tbuckley/cabot-search huggingface dataset:
Abstract P133: Epigenome-Wide Association Study of Moderate-Vigorous Physical Activity in Adult African Americans Identifies Loci Near <i>HCCA2</i>
Authors: Steven Nguyen, Weihua Guan, Chong Wu, Megan Grove, Rui Xia, Nicholas S Roetker, Katie Holliday, Elizabeth Hibler, Yinan Zheng, Eric Whitsel, Jan Bressler, Kari North, Myriam Fornage, Eric Boerwinkle, Jim Pankow, Ellen Demerath
Journal: Circulation (2018)

Regular moderate-vigorous physical activity (MVPA) reduces the risk of cardiovascular and other chronic diseases, among other important benefits at all life stages. It is hypothesized that physical activity may alter disease risk via epigenetic modifications, including potentially long-standing changes in DNA methylation as previous research has shown epigenetic changes following exercise interventions. Most existing reports examine global methylation or study acute exercise effects on DNA methylation. To our knowledge, there are no published epigenome-wide association studies (EWAS) of habitual MVPA. In this analysis, we tested associations between leisure time MVPA and genome-wide variation in CpG methylation, an epigenetic mark, in 2,601 African American participants (1,663 women; mean age 56.6 years) in the Atherosclerosis Risk in Communities (ARIC) study. The Illumina HM450K Bead Chip was used to measure methylation in 471,035 CpG sites in stored frozen leukocyte samples, from visit 2 (1990-1992) or 3 (1993-1995). Linear regression models tested the cross-sectional association of DNA methylation M-value with self-reported leisure time MVPA at the visit of sample collection, modeled as minutes of MVPA per week and by category based on the AHA guidelines for physical activity in adults (none, less than 150, or at least 150 minutes MVPA per week), adjusting for age, sex, body mass index, education, alcohol use in grams per week, smoking status, cancer status, white blood cell count, imputed cell-type proportions using the Houseman method, and batch effects with the top 30 HM450K built-in nonnegative control probe principal components. Three CpGs, cg08269485, cg20272155, and cg08966208, upstream of the cathepsin D encoding gene, CTSD, were observed to be significantly inversely associated (q&lt;0.05, FDR) with MVPA minutes/week. This is a strongly imprinted genomic region (chr11p15.5) and the region has also been reported to include DNA methylation variants that changed in response to an exercise training intervention. Additionally, 163 CpGs that we identified in the literature to be associated with habitual MVPA were also tested using the same models. One CpG, cg07863043, upstream of the adenomatosis polyposis coli gene, APC, in the 5q22.2 genomic region, was observed to be significantly positively associated with achieving at least 150 minutes of MVPA per week compared to none (q=0.0001, FDR). APC encodes a tumor suppressor protein that is an antagonist of the Wnt signaling pathway, and is involved in carcinogenesis and embryonic development. Replication in other populations is ongoing to confirm these findings as well as to identify additional physical activity-related DNA methylation variants.
Social motivation in autism: Gaps and directions for measurement of a putative core construct
Authors: Cara M. Keifer, Gabriel S. Dichter, James C. McPartland, Matthew D. Lerner
Journal: Behavioral and Brain Sciences (2019)

Abstract This commentary highlights the observation that social motivation is usually an imprecisely specified construct. We suggest four social motivation conceptualizations across levels of analysis and explore where the target article situates among these. We then offer theoretical and practical guidance for operationalization and measurement of social motivation to support more comprehensive future research on this complex construct in the autism literature.
The benefits of modesty
Authors: Danilyn Rutherford
Journal: Behavioral and Brain Sciences (2019)

