tbuckley/cabot-search huggingface dataset:
Mass Spectrometry–Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers
Authors: Filip Mundt, Sandeep Rajput, Shunqiang Li, Kelly V. Ruggles, Arshag D. Mooradian, Philipp Mertins, Michael A. Gillette, Karsten Krug, Zhanfang Guo, Jeremy Hoog, Petra Erdmann-Gilmore, Tina Primeau, Shixia Huang, Dean P. Edwards, Xiaowei Wang, Xuya Wang, Emily Kawaler, D.R. Mani, Karl R. Clauser, Feng Gao, Jingqin Luo, Sherri R. Davies, Gary L. Johnson, Kuan-lin Huang, Christopher J. Yoon, Li Ding, David Fenyö, Matthew J. Ellis, R. Reid Townsend, Jason M. Held, Steven A. Carr, Cynthia X. Ma
Journal: Cancer Research (2018)

Activation of PI3K signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib
WHICH OBJECTIVE NUTRITIONAL INDEX IS THE MOST USEFUL FOR THE PREDICTION OF ONE-YEAR HEART FAILURE READMISSION IN ELDERLY PATIENTS WITH ACUTE DECOMPENSATED HEART FAILURE?
Authors: Yoshihiro Sato, Masahiro Kumada, Takuma Iida, Yukinori Okazaki, Tsutomu Nakagawa
Journal: Journal of the American College of Cardiology (2018)
INTERLEUKIN-1 BLOCKADE REDUCES PATIENT PERCEPTIONS OF EXERTION AND DYSPNEA AMONG PATIENTS WITH RECENTLY DECOMPENSATED SYSTOLIC HEART FAILURE: A SUBGROUP ANALYSIS OF THE REDHART TRIAL
Authors: Benjamin W. Van Tassell, George Wohlford, Francine Kim, Justin Canada, Salvatore Carbone, Dinesh Kadariya, Hayley Billingsley, Cory Trankle, Leo Buckley, Dave Dixon, Michele Viscusi, Marco Del Buono, Horacio Medina, Ross Arena, Antonio Abbate
Journal: Journal of the American College of Cardiology (2018)
O019 IL-17A at crossroad between keratinocytes and fibroblasts in human skin within systemic sclerosis
Authors: AM Dufour, M Alvarez, M-E Truchetet, NC Brembilla, C Chizzolini
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Increased levels of IL-17A have been reported in systemic sclerosis (SSc) but its role in fibrosis development is still debated.<sup>1</sup> Recent findings suggest a role for keratinocytes in the development of fibrosis.<sup>2</sup> Of interest, epithelial cells are preferential targets of IL-17A. <h3>Objectives</h3> Our aim was to investigate the interactions between epidermis and dermis in the presence of IL-17A, taking into perspective the fibrotic process. <h3>Methods</h3> Conditioned-media of primary human keratinocytes primed with IL-17A and/or TGF-β were used to stimulate healthy donors (HD) and SSc fibroblasts. Alternatively, organotypic cultures of HD full human skin were treated with these cytokines. Responses were assessed by quantifying inflammatory mediators and type I collagen (Col-I) levels. The factors produced by keratinocytes were identified by a proteomic approach and their contribution was evaluated by their neutralisation. MicroRNA expression was examined by µParaflo technology platform. <h3>Results</h3> Unstimulated HD- and SSc-derived keratinocyte-conditioned media (KCM) promoted collagen production by fibroblasts to a similar extent and in a dose-dependent manner. Cytokine array analysis and neutralising assays showed that TGF-β was, at least in part, responsible for the pro-fibrotic effect of KCM. Although priming of keratinocytes with IL-17A alone did not influence Col-I, it significantly decreased Col-I production induced by TGF-β by fibroblasts (p=0.02). In full human skin, IL-17A promoted pro-inflammatory responses by inducing 2- to 4-fold increase of IL-8, IL-6, MCP-1 and MMP-1 levels, while showing direct anti-fibrotic effects and decreasing by 2-fold collagen production triggered by TGF-β (p=0.02). The combined injection of IL-17A and TGF-β in the full human skin resulted in a distinct pattern of miRNA expression, particularly driven by miR-4343, when compared to the expression induced by the separate injection of IL-17A and TGF-β. <h3>Conclusions</h3> Keratinocytes profoundly influence dermal fibroblast responses, which are further modulated in the presence of IL-17A. These data support a role for keratinocytes in the pathogenesis of SSc. IL-17A acts as a potent anti-fibrotic factor in the model of keratinocyte – fibroblast interactions, as well as in the full human skin, which mechanisms are currently explored. <h3>References</h3> . Truchetet ME, et al. <i>Arthritis &amp; Rheumatol</i>2013. . Takahashi T, et al. <i>J Exp Med</i>2017. <h3>Acknowledgements</h3> Work supported in part by grant 310030–1 59 999 from the SNF to CC. <h3>Disclosure of interest</h3> None declared
Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?
Authors: Charlotte Pawlyn, Andrea Loehr, Cody Ashby, Ruslana Tytarenko, Shayu Deshpande, James Sun, Kyle Fedorchak, Tariq Mughal, Faith E. Davies, Brian A. Walker, Gareth J. Morgan
Journal: Leukemia (2018)

PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.
Role model: Anita Thapar
Authors: Anne Gulland
Journal: BMJ (2018)

When Anita Thapar began training as a child psychiatrist in the 1980s the myth that parents were to blame for their children’s neurodevelopmental conditions persisted in some quarters. Some still believed the “refrigerator mother” hypothesis for autism—that a lack of maternal warmth and affection were responsible for a child’s condition.

The idea that genetic factors were relevant to childhood psychiatric disorders was so unusual that when Thapar told her colleagues she was going to do her PhD in genetics some thought she was quitting psychiatry.

“At that time, genetics and psychiatry were poles apart,” she says.

During her PhD she became interested in attention-deficit/hyperactivity disorder (ADHD).

“There’s so much stigma around mental health and ADHD, and some people still think it’s a made up condition. But there’s lots of research, not just my work, which shows it does behave like a neurodevelopmental disorder. The brain is affected, it starts early on, and there is a close overlap with autism, intellectual disability, and learning and language problems.” Thapar says. …
Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors
Authors: Etienne Patin, Milena Hasan, Jacob Bergstedt, Vincent Rouilly, Valentina Libri, Alejandra Urrutia, Cécile Alanio, Petar Scepanovic, Christian Hammer, Friederike Jönsson, Benoît Beitz, Hélène Quach, Yoong Wearn Lim, Julie Hunkapiller, Magge Zepeda, Cherie Green, Barbara Piasecka, Claire Leloup, Lars Rogge, François Huetz, Isabelle Peguillet, Olivier Lantz, Magnus Fontes, James P. Di Santo, Stéphanie Thomas, Jacques Fellay, Darragh Duffy, Lluís Quintana-Murci, Matthew L. Albert
Journal: Nature Immunology (2018)
Evidence of Alternative Modes of B Cell Activation Involving Acquired Fab Regions of <i>N</i>‐Glycosylation in Antibody‐Secreting Cells Infiltrating the Labial Salivary Glands of Patients With Sjögren’s Syndrome
Authors: Kristi A. Koelsch, Joshua Cavett, Kenneth Smith, Jacen S. Moore, Sylvain D. Lehoux, Nan Jia, Tim Mather, Syed M. S. Quadri, Astrid Rasmussen, C. Erick Kaufman, David M. Lewis, Lida Radfar, Teresa A. Scordino, Christopher J. Lessard, Biji T. Kurien, Richard D. Cummings, Judith A. James, Kathy L. Sivils, A. Darise Farris, R. Hal Scofield
Journal: Arthritis & Rheumatology (2018)

