tbuckley/cabot-search huggingface dataset:
Prevalence of incidental germline pathogenic (PV) and likely pathogenic (LPV) variants in hereditary cancer-related genes identified in matched tumor/normal sequencing of advanced solid tumors.
Authors: Ecaterina Elena Ileana Dumbrava, Lauren Brusco, Molly S Daniels, Chetna Wathoo, Kenna Rael Shaw, Karen H. Lu, Xiaofeng Zheng, Louise C. Strong, Jennifer Keating Litton, Banu Arun, Agda Karina Eterovic, Mark Routbort, Sarina Anne Piha-Paul, Vivek Subbiah, David S. Hong, Scott Kopetz, John Mendelsohn, Gordon B. Mills, Ken Chen, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2017)

1524 Background: Next-generation sequencing (NGS) for tumor molecular profiling can reveal germline incidental mutations in hereditary cancer-related genes. The American College of Medical Genetics and Genomics (ACMG) has recommended that laboratories performing clinical sequencing seek and report PV and LPV in 56 genes. We assessed the prevalence of incidental germline LPV and PV in other cancer-related genes among patients undergoing hybrid capture sequencing of 201 cancer-related genes. Methods: Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in 1000 patients (pts) with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771) in a research laboratory. We previously reported germline alterations in the putative most actionable genes as designated by ACMG (PMID: 26787237). We assessed the germline LPV and PV in 54 additional cancer-related genes. Results: Among the 1000 patients who underwent tumor and normal DNA sequencing, 37 patients (3.7%) were found to have a germline PV or LPV in the following genes: ATM (4); BAP1 (1); CDH1 (1); CDKN2A (1); CHEK1 (2); CHEK2 (10); EGFR (1); ERCC3 (4); ERCC5 (1); HNF1B (1); HRAS (1); MLL3 (1); NF1 (3); PKHD1 (4); PTCH1 (1) and SMARCA4 (1). Eight pts (22%) had previous genetic counseling and testing for various reasons, but only 3 pts (8%) had previously identified alterations (all with NF1 mutations). After discussion in our return of germline results board, it was decided to return the findings in established hereditary cancer predisposition genes with high penetrance: BAP1 (p.Y401X), CDH1 (p.C688X), CDKN2A (p.G101W), EGFR (p.T790M) and SMARCA4 (p.S332FfsX55) after validation in a CLIA laboratory. Conclusions: Return of the previously unrecognized germline LPV or PV in patients with advanced or metastatic cancers who undergo somatic profiling is of great interest. The exact genes for which the germline results should be returned is controversial. Broader genomic testing is likely to identify additional incidental germline alterations with potential clinical utility to patients and their relatives.
Genome-Wide Analysis of Colonization History and Concomitant Selection in Arabidopsis lyrata
Authors: Tiina M. Mattila, Jaakko Tyrmi, Tanja Pyhäjärvi, Outi Savolainen
Journal: Molecular Biology and Evolution (2017)

The high climatic variability in the past hundred thousand years has affected the demographic and adaptive processes in many species, especially in boreal and temperate regions undergoing glacial cycles. This has also influenced the patterns of genome-wide nucleotide variation, but the details of these effects are largely unknown. Here we study the patterns of genome-wide variation to infer colonization history and patterns of selection of the perennial herb species Arabidopsis lyrata, in locally adapted populations from different parts of its distribution range (Germany, UK, Norway, Sweden, and USA) representing different environmental conditions. Using site frequency spectra based demographic modeling, we found strong reduction in the effective population size of the species in general within the past 100,000 years, with more pronounced effects in the colonizing populations. We further found that the northwestern European A. lyrata populations (UK and Scandinavian) are more closely related to each other than with the Central European populations, and coalescent based population split modeling suggests that western European and Scandinavian populations became isolated relatively recently after the glacial retreat. We also highlighted loci showing evidence for local selection associated with the Scandinavian colonization. The results presented here give new insights into postglacial Scandinavian colonization history and its genome-wide effects.
Lenalidomide, Adriamycin, and Dexamethasone (RAD) As Induction Therapy for Patients with Newly Diagnosed Multiple Myeloma Who Are Eligible for Autologous Transplantation (ASCT): A Phase 2 Study from the Greek Myeloma Study Group
Authors: Evangelos Terpos, Eirini Katodritou, Argiris Symeonidis, Flora Zagouri, Antonis Gerofotis, Georgia Christopoulou, Maria Gavriatopoulou, Dimitrios Christoulas, Alexandra Kourakli, Pavlina Konstantinidou, Efstathios Kastritis, Meletios A Dimopoulos
Journal: Blood (2016)
Secular Trends of Amyotrophic Lateral Sclerosis
Authors: Adriano Chiò, Gabriele Mora, Cristina Moglia, Umberto Manera, Antonio Canosa, Stefania Cammarosano, Antonio Ilardi, Davide Bertuzzo, Enrica Bersano, Paolo Cugnasco, Maurizio Grassano, Fabrizio Pisano, Letizia Mazzini, Andrea Calvo
Journal: JAMA Neurology (2017)

