tbuckley/cabot-search huggingface dataset:
Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association
Authors: Marvin A. Konstam, Michael S. Kiernan, Daniel Bernstein, Biykem Bozkurt, Miriam Jacob, Navin K. Kapur, Robb D. Kociol, Eldrin F. Lewis, Mandeep R. Mehra, Francis D. Pagani, Amish N. Raval, Carey Ward
Journal: Circulation (2018)

The diverse causes of right-sided heart failure (RHF) include, among others, primary cardiomyopathies with right ventricular (RV) involvement, RV ischemia and infarction, volume loading caused by cardiac lesions associated with congenital heart disease and valvular pathologies, and pressure loading resulting from pulmonic stenosis or pulmonary hypertension from a variety of causes, including left-sided heart disease. Progressive RV dysfunction in these disease states is associated with increased morbidity and mortality. The purpose of this scientific statement is to provide guidance on the assessment and management of RHF.The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through September 2017. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or reference to contemporary clinical practice recommendations.Chronic RHF is associated with decreased exercise tolerance, poor functional capacity, decreased cardiac output and progressive end-organ damage (caused by a combination of end-organ venous congestion and underperfusion), and cachexia resulting from poor absorption of nutrients, as well as a systemic proinflammatory state. It is the principal cause of death in patients with pulmonary arterial hypertension. Similarly, acute RHF is associated with hemodynamic instability and is the primary cause of death in patients presenting with massive pulmonary embolism, RV myocardial infarction, and postcardiotomy shock associated with cardiac surgery. Functional assessment of the right side of the heart can be hindered by its complex geometry. Multiple hemodynamic and biochemical markers are associated with worsening RHF and can serve to guide clinical assessment and therapeutic decision making. Pharmacological and mechanical interventions targeting isolated acute and chronic RHF have not been well investigated. Specific therapies promoting stabilization and recovery of RV function are lacking.RHF is a complex syndrome including diverse causes, pathways, and pathological processes. In this scientific statement, we review the causes and epidemiology of RV dysfunction and the pathophysiology of acute and chronic RHF and provide guidance for the management of the associated conditions leading to and caused by RHF.
Cortical drive and thalamic feed-forward inhibition control thalamic output synchrony during absence seizures
Authors: Cian McCafferty, François David, Marcello Venzi, Magor L. Lőrincz, Francis Delicata, Zoe Atherton, Gregorio Recchia, Gergely Orban, Régis C. Lambert, Giuseppe Di Giovanni, Nathalie Leresche, Vincenzo Crunelli
Journal: Nature Neuroscience (2018)
Clinical utility of clonality testing by next generation sequencing in the monitoring of B-cell and T-cell malignancies.
Authors: Mustafa H. Syed, Caleb Ho, Kseniya Petrova-Drus, JinJuan Yao, Wayne Yu, Ahmet Zehir, Khedoudja Nafa, Maria E. Arcila
Journal: Journal of Clinical Oncology (2017)

