tbuckley/cabot-search huggingface dataset:
Eosinophilic esophagitis and allergic comorbidities in a US‐population‐based study
Authors: Antonella Cianferoni, Christopher M. Warren, Terri Brown‐Whitehorn, Fallon Schultz‐Matney, Anna Nowak‐Wegrzyn, Ruchi S. Gupta
Journal: Allergy (2019)

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Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity
Authors: Antje Arnold, Ming Yuan, Antionette Price, Lauren Harris, Charles G Eberhart, Eric H Raabe
Journal: Neuro-Oncology (2019)

Abstract Background Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Many patients with unresectable or recurrent/refractory tumors have significant lifelong disability. The majority of pLGG have mutations increasing the activity of the Ras/mitogen-activated protein kinase (MAPK) pathway. Activation of mammalian target of rapamycin (mTOR) is also a hallmark of pLGG. We therefore hypothesized that the dual target of rapamycin complexes 1 and 2 (TORC1/2) kinase inhibitor TAK228 would synergize with the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in pLGG. Methods We tested TAK228 and trametinib in patient-derived pLGG cell lines harboring drivers of pLGG including BRAFV600E and neurofibromatosis type 1 loss. We measured cell proliferation, pathway inhibition, cell death, and senescence. Synergy was analyzed via MTS assay using the Chou–Talalay method. In vivo, we tested for overall survival and pathway inhibition and performed immunohistochemistry for proliferation and vascularization. We performed a scratch assay and measured angiogenesis protein activation in human umbilical vein endothelial cells (HUVECs). Results TAK228 synergized with trametinib in pLGG at clinically relevant doses in all tested cell lines, suppressing proliferation, inducing apoptosis, and causing senescence in a cell line–dependent manner. Combination treatment increased median survival by 70% and reduced tumor volume compared with monotreatment and control cohorts. Vascularization of tumors decreased as measured by CD31 and CD34. Combination treatment blocked activation of focal adhesion kinase (FAK) and sarcoma proto-oncogene non-receptor tyrosine kinase (SRC) in HUVEC cells and reduced HUVEC migration compared with each drug alone. Conclusions The combination of TAK228 and trametinib synergized to suppress the growth of pLGG. These agents synergized to reduce tumor vascularity and endothelial cell growth and migration by blocking activation of FAK and SRC.
Abstract C61: Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer
Authors: Shouhui Yang, Wei Tang, Peijun He, Limin Wang, Jochen Gaedcke, B. Michael Ghadim, Philipp Ströbel, Azadeh Azizian, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, S. Perwez Hussain
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments with heterogenous chemotherapeutic response in subsets of patients. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcome. We used a strategy of examining the molecular subset of PDAC patients with worst survival to understand the underlying mechanisms of disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering using gene expression profile revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival predicted prognosis and stratified patients in two clusters in a test (N=126) and validation (N=176) cohorts with significantly different survival. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of hepatocyte nuclear factor 1-B (HNF1B)/Clusterin (CLU) axis in the highly aggressive patient subset. HNF1B positively regulated CLU and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, migration, invasion, and 3D spheroid growth and epithelial-to-mesenchymal transition in pancreatic cancer cells. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells, representing the aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, targeting HNF1B/CLU axis may attenuate disease progression with potential therapeutic implication in a subset of pancreatic cancer. Citation Format: Shouhui Yang, Wei Tang, Peijun He, Limin Wang, Jochen Gaedcke, B. Michael Ghadim, Philipp Ströbel, Azadeh Azizian, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, S. Perwez Hussain. Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C61.
Matt Morgan: Cold food on hot desks
Authors: Matt Morgan
Journal: BMJ (2019)

As I approach the hospital, my day is already planned out. Handover, then a ward round, and family discussions, before an attempt to eat a sandwich, one handed, while balancing on the corner of a crowded “hot” desk. Then a meeting here and a meeting there, before another ward round and a late exit, probably hitting the traffic at just the wrong time to get home for a family dinner.

However, as the hospital doors slide open I see a colleague I need to speak to about a problematic research project, who’s just finishing a …
Prognostic Implications of Diffuse Interstitial Fibrosis in Asymptomatic Primary Mitral Regurgitation
Authors: Danai Kitkungvan, Eric Y. Yang, Kinan C. El Tallawi, Sherif F. Nagueh, Faisal Nabi, Mohammad A. Khan, Duc T. Nguyen, Edward A. Graviss, Gerald M. Lawrie, William A. Zoghbi, Robert O. Bonow, Miguel A. Quinones, Dipan J. Shah
Journal: Circulation (2019)
Youth sport specialisation: the need for an evidence-based definition
Authors: Neeru Jayanthi, Stephanie A Kliethermes, Jean Côté
Journal: British Journal of Sports Medicine (2019)