This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register.To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d'Aosta regions of Italy.The Piemonte and Valle d'Aosta Register for ALS (PARALS) is an epidemiologic prospective register that covers 2 Italian regions (population of 4 476 931 inhabitants according to the 2011 census) from January 1, 1995, through December 31, 2014. Case ascertainment is based on multiple sources (neurologic departments, hospital discharge archives, and mortality records). Incidence rates are age and sex standardized for the Italian population of the 2011 census. Age-period-cohort (APC) analysis was performed using a Poisson regression model.The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants.During the study period, a total of 2702 patients (mean [SD] age at onset, 65.7 [11.1] years; 1246 [46.1%] female and 1456 [53.9%] male) received a diagnosis of ALS between 1995 and 2014, corresponding to a crude annual incidence rate of 3.03 per 100 000 population (95% CI, 2.85-3.23) and an adjusted incidence rate of 2.78 per 100 000 population (95% CI, 2.57-2.96). The age-adjusted incidence rate increased in the 2 decades of the study (1995-2004: 2.66; 95% CI, 2.50-2.83; 2005-2014: 2.89; 95% CI, 2.71-3.07; P = .04), mostly in women. The adjusted rate ratio of men to women decreased from 1.27:1 (1995-2004) to 1.17:1 (2005-2014). The analysis of deviance for the APC regression models indicated that the drift variable is relevant in explaining the variation of ALS incidence rates over time in the overall population (change in deviance, 4.6553; P = .03) and in women (change in deviance, 3.8821; P = .05) but not in men (change in deviance, 0.77215; P = .38). A total of 479 patients with ALS were alive and had not undergone tracheostomy at the prevalence day (December 31, 2014), corresponding to a crude prevalence rate of 10.54 per 100 000 population (95% CI, 9.64-11.52).During the 1995 to 2014 period, the crude and adjusted incidences of ALS increased in Piemonte and Valle d'Aosta, mostly in women. The APC model revealed that the increase of ALS incidence is attributable to a birth cohort effect in women, with a peak in the 1930 cohort. The different increase of ALS incidence in men and women points to an effect of exogenous factors with a differential effect on the 2 sexes, acting on a genetic background.
Incidence and survival trends of cancers diagnosed in young adults (20-39 years): A population-based study.
Authors: Husson Olga, Marianne van der Mark, Rhode Bijlsma, Anneke M. Westermann, Katja Aben, Winette T.A. Van Der Graaf
Journal: Journal of Clinical Oncology (2017)

