tbuckley/cabot-search huggingface dataset:
Use of Ebola Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020
Authors: Mary J. Choi, Caitlin M. Cossaboom, Amy N. Whitesell, Jonathan W. Dyal, Allison Joyce, Rebecca L. Morgan, Doug Campos-Outcalt, Marissa Person, Elizabeth Ervin, Yon C. Yu, Pierre E. Rollin, Brian H. Harcourt, Robert L. Atmar, Beth P. Bell, Rita Helfand, Inger K. Damon, Sharon E. Frey
Journal: MMWR Recommendations and Reports (2021)

This report summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of the rVSVΔG-ZEBOV-GP Ebola vaccine (Ervebo) in the United States. The vaccine contains rice-derived recombinant human serum albumin and live attenuated recombinant vesicular stomatitis virus (VSV) in which the gene encoding the glycoprotein of VSV was replaced with the gene encoding the glycoprotein of Ebola virus species Zaire ebolavirus. Persons with a history of severe allergic reaction (e.g., anaphylaxis) to rice protein should not receive Ervebo. This is the first and only vaccine currently licensed by the Food and Drug Administration for the prevention of Ebola virus disease (EVD). These guidelines will be updated based on availability of new data or as new vaccines are licensed to protect against EVD.ACIP recommends preexposure vaccination with Ervebo for adults aged ≥18 years in the U.S. population who are at highest risk for potential occupational exposure to Ebola virus species Zaire ebolavirus because they are responding to an outbreak of EVD, work as health care personnel at federally designated Ebola treatment centers in the United States, or work as laboratorians or other staff at biosafety level 4 facilities in the United States. Recommendations for use of Ervebo in additional populations at risk for exposure and other settings will be considered and discussed by ACIP in the future.
Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1
Authors: Zhaoji Liu, Linchong Sun, Yongping Cai, Shengqi Shen, Tong Zhang, Nana Wang, Gongwei Wu, Wenhao Ma, Shi-Ting Li, Caixia Suo, Yijie Hao, Wei-Dong Jia, Gregg L. Semenza, Ping Gao, Huafeng Zhang
Journal: Cancer Research (2021)

Metastasis is responsible for the majority of breast cancer-related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. SIGNIFICANCE: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
Why I . . . collaborate with European colleagues
Authors: Helen Jones
Journal: BMJ (2021)

I've been actively involved in WONCA Europe since my first year of GP training and I am evangelical about it," says Stuart Holmes."Nothing nourishes your resilience like getting to know international colleagues who share your enthusiasm for your specialty."He has found that being part of an international organisation has improved his work life."It's helped me develop my sense of vocation as a GP," Holmes says."There's sometimes negativity about being a GP in the UK-even from GPs-and engaging
HDAC5 Loss Impairs RB Repression of Pro-Oncogenic Genes and Confers CDK4/6 Inhibitor Resistance in Cancer
Authors: Yingke Zhou, Xin Jin, Jian Ma, Donglin Ding, Zhenlin Huang, Haoyue Sheng, Yuqian Yan, Yunqian Pan, Ting Wei, Liguo Wang, Heshui Wu, Haojie Huang
Journal: Cancer Research (2021)

Abstract The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle–related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells in vitro and prostate tumors in vivo, but this effect was overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells. Significance: This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.
Post-acute COVID-19 syndrome. Incidence and risk factors: A Mediterranean cohort study
Authors: Oscar Moreno-Pérez, Esperanza Merino, Jose-Manuel Leon-Ramirez, Mariano Andres, Jose Manuel Ramos, Juan Arenas-Jiménez, Santos Asensio, Rosa Sanchez, Paloma Ruiz-Torregrosa, Irene Galan, Alexander Scholz, Antonio Amo, Pilar González-delaAleja, Vicente Boix, Joan Gil
Journal: Journal of Infection (2021)

This study aims to analyze the incidence of Post-acute COVID-19 syndrome (PCS) and its components, and to evaluate the acute infection phase associated risk factors.A prospective cohort study of adult patients who had recovered from COVID-19 (27th February to 29th April 2020) confirmed by PCR or subsequent seroconversion, with a systematic assessment 10-14 weeks after disease onset. PCS was defined as the persistence of at least one clinically relevant symptom, or abnormalities in spirometry or chest radiology. Outcome predictors were analyzed by multiple logistic regression (OR; 95%CI).Two hundred seventy seven patients recovered from mild (34.3%) or severe (65.7%) forms of SARS-CoV-2 infection were evaluated 77 days (IQR 72-85) after disease onset. PCS was detected in 141 patients (50.9%; 95%CI 45.0-56.7%). Symptoms were mostly mild. Alterations in spirometry were noted in 25/269 (9.3%), while in radiographs in 51/277 (18.9%). No baseline clinical features behaved as independent predictors of PCS development.A Post-acute COVID-19 syndrome was detected in a half of COVID19 survivors. Radiological and spirometric changes were mild and observed in less than 25% of patients. No baseline clinical features behaved as independent predictors of Post-acute COVID-19 syndrome development.
Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth
Authors: Katelyn D. Miller, Katherine Pniewski, Caroline E. Perry, Sara B. Papp, Joshua D. Shaffer, Jesse N. Velasco-Silva, Jessica C. Casciano, Tomas M. Aramburu, Yellamelli V.V. Srikanth, Joel Cassel, Emmanuel Skordalakes, Andrew V. Kossenkov, Joseph M. Salvino, Zachary T. Schug
Journal: Cancer Research (2021)

