018}, author = {Farrukee, R and Zarebski, AE and McCaw, JM and Bloom, JD and Reading, PC and Hurt, AC}, title = {Characterization of Influenza B Virus Variants with Reduced Neuraminidase Inhibitor Susceptibility.}, journal = {Antimicrobial agents and chemotherapy}, volume = {62}, number = {11}, pages = {}, doi = {10.1128/AAC.01081-18}, pmid = {30201817}, issn = {1098-6596}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; }, abstract = {Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs), which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B virus infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to those of NAI-sensitive wild-type viruses. In vivo studies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyze within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had NA enzyme function similar to that of its wild type but had slightly reduced replication and transmission efficiency in vivo The D197N variant had impaired NA enzyme function, but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B virus variant with the H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.}, }
@article {pmid30198067, year = {2018}, author = {Checkoway, H and Ilango, S and Li, W and Ray, RM and Tanner, CM and Hu, SC and Wang, X and Nielsen, S and Gao, DL and Thomas, DB}, title = {Occupational exposures and parkinsonism among Shanghai women textile workers.}, journal = {American journal of industrial medicine}, volume = {61}, number = {11}, pages = {886-892}, doi = {10.1002/ajim.22906}, pmid = {30198067}, issn = {1097-0274}, support = {R01ES017462//National Institute of Environmental Health Sciences (NIEHS),/ ; R01ES017462//National Institute of Environmental Health Service/ ; }, abstract = {BACKGROUND: Endotoxin, a contaminant of cotton dust, is an experimental model for parkinsonism (PS).
METHODS: We investigated associations between exposures to endotoxin, solvents, magnetic fields, and night shift work, and neurologist-determined PS among Shanghai women textile workers, including 537 retired cotton factory workers ages ≥50 years and an age-matched reference group of 286 retired textile workers not exposed to cotton dust. Repeat exams were conducted 2.5 years after enrollment among 467 cotton workers and 229 reference workers.
RESULTS: We identified 39 prevalent PS cases and 784 non-cases. No consistent or statistically significant associations were observed for endotoxin, solvents, magnetic fields, or shift work with PS risk, severity, or progression.
CONCLUSIONS: Despite the null findings, additional studies of endotoxin exposure and risk of PS in other well-characterized occupational cohorts are warranted in view of toxicological evidence that endotoxin is a pathogenic agent and its widespread occurrence in multiple industries worldwide.}, }
@article {pmid30197040, year = {2018}, author = {Svatek, RS and Tangen, C and Delacroix, S and Lowrance, W and Lerner, SP}, title = {Background and Update for S1602 "A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming with Intradermal BCG Before Intravesical Therapy for BCG-naïve High-grade Non-muscle-invasive Bladder Cancer.}, journal = {European urology focus}, volume = {4}, number = {4}, pages = {522-524}, doi = {10.1016/j.euf.2018.08.015}, pmid = {30197040}, issn = {2405-4569}, abstract = {The S1602 Intergroup trial is a randomized phase III clinical trial that aims to test two important hypotheses: (1) priming with intradermal bacillus Calmette-Guérin (BCG) vaccine prior to standard intravesical BCG improves response to BCG in terms of recurrence-free survival and (2) Tokyo-172 BCG strain is non-inferior to TICE BCG in terms of time to high-grade recurrence. The study was approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and activated in spring 2017. Here, we provide a synopsis of the study background, design, and update of the clinical trial.}, }
@article {pmid30196073, year = {2018}, author = {LaMonte, MJ and Manson, JE and Chomistek, AK and Larson, JC and Lewis, CE and Bea, JW and Johnson, KC and Li, W and Klein, L and LaCroix, AZ and Stefanick, ML and Wactawski-Wende, J and Eaton, CB}, title = {Physical Activity and Incidence of Heart Failure in Postmenopausal Women.}, journal = {JACC. Heart failure}, volume = {6}, number = {12}, pages = {983-995}, doi = {10.1016/j.jchf.2018.06.020}, pmid = {30196073}, issn = {2213-1787}, support = {HHSN268201600018C/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVES: This study prospectively examined physical activity levels and the incidence of heart failure (HF) in 137,303 women, ages 50 to 79 years, and examined a subset of 35,272 women who, it was determined, had HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF).
BACKGROUND: The role of physical activity in HF risk among older women is unclear, particularly for incidence of HFpEF or HFrEF.