Abstract Speaking as an anthropologist, I comment on three striking features of Jaswal &amp; Akhtar's argument. I suggest that the boldness of their intervention lies in its modesty. In challenging a parsimonious explanation for autistic behavior, they invite a conversation including scholars from other disciplines, as well as autistic people themselves.
Quantitative measurements of p95HER2 (p95) protein expression in tumors from patients with metastatic breast cancer (MBC) treated with trastuzumab: Independent confirmation of the p95 clinical cutoff.
Authors: Renata Duchnowska, Jeff Sperinde, Mojgan Haddad, Ahmed Chenna, Agnes Paquet, Yolanda Lie, Jodi Weidler, Weidong Huang, John William Winslow, Tomasz Jankowski, Bogumila Czartoryska-Arlukowicz, Piotr Jan Wysocki, Malgorzata Foszczynska-Kloda, Barbara Radecka, Maria Malgorzata Litwiniuk, Jolanta Zok, Michal Wisniewski, Dorota Zuziak, Wojciech Biernat, Jacek Jassem
Journal: Journal of Clinical Oncology (2013)

604 Background: Expression of p95 in HER2-positive breast cancer is potentially a major determinant of trastuzumab resistance because p95 lacks the trastuzumab binding site while retaining kinase activity. Previously, an optimal clinical cutoff for a continuous measurement of p95 expression was defined in a training set of trastuzumab-treated MBC patients (Clin Cancer Res, 16:4226, 2010). Methods: Quantitative H2T (HERmark HER2-total) and p95 assays (VeraTag, Monogram Biosciences) were retrospectively performed on formalin-fixed, paraffin-embedded tumors from an independent series of 240 trastuzumab-treated MBC patients. The pre-specified cutoff for p95 was tested to determine whether p95 above the cutoff in the HER2-positive subset correlated with worse progression-free survival (PFS) and overall survival (OS), as was observed in the training set. P95 expression was also assessed by immunohistochemistry (IHC) using the same antibody as the p95 VeraTag assay. Results: In the subset of tumors assessed as H2T-positive (N=190), p95 VeraTag values above the pre-defined cutoff correlated with shorter PFS (HR=1.41; p=0.043) and shorter OS (HR=1.72; p=0.021) where both outcomes were stratified by hormone receptor status and tumor grade. The hormone receptor positive patients (N=78) primarily drove the shorter PFS (HR=2.08, p=0.0026) and OS (HR=2.28, p=0.0099) observed in the p95-high subset. In contrast to the quantitative p95 VeraTag measurements, p95 IHC was not significantly correlated with outcomes. Conclusions: A clinical p95 cutoff (VeraTag assay) predictive of clinical outcomes derived from a previous training dataset was confirmed in a second independent clinical series. In contrast, p95 IHC did not correlate with outcomes. The observed consistency in the p95 VeraTag cutoff across different cohorts of MBC patients treated with trastuzumab justifies additional studies employing blinded analyses in larger series of patients. Clinical relevance of p95 protein expression remains to be established in a controlled clinical trial.
Pazopanib for treatment of advanced extraskeletal myxoid chondrosarcoma: a multicentre, single-arm, phase 2 trial
Authors: Silvia Stacchiotti, Stefano Ferrari, Andres Redondo, Nadia Hindi, Emanuela Palmerini, Maria Angeles Vaz Salgado, Anna Maria Frezza, Paolo Giovanni Casali, Antonio Gutierrez, Antonio Lopez-Pousa, Giovanni Grignani, Antoine Italiano, Axel LeCesne, Sarah Dumont, Jean Yves Blay, Nicolas Penel, Daniel Bernabeu, Enrique de Alava, Marie Karanian, Carlo Morosi, Silvia Brich, Gian Paolo Dagrada, Viviana Vallacchi, Chiara Castelli, Monica Brenca, Dominga Racanelli, Roberta Maestro, Paola Collini, Josefina Cruz, Javier Martin-Broto
Journal: The Lancet Oncology (2019)
Tools to facilitate communication during physician‐patient consultations in cancer care: An overview of systematic reviews
Authors: Sharon M. Licqurish, Olivia Y. Cook, Loyal P. Pattuwage, Christobel Saunders, Michael Jefford, Bogda Koczwara, Claire E. Johnson, Jon D. Emery
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract Tools have been developed to facilitate communication and support information exchange between people diagnosed with cancer and their physicians. Patient‐reported outcome measures, question prompt lists, patient‐held records, tape recordings of consultations, decision aids, and survivorship care plans have all been promoted as potential tools, and there is extensive literature exploring their impact on patient outcomes. Eleven systematic reviews of studies evaluating tools to facilitate patient‐physician communication were reviewed and summarized in this overview of systematic reviews. Across the systematic reviews, 87 publications reported on 84 primary studies involving 15,381 participants. Routine use of patient‐reported outcome measures and feedback of results to clinicians can improve pain management, physician‐patient communication, and symptom detection and control; increase utilization of supportive care; and increase patient involvement in care. Question prompt lists can increase the number of questions asked by patients without increasing consultation length and may encourage them to reflect and plan questions before the consultation. There is limited benefit in audio recording consultations or using patient‐held records during consultations. Physicians should be supported by adequately resourced health services to respond effectively to the range of clinical and broader patient needs identified through the routine use of tools to facilitate communication.
Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana
Authors: Rebecca Zash, Lewis Holmes, Modiegi Diseko, Denise L. Jacobson, Sean Brummel, Gloria Mayondi, Arielle Isaacson, Sonya Davey, Judith Mabuta, Mompati Mmalane, Tendani Gaolathe, M. Essex, Shahin Lockman, Joseph Makhema, Roger L. Shapiro
Journal: New England Journal of Medicine (2019)