Objective To better understand the role of B cells, the potential mechanisms responsible for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjögren's syndrome (SS), this study explored patterns of selection pressure and sites of N ‐glycosylation acquired by somatic mutation (ac N ‐glyc) in the IgG variable (V) regions of antibody‐secreting cells (ASCs) isolated from the minor salivary glands of patients with SS and non‐SS control patients with sicca symptoms. Methods A novel method to produce and characterize recombinant monoclonal antibodies (mAb) from single cell–sorted ASC infiltrates was applied to concurrently probe expressed genes (all heavy‐ and light‐chain isotypes as well as any other gene of interest not related to immunoglobulin) in the labial salivary glands of patients with SS and non‐SS controls. V regions were amplified by reverse transcription–polymerase chain reaction, sequenced, and analyzed for the incidence of N ‐glycosylation and selection pressure. For specificity testing, the amplified regions were expressed as either the native mAb or mutant mAb lacking the ac N ‐glyc motif. Protein modeling was used to demonstrate how even an ac N ‐glyc site outside of the complementarity‐determining region could participate in, or inhibit, antigen binding. Results V‐region sequence analyses revealed clonal expansions and evidence of secondary light‐chain editing and allelic inclusion, of which neither of the latter two have previously been reported in patients with SS. Increased frequencies of ac N ‐glyc were found in the sequences from patients with SS, and these ac N ‐glyc regions were associated with an increased number of replacement mutations and lowered selection pressure. A clonal set of polyreactive mAb with differential framework region 1 ac N ‐glyc motifs was also identified, and removal of the ac N ‐glyc could nearly abolish binding to autoantigens. Conclusion These findings support the notion of an alternative mechanism for the selection and proliferation of some autoreactive B cells, involving V‐region N ‐glycosylation, in patients with SS.
Transforming growth factor–β signaling pathways in renal cell carcinoma are regulated by VHL status.
Authors: Borje Ljungberg, Pramod Mallikarjuna, Tumkur sitaram Raviprakash, Marene Landstrom
Journal: Journal of Clinical Oncology (2018)

661 Background: To evaluate the role of pVHL in the regulation of the TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC, and to evaluate the expression pVHL and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival. Methods: Snap frozen tissue samples from 143 ccRCC, and 56 non-ccRCC patients were examined by Western blot. Two ccRCC cell lines were utilized for in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Based on the median pVHL level the ccRCCs were divided into pVHL-low and pVHL-high. Results: Non-ccRCCs and pVHL-high ccRCCs expressed similar levels of pVHL. Expression of the ALK5-FL and ALK5-ICD, TGF-βRI, were significantly higher in ccRCC compared with non-ccRCC while pSmad2/3 and PAI-1did not differ. In non-ccRCC patients, expressions of ALK5-FL, ALK-5-ICD, pSmad2/3, and PAI1-1 did not associate to clinicopathological parameters and survival. In the ccRCC pVHL-high, expression of ALK5-ICD and PAI-1 associated significantly only to tumor stage and patients survival. Contrastingly, in ccRCC pVHL-low, ALK5-FL, ALK5-ICD, pSmad2/3 and PAI1 all associated to tumor stage and size, and patient’s survival. In-vitro studies on ccRCC cell lines, A498 and ACHN, revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked polyubiquitination thus negatively controlling TGF- β induced invasiveness of cells. Conclusions: The pVHL status regulates the TGF-β signaling pathway as well as the aggressiveness of tumors and survival of the ccRCC and non-ccRCC patients.
Queen’s speech missed “once in a generation” opportunity, says GMC
Authors: Abi Rimmer
Journal: BMJ (2014)

The Queen’s speech missed a “once in a generation” opportunity to reform medical regulation, the General Medical Council has said.