METHODS: Women were free of HF and reported ability to walk at least 1 block without assistance at baseline. Recreational physical activity was self-reported. The study documented 2,523 cases of total HF, and 451 and 734 cases of HFrEF and HFpEF, respectively, during a mean 14-year follow-up.
RESULTS: After controlling for age, race, education, income, smoking, alcohol, hormone therapy, and hysterectomy status, compared with women who reported no physical activity (reference group), inverse associations were observed across incremental tertiles of total physical activity for overall HF (hazard ratio [HR]: Tertile 1 = 0.89, Tertile 2 = 0.74, Tertile 3 = 0.65; trend p < 0.001), HFpEF (HR: 0.93, 0.70, 0.68; p < 0.001), and HFrEF (HR: 0.81, 0.59, 0.68; p = 0.01). Additional controlling for potential mediating factors included attenuated time-varying coronary heart disease (CHD) (nonfatal myocardial infarction, coronary revascularization) diagnosis but did not eliminate the inverse associations. Walking, the most common form of physical activity in older women, was also inversely associated with HF risks (overall: 1.00, 0.98, 0.93, 0.72; p < 0.001; HFpEF: 1.00, 0.98, 0.87, 0.67; p < 0.001; HFrEF: 1.00, 0.75, 0.78, 0.67; p = 0.01). Associations between total physical activity and HF were consistent across subgroups, defined by age, body mass index, diabetes, hypertension, physical function, and CHD diagnosis. Analysis of physical activity as a time-varying exposure yielded findings comparable to those of baseline physical activity.
CONCLUSIONS: Higher levels of recreational physical activity, including walking, are associated with significantly reduced HF risk in community-dwelling older women.}, }
@article {pmid30195835, year = {2018}, author = {Kearns, JT and Newcomb, LF and Lin, DW}, title = {Reply to Runqiang Yuan's Letter to the Editor re: James T. Kearns, Anna V. Faino, Lisa F. Newcomb, et al. Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study. Eur Urol 2018;73:706-12.}, journal = {European urology}, volume = {74}, number = {6}, pages = {e151}, doi = {10.1016/j.eururo.2018.08.021}, pmid = {30195835}, issn = {1873-7560}, }
@article {pmid30193108, year = {2018}, author = {Sullivan, LB}, title = {Metabolic Frugality Marks Cancer Cells for Immune Targeting.}, journal = {Cell}, volume = {174}, number = {6}, pages = {1344-1346}, doi = {10.1016/j.cell.2018.08.023}, pmid = {30193108}, issn = {1097-4172}, abstract = {Altered cell metabolism is ubiquitous in cancer cells; however, it remains challenging to exploit these alterations for cancer therapy. A new study reveals that metabolic alterations to the urea cycle promote tumor growth but unexpectedly also trigger mutations that mark cancer cells for recognition by immunotherapy.}, }
@article {pmid30192919, year = {2018}, author = {Chang, ET and Lau, EC and Van Landingham, C and Crump, KS and McClellan, RO and Moolgavkar, SH}, title = {Response to "Invited commentary: diesel exhaust and lung cancer -- aftermath of becoming an IARC Group 1 carcinogen" by Debra T. Silverman. Am J Epidemiol 2018 Mar 7. doi: 10.1093/aje/kwy036.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwy176}, pmid = {30192919}, issn = {1476-6256}, }
@article {pmid30191867, year = {2018}, author = {Tseng, YD and Nguyen, MH and Baker, K and Cook, M and Redman, M and Lachance, K and Bhatia, S and Liao, JJ and Apisarnthanarax, S and Nghiem, PT and Parvathaneni, U}, title = {Effect of Patient Immune Status on the Efficacy of Radiation Therapy and Recurrence-Free Survival Among 805 Patients With Merkel Cell Carcinoma.}, journal = {International journal of radiation oncology, biology, physics}, volume = {102}, number = {2}, pages = {330-339}, doi = {10.1016/j.ijrobp.2018.05.075}, pmid = {30191867}, issn = {1879-355X}, abstract = {PURPOSE: Patients with Merkel cell carcinoma (MCC) with chronic immunosuppression (IS) have worse outcomes, but the mechanisms are not well understood. We hypothesized that these differences may be mediated in part by differential response to treatment, and we evaluated whether radiation therapy (RT) efficacy is altered among IS compared with immune-competent (IC) patients with MCC.