Abstract Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. Significance: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer.
エンドセリン受容体拮抗剤による、レニン-アンジオテンシン遺伝子を持つ高血圧性トランスジェニックマウスの高血圧性表現型の回復と、トランスジェニックマウスにおけるエンドセリン系の器官特有の活性化の役割開示
Authors: Maki S, Miyauchi T, Kakinuma Y, Sakai S, Kobayashi T, Sugiyama F, Fukamizu A, Goto K, Yamaguchi I, Sugishita Y
Journal: Circulation (1998)
Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Massar Omar, Jesper Jensen, Mulham Ali, Peter H. Frederiksen, Caroline Kistorp, Lars Videbæk, Mikael Kjær Poulsen, Christian D. Tuxen, Sören Möller, Finn Gustafsson, Lars Køber, Morten Schou, Jacob Eifer Møller
Journal: JAMA Cardiology (2021)

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated.To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF.This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019.Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks.Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness.A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03).In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study.ClinicalTrials.gov Identifier: NCT03198585.
Susceptibility to paediatric B-cell precursor acute lymphoblastic leukemia is associated with polymorphic HLA-DPB1 peptide-binding supertypes
Authors: Graham M. Taylor, Adiba Hussain, Jillian M. Birch, Tim Ob Eden, Mel F. Greaves
Journal: Cancer Research (2006)

4586  A number of studies have shown that HLA-DR, DQ and DP alleles are associated with an increased risk of paediatric acute lymphoblastic leukaemia (ALL), but the significance of these multiple HLA locus/allele associations for the aetiology of childhood ALL remains uncertain. One possibility is that they denote differences in immune responsiveness to a causative infection(s), mediated by the differential antigenic peptide-binding efficiency of HLA class II alleles. We previously reported that B cell precursor ALL [BCP] was associated with HLA-DPB1*0201 and related alleles with glutamic acid (E) at position DPβ169 in the P4 peptide binding pocket (PBP). However, recent studies suggest that DPB1 alleles can be clustered into a small number of functional supertypes based on the shared peptide binding characteristics of several PBP. To determine whether these influence the risk of BCP ALL, we clustered DPB1 alleles into 3 pairs of supertypes, defined by di-allelic polymorphisms at DPβ184, 69 and 11, anchoring amino acids at the P1, P4 and P6 positions of a putative antigenic peptide. This allowed us to distinguish 0201-like from 0201-unlike supertypes with DPβ169E. In case-control comparisons with normal newborns (n=864) we found that both supertypes were associated with an increased risk of paediatric leukaemia (n=895), but not solid tumours (ST;n=409), whereas supertypes with DPβ169K were associated with protection from leukaemia. Stratification of leukaemias into BCP (n=687) and non-BCP (NBCP; n=208) leukaemia, or by molecular subtype (TEL-AML1:n=95; hyperdiploid:n=300) also revealed significant risks associated with the DPβ169E supertypes. Frequency comparisons of genotypes consisting of both supertype alleles (“supergenotypes”) revealed significant risks of BCP, NBCP and ST associated with 3/15, 1/15 and 1/15 heterozygous supergenotypes, respectively, but not with 6/6 homozygous supergenotypes. Risk ratios for TEL-AML1 and hyperdiploid leukaemia were significant for 5/15 and 4/15 heterozygous supergenotypes, respectively, but not for 6/6 homozygous supergenotypes. The association of BCP ALL, TEL-AML1 and hyperdiploid leukaemia with heterozygous DPβ1 supergenotypes implies a greater diversity of bound peptides than in homozygotes, suggesting that activation of a broader T cell repertoire by infection may be a factor in the development of these leukaemias.
Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits
Authors: Jenolyn F Alexander, Alexandre V Seua, Luis D Arroyo, Pradipta R Ray, Andi Wangzhou, Laura Heiβ-Lückemann, Manfred Schedlowski, Theodore J Price, Annemieke Kavelaars, Cobi J Heijnen
Journal: Theranostics (2021)

Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits.
PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF
Authors: Jiang Li, Xi Liang, Jing Jiang, Lingling Yang, Jiaojiao Xin, Dongyan Shi, Yingyan Lu, Jun Li, Keke Ren, Hozeifa Mohamed Hassan, Jianing Zhang, Pengcheng Chen, Heng Yao, Jiaqi Li, Tianzhou Wu, Linfeng Jin, Ping Ye, Tan Li, Huafen Zhang, Suwan Sun, Beibei Guo, Xingping Zhou, Qun Cai, Jiaxian Chen, Xiaowei Xu, Jianrong Huang, Shaorui Hao, Jinqiu He, Shaojie Xin, Di Wang, Jonel Trebicka, Xin Chen, Jun Li
Journal: Gut (2021)

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.
THU0583 STRATEGIES FOR ASSESSMENT OF COMPETENCES DURING RHEUMATOLOGY TRAINING ACROSS EUROPE: RESULTS OF A QUALITATIVE STUDY.
Authors: A. Najm, A. Alunno, F. Sivera, S. Ramiro, C. Haines
Journal: Annals of the Rheumatic Diseases (2020)

Background: In order to become a rheumatologist, trainees must successfully complete a rheumatology training program. Both the content and the assessments within these programs are regulated by national authorities, and therefore a wide heterogeneity between countries is expected. Objectives: To gain insight into current methods and practices for the assessment of competences during rheumatology training, and to explore the underlying priorities and rationales for competence assessment across EULAR countries. Methods: We used a qualitative approach through online focus groups of rheumatology trainers and trainees, separately. The study included five countries - Denmark, The Netherlands, Slovenia, Spain and United Kingdom. A summary of current practices of assessment of competences was developed, modified and validated during the focus groups. A prioritising method (9 diamond technique) was then used to identify key assessment priorities. Results: Overall, 26 participants (12 trainers, 14 trainees), participated in 9 online focus groups (2 per country, except Slovenia), totalling 12 hours of online discussion. Strong nationally (Netherlands, UK) or institutionally (Spain, Slovenia, Denmark) standardised approaches were described. Current practices were described as follows: two countries only provide national summative assessments (Slovenia, UK), while all were providing formative assessments regularly at varying frequencies. All groups identified providing frequent formative feedback to trainees for developmental purposes as the highest priority (figure 1). Most discussions identified a need for improvement, particularly in developing streamlined approaches to portfolios that remain close to clinical practice, protecting time for quality observation and feedback, and adopting systematic approaches to incorporating teamwork and professionalism into assessment systems. Figure 1. Priorities on assessment of competences for all participants and stratified by trainees and trainers. Conclusion: This paper presents a clearer picture of the current practice on the assessment of competences in rheumatology in key countries and the underlying rationale of trainers’ and trainees’ priorities. This work informed the EULAR Points-to-Consider for the assessment of competences in rheumatology training across Europe. Acknowledgments: This work was funded by EULAR (EDU043) Disclosure of Interests: Aurelie Najm: None declared, Alessia Alunno: None declared, Francisca Sivera: None declared, Sofia Ramiro Grant/research support from: MSD, Consultant of: Abbvie, Lilly, Novartis, Sanofi Genzyme, Speakers bureau: Lilly, MSD, Novartis, Catherine Haines: None declared
Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia
Authors: Eleni Louka, Benjamin Povinelli, Alba Rodriguez-Meira, Gemma Buck, Wei Xiong Wen, Guanlin Wang, Nikolaos Sousos, Neil Ashley, Angela Hamblin, Christopher A.G. Booth, Anindita Roy, Natalina Elliott, Deena Iskander, Josu de la Fuente, Nicholas Fordham, Sorcha O’Byrne, Sarah Inglott, Ruggiero Norfo, Mariolina Salio, Supat Thongjuea, Anupama Rao, Irene Roberts, Adam J. Mead
Journal: The Journal of Experimental Medicine (2021)

Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin−CD34+CD38−CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a “first hit,” (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.
The variant call format provides efficient and robust storage of GWAS summary statistics
Authors: Matthew S. Lyon, Shea J. Andrews, Ben Elsworth, Tom R. Gaunt, Gibran Hemani, Edoardo Marcora
Journal: Genome biology (2021)

Abstract GWAS summary statistics are fundamental for a variety of research applications yet no common storage format has been widely adopted. Existing tabular formats ambiguously or incompletely store information about genetic variants and associations, lack essential metadata and are typically not indexed yielding poor query performance and increasing the possibility of errors in data interpretation and post-GWAS analyses. To address these issues, we adapted the variant call format to store GWAS summary statistics (GWAS-VCF) and developed open-source tools to use this format in downstream analyses. We provide open access to over 10,000 complete GWAS summary datasets converted to this format ( https://gwas.mrcieu.ac.uk ).
Pre-Operative Cardiac Risk Assessment in Noncardiac Surgery: Are Natriuretic Peptides the Magic Bullet?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Daniel Bolliger, Manfred D. Seeberger, Miodrag Filipovic
Journal: Journal of the American College of Cardiology (2009)