The GMC had hoped that the Regulation of Health and Social Care Professionals Bill would be included in the Queen’s speech on Wednesday 4 June. The bill is designed to modernise medical legislation and to provide regulators such as the …
Abstract 15838: Vascular Endothelial Growth Factor Myocardial Cell Anti-apoptotic Events Requires S100A6 Signaling
Authors: James Tsoporis, Ioannis K Rizos, Vasileios Salpeas, Shehla Izhar, Gerald Proteau, Thomas G Parker
Journal: Circulation (2016)

Introduction: Coronary artery bypass graft (CABG)-related cardiomyocyte apoptosis can result from overproduction of reactive oxygen species (ROS) following restoration of coronary blood flow. A num...
ASSOCIATION BETWEEN SLEEP DISORDERED BREATHING AND LIFE THREATENING VENTRICULAR ARRHYTHMIA AMONG LEFT VENTRICULAR ASSIST DEVICE PATIENTS
Authors: Rafath Ullah, Beneet Pandey, John Crouch, Francis X. Downey, Nasir Sulemanjee, Arshad Jahangir, Vinay Thohan
Journal: Journal of the American College of Cardiology (2018)
Trainee doctors to promote medical careers in primary schools
Authors: Caroline White
Journal: BMJ (2015)

The Medical Schools Council has teamed up with a professional educational body to gather a group of medical students and trainee doctors willing to talk to primary school children about their work.

The collaboration is part of the national Primary Futures initiative (www.inspiringthefuture.org/primary-futures), which aims to broaden children’s career aspirations and reinforce the importance of learning. The initiative was developed jointly by the National Association of Head Teachers and the charity Education and Employers and launched six months ago. It has already partnered primary schools with volunteers in work, including healthcare professionals, to help children make connections between what they are learning in the classroom and their futures.

In partnership with the Medical Schools Council, Primary Futures is now planning a special focus on medicine, culminating in a month of activities with medical student and trainee doctor volunteers in October this year, known as Medics Month.

In November last year …
CHARACTERIZATION OF 6,122 PATIENTS WITH ACUTE VENOUS THROMBOEMBOLISM IN ROUTINE CLINICAL PRACTICE: RE-COVERY DVT/PETM PROSPECTIVE GLOBAL COHORT STUDY
Authors: Samuel Z. Goldhaber, Walter Ageno, Ivan Casella, Chee Kok Han, Gary Raskob, Sebastian Schellong, Daniel Singer, Isabelle Voccia, Wenbo Tang, Esther Donado, Sam Schulman
Journal: Journal of the American College of Cardiology (2018)
PROGNOSTIC ROLE OF MYOCARDIAL EDEMA AT CARDIAC MAGNETIC RESONANCE IN HYPERTROPHIC CARDIOMYOPATHY
Authors: Giancarlo Todiere, Francesco Radico, Fabiola Cosentino, Chrysanthos Grigoratos, Andrea Barison, Michele Emdin, Giovanni Donato Aquaro
Journal: Journal of the American College of Cardiology (2018)
INCREASED CLINICAL AND FINANCIAL BURDEN OF HEART FAILURE HOSPITALIZATIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS: INSIGHTS FROM THE NATIONAL INPATIENT SAMPLE
Authors: Aditya A. Joshi, Joseph Lerman, Tsion Aberra, Amit Dey, Tarun Sharma, Mario Castagnaro, Maria Patarroyo, Srinivas Murali, Raymond Benza, Amresh Raina
Journal: Journal of the American College of Cardiology (2018)
Abstract ES3-1: Drugging protein synthesis in cancer therapy
Authors: RJ Schneider
Journal: Cancer Research (2018)

