tbuckley/cabot-search huggingface dataset:
What is driving the pandemic related surge in disordered eating?
Authors: Sara J Hansen, David B Menkes
Journal: BMJ (2021)

As Feinmann points out, the effect of the covid-19 pandemic on disordered eating is striking and seems to be international.1 Reports from North America and Europe accord with our observations in New Zealand of distinct increases in both adult and paediatric patients requiring treatment.2 Identifying relevant mechanisms is crucial to guide the effective management of these disabling and potentially lethal disorders.

Feinmann’s conference report includes the suggestion that “enforced social avoidance” during lockdowns might occur …
Trajectories of Suffering in the Last Year of Life Among Patients With a Solid Metastatic Cancer
Authors: Chetna Malhotra, Rahul Malhotra, Filipinas Bundoc, Irene Teo, Semra Ozdemir, Noreen Chan, Eric Finkelstein
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Reducing suffering at the end of life is important. Doing so requires a comprehensive understanding of the course of suffering for patients with cancer during their last year of life. This study describes trajectories of psychological, spiritual, physical, and functional suffering in the last year of life among patients with a solid metastatic cancer. Patients and Methods: We conducted a prospective cohort study of 600 patients with a solid metastatic cancer between July 2016 and December 2019 in Singapore. We assessed patients’ psychological, spiritual, physical, and functional suffering every 3 months until death. Data from the last year of life of 345 decedents were analyzed. We used group-based multitrajectory modeling to delineate trajectories of suffering during the last year of a patient’s life. Results: We identified 5 trajectories representing suffering: (1) persistently low (47% of the sample); (2) slowly increasing (14%); (3) predominantly spiritual (21%); (4) rapidly increasing (12%); and (5) persistently high (6%). Compared with patients with primary or less education, those with secondary (high school) (odds ratio [OR], 3.49; 95% CI, 1.05–11.59) education were more likely to have rapidly increasing versus persistently low suffering. In multivariable models adjusting for potential confounders, compared with patients with persistently low suffering, those with rapidly increasing suffering had more hospital admissions (β=0.24; 95% CI, 0.00–0.47) and hospital days (β=0.40; 95% CI, 0.04–0.75) during the last year of life. Those with persistently high suffering had more hospital days (β=0.70; 95% CI, 0.23–1.17). Conclusions: The course of suffering during the last year of life among patients with cancer is variable and related to patients’ hospitalizations. Understanding this variation can facilitate clinical decisions to minimize suffering and reduce healthcare costs at the end of life.
Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity
Authors: Ottavia M. Delmonte, Jenna R.E. Bergerson, Peter D. Burbelo, Jessica R. Durkee-Shock, Kerry Dobbs, Marita Bosticardo, Michael D. Keller, David H. McDermott, V. Koneti Rao, Dimana Dimitrova, Eugenia Quiros-Roldan, Luisa Imberti, Elise M.N. Ferrè, Monica Schmitt, Christine Lafeer, Justina Pfister, Dawn Shaw, Deborah Draper, Meng Truong, Jean Ulrick, Tom DiMaggio, Amanda Urban, Steven M. Holland, Michail S. Lionakis, Jeffrey I. Cohen, Emily E. Ricotta, Luigi D. Notarangelo, Alexandra F. Freeman
Journal: Journal of Allergy and Clinical Immunology (2021)

SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients.
Histone lysine demethylase 4B regulates general and unique gene expression signatures in hypoxic cancer cells
Authors: Lei Qiu, Yang Meng, Lingli Wang, Sumedha Gunewardena, Sicheng Liu, Junhong Han, Adam J. Krieg
Journal: MedComm (2021)