72 Background: Clonality testing is an integral part of the initial assessment of B and T cell malignancies. The further use of conventional clonality assays for monitoring of disease post treatment is limited by low assay sensitivity and inability to track clones based on their unique sequences. Clonality assessment by next generation sequencing (NGS) provides increased diagnostic capabilities, allowing the tracking of disease specific clones as well as the full spectrum of clonal sequences that arise in response to therapy. Here we describe our initial experience using an NGS based assay for monitoring and our comparison to conventional clonality assays and flow cytometry. Methods: DNA was extracted from hematologic samples received for routine clonality assessment including diagnostic (DS) and follow-up post therapy (PT) samples. Clonality testing was performed by conventional PCR-based assays using biomed II primers and by NGS utilizing Lymphotrack IGH FR1 and TRG kits (Invivoscribe). The amplified products were sequenced on Illumina MiSeq. For MRD assessment, we created dedicated laboratory protocols as well as in-house developed software, MSK-LymphoClone (LC), containing a data analysis pipeline, analytical tools for clonality assessment and a signout portal for easy search and retrieval of pertinent clones. Results: Samples from 48 patients were included (48 DS and 60 PT) encompassing 12 plasma cell neoplasms, 11 acute lymphoblastic leukemias, 16 mature B-cell and 9 T-cell lymphomas. All diagnostic samples showed clonal rearrangement with 100% concordance between conventional and NGS assays. Residual disease was detected in 27/60 (45%) PT samples using conventional fragment size based assays, 27/57 (47%) using flow and 38/60 (63%) using NGS. Diagnostic clonal sequences were detected in as low as 0.0019% of total reads in PT samples tested by NGS. 18/60 (30.0%) PT samples (17 patients) were disease negative by all assays; 16 patients remained disease-free (median follow-up - 2.4 months). Conclusions: NGS clonality testing is a valuable tool for monitoring patients with B and T cell neoplasms showing higher sensitivity and specificity than conventional assays.
Time to personalize the treatment of anti-MDA-5 associated lung disease
Authors: Michael Lake, Gautam George, Ross Summer
Journal: Annals of the Rheumatic Diseases (2018)

We read with interest the article by the European League Against Rheumatism/American College of Rheumatology on the classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups.1 While we believe these criteria will help with the diagnosis of most of the major subgroups of idiopathic inflammatory myopathies, we anxiously await society guidelines that direct physicians on how best to individualise the treatment for specific subgroups of this disease.

For example, one subgroup we seek immediate direction is on the treatment of patients with antibodies directed against the melanoma differentiation associated protein 5 (anti-MDA5). This antibody is typically identified in patients with clinically amyopathic dermatomyositis (CADM), and it is now increasingly appreciated that some of these individuals …
Model-based meta-analysis of safety for immune checkpoint inhibitor combinations and monotherapy.
Authors: Kald Abdallah, Boris Shulgin, Kirill Peskov, Yuri Kosinsky, Andrea Vergara-Silva, Gabriel Helmlinger, Lulu Chu, Eric Masson
Journal: Journal of Clinical Oncology (2017)

89 Background: Immune checkpoint inhibitors (ICIs) have shown efficacy across multiple cancer types; however, ICIs are also associated with immune-mediated (im) adverse events (AEs) especially when used in combination. Methods: Published safety data from 35 melanoma and non-small cell lung cancer clinical trials was normalized for drug exposure using drug concentrations at 50% inhibition (IC 50 ). Pharmacokinetic models from FDA, EMEA, and our own model were used to compare AEs across 4 ICIs: anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilumumab, tremelimumab). Data was analyzed by ICI target and organ class (ie, GI, skin, liver, lung, and endocrine). To test dependence of AE rate (%) on drug dose dependence (DD) we calculated mean AE rates for low and high halves of the dose range, and used Pearson’s χ 2 -squared test for statistical significance (SS) ( p&lt; 0.05). Results: We found AEs to be DD for anti-CTLA-4 monotherapies and anti-CTLA-4 + anti-PD-1 combinations, whereas DD was not SS for anti-PD-1 monotherapies (Table). For anti-CTLA-4 drugs DD was SS for GI, hepatic, skin, and endocrine AEs. In combination, there was DD upon anti-CTLA-4, but data were insufficient to confirm SS. For PD-1 drugs there was no significant DD found. Conclusions: For anti-PD-1 therapy, no DD for Grade 3/4 AEs was found across organ classes. However, for anti-CTLA-4 therapies, DD was SS for GI, skin, hepatic, and endocrine im AEs. Although not all data were sufficient to confirm SS, dose intensity of anti-CTLA-4 may be an important determinant of AEs, when co-administered with anti-PD-1. [Table: see text]
Postpartum breastfeeding status
Authors: Christine Betzold
Journal: Annals of the Rheumatic Diseases (2018)