1567 Background: Cancer in young adults (YAs; 20–39 years) is rare but its incidence is increasing globally. In The Netherlands, care for YA cancer patients is mostly dispersed, in contrast to centralized care for all pediatric cancer patients. Aim of this population-based study was to examine trends in YA cancer incidence and survival. Methods: Data from all YAs diagnosed between 1989-2015 (n = 89,675) were obtained from The Netherlands Cancer Registry. Age-standardized incidence rates with estimated annual percentage of change and five-year relative survival rates were calculated. Results: Cancer incidence in YAs increased significantly from 48 to 67 per 100,000 person years in males (1.7%) and from 78 to 97 per 100,000 person years in females (1.1%). In both males and females, significant rising incidence trends were found for melanoma (2.3%), skin (2.3%) and thyroid cancer (3.2%), CML (7.2%), Hodgkin (1.3%) and Non-Hodgkin lymphoma (0.9%). In females, the incidence of breast cancer increased (1.2%), while it decreased for lung (-1.3%) and ovarian cancer (-4.3%). In males, testicular cancer incidence increased significantly (4.1%). The most common cancers in male YAs were testicular cancer (33%), melanoma (15%), gastrointestinal cancer (8%), Non-Hodgkin and Hodgkin lymphoma (both 7%), whereas in females breast cancer (34%), melanoma (19%), gynecological (14%), thyroid and gastro-intestinal cancer (both 5%) were most frequently diagnosed. Over time, the five-year relative survival increased significantly from 72% to 85%. Survival improved for almost all tumor types, except for pediatric tumors: medulloblastoma (~60%), Ewing sarcoma (~43%) and rhabdomyosarcoma (~41%). A &lt; 80% five-year survival rate was also found for tumors of the lung (36%), gastro-intestinal tract (61%), ALL (60%), AML (65%) and soft tissue sarcomas (77%). Conclusions: Over the last 26 years, a marked increase in the incidence of a diverse spectrum of hematological and solid malignancies, pediatric and adult-type cancers was found for YAs. Survival improved over time, however remains poor for certain tumor types. Our data underpin the importance of knowledge of tumors at YA age to guide centralization of care and clinical research.
Increased expression of high affinity IGE receptor (FCεRI) α chain mRNA and protein bearing eosinophils in human allergen-induced atopic asthma
Authors: K. Rajakulasingam, S. Till, S. Ying, M. Humbert, J. Barkans, M. Sullivan, Q. Meng, C. J. Corrigan, J. Bungre, J. A. Grant, A. B. Kay, S. R. Durham
Journal: Thorax (1998)
CheckMate 331: An open-label, randomized phase III trial of nivolumab versus chemotherapy in patients (pts) with relapsed small cell lung cancer (SCLC) after first-line platinum-based chemotherapy (PT-DC).
Authors: Leora Horn, Martin Reck, Scott N. Gettinger, David R. Spigel, Scott Joseph Antonia, Brent A. Rupnow, Anne Pieters, Giovanni Selvaggi, Justin P. Fairchild, Solange Peters
Journal: Journal of Clinical Oncology (2016)

TPS8578 Background: Overall survival (OS) remains poor in pts with advanced SCLC, and treatment options are limited for pts who relapse after first-line PT-DC. Nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, has demonstrated superior survival and favorable safety over docetaxel in two phase III trials in previously treated advanced non-small cell lung cancer (NSCLC). These results led to the approval of nivolumab in the US for previously treated metastatic NSCLC and in the EU for previously treated squamous (SQ) NSCLC. In a phase I/II trial (CheckMate 032) in pts with advanced/metastatic solid tumors, nivolumab monotherapy showed antitumor activity with durable tumor responses in pts with SCLC whose disease progressed after ≥ 1 prior therapy. In this study, responses were observed regardless of programmed death ligand-1 (PD-L1) expression or platinum sensitivity/resistance. Adverse event profiles of nivolumab were manageable and favorable compared to safety profiles of historical topotecan or amrubicin data. These encouraging data have led to a phase III trial, CheckMate 331, designed to evaluate nivolumab monotherapy versus chemotherapy in pts with relapsed SCLC. Methods: Adult pts with limited or extensive disease SCLC, disease progression or recurrence after first-line PT-DC or chemoradiation therapy, and ECOG performance status 0–1 are eligible. Pts with symptomatic and active brain metastases are ineligible. The primary endpoint is OS. Secondary endpoints include progression-free survival and objective response rate. An estimated 480 pts will be enrolled and randomized 1:1 to nivolumab or chemotherapy (topotecan in the US or EU, and topotecan or amrubicin in Japan). Clinical trial information: NCT02481830.
DA-EPOCH-R in Primary Mediastinal B-Cell Lymphoma; Analysis of End of Therapy FDG-PET and Outcome
Authors: Christopher Joseph Melani, Ranjana Advani, Clara C. Chen, Kelsey M. Walters, David Venzon, Seth M. Steinberg, Margaret Shovlin, Elaine S. Jaffe, Stefania Pittaluga, Mark Roschewski, Wyndham H. Wilson, Kieron Dunleavy
Journal: Blood (2016)
Real-World Outcomes with Panobinostat in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Noa Biran, David H. Vesole, Shijia Zhang, Joshua R. Richter, Yen-Hong Kuo, Linda Schmidt, Laura McBride, Palka Anand, Kristin Ivanovski, Amy Pierre, Susan Kumka, Carmela Cuccurullo, David S. Siegel
Journal: Blood (2016)
Serum VEGF in patients (PTS) receiving bevacizimab (BEV) for early-stage breast cancer (ESBC): ICORG 08-10.
Authors: Norma O'Donovan, Alexandra Canonici, Imelda Parker, Tanya O'Shea, Brian Moulton, Giuseppe Gullo, John Kennedy, Dimitrios Tryfonopoulos, Naomi Walsh, John Crown
Journal: Journal of Clinical Oncology (2012)