The hypoxic tumor microenvironment promotes tumor survival by inducing the expression of genes involved in angiogenesis and metastasis. As a direct target of hypoxia-inducible factor, lysine demethylase 4B (KDM4B) is overexpressed in multiple cancers, suggesting that a general KDM4B regulatory mechanism may exist in these cancer types. In this study, we sought to further investigate the general and unique roles of KDM4B in ovarian, colon, and renal cancer cells. We first identified a set of potential KDM4B targets shared by SKOV3ip.1, HCT116, and RCC4 cell lines, as well as numerous genes specifically regulated in each cell line. Through Gene Ontology, KEGG, and Oncobox pathway analyses, we found that KDM4B primarily regulated biosynthetic and cell cycle pathways in normoxia, whereas in hypoxia, it regulated pathways associated with inflammatory response and migration. TCGA data analyses reveal high expression of KDM4B in multiple cancer types and differential expression across cancer stages. Kaplan-Meier plots suggest that elevated KDM4B expression may contribute to a better or worse prognosis in a manner specific to each cancer type. Overall, our findings suggest that KDM4B plays complex roles in regulating multiple cancer processes, providing a useful resource for the future development of cancer therapies that target KDM4B expression.
Combining simple blood tests to identify primary care patients with unexpected weight loss for cancer investigation: Clinical risk score development, internal validation, and net benefit analysis
Authors: Brian D. Nicholson, Paul Aveyard, Constantinos Koshiaris, Rafael Perera, Willie Hamilton, Jason Oke, F. D. Richard Hobbs
Journal: PLoS Medicine (2021)

Unexpected weight loss (UWL) is a presenting feature of cancer in primary care. Existing research proposes simple combinations of clinical features (risk factors, symptoms, signs, and blood test data) that, when present, warrant cancer investigation. More complex combinations may modify cancer risk to sufficiently rule-out the need for investigation. We aimed to identify which clinical features can be used together to stratify patients with UWL based on their risk of cancer.We used data from 63,973 adults (age: mean 59 years, standard deviation 21 years; 42% male) to predict cancer in patients with UWL recorded in a large representative United Kingdom primary care electronic health record between January 1, 2000 and December 31, 2012. We derived 3 clinical prediction models using logistic regression and backwards stepwise covariate selection: Sm, symptoms-only model; STm, symptoms and tests model; Tm, tests-only model. Fifty imputations replaced missing data. Estimates of discrimination and calibration were derived using 10-fold internal cross-validation. Simple clinical risk scores are presented for models with the greatest clinical utility in decision curve analysis. The STm and Tm showed improved discrimination (area under the curve ≥ 0.91), calibration, and greater clinical utility than the Sm. The Tm was simplest including age-group, sex, albumin, alkaline phosphatase, liver enzymes, C-reactive protein, haemoglobin, platelets, and total white cell count. A Tm score of 5 balanced ruling-in (sensitivity 84.0%, positive likelihood ratio 5.36) and ruling-out (specificity 84.3%, negative likelihood ratio 0.19) further cancer investigation. A Tm score of 1 prioritised ruling-out (sensitivity 97.5%). At this threshold, 35 people presenting with UWL in primary care would be referred for investigation for each person with cancer referred, and 1,730 people would be spared referral for each person with cancer not referred. Study limitations include using a retrospective routinely collected dataset, a reliance on coding to identify UWL, and missing data for some predictors.Our findings suggest that combinations of simple blood test abnormalities could be used to identify patients with UWL who warrant referral for investigation, while people with combinations of normal results could be exempted from referral.
Excess Serum Interleukin‐18 Distinguishes Patients With Pathogenic Mutations in <scp><i>PSTPIP1</i></scp>
Authors: Deborah L. Stone, Amanda Ombrello, Juan I. Arostegui, Corinne Schneider, Vinh Dang, Adriana de Jesus, Charlotte Girard‐Guyonvarc'h, Cem Gabay, Wonyong Lee, Jae Jin Chae, Ivona Aksentijevich, Raphaela T. Goldbach‐Mansky, Daniel L. Kastner, Scott W. Canna
Journal: Arthritis & Rheumatology (2021)