Sport specialisation, conceptually understood to involve mono-training and repetition for the purpose of skill acquisition and athlete development for a single sport, is increasingly common in youth sports. However, it has not always been this way. Over the past 30 years, research on expertise and skill acquisition has profoundly influenced the focus and structure of youth sport programme. Particularly, Ericsson, Kramp and Tesch-Romer’s (1993) work in music renewed research interests related to the importance of deliberate practice in the development of expertise.1 Some studies in sport, using retrospective questionnaires, suggested that high volume of intense, sport-specific practice at a young age is necessary to attain expertise in one sport.2 This body of research has promoted the idea that a large quantity of intense sport-specific practice and early specialisation is a logical pathway towards adult elite sport performance, and has contributed to the popularity of youth sport specialisation.

Simultaneously, biographical studies of elite level athletes suggested that their childhood sport experiences involved sport-specific practice, and play activities and engagement in various sports. In contrast with the early specialisation approach, Cote (1999) defined sampling as an early sport participation environment characterised by diversity, both within (eg, play, practice) and between sports.3 Considering both distinctive lines of research led to equivocal results, Cote, Ericsson and Law (2005) …
Targeting the BMP Receptor Inhibitor FKBP12 to Upregulate Hepcidin in Wild-Type and Hemojuvelin-Hemochromatosis Models
Authors: Mariateresa Pettinato, Mariam Aghajan, Violante Olivari, Alessandro Dulja, Antonella Nai, Jessica Bordini, Alessandro Campanella, Alessia Pagani, Shuling Guo, Clara Camaschella, Laura Silvestri
Journal: Blood (2019)
Burnout and career satisfaction in neuro-oncology: a survey of the Society for Neuro-Oncology and the European Association of Neuro-Oncology memberships
Authors: Shlomit Yust-Katz, Barbara O’Brien, Elizabeth Vera, Alvina Acquaye, Michael Weller, Terri Armstrong
Journal: Neuro-Oncology (2019)

Abstract Background Professional burnout is a syndrome characterized by emotional exhaustion, depersonalization, and loss of personal achievement. Burnout is a significant issue among health care providers, and neuro-oncology providers may be at high risk. We conducted a survey to evaluate burnout and career satisfaction among those caring for patients with brain tumors, and to identify risk factors for burnout. Methods We distributed an anonymous online survey to Society for Neuro-Oncology (SNO) members in 2016 and to European Association of Neuro-Oncology (EANO) members in 2017. The survey comprised questions about personal and professional characteristics and the validated Maslach Burnout Inventory–Human Services Survey (MBI-HSS) questionnaire. Statistical analysis included descriptive statistics, univariate and multivariate analyses, and incorporation of recently defined burnout profiles. Results Sixty-three percent of SNO and 61% of EANO participants were identified as having high burnout according to MBI-HSS. Among SNO participants, physicians had a lower rate of high burnout (61%) compared with allied health professionals (68%, P &amp;lt; 0.01) and basic scientists (83%, P &amp;lt; 0.01). Regarding the factors most commonly contributing to high burnout, SNO participants most commonly experienced high emotional exhaustion (48% of SNO participants vs 34% of EANO participants), whereas EANO participants most commonly experienced low personal achievement (40% vs 28%). Among both SNO and EANO participants, increasing job satisfaction reduced the likelihood of high burnout. Conclusions The prevalence of burnout among neuro-oncology professionals is high and personal risk factors were identified. Burnout profiles recognize a continuum of well-being and warrant further research.
Tenofovir may be superior to entecavir for preventing hepatocellular carcinoma and mortality in individuals chronically infected with HBV: a meta-analysis
Authors: Yu-Xian Teng, Min-Jun Li, Bang-De Xiang, Jian-Hong Zhong
Journal: Gut (2019)

Many studies have demonstrated that monotherapy with tenofovir disoproxil fumarate (TDF) or entecavir (ETV) can reduce the risk of liver complications in individuals chronically infected with HBV (CHB). Unclear is whether one monotherapy is more effective than the other at preventing these outcomes. In a recent issue of this journal, Lee and coworkers1 reported data from a large population of treatment-naive CHB patients in which risk of hepatocellular carcinoma (HCC), all-cause mortality or liver transplantation was similar with either monotherapy. Similar results were observed in subgroups of patients with chronic hepatitis or cirrhosis. While this study involved more than 7000 South Korean patients who were enrolled during more than a decade and whose virological and biochemical data over several years were analysed, its findings must be treated with caution because the two groups differed substantially in median …
Deletion of <i>Slam</i> locus in mice reveals inhibitory role of SLAM family in NK cell responses regulated by cytokines and LFA-1
Authors: Huaijian Guo, Stacey A. Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E. Mahl, Ning Wu, Dominique Davidson, Stephen N. Waggoner, André Veillette
Journal: The Journal of Experimental Medicine (2016)

Signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) can mediate either activating or inhibitory effects during natural killer cell (NK cell) activation. In this study, we addressed the global role, regulation, and mechanism of action of the SLAM family in NK cells by analyzing a mouse lacking the entire ∼400-kilobase Slam locus, which encodes all six SFRs and CD48, the ligand of SFR 2B4. This mouse displayed enhanced NK cell activation responses toward hematopoietic target cells. Analyses of mice lacking individual SFRs showed that the inhibitory function of the Slam locus was due solely to 2B4 and was not influenced positively or negatively by other SFRs. Differences in NK cell responses between recognition of targets expressing or lacking ligands for SFRs were enhanced by IL-12 but suppressed by type I interferon. Cytokines also changed the levels of SLAM-associated protein adaptors, which prevent the inhibitory function of SFRs. The enhanced activation responses of SFR-deficient NK cells were dependent on integrin LFA-1 but not on DNAM-1 or NKG2D. SFR-mediated inhibition prevented the generation of activated forms of LFA-1. Hence, the Slam locus has an overall inhibitory role during NK cell activation that is solely dependent on 2B4. This effect is influenced by cytokines and leads to suppression of LFA-1 activity.
Abstract B18: Defining the role of chromatin remodeling complexes in pancreatic cancer stem cells
Authors: Lesley Paige Ferguson, Jovylyn Gatchalian, Nikki K. Lytle, Nirakar Rajbhandari, Kendall Chambers, Sonia Albini, Benoit Bruneau, Lorenzo Puri, Maike Sander, Andrew Lowy, Diana Hargreaves, Tannishtha Reya
Journal: Cancer Research (2019)

Abstract Pancreatic adenocarcinoma (PDAC) is a devastating disease characterized by high rates of metastasis and poor therapeutic response. It is currently the 4th leading cause of cancer-related deaths in developed countries, and despite efforts to improve therapy, the five-year survival rate remains at 9%. Therefore, it is critical to identify new programs that drive pancreatic cancer progression and therapeutic resistance. To define new cancer dependencies, work in the Reya lab has focused on characterizing stem cell programs that drive cancer initiation, propagation, and relapse. Previously published studies have demonstrated that the fate determinant Musashi2 (Msi2) functionally marks a drug-resistant stem population in pancreatic cancer. More recent work has revealed that this aggressive subpopulation is characterized by a unique transcriptional and epigenetic profile. Given the crucial role for epigenetic regulation in development, we hypothesized that differential expression of epigenetic regulatory factors could be responsible for the establishment or maintenance of a stem cell state in pancreatic cancer. To identify epigenetic factors critical to stem function, we used a functional shRNA screen to profile the impact of inhibition of stem-enriched candidate factors on 3D growth of Msi2+ pancreatic cancer cells in vitro. From this screen, we identified the gene Smarcd3 as a critical mediator of stem cell growth in pancreatic cancer. Smarcd3 encodes Baf60c, a component of the SWI/SNF nucleosome remodeling complex with known functions in cardiac and neural development. Though Smarcd3 function has not been studied in PDAC, the SWI/SNF complex at large is known to be dysregulated in pancreatic cancer. Preliminary studies have shown that Smarcd3 inhibition leads to reduced growth of both mouse and human pancreatic cancer cells in vitro and in vivo. Current studies are ongoing to 1) elucidate the mechanism by which Smarcd3 controls growth of pancreatic cancer cells through binding of developmental transcription factors, and 2) use genetically engineered mouse models of pancreatic cancer to define the role of Smarcd3 in pancreatic cancer initiation and progression. Citation Format: Lesley Paige Ferguson, Jovylyn Gatchalian, Nikki K. Lytle, Nirakar Rajbhandari, Kendall Chambers, Sonia Albini, Benoit Bruneau, Lorenzo Puri, Maike Sander, Andrew Lowy, Diana Hargreaves, Tannishtha Reya. Defining the role of chromatin remodeling complexes in pancreatic cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B18.
Nintedanib (N) + docetaxel (D) after immunotherapy in adenocarcinoma non-small cell lung cancer (NSCLC): First results from the non-interventional LUME-BioNIS study
Authors: M. Reck, K. Syrigos, S. Miliauskas, S. Zöchbauer-Müller, H. Buchner, T. Kitzing, K.M. Kerr
Journal: Annals of Oncology (2019)
KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC
Authors: S. Gadgeel, D. Rodriguez-Abreu, E. Felip, E. Esteban, G. Speranza, M. Reck, R. Hui, M. Boyer, E.B. Garon, H. Horinouchi, R. Cristescu, D. Aurora-Garg, J. Lunceford, J. Kobie, M. Ayers, B. Piperdi, M.C. Pietanza, M.C. Garassino
Journal: Annals of Oncology (2019)
Ipilimumab in metastatic malignant melanoma: The Irish experience.
Authors: Paul P. Donnellan, Richard Bambury, Jodie E Battley, Derek Gerard Power, Kenneth John O'Byrne, John Crown, Oscar S. Breathnach, MinYuen Teo, Muhammad Faisal Jamaluddin, Oleksandr Volodymyrovych Boychak, Tomas Lyons, John Greene, Anuradha Jayaram
Journal: Journal of Clinical Oncology (2012)