METHODS AND MATERIALS: Among 805 patients with MCC, recurrence-free survival (RFS) and patterns of first recurrence were compared between 89 IS and 716 IC patients with stage I to III MCC treated with curative intent. We used a Fine and Gray's competing risk multivariable analysis to estimate associations with RFS.
RESULTS: IS and IC patients with MCC had similar demographic and disease characteristics. Most (77% IC, 86% IS) were irradiated (median, 50.4 Gy IC, 50.3 Gy IS), although more IS patients were irradiated to the primary site (97% vs 81%). With a median follow-up of 54.4 months, IS patients had inferior RFS (2-year: 30% vs 57%; P < .0001) and higher rates of local recurrence as the first site of relapse (25% vs 12%; P = .0002). The association between RT and RFS differed by immune status (interaction P = .01). Although RT was associated with significantly improved RFS among IC patients (hazard ratio 0.56, 95% confidence interval 0.44-0.72), no difference in RFS was observed with RT among IS patients (hazard ratio 1.49, 95% confidence interval 0.70-3.17).
CONCLUSIONS: Radiation therapy efficacy at current standard RT doses for MCC is impaired among immunosuppressed patients with MCC. Although a strong link between durability of RT response and immune function does not appear to be evident in most cancers, our results may reflect an especially dynamic interaction between immune status and RT efficacy in MCC.}, }
@article {pmid30191830, year = {2018}, author = {Miller, WC and Hoffman, IF and Hanscom, BS and Ha, TV and Dumchev, K and Djoerban, Z and Rose, SM and Latkin, CA and Metzger, DS and Lancaster, KE and Go, VF and Dvoriak, S and Mollan, KR and Reifeis, SA and Piwowar-Manning, EM and Richardson, P and Hudgens, MG and Hamilton, EL and Sugarman, J and Eshleman, SH and Susami, H and Chu, VA and Djauzi, S and Kiriazova, T and Bui, DD and Strathdee, SA and Burns, DN}, title = {A scalable, integrated intervention to engage people who inject drugs in HIV care and medication-assisted treatment (HPTN 074): a randomised, controlled phase 3 feasibility and efficacy study.}, journal = {Lancet (London, England)}, volume = {392}, number = {10149}, pages = {747-759}, doi = {10.1016/S0140-6736(18)31487-9}, pmid = {30191830}, issn = {1474-547X}, support = {P30 AI050410/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; *Antiretroviral Therapy, Highly Active ; CD4 Lymphocyte Count ; Counseling ; Feasibility Studies ; Female ; HIV Infections/complications/*drug therapy/mortality ; Humans ; Incidence ; Indonesia ; Male ; Methadone/therapeutic use ; Opiate Substitution Treatment/*methods ; Proportional Hazards Models ; Substance Abuse, Intravenous/complications/*drug therapy/mortality ; Ukraine ; Vietnam ; Viral Load/*drug effects ; Young Adult ; }, abstract = {BACKGROUND: People who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use.
METHODS: This randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants.
FINDINGS: Between Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded.
INTERPRETATION: This vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered.