e13520 Background: Approximately 30% of pts with ESBC develop metastasis despite apparently curative loco-regional therapy. Angiogenesis, partly mediated by vascular endothelial growth factor (VEGF), may promote metastases. BEV, an anti-VEGF monoclonal antibody which has some efficacy in metastatic BC is being studied as an adjuvant in ESBC, but there are no validated biomarkers, and the effect on VEGF levels in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC receiving BEV. Methods: 106 pts with HER-2 negative ESBC were included in this study. Patients received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected prior to commencement of treatment, at 6 months and 12 months. The VEGF levels in serum samples were determined, at each time point, using a VEGF enzyme-linked immunosorbent assay (ELISA). Results: VEGF concentration was determined in serum samples from 65 patients. Three pts (5%) had no detectable VEGF at 0, 6 and 12 months. The median level of serum VEGF in the remaining 62 patients was 325.4 ± 244 pg/ml. These 62 patients showed a significant decrease in VEGF concentration after 6 and 12 months of treatment (median 9 ± 42.1 pg/ml, p&lt;0.001 and 9 ± 43.9 pg/ml, p&lt;0.001 respectively). However, no significant change in VEGF levels were observed at 12 months compared to 6 months (median 0 ± 60.3 pg/ml, p=0.704). Conclusions: Adjuvant therapy with chemotherapy and BEV is associated with a significant reduction in VEGF levels at 6 months.
Mortality from Amyotrophic Lateral Sclerosis and Parkinson’s Disease Among Different Occupation Groups — United States, 1985–2011
Authors: John D. Beard, Andrea L. Steege, Jun Ju, John Lu, Sara E. Luckhaupt, Mary K. Schubauer-Berigan
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Amyotrophic lateral sclerosis (ALS) and Parkinson's disease, both progressive neurodegenerative diseases, affect >1 million Americans (1,2). Consistently reported risk factors for ALS include increasing age, male sex, and cigarette smoking (1); risk factors for Parkinson's disease include increasing age, male sex, and pesticide exposure, whereas cigarette smoking and caffeine consumption are inversely associated (2). Relative to cancer or respiratory diseases, the role of occupation in neurologic diseases is much less studied and less well understood (3). CDC evaluated associations between usual occupation and ALS and Parkinson's disease mortality using data from CDC's National Institute for Occupational Safety and Health (NIOSH) National Occupational Mortality Surveillance (NOMS), a population-based surveillance system that includes approximately 12.1 million deaths from 30 U.S. states.* Associations were estimated using proportionate mortality ratios (PMRs), standardizing indirectly by age, sex, race, and calendar year to the standard population of all NOMS deaths with occupation information. Occupations associated with higher socioeconomic status (SES) had elevated ALS and Parkinson's disease mortality. The shifts in the U.S. workforce toward older ages and higher SES occupations† highlight the importance of understanding this finding, which will require studies with designs that provide evidence for causality, detailed exposure assessment, and adjustment for additional potential confounders.
Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression
Authors: Donal McHugh, Nicole Caduff, Mario Henrique M. Barros, Patrick C. Rämer, Ana Raykova, Anita Murer, Vanessa Landtwing, Isaak Quast, Christine T. Styles, Michael Spohn, Adeola Fowotade, Henri-Jacques Delecluse, Alexandra Papoudou-Bai, Yong-Moon Lee, Jin-Man Kim, Jaap Middeldorp, Thomas F. Schulz, Ethel Cesarman, Andrea Zbinden, Riccarda Capaul, Robert E. White, Martin J. Allday, Gerald Niedobitek, David J. Blackbourn, Adam Grundhoff, Christian Münz
Journal: Cell Host & Microbe (2017)
Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals
Authors: Giuliana Magri, Laura Comerma, Marc Pybus, Jordi Sintes, David Lligé, Daniel Segura-Garzón, Sabrina Bascones, Ada Yeste, Emilie K. Grasset, Cindy Gutzeit, Mathieu Uzzan, Meera Ramanujam, Menno C. van Zelm, Raquel Albero-González, Ivonne Vazquez, Mar Iglesias, Sergi Serrano, Lucía Márquez, Elena Mercade, Saurabh Mehandru, Andrea Cerutti
Journal: Immunity (2017)