e19059 Background: Ipilimumab (Ipi) is a potent anti CLA-4 immunotherapy recently shown to improve overall survival (OS) in a phase III study in patients (pts) with previously-treated, unresectable or metastatic malignant melanoma. Ipilimumab (3 mg/kg) has been available on compassionate grounds to pts in Ireland since June 2010. Methods: In this retrospective observational study we examine the Irish experience with ipilimumab specifically regarding patient-factors, treatment toxicity, and outcomes including response rate and survival. Results: Between June 2010 and December 2011, a total of 93 patients received ipilimumab. Data available for analyses was conducted in 46patients. Median age of patients was 56 yrs (ranging 28 – 84). M1c disease was identified in 40 patients (83.3%). Median number of prior lines of chemotherapy is 1 (ranging from 1-4). 22 (47.8%) patients received all four planned induction doses of ipilimumab. All patients received full doses of treatment and on schedule. There are no grade 4 toxicities reported and 13% (n= 6) had grade 3 adverse events. This included renal autoimmune toxicity (n=3), diarrhoea (n=1) elevated AST/ALT (n=1), ocular toxicity (n=1) and skin (n=1). Grade 3 adverse events occurred in 3 patients who received all 4 cycles of Ipilimumab. No intestinal perforations or hypophysitis were noted. There were no drug-related deaths. From available survival follow-up data there are 22 reported deaths. Due to paucity of the data, surrogate marker for response of treatment was expressed as absence of disease progression at the time of assessment. Among the 11 (23.9%) patients who responded to treatment, 45.5% of these patients received 4 cycles of ipilimumab. Conclusions: Ipilimumab was well tolerated with a manageable side effect profile. Response rates to ipilimumab in metastatic melanoma in an Irish population are in keeping with internationally reported figures. Comprehensive survival data will be reported as well as correlation of response with hematologic and biochemical blood tests.
Within-species contamination of bacterial whole-genome sequence data has a greater influence on clustering analyses than between-species contamination
Authors: Arthur W. Pightling, James B. Pettengill, Yu Wang, Hugh Rand, Errol Strain
Journal: Genome biology (2019)

Although it is assumed that contamination in bacterial whole-genome sequencing causes errors, the influences of contamination on clustering analyses, such as single-nucleotide polymorphism discovery, phylogenetics, and multi-locus sequencing typing, have not been quantified. By developing and analyzing 720 Listeria monocytogenes, Salmonella enterica, and Escherichia coli short-read datasets, we demonstrate that within-species contamination causes errors that confound clustering analyses, while between-species contamination generally does not. Contaminant reads mapping to references or becoming incorporated into chimeric sequences during assembly are the sources of those errors. Contamination sufficient to influence clustering analyses is present in public sequence databases.
US set to raise smoking age to 21 and to fund gun violence research after 20 year freeze
Authors: Owen Dyer
Journal: BMJ (2019)

The annual spending bill advancing through Congress this week1 will ban the sale of tobacco and vaping products to people aged under 21 across the United States, in an unexpected win for anti-smoking groups.

The omnibus bill, which sets the federal budget for the year ahead, will also allocate $25m (£18m; €21m) to study gun violence, ending a 23 year freeze on public funding of such research.

Legislators often tack unrelated amendments onto the spending bill, and these can become obstacles to its passage. But both parties are eager to rack up legislative wins as the election approaches and a series of swift compromises saw the bill sail through the House.

In the Senate, both parties have already said they will back it. That leaves only the president’s signature, which is expected to be a formality.

Anti-smoking groups have long pushed for the minimum age of legal access to be raised to 21, but only recently has legislators’ resistance started to crumble, as the tobacco industry itself began advocating the change.

Tobacco giant …
Anxiety and Depression Prevalence in Children, Adolescents, and Young Adults With Life-Limiting Conditions—Reply
Authors: Mary M. Barker, Martin Bland, Lorna K. Fraser
Journal: JAMA Pediatrics (2019)

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