Dominantly inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.). The connections between PSTPIP1 and PAPA syndrome are poorly understood, although evidence suggests involvement of pyrin inflammasome activation. Interleukin-18 (IL-18) is an inflammasome-activated cytokine associated with susceptibility to macrophage activation syndrome (MAS). This study was undertaken to investigate an association of IL-18 with PAPA syndrome.Clinical and genetic data and serum samples were obtained from patients referred to institutions due to symptoms indicative of PAPA syndrome. Serum IL-18, IL-18 binding protein (IL-18BP), and CXCL9 levels were assessed by bead-based assay, and free IL-18 levels were assessed by enzyme-linked immunosorbent assay.The symptoms of PSTPIP1-positive patients with PAPA syndrome overlapped with those of mutation-negative patients with PAPA-like conditions, but mutation-positive patients had earlier onset and a greater proportion had a history of arthritis. We found uniform elevation of total serum IL-18 in treated PAPA syndrome patients at levels nearly as high as those seen in NLRC4-associated autoinflammation with infantile enterocolitis patients, and well above levels found in most familial Mediterranean fever patients. Serum IL-18 elevation in PAPA syndrome patients persisted despite fluctuations in disease activity. Levels of the soluble IL-18 antagonist IL-18BP were modestly elevated, and PAPA syndrome patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon-γ activity, but no PAPA syndrome patients had a history of MAS.PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 levels but not with risk of MAS. These findings affect our understanding of the diseases in which IL-18 is overproduced and suggest a link between pyrin inflammasome activation, IL-18, and autoinflammation, without susceptibility to MAS.
Rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome shared megakaryocyte expansion in peripheral blood
Authors: Yukai Wang, Xuezhen Xie, Chengpeng Zhang, Miaotong Su, Sini Gao, Jing Wang, Changhao Lu, Qisheng Lin, Jianqun Lin, Marco Matucci-Cerinic, Daniel E Furst, Guohong Zhang
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) share many clinical manifestations and serological features. The aim of this study was to identify the common transcriptional profiling and composition of immune cells in peripheral blood in these autoimmune diseases (ADs). Methods We analysed bulk RNA-seq data for enrichment of biological processes, transcription factors (TFs) and deconvolution-based immune cell types from peripheral blood mononuclear cells (PBMCs) in 119 treatment-naive patients (41 RA, 38 pSS, 28 SLE and 12 polyautoimmunity) and 20 healthy controls. The single-cell RNA-seq (scRNA-seq) and flow cytometry had been performed to further define the immune cell subsets on PBMCs. Results Similar transcriptional profiles and common gene expression signatures associated with nucleosome assembly and haemostasis were identified across RA, SLE, pSS and polyautoimmunity. Distinct TF ensembles and gene regulatory network were mainly enriched in haematopoiesis. The upregulated cell-lineage-specific TFs PBX1 , GATA1 , TAL1 and GFI1B demonstrated a strong gene expression signature of megakaryocyte (MK) expansion. Gene expression-based cell type enrichment revealed elevated MK composition, specifically, CD41b + CD42b + and CD41b + CD61 + MKs were expanded, further confirmed by flow cytometry in these ADs. In scRNA-seq data, MKs were defined by TFs PBX1/GATA1/TAL1 and pre-T-cell antigen receptor gene, PTCRA . Cellular heterogeneity and a distinct immune subpopulation with functional enrichment of antigen presentation were observed in MKs. Conclusions The identification of MK expansion provided new insights into the peripheral immune cell atlas across RA, SLE, pSS and polyautoimmunity. Aberrant regulation of the MK expansion might contribute to the pathogenesis of these ADs.
Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor
Authors: Lucie Larigot, Louise Benoit, Meriem Koual, Céline Tomkiewicz, Robert Barouki, Xavier Coumoul
Journal: The Annual Review of Pharmacology and Toxicology (2021)