FUNDING: US National Institutes of Health.}, }
@article {pmid30191060, year = {2018}, author = {Begcevic, I and Tsolaki, M and Brinc, D and Brown, M and Martinez-Morillo, E and Lazarou, I and Kozori, M and Tagaraki, F and Nenopoulou, S and Gkioka, M and Lazarou, E and Lim, B and Batruch, I and Diamandis, EP}, title = {Neuronal pentraxin receptor-1 is a new cerebrospinal fluid biomarker of Alzheimer's disease progression.}, journal = {F1000Research}, volume = {7}, number = {}, pages = {1012}, doi = {10.12688/f1000research.15095.1}, pmid = {30191060}, issn = {2046-1402}, abstract = {Background: Alzheimer's disease (AD) is the most common type of dementia, with progressive onset of clinical symptoms. The main pathological hallmarks are brain deposits of extracellular amyloid beta plaques and intracellular neurofibrillary tangles (NFT). Cerebrospinal fluid reflects pathological changes in the brain; amyloid beta 1-42 is a marker of amyloid plaques, while total and phosphorylated tau are markers of NFT formation. Additional biomarkers associated with disease pathogenesis are needed, for better prognosis, more specific diagnosis, prediction of disease severity and progression and for improved patient classification in clinical trials. The aim of the present study was to evaluate brain-specific proteins as potential biomarkers of progression of AD. Methods: Overall, 30 candidate proteins were quantified in cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment (MCI) and mild, moderate and severe AD dementia (n=101) using mass spectrometry-based selected reaction monitoring assays. ELISA was used for neuronal pentraxin receptor-1 (NPTXR) confirmation. Results: The best discrimination between MCI and more advanced AD stages (moderate and severe dementia) was observed for protein NPTXR (area under the curve, AUC=0.799). A statistically different abundance of this protein was observed between the two groups, with severe AD patients having progressively lower levels (p<0.05). ELISA confirmed lower levels in AD, in a separate cohort that included controls, MCI and AD patients. Conclusions: We conclude that NPTXR protein in CSF is a novel potential biomarker of AD progression and could have important utility in assessing treatment success in clinical trials.}, }
@article {pmid30189119, year = {2018}, author = {Weinstein, AG and Henrich, CC and Armstrong, GT and Stratton, KL and King, TZ and Leisenring, WM and Krull, KR}, title = {Roles of positive psychological outcomes in future health perception and mental health problems: A report from the Childhood Cancer Survivor Study.}, journal = {Psycho-oncology}, volume = {27}, number = {12}, pages = {2754-2760}, doi = {10.1002/pon.4881}, pmid = {30189119}, issn = {1099-1611}, support = {CA21765//Cancer Center Support (CORE)/ ; CA55727//National Cancer Institute/ ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Positive psychological outcomes among adolescent and young adult survivors of childhood cancer may influence long-term health status. We examined posttraumatic growth (PTG) and Life satisfaction (LS) in adolescence, and their impact on future emotional and physical health status in young adulthood.
METHODS: Survivors (n = 2802) from the Childhood Cancer Survivor Study were longitudinally analyzed across social, emotional, and physical factors during adolescence (12-17 years old), and PTG (PTG-Inventory) and LS (Cantril-Ladder-of-Life) during young adulthood (19-24 years old). The impact of PTG and LS on survivors' future long-term mental health, physical health, and social skills was also examined (23-28 years old) using Structural Equation Modeling.
RESULTS: Survivors reported high levels of LS (M = 7.43, range 1 to 10) and a positive impact from their cancer experience (M = 48.78, range 0 to 105). Adolescent predictors of higher PTG included older age at diagnosis (p = 0.001), experiencing more severe chronic health conditions (p = 0.01), cancer recurrence/relapse (p = 0.01), and being diagnosed with a non-CNS cancer (p = 0.001). Higher perceived general health (p = 0.01), higher social skills (p = 0.001), and diagnosis with a non-CNS cancer (p = 0.02) were associated with higher LS. Higher PTG during young adulthood predicted poorer perceived health (p = 0.04) and worse emotional health (p = 0.001) in later adulthood. Higher LS predicted better emotional health (p = 0.001) and better perceived health (p = 0.001).
CONCLUSIONS: While LS was found to help survivors have better perceived long-term emotional and physical health outcomes, survivors with higher PTG fond both positive and negative impacts from cancer. Future therapeutic trials to improve LS should be considered.}, }