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.
Effect of provision of home-based curative health services by public sector health-care providers on neonatal survival: a community-based cluster-randomised trial in rural Pakistan
Authors: Sajid Soofi, Simon Cousens, Ali Turab, Yaqub Wasan, Shah Mohammed, Shabina Ariff, Zaid Bhatti, Imran Ahmed, Steve Wall, Zulfiqar A Bhutta
Journal: The Lancet Global Health (2017)

BackgroundAlthough the effectiveness of community mobilisation and promotive care delivered by community health workers in reducing perinatal and neonatal mortality is well established, evidence in support of home-based neonatal resuscitation and infection management is mixed. We assessed the effectiveness of adding training in neonatal bag and mask resuscitation and oral antibiotic therapy for suspected neonatal infections to a basic preventive and promotive interventions package delivered by public sector community-based lady health workers (LHWs) in rural Pakistan.MethodsWe did a cluster-randomised controlled trial in two subdistricts of Naushahro Feroze in rural Sindh, Pakistan, between April 15, 2009, and Dec 10, 2012. LHWs, trained in basic newborn resuscitation and in recognition and treatment (with oral amoxicillin) of suspected neonatal respiratory infections, were linked with traditional birth attendants and encouraged to attend home births. Control clusters received routine care through the existing national programme. The primary outcome was all-cause neonatal mortality. Independent data collection teams recorded data for all pregnancies and their outcomes, morbidity, mortality, and household practices related to maternal and newborn care.FindingsOf the 27 randomised clusters with functional LHW programmes, 13 were allocated to the intervention group (n=242 749) and 14 to the control group (n=256 985). In the intervention group, LHWs did 80% of the planned community mobilisation sessions, but were able to attend only 1184 (14%) of 8425 deliveries and 4318 (25%) of 17 288 neonatal visits within 72 h of birth (p<0·0001 for both variables compared with the control group). The neonatal mortality rate was 42 deaths per 1000 livebirths in intervention clusters compared with 55 per 1000 in the control group (risk ratio 0·80, 95% CI 0·68–0·93; p=0·005).InterpretationThe reduction in neonatal mortality in intervention clusters occurred against a background of improvements in domiciliary practices for maternal and newborn care. However, the poor reach of LHWs in accessing newborn infants at birth and in the early postnatal period underscores the limitations of tasking community health workers in public sector programmes working in similar circumstances with such complex interventions. Such community-based interventions in health systems should be accompanied by concerted efforts to improve quality of care in facilities and referral systems.FundingSaving Newborn Lives, Save the Children USA.
Neural control of sweat secretion: a review
Authors: Y. Hu, C. Converse, M.C. Lyons, W.H. Hsu
Journal: British Journal of Dermatology (2017)

Humans have 4 million exocrine sweat glands, which can be classified into two types: eccrine and apocrine glands. Sweat secretion, a constitutive feature, is directly involved in thermoregulation and metabolism, and is regulated by both the central nervous system (CNS) and autonomic nervous system (ANS).To explore how sweat secretion is controlled by both the CNS and the ANS and the mechanisms behind the neural control of sweat secretion.We conducted a literature search on PubMed for reports in English from 1 January 1950 to 31 December 2016.Acetylcholine acts as a potent stimulator for sweat secretion, which is released by sympathetic nerves. β-adrenoceptors are found in adipocytes as well as apocrine glands, and these receptors may mediate lipid secretion from apocrine glands for sweat secretion. The activation of β-adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration. Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion. The translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands. Dysfunction of the ANS, especially the sympathetic nervous system, may cause sweating disorders, such as hypohidrosis and hyperhidrosis.
Psychosocial Risk Is Associated with High Readmission Rates and Increased Length of Stay for Patients Following Hematopoietic Stem Cell Transplantation
Authors: Daniel R Richardson, Ying Huang, Patrick Elder, Joanna Newlin, Cyndi Kirkendall, Steven M Devine, Leslie A. Andritsos, Don M Benson, William Blum, Yvonne A Efebera, Craig C Hofmeister, Samantha Jaglowski, Rebecca B Klisovic, Heather L McGinty, Sam Penza, Sumithra Vasu, Basem M William, Ashley E Rosko
Journal: Blood (2016)