A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies.
An Intelligent Person9s Guide to Medicine
Authors: Christopher Martyn
Journal: BMJ (2001)

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Theodore Dalrymple 

Duckworth, £12.95, pp 138

ISBN 0 7516 2973 5

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Nietzsche famously diagnosed the death of God more than 100 years ago. Nowadays, even church leaders seem to agree with his diagnosis. The trouble is that, without the consolation of religion and the hope of eternity, it becomes harder to find a meaning to life. According to Dalrymple, man's search for transcendence has degenerated into a self absorbed quest for health. Instead of praying for deliverance …

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Topical Itraconazole for the Treatment of Basal Cell Carcinoma in Patients With Basal Cell Nevus Syndrome or High-Frequency Basal Cell Carcinomas
Authors: Grace K. Sohn, Gina P. Kwon, Irene Bailey-Healy, Amar Mirza, Kavita Sarin, Anthony Oro, Jean Y. Tang
Journal: JAMA Dermatology (2019)

alopecia.Finally, patients with serine protease inhibitor Kazal type 5 (SPINK5) mutations reported alopecia, consistent with phenotypic characterizations of Netherton syndrome (Figure ). 6 Within the ABCA12 and TGM1 subgroups, severity of alopecia correlated positively with severity of ichthyosis.Thus, while severities did not appear to be associated in patients with ichthyosis overall, they may have been associated in patients with ABCA12 and TGM1 mutations.Our study was limited by a small sample size and inability to control for age.Some experts report anecdotally that alopecia in this population improves or worsens.The population was composed of 8 genotypes, and larger studies focusing on single genotypes might bear different results.Nevertheless, the findings suggest that in patients with TGM1 and ABCA12 genotypes, alopecia may be more extensive in cases of severe skin disease.
Impact of <i>ADCY9</i> Genotype on Response to Anacetrapib
Authors: Jemma C. Hopewell, Maysson Ibrahim, Michael Hill, Peter M. Shaw, Eugene Braunwald, Robert O. Blaustein, Louise Bowman, Martin J. Landray, Marc S. Sabatine, Rory Collins, L Jiang, CP Cannon, SD Wiviott, J Armitage, R Haynes, AP Maggioni, CE Angermann, G Ertl, C Wanner, T Pedersen, S Goto, T Teramoto, C Baigent, P Barter, Y Chen, Z Chen, A Gray, B Mihaylova, P Sleight, J Tobert, P DeLucca, Y Mitchel, G van Leijenhorst
Journal: Circulation (2019)

Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by
Implications of an Aging Rural Physician Workforce
Authors: Lucy Skinner, Douglas O. Staiger, David I. Auerbach, Peter I. Buerhaus
Journal: New England Journal of Medicine (2019)