@article {pmid30188971, year = {2018}, author = {Dai, JY and Peters, U and Wang, X and Kocarnik, J and Chang-Claude, J and Slattery, ML and Chan, A and Lemire, M and Berndt, SI and Casey, G and Song, M and Jenkins, MA and Brenner, H and Thrift, AP and White, E and Hsu, L}, title = {Diagnostics for Pleiotropy in Mendelian Randomization Studies: Global and Individual Tests for Direct Effects.}, journal = {American journal of epidemiology}, volume = {187}, number = {12}, pages = {2672-2680}, doi = {10.1093/aje/kwy177}, pmid = {30188971}, issn = {1476-6256}, support = {R01 CA189532/CA/NCI NIH HHS/United States ; }, abstract = {Diagnosing pleiotropy is critical for assessing the validity of Mendelian randomization (MR) analyses. The popular MR-Egger method evaluates whether there is evidence of bias-generating pleiotropy among a set of candidate genetic instrumental variables. In this article, we propose a statistical method-global and individual tests for direct effects (GLIDE)-for systematically evaluating pleiotropy among the set of genetic variants (e.g., single nucleotide polymorphisms (SNPs)) used for MR. As a global test, simulation experiments suggest that GLIDE is nearly uniformly more powerful than the MR-Egger method. As a sensitivity analysis, GLIDE is capable of detecting outliers in individual variant-level pleiotropy, in order to obtain a refined set of genetic instrumental variables. We used GLIDE to analyze both body mass index and height for associations with colorectal cancer risk in data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry (multiple studies). Among the body mass index-associated SNPs and the height-associated SNPs, several individual variants showed evidence of pleiotropy. Removal of these potentially pleiotropic SNPs resulted in attenuation of respective estimates of the causal effects. In summary, the proposed GLIDE method is useful for sensitivity analyses and improves the validity of MR.}, }
@article {pmid30188321, year = {2018}, author = {Phillips, AM and Doud, MB and Gonzalez, LO and Butty, VL and Lin, YS and Bloom, JD and Shoulders, MD}, title = {Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin.}, journal = {eLife}, volume = {7}, number = {}, pages = {}, doi = {10.7554/eLife.38795}, pmid = {30188321}, issn = {2050-084X}, support = {Graduate Research Fellowship//National Science Foundation/International ; Koch Institute Support (core) Grant P30-CA14051/CA/NCI NIH HHS/United States ; MIT Center for Environmental Health Sciences (core) Grant P30-ES002109/ES/NIEHS NIH HHS/United States ; Al127893/NH/NIH HHS/United States ; Faculty Scholars grant/HHMI/Howard Hughes Medical Institute/United States ; Faculty Scholars grant//Simons Foundation/International ; CAREER Award 1652390//National Science Foundation/International ; Award for Excellence in Biomedical Research//Richard and Susan Smith Family Foundation/International ; 1DP2GM119162/NH/NIH HHS/United States ; R01 AI127893/AI/NIAID NIH HHS/United States ; R35 GM126911/GM/NIGMS NIH HHS/United States ; P30 CA014051/CA/NCI NIH HHS/United States ; P30 ES002109/ES/NIEHS NIH HHS/United States ; }, abstract = {We systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemaggluttinin (HA), a viral membrane protein that folds in the host's ER via a complex pathway. By integrating chemical methods to modulate ER proteostasis with deep mutational scanning to assess mutational tolerance, we discover that upregulation of ER proteostasis factors broadly enhances HA mutational tolerance across diverse structural elements. Remarkably, this proteostasis network-enhanced mutational tolerance occurs at the same sites where mutational tolerance is most reduced by propagation at fever-like temperature. These findings have important implications for influenza evolution, because influenza immune escape is contingent on HA possessing sufficient mutational tolerance to evade antibodies while maintaining the capacity to fold and function. More broadly, this work provides the first experimental evidence that ER proteostasis mechanisms define the mutational tolerance and, therefore, the evolution of secretory pathway proteins.}, }
@article {pmid30187228, year = {2018}, author = {Mueller, BA and Doody, DR and Weiss, NS and Chow, EJ}, title = {Hospitalization and mortality among pediatric cancer survivors: a population-based study.}, journal = {Cancer causes & control : CCC}, volume = {29}, number = {11}, pages = {1047-1057}, doi = {10.1007/s10552-018-1078-0}, pmid = {30187228}, issn = {1573-7225}, support = {HHSN261201300012I//National Cancer Institute/ ; DP12-1205DP003899-02//Centers for Disease Control and Prevention/ ; }, abstract = {PURPOSE: We examined serious long-term outcomes among childhood cancer survivors using population-based data.
METHODS: We used 1982-2014 Washington State data to compare hospitalization and/or death (including cause-specific) during up to 27 years follow-up among all 5+ year childhood cancer survivors < 20 years at diagnosis (n = 3,152) and a sample of comparison children within birth cohorts, with assessment by cancer type and child/family characteristics.
RESULTS: During follow-up (9 years median), 12% of survivors had hospitalizations; 4% died. Greatest absolute risks/1,000 person-years were for hospitalization/deaths due to cancers (8.1), infection (6.2), injuries (6.0), and endocrine/metabolic disorders (5.8). Hazard ratios (HR) and 95% confidence intervals (CI) for hospitalization (2.7, 95% CI 2.4-3.0) and any-cause death (14.7, 95% CI 11.3-19.1) were increased, and for all cause-specific outcomes examined, most notably cancer- (35.1, 95% CI 23.7-51.9), hematological- (6.7, 95% CI 5.3-8.5), nervous system- (6.4, 95% CI 5.2-7.8), and circulatory- (5.2, 95% CI 4.1-6.5) related outcomes. Hospitalizations occurred more often among females and those receiving radiation, with modest differences by urban/rural birth residence and race/ethnicity. Cause-specific outcomes varied by cancer type.