The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Indeed, in addition to its well-established detoxication function, it has several functions at physiological barriers, and it plays a critical role in immunomodulation. The AhR is also involved in the development of several organs and their homeostatic maintenance. Its activity depends on the type of ligand and on the time frame of the receptor activation, which can be either sustained or transient, leading in some cases to opposite modes of regulations as illustrated in the regulation of different cancer pathways. The development of selective modulators and their pharmacological characterization are important areas of research.
Health Status Predicts Short- and Long-Term Risk of Composite Clinical Outcomes in Acute Heart Failure
Authors: Danli Hu, Jiamin Liu, Lihua Zhang, Xueke Bai, Aoxi Tian, Xinghe Huang, Ke Zhou, Min Gao, Runqing Ji, Fengyu Miao, Jiaying Li, Wei Li, Jinzhuo Ge, Guangda He, Jing Li
Journal: JACC Heart Failure (2021)

This study aims to examine the association between the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score and the 30-day and 1-year rates of composite events of cardiovascular death and heart failure (HF) rehospitalization in patients with acute HF.Few studies reported the prognostic effects of KCCQ in acute HF.This study prospectively enrolled adult patients hospitalized for HF from 52 hospitals in China and collected the KCCQ-12 score within 48 hour of index admission. The study used multivariable Cox regression to examine the association between KCCQ-12 score and 30-day and 1-year composite events and was further stratified by new-onset HF and acutely decompensated chronic heart failure (ADCHF). Subgroup analyses were performed to explore the potential heterogeneity. The study evaluated the incremental prognostic value of KCCQ-12 score over N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and established risk scores by C-statistics, net reclassification improvement, and integrated discrimination improvement.Among 4,898 patients, 29.4% had new-onset HF. After adjustment, each 10-point decrease in the KCCQ-12 score was associated with a 13% increase in 30-day risk and a 7% increase in 1-year risk. The associations were consistent regardless of new-onset HF or ADCHF, age, sex, left ventricular ejection fraction, New York Heart Association functional class, NT-proBNP level, comorbidities, and renal function. Adding KCCQ-12 score to NT-proBNP and established risk scores significantly improved prognostic capabilities measured by C-statistics, net reclassification improvement, and integrated discrimination improvement.In acute HF, a poor KCCQ-12 score predicted short- and long-term risks of cardiovascular death and HF rehospitalization. KCCQ-12 could serve as a convenient tool for rapid initial risk stratification and provide additional prognostic value over NT-proBNP and established risk scores.
Abstract 14541: Correlation of Biomarker ST2 and Right Ventricular Function by Echocardiography in Pediatric Pulmonary Arterial Hypertension
Authors: Melanie Nies, Jun Yang, Megan Griffiths, Jie Zhu, Stephanie Brandal, Eric D Austin, Pei-Ni Jone, Dunbar D Ivy, Dhananjay Vaidya, Allen D Everett
Journal: Circulation (2019)

Introduction: Right ventricular (RV) function is a key predictor of death in pulmonary arterial hypertension (PAH), but difficult to assess given the complex geometry of the RV. A biomarker that re...
Arkadia-SKI/SnoN signaling differentially regulates TGF-β–induced iTreg and Th17 cell differentiation
Authors: Hao Xu, Lin Wu, Henry H. Nguyen, Kailin R. Mesa, Varsha Raghavan, Vasso Episkopou, Dan R. Littman
Journal: The Journal of Experimental Medicine (2021)

TGF-β signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-β signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORγt+FOXP3+ iTreg cells in the intestinal lamina propria, which increased susceptibility to microbiota-induced mucosal inflammation. In contrast, Arkadia was dispensable for Th17 cell responses. Furthermore, genetic ablation of two Arkadia substrates, the transcriptional corepressors SKI and SnoN, rescued Arkadia-deficient iTreg cell differentiation both in vitro and in vivo. These results reveal distinct TGF-β signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.
Tissue-Agnostic Drug Development: A New Path to Drug Approval
Authors: Kyaw Z. Thein, Steven J. Lemery, Shivaani Kummar
Journal: Cancer Discovery (2021)