As fewer younger physicians enter rural practice in the United States, the rural physician workforce is graying and nearing retirement. The uneven distribution of doctors presents serious access problems, exacerbates health needs, and has important equity implications.
The tumor-log odds of positive lymph nodes-metastasis staging system, a new staging system for gastric cancer after D2 resection in China.
Authors: Rui-hua Xu, Miao-zhen Qiu
Journal: Journal of Clinical Oncology (2012)

e14655 Background: In this study, we established a hypothetical tumor-lodds-metastasis (TLM) and tumor-ratio-metastasis (TRM) staging system. Moreover we compared them with the 7 th edition of American Joint Committee on Cancer tumor-nodes-metastasis (AJCC TNM) staging system in gastric cancer patients after D2 resection. Methods: A total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Finally, 730 patients who received D2 resection were retrospectively studied. Patients were staged using the TLM, TRM and the 7 th edition AJCC TNM system. Survival analysis was performed with a Cox regression model. We used two parameters to compare the TNM, TRM and TLM staging system, the -2log likelihood and the hazard ratio. Results: The cut points of lymph node ratio (LNR) were set as 0, 0-0.3, 0.3-0.6, 0.6-1.0. And for the log odds of positive lymph nodes (LODDS), the cut points were established as≤-0.5, -0.5-0, 0-0.5, &gt;0.5. There were significant differences in survival among patients in different LODDS classifications for each pN or LNR groups. When stratified by the LODDS classifications, the prognosis was highly homologous between those in the according pN or LNR classifications. Multivariate analysis shown that TLM staging system was better than the TRM or TNM system for the prognostic evaluation. Conclusions: The TLM systems was superior to the TRM or TNM system for prognostic assessment of gastric adenocarcinoma patients after D2 resection.
A Firm Plaque on the Occipital Scalp
Authors: Qiong Wu, Hongxiao Chen, Dirk M. Elston
Journal: JAMA Dermatology (2019)

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Breastfeeding, HIV exposure, childhood obesity, and prehypertension: A South African cohort study
Authors: Brian Houle, Tamsen J. Rochat, Marie-Louise Newell, Alan Stein, Ruth M. Bland
Journal: PLoS Medicine (2019)

Background Evidence on the association between breastfeeding and later childhood obesity and blood pressure (BP) is inconsistent, especially in HIV-prevalent areas where, until recently, HIV-infected women were discouraged from breastfeeding, but obesity is increasingly prevalent. Methods and findings The Siyakhula cohort (2012–2014), a population-based prospective cohort study, collected data over 3 visits on HIV-negative children ages 7 to 11 years in rural South Africa. We used weight (body mass index [BMI]), fat, and BP as outcome variables and incorporated early life (including mother's age at delivery and HIV status) and current life factors (including maternal education and current BMI). Our primary exposure was breastfeeding duration. We dichotomized 3 outcome measures using pre-established thresholds for clinical interpretability: (1) overfat: ≥85th percentile of body fat; (2) overweight: >1 SD BMI z score; and (3) prehypertension: ≥90th percentile for systolic BP (SBP) or diastolic BP (DBP). We modelled each outcome using multivariable logistic regression, including stopping breastfeeding, then early life, and finally current life factors. Of 1,536 children (mean age = 9.3 years; 872 girls; 664 boys), 7% were overfat, 13.2% overweight, and 9.1% prehypertensive. Over half (60%) of the mothers reported continued breastfeeding for 12+ months. In multivariable analyses, continued breastfeeding between 6 and 11 months was associated with approximately halved odds of both being overfat (adjusted odds ratio [aOR] = 0.43, 95% confidence interval [CI] 0.21–0.91, P = 0.027) and overweight (aOR = 0.46, CI 0.26–0.82, P = 0.0083), but the association with prehypertension did not reach statistical significance (aOR = 0.72, CI 0.38–1.37, P = 0.32). Children with a mother who was currently obese were 5 times more likely (aOR = 5.02, CI 2.47–10.20, P < 0.001) to be overfat and over 4 times more likely to be overweight (aOR = 4.33, CI 2.65–7.09, P < 0.001) than children with normal weight mothers. Differences between HIV-exposed and unexposed children on any of the outcomes were minimal and not significant. The main study limitation was that duration of breastfeeding was based on maternal recall. Conclusions To our knowledge, this is the first study examining and quantifying the association between breastfeeding and childhood obesity in an African setting with high HIV prevalence. We observed that breastfeeding was independently associated with reduced childhood obesity for both HIV-exposed and unexposed children, suggesting that promoting optimal nutrition throughout the life course, starting with continued breastfeeding, may be critical to tackling the growing obesity epidemic. In the era of widespread effective antiretroviral treatment for HIV-infected women for life, these data further support the recommendation of breastfeeding for all women.
Phase II multicenter, two-stage study of E7389 in patients with hormone refractory prostate cancer with advanced and/or metastatic disease stratified by prior chemotherapy
Authors: R. Molife, T. H. Cartwright, D. M. Loesch, L. E. Garbo, G. Sonpavde, E. Calvo, A. Das, J. Wanders, D. P. Petrylak, J. de Bono
Journal: Journal of Clinical Oncology (2007)