Postpartum breastfeeding statusAccording to the abstract, 1 it does not appear that the postpartum woman's lactation status was taken into account.So I am wondering, couldn't their status alter the findings, given some of the major hormonal, immune function, and metabolic differences between woman that exclusively breast feed vs formula feed?
Trends in Incidence and Factors Affecting Survival of Patients With Cholangiocarcinoma in the United States
Authors: Shiva Kumar R. Mukkamalla, Hussain M. Naseri, Byung M. Kim, Steven C. Katz, Vincent A. Armenio
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Cholangiocarcinoma (CCA) includes cancers arising from the intrahepatic and extrahepatic bile ducts. The etiology and pathogenesis of CCA remain poorly understood. This is the first study investigating both incidence patterns of CCA from 1973 through 2012 and demographic, clinical, and treatment variables affecting survival of patients with CCA. Patients and Methods: Using the SEER database, age-adjusted incidence rates were evaluated from 1973–2012 using SEER*Stat software. A retrospective cohort of 26,994 patients diagnosed with CCA from 1973–2008 was identified for survival analysis. Cox proportional hazards models were used to perform multivariate survival analysis. Results: Overall incidence of CCA increased by 65% from 1973–2012. Extrahepatic CCA (ECC) remained more common than intrahepatic CCA (ICC), whereas the incidence rates for ICC increased by 350% compared with a 20% increase seen with ECC. Men belonging to non–African American and non-Caucasian ethnicities had the highest incidence rates of CCA. This trend persisted throughout the study period, although African Americans and Caucasians saw 50% and 59% increases in incidence rates, respectively, compared with a 9% increase among other races. Median overall survival (OS) was 8 months in patients with ECC compared with 4 months in those with ICC. Our survival analysis found Hispanic women to have the best 5-year survival outcome (P<.0001). OS diminished with age (P<.0001), and ECC had better survival outcomes compared with ICC (P<.0001). Patients who were married, were nonsmokers, belonged to a higher income class, and underwent surgery had better survival outcomes compared with others (P<.0001). Conclusions: This is the most up-to-date study of CCA from the SEER registry that shows temporal patterns of increasing incidence of CCA across different races, sexes, and ethnicities. We identified age, sex, race, marital status, income, smoking status, anatomic location of CCA, tumor grade, tumor stage, radiation, and surgery as independent prognostic factors for OS in patients with CCA.
Medicare Expenditures by Race/Ethnicity After Hospitalization for Heart Failure With Preserved Ejection Fraction
Authors: Boback Ziaeian, Paul A. Heidenreich, Haolin Xu, Adam D. DeVore, Roland A. Matsouaka, Adrian F. Hernandez, Deepak L. Bhatt, Clyde W. Yancy, Gregg C. Fonarow
Journal: JACC Heart Failure (2018)
The Association Between Mutations in BRAF and Colorectal Cancer–Specific Survival Depends on Microsatellite Status and Tumor Stage
Authors: Hendrik Bläker, Elizabeth Alwers, Alexander Arnold, Esther Herpel, Katrin E. Tagscherer, Wilfried Roth, Lina Jansen, Viola Walter, Matthias Kloor, Jenny Chang-Claude, Hermann Brenner, Michael Hoffmeister
Journal: Clinical Gastroenterology and Hepatology (2018)
David Oliver: Will the public use alternatives to emergency departments?
Authors: David Oliver
Journal: BMJ (2018)

I’ve argued before that we shouldn’t blame the public for using emergency departments,1 as has a joint observational study from the Royal College of Emergency Medicine and the Patients Association.2 The position was that urgent need is defined by service users in real time. The public are intelligent consumers who go where the lights are on, and many are in any case directed to acute hospitals by NHS emergency numbers.