Abstract Translation of mRNAs that encode proteins with transforming, cell survival, DNA damage DNA repair and angiogenic functions requires increased levels of specific translation factors that are often overexpressed in many human cancers. Translation of these same classes of oncogenic mRNAs also requires increased activation of the protein synthesis machinery, which is stimulated by well-known signal transduction pathways, particularly the P3K-AKT-mTOR pathway and the ERK-MAPK-MNK pathway. Targeted inhibition of selective oncogenic mRNA translation through inhibition of translation-specific signal transduction pathways, or the specific inhibition of certain translation factors that are required in greater amounts for oncogenic mRNA translation, are emerging new areas in human cancer therapeutics and are in active clinical trials. Small molecule drugs have been developed that are highly specific for the key translation factors that are overexpressed in many human cancers, including breast cancers. In breast cancer, specific stage and grade-dependent alterations occur in the translation machinery and in its signal transduction pathways that correspond to locally advanced, inflammatory, endocrine-resistant ER+, hormone receptor negative and metastatic breast cancer. Many of these alterations provide actionable targets with existing drugs for exploitation of translation-specific vulnerabilities that do not target normal cells and can be synergistically combined with existing genotoxic chemotherapies, endocrine therapies, radiation therapy and immunotherapies. Current research has also begun to elucidate previously unknown translational control pathways that provide additional novel targets and potentially lower toxicity approaches. Targeting translational regulation and the protein synthetic machinery in cancer cells provides the advantage of being able to impair the expression of classes of mRNAs that are essential for cancer progression, metastasis and drug resistance, rather than targeting individual proteins or genes. These promising new therapeutics and clinical treatment strategies will be discussed. Citation Format: Schneider RJ. Drugging protein synthesis in cancer therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES3-1.
Belfast focused ultrasound course
Authors: Steven Kinnear
Journal: BMJ (2009)

This one day course is taught by consultants in anaesthesia, intensive care medicine, and emergency medicine, and is aimed at consultants and trainees working in critical care, emergency medicine, and in any acute specialty looking after acutely unwell patients.

May 2008 during my intensive care medicine placement.

My first encounter with ultrasound outside of a radiology department was during my emergency medicine attachment in foundation year 2. I could see what a useful tool it was and how relatively quickly a novice could acquire the basic skills. Then during my intensive care medicine attachment I was fortunate to work in a department with a dedicated ultrasound scanner. I soon learnt how …
Policy makers must tackle doctors’ dissatisfaction with leisure time, researchers say
Authors: Matthew Limb
Journal: BMJ (2016)

UK doctors’ low satisfaction with the amount of leisure time available to them is an issue that should be taken up by policy makers, researchers have said.

A team from Oxford University’s Nuffield Department of Population Health examined how doctors viewed their work and leisure up to five years after graduating. They found that doctors’ job enjoyment and satisfaction with leisure time had fluctuated since the mid-1990s but had improved overall.

Nonetheless, satisfaction with leisure time was still low, the researchers said. “Adequate leisure time is an important component of overall job satisfaction, yet it was common for doctors to score this lower than their job enjoyment,” they wrote. “Policy initiatives should address why this aspect of satisfaction is so low, particularly in the first year after graduation, and among hospital doctors 5 years after graduation.”

The researchers examined how doctors viewed …
Disabled, male, and older workers are “far less engaged” than other groups, report says
Authors: Matthew Limb
Journal: BMJ (2015)

Disabled workers, as well as male and older employees, are “far less engaged” than other groups of staff, a study of the NHS and other workplaces has found.

The researchers said that employers should view raising engagement levels in tandem with issues of diversity and inclusion, to drive up organisational performance and employee wellbeing. The Diverse Voices study was carried out by the non-profit organisation IPA and the consultancy Astar-Fanshawe.1

The study sought to examine the relation between effective employee engagement and diversity and inclusion. Nita Clarke, IPA director, said that employers needed to look at employee engagement and at diversity and inclusion as “two sides of the same coin.” The researchers said that developing engagement was a “two way process” between employers and employees to improve performance.

The research consisted of a literature review and data analysis of large scale employee …
Impact by age on dose-limiting toxicities in phase 1 oncology trials of cytotoxic agents and molecular targeted agents
Authors: T. Ebata, A. Shimomura, T. Koyama, S. Iwasa, S. Kondo, S. Kitano, K. Yonemori, Y. Fujiwara, T. Shimizu, N. Yamamoto
Journal: Annals of Oncology (2018)