15513 Background: E7389 is a synthetic macrocyclic ketone derivative of the marine sponge product halichondrin B. A unique tubulin depolymerizer, E7389 induces nonproductive tubulin aggregates and inhibits tubulin polymerization. E7389 has demonstrated activity in refractory breast cancer and non small cell lung cancer with response rates of 14.7% and 9.7%, respectively. E7389 inhibits the growth of prostate cancer cell lines, including those (DU145) with over-expression of beta-tubulin III, which may confer resistance to taxanes. Methods: Phase II Simon two-stage study explores the activity and safety of E7389 as monotherapy without concomitant steroids in patients with histologically proven adenocarcinoma of the prostate that has progressed despite maintained castration. Patients are stratified into two groups that are analyzed separately, including those who failed either no prior chemotherapy (except mitoxanthrone or estramustine) or no more than one prior regimen with a tubulin binding agent, such as docetaxel. E7389 1.4 mg/m 2 is administered as a 2 to 5 minute bolus IV infusion on Days 1 and 8 of 21-day cycles. PSA measurements are obtained at the end of each cycle. The primary objective is to assess PSA response using Bubley criteria. Results: Thus far, 57 patients (37 taxane pretreated and 20 taxane naïve) have been treated. The median age is 71 (range 48–91) with 43% of patients over 75. A total of 160 treatment cycles have been given (median: 2; range: 2–7). Twelve study drug related serious adverse events have been reported in 9 patients: PE (2), melena (2), fever, neutropenia, febrile neutropenia, UTI, anemia, DVT, chest pain, and renal failure (1). Based on preliminary data, the taxane-treated group has 2 PSA responses in the first 21 patients, and the taxane-naïve group has 4 PSA responses in the first 14 patients, allowing both groups to progress to Stage 2 with further accrual. Conclusions: In patients with hormone refractory prostate cancer, there is some evidence of single agent activity for E7389 in taxane naïve and taxane pretreated patients with acceptable toxicity. Preliminary results of activity allow further recruitment to proceed. [Table: see text]
A Mutation in Histone H2B Represents a New Class of Oncogenic Driver
Authors: Richard L. Bennett, Aditya Bele, Eliza C. Small, Christine M. Will, Behnam Nabet, Jon A. Oyer, Xiaoxiao Huang, Rajarshi P. Ghosh, Adrian T. Grzybowski, Tao Yu, Qiao Zhang, Alberto Riva, Tanmay P. Lele, George C. Schatz, Neil L. Kelleher, Alexander J. Ruthenburg, Jan Liphardt, Jonathan D. Licht
Journal: Cancer Discovery (2019)

Abstract By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression. Significance: Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation. See related commentary by Sarthy and Henikoff, p. 1346. This article is highlighted in the In This Issue feature, p. 1325