But I’m always prepared to reflect and reconsider. A study in January of emergency department attenders at North Middlesex University Hospital has made me wonder.3 Researchers examined 37 000 pieces of data and interviewed 630 patients, seeking to determine what brings patients to emergency departments even for conditions …
Abstract 16235: Examining the Relationship Between Perceived Control Over the Heart Disease, Depressive Symptoms and Wellbeing and in Patients With Heart Failure and Their Spouses, an Actor-Partner Interdependence Model
Authors: Anna Strömberg, Maria Liljeroos, Kristofer Årestedt, Misook Chung
Journal: Circulation (2016)

Introduction:  Patients often perceive low control over their heart failure condition. Caregivers’ perception of control is related to their own well-being and caregiver burden. There is a knowledge gap on the reciprocal influences of perceived control over the heart failure in relation to physical and emotional distress in patients with heart failure and their caregiving spouses.   Aims:  The aim of this study was to examine the dyadic associations of perceived control, depressive symptoms, physical and emotional well-being in patients with heart failure and their spouses.   Methods:  155 patient-spouse dyads (patients 75% males, mean age 71 years, 53% in NYHA III and spouses 75% females, mean age 69 years) participated. Data were collected using Control Attitude Scale, Beck Depression Inventory, and Short-Form 36 and analyzed using the Actor-Partner Interdependence Model investigating the relationship within dyads using a regression framework.   Results:  Perceived control had an actor effect in patients on emotional health ( β  = .243. p= .006 ) and symptoms of depression ( β  = -.284. p= .004 ). This was not seen in the spouses. A partner effect of perceived control on emotional well-being was revealed for both patients ( β  = .334. p ) and spouses ( β  = .381. p ). A partner effect was revealed between perceived control and depression for both patients ( β  = -.269. p= .004 ) and spouses ( β  = -.269. p= .002 ). Depressive symptoms exhibited an actor effect, for patients and spouses, on both physical and emotional health. No partner effects of depressive symptoms or perceived control were found on the physical health, in neither patients nor spouses.   Conclusions:  Both patients’ and spouses’ perceived control influenced the emotional health of the other part. Patients’ with higher perceived control had better emotional well-being and less depressive symptoms, but the same was not found in spouses. Having depressive symptoms was related to one’s own physical and emotional health in patients and spouses, but they did not influence each other. More research on the relationship between perceived control and health is needed to guide the development of dyadic interventions that can increase control over the heart disease.
A 3D image-based quantification of immune cell-tumor spheroid interactions in the presence of checkpoint inhibition.
Authors: Lidia Daszkiewicz, Maarten Klop, Kuan Yan, Leo Price
Journal: Journal of Clinical Oncology (2017)

82 Background: Delivering on the promises of cancer immunotherapy is hampered by a lack of in vitro testing platforms that enable the early selection of promising drugs candidates. While quantification of the number of cytotoxic T cells and IFNγ secretion can give an indication of the drug effect, it is often critical to assess the functional cytotoxicity and infiltration capacity. In addition, immunomodulatory effects of drug combinations need to be carefully assessed before these treatment modalities reach patients. However there are unlimited possibilities of new combinations, especially in the view of synergy effects observed with double checkpoint inhibition blockade and combination with standard of care drugs. To specifically address the needs of immunotherapy cancer drug developers, we developed robust assays that incorporate the human immune system into tumor spheroid cultures, with functional read-outs in a high throughput (384well plate) format. Methods: Breast cancer cells were grown in a hydrogel to form 3D tumoroids. HLA-matched PBMCs with and without pre-activation/exhaustion were added and the infiltration of T cells and subsequent tumoroid killing was quantified. The effect of immune checkpoint blockade was also assessed with the addition of pembrolizumab. Quantification of effects of stimulators and checkpoint inhibition was achieved with 3D imaging and morphometric analysis with OMiner software. Results: Automated 3D image and data analysis enabled discrimination of immune-tumour cell interactions depending on activation status of T cells. Activated T cells more efficiently infiltrated and killed tumoroids than non-activated ones. Cytotoxic activity of overactivated/exhausted T cells was supressed but this could be reversed by the presence of checkpoint inhibitor in the coculture. Conclusions: A 3D environment allows the different cell types to engage in a more realistic setting than when cells are grow in a monolayer. Using image-based analysis, immune-tumor interactions can be dissected. This represents a new, highly powerful tool for cancer immunotherapy drug developers to select the most promising compounds, allowing faster progression towards the clinic.
Identification of T-cell-inflamed gastric adenocarcinoma in The Cancer Genome Atlas (TCGA).
Authors: Steven Brad Maron, Jason John Luke, Raymond Hovey, Riyue Bao, Thomas Gajewski, Yuan Ji, Daniel V.T. Catenacci
Journal: Journal of Clinical Oncology (2017)