Abstract Summary: In recent years, there has been remarkable progress in our understanding of cancer biology, host responses, and the concept of precision oncology. These advances have focused attention on biomarker-driven, tissue-agnostic drug development strategies. The recent approvals by the FDA of pembrolizumab for the treatment of unresectable or metastatic, microsatellite instability–high or deficient mismatch repair solid tumors, and more recently for the treatment of tumor mutational burden–high tumors; and of larotrectinib and entrectinib for the treatment of neurotrophic tyrosine kinase (NTRK) fusion–positive solid tumors, have further heightened interest in target-driven as opposed to histology-driven drug development. Herein, we focus on tissue-agnostic clinical drug development with an understanding of target modulation in the context of histology. The use of molecular genetics and biomarker-driven strategies rather than traditional histology based on organ of origin has reinforced the concept of tissue-agnostic drug development. Recent approvals in the United States, Europe, Japan, Australia, and other regions have further heightened interest in target-driven as opposed to histology-driven drug development.
The benefit of early surgery on overall survival in incidental low-grade glioma patients: A multicenter study
Authors: Tamara Ius, Sam Ng, Jacob S Young, Barbara Tomasino, Maurizio Polano, David Ben-Israel, John J P Kelly, Miran Skrap, Hugues Duffau, Mitchel S Berger
Journal: Neuro-Oncology (2021)

Abstract Background The role of surgery for incidentally discovered diffuse incidental low-grade gliomas (iLGGs) is debatable and poorly documented in current literature. Objective The aim was to identify factors that influence survival for patients that underwent surgical resection of iLGGs in a large multicenter population. Methods Clinical, radiological, and surgical data were retrospectively analyzed in 267 patients operated for iLGG from 4 neurosurgical Centers. Univariate and multivariate analyses were performed to identify predictors of overall survival (OS) and tumor recurrence (TR). Results The OS rate was 92.41%. The 5- and 10-year estimated OS rates were 98.09% and 93.2%, respectively. OS was significantly longer for patients with a lower preoperative tumor volume (P = .001) and higher extent of resection (EOR) (P = .037), regardless the WHO-defined molecular class (P = .2). In the final model, OS was influenced only by the preoperative tumor volume (P = .006), while TR by early surgery (P = .028). A negative association was found between preoperative tumor volumes and EOR (rs = −0.44, P &amp;lt; .001). The median preoperative tumor volume was 15 cm3. The median EOR was 95%. Total or supratotal resection of T2-FLAIR abnormality was achieved in 61.62% of cases. Second surgery was performed in 26.22%. The median time between surgeries was 5.5 years. Histological evolution to high-grade glioma was detected in 22.85% of cases (16/70). Permanent mild deficits were observed in 3.08% of cases. Conclusions This multicenter study confirms the results of previous studies investigating surgical management of iLGGs and thereby strengthens the evidence in favor of early surgery for these lesions.
Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial
Authors: Kevin R. Flaherty, Athol U. Wells, Vincent Cottin, Anand Devaraj, Yoshikazu Inoue, Luca Richeldi, Simon L.F. Walsh, Martin Kolb, Dirk Koschel, Teng Moua, Susanne Stowasser, Rainer-Georg Goeldner, Rozsa Schlenker-Herceg, Kevin K. Brown
Journal: European Respiratory Journal (2021)

Background The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial. Methods Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean± sd exposure to trial medication was 15.6±7.2 and 16.8±5.8 months in the nintedanib and placebo groups, respectively. Results In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (hazard ratio (HR) 0.66, 95% CI 0.53–0.83; p=0.0003) and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69, 95% CI 0.53–0.91; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67, 95% CI 0.46–0.98; p=0.04) and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62, 95% CI 0.39–0.97; p=0.03). Conclusion Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.