CONCLUSIONS: This study suggests increased risks for the rarely-studied outcomes of long-term fracture and injury, and confirms increased risks of selected other conditions among survivors. Multi-state pooling of population-based data would increase the ability to evaluate outcomes for uncommon cancer types and by racial/ethnic groups under-represented in many studies.}, }
@article {pmid30183089, year = {2018}, author = {Falk, RT and Manson, JE and Barnabei, VM and Anderson, GL and Brinton, LA and Rohan, TE and Cauley, JA and Chen, C and Coburn, SB and Pfeiffer, RM and Reding, KW and Sarto, GE and Wentzensen, N and Chlebowski, RT and Xu, X and Trabert, B}, title = {Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.31851}, pmid = {30183089}, issn = {1097-0215}, support = {//The Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute/ ; HHSN268201600004C//U.S. Department of Health and Human Services/ ; HHSN268201600003C//U.S. Department of Health and Human Services/ ; HHSN268201600002C//U.S. Department of Health and Human Services/ ; HHSN268201600001C//U.S. Department of Health and Human Services/ ; HHSN268201600018C//U.S. Department of Health and Human Services/ ; //National Institutes of Health/ ; //National Heart, Lung, and Blood Institute/ ; }, abstract = {The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.}, }
@article {pmid30181600, year = {2018}, author = {Ishibashi, M and Toyoshima, M and Zhang, X and Hasegawa-Minato, J and Shigeta, S and Usui, T and Kemp, CJ and Grandori, C and Kitatani, K and Yaegashi, N}, title = {Tyrosine kinase receptor TIE-1 mediates platinum resistance by promoting nucleotide excision repair in ovarian cancer.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {13207}, doi = {10.1038/s41598-018-31069-2}, pmid = {30181600}, issn = {2045-2322}, support = {U01 CA176303/CA/NCI NIH HHS/United States ; }, abstract = {Platinum resistance is one of the most challenging problems in ovarian cancer treatment. High-throughput functional siRNA screening identified tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) as a gene that confers cells resistant to cisplatin. Conversely enforced over-expression of TIE-1 was validated to decrease cisplatin sensitivity in multiple ovarian cancer cell lines and up-regulation of TIE-1 was correlated with poor prognosis and cisplatin resistance in patients with ovarian cancer. Mechanistically, TIE-1 up-regulates the nucleotide excision repair (NER) system mediated by xeroderma pigmentosum complementation group C (XPC), thereby leading to decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake and excretion. Importantly potentiation of therapeutic efficacy by TIE-1 inhibition was selective to DNA-adduct-type chemotherapeutic platinum reagents. Therefore, TIE-1 is suggested to promote XPC-dependent NER, rendering ovarian cancer cells resistant to platinum. Accompanied with novel findings, TIE-1 could represent as a novel therapeutic target for platinum-resistant ovarian cancer.}, }
@article {pmid30181421, year = {2018}, author = {Ogba, N and Arwood, NM and Bartlett, NL and Bloom, M and Brown, P and Brown, C and Budde, EL and Carlson, R and Farnia, S and Fry, TJ and Garber, M and Gardner, RA and Gurschick, L and Kropf, P and Reitan, JJ and Sauter, C and Shah, B and Shpall, EJ and Rosen, ST}, title = {Chimeric Antigen Receptor T-Cell Therapy.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {16}, number = {9}, pages = {1092-1106}, doi = {10.6004/jnccn.2018.0073}, pmid = {30181421}, issn = {1540-1413}, abstract = {Patients with relapsed or refractory (R/R) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for R/R B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.}, }
@article {pmid30181386, year = {2018}, author = {Mostaghel, EA and Zhang, A and Hernandez, S and Marck, BT and Zhang, X and Tamae, D and Biehl, HE and Tretiakova, M and Bartlett, J and Burns, J and Dumpit, R and Ang, L and Matsumoto, AM and Penning, TM and Balk, SP and Morrissey, C and Corey, E and True, LD and Nelson, PS}, title = {Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castratio