16 Background: Gastroesophageal adenocarcinoma (GEC) is a significant global health problem. KEYNOTE-012 demonstrated a 22% objective response rate in patients with PD-L1 expressing GEC that received pembrolizumab. A subset of patients (pts) tumors express a T cell “inflamed” (TCI) phenotype, which can be measured using an IFN-γ-based immune signature and may prove more predictive of clinical benefit. Using a 160 gene RNA-Seq immune expression profile, we sought to characterize the molecular environments of TCI versus non-TCI GEC patients in The Cancer Genome Atlas (TCGA). Methods: 395 GEC pts with primary tumors in TCGA were clustered into TCI, non-TCI, and intermediate subtypes using both unsupervised hierarchical and K-means clustering (k = 3). Molecular characteristics were categorized using data acquired via CbioPortal and the UCSC Xena repository. Only non-silent somatic mutations and copy number variations (CNVs) reaching GISTIC2 -2 or +2 thresholds were considered. Statistical comparisons were performed using chi-square, ANOVA, and t-test. Results: The TCI subtype contained patients from all TCGA-defined subtypes - EBV-associated (56%), MSI-high (16%), chromosomal unstable (6%), and genomically stable (27%). No significant differences were seen between TCI and non-TCI for tumor site or stage. Mutations in PTEN, PIK3CA, CDH1, and RHOA were more frequent in TCI patients. ERBB2, CCNE1, and KRAS CNVs were infrequent in TCI patients as were PDE4D deletions ( p&lt; 0.05 ). TCI tumors had higher expression of both co-inhibitory (PD-1, PD-L1/L2, CD28/80, BTLA, LAG3) and co-stimulatory (CD137/40/27, OX40, GITR, ICOS) checkpoint molecules ( p&lt; 10 -7 ). Total mutation burden was no different between TCI and non-TCI pts when excluding MSI-high pts nor when assessing MSI-high alone. Conclusions: The IFN immune phenotype encompassed GEC patients from all TCGA subsets. Correlation of clinical outcome with checkpoint blockade is necessary to confirm these molecular associations and the independent predictive utility of this immune-profile stratification.
Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer
Authors: Diana C. West, Masha Kocherginsky, Eva Y. Tonsing-Carter, D. Nesli Dolcen, David J. Hosfield, Ricardo R. Lastra, Jason P. Sinnwell, Kevin J. Thompson, Kathleen R. Bowie, Ryan V. Harkless, Maxwell N. Skor, Charles F. Pierce, Sarah C. Styke, Caroline R. Kim, Larischa de Wet, Geoffrey L. Greene, Judy C. Boughey, Matthew P. Goetz, Krishna R. Kalari, Liewei Wang, Gini F. Fleming, Balázs Györffy, Suzanne D. Conzen
Journal: Clinical Cancer Research (2018)

Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone.Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig).Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012).Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. Clin Cancer Res; 24(14); 3433-46. ©2018 AACR.
The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol
Authors: Parkyong Song, Christoph Zechner, Genaro Hernandez, José Cánovas, Yang Xie, Varun Sondhi, Martin Wagner, Vanessa Stadlbauer, Angela Horvath, Bettina Leber, Ming Chang Hu, Orson W. Moe, David J. Mangelsdorf, Steven A. Kliewer
Journal: Cell Metabolism (2018)