tbuckley/cabot-search huggingface dataset:
Duodenal <i>Anaerobutyricum soehngenii</i> infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study
Authors: Annefleur Koopen, Julia Witjes, Koen Wortelboer, Soumia Majait, Andrei Prodan, Evgeni Levin, Hilde Herrema, Maaike Winkelmeijer, Steven Aalvink, Jacques J G H M Bergman, Stephan Havik, Bolette Hartmann, Han Levels, Per-Olof Bergh, Jamie van Son, Manon Balvers, Diogo Mendes Bastos, Erik Stroes, Albert K Groen, Marcus Henricsson, Ellis Marleen Kemper, Jens Holst, Christopher M Strauch, Stanley L Hazen, Fredrik Bäckhed, Willem M De Vos, Max Nieuwdorp, Elena Rampanelli
Journal: Gut (2021)

Objective Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS. Design In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii / placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring. Results A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B ( REG1B )-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated. Conclusions A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity. Trial registration number NTR-NL6630.
Prevalence and Association of Dysnatremia with Outcomes in Hospitalized COVID-19 Patients
Authors: Pattharawin Pattharanitima, Kinsuk Chauhan, Steven G. Coca, Girish N. Nadkarni, Lili Chan
Journal: Journal of the American Society of Nephrology (2021)

Pattharanitima, Pattharawin; Chauhan, Kinsuk; Coca, Steven G.; Nadkarni, Girish N.; Chan, Lili Author Information
Repeated hippocampal seizures lead to brain-wide reorganization of circuits and seizure propagation pathways
Authors: ManKin Choy, Ehsan Dadgar-Kiani, Greg O. Cron, Ben A. Duffy, Florian Schmid, Bradley J. Edelman, Mazen Asaad, Russell W. Chan, Shahabeddin Vahdat, Jin Hyung Lee
Journal: Neuron (2021)
Risankizumab in Severe Asthma — A Phase 2a, Placebo-Controlled Trial
Authors: Christopher E. Brightling, Parameswaran Nair, David J. Cousins, Renaud Louis, Dave Singh
Journal: New England Journal of Medicine (2021)

Interleukin-23 has been implicated in airway inflammation that is mediated by type 2 and type 17 cytokines. Whether targeting interleukin-23 in the treatment of asthma improves disease control and reduces airway inflammation is unclear.We conducted a phase 2a, multicenter, randomized, double-blind, placebo-controlled, 24-week, parallel-group trial to assess the efficacy and safety of risankizumab, an anti-interleukin-23p19 monoclonal antibody, in adults with severe asthma. Patients were assigned to receive 90 mg of risankizumab or placebo, administered subcutaneously once every 4 weeks. The primary end point was the time to the first asthma worsening. Asthma worsening was defined as deterioration from baseline on 2 or more consecutive days; deterioration was considered to be a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in the number of puffs of rescue medication in a 24-hour period (equating to at least four additional puffs), a severe asthma exacerbation, or an increase of 0.75 or more points on the 5-item Asthma Control Questionnaire (ACQ-5; scores range from 0 to 6, with higher scores indicating less control). Secondary end points were the annualized rate of asthma worsening, the annualized rate of severe exacerbations, the ACQ-5 score, and the forced expiratory volume in 1 second. Exploratory end points were assessed with the use of sputum cytologic analysis and gene expression analysis, and safety was assessed.A total of 105 patients received risankizumab and 109 received placebo. The clinical characteristics of the patients were similar in the two groups. The time to the first asthma worsening was shorter with risankizumab than with placebo (median, 40 days vs. 86 days; hazard ratio, 1.46; 95% confidence interval [CI], 1.05 to 2.04; P = 0.03). The rate ratio for annualized asthma worsening with risankizumab as compared with placebo was 1.49 (95% CI, 1.12 to 1.99), and the rate ratio for severe exacerbations was 1.13 (95% CI, 0.75 to 1.70). Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of the type 1 helper T and type 17 helper T transcription factors were down-regulated by risankizumab. No safety concerns were associated with risankizumab therapy.Risankizumab treatment was not beneficial in severe asthma. The time to the first asthma worsening was shorter and the annualized rate of asthma worsening was higher with risankizumab than with placebo. (Funded by AbbVie and Boehringer Ingelheim; ClinicalTrials.gov number, NCT02443298.).
IDENTIFICATION OF PREDICTIVE BIOMARKERS FOR INDIVIDUAL RESPONSE TO MFOLFOX6 IN COLORECTAL CANCER PATIENTS
Authors: Wada S, Eguchi H, Tomita N, Watanabe M, Ikeda R, Ohue M, Takemoto H, Fukunaga M, Murata K, Nishiyama M
Journal: Annals of Oncology (2010)
Nanomedicine Strategies to Circumvent Intratumor Extracellular Matrix Barriers for Cancer Therapy
Authors: Xiaoxuan Xu, Yao Wu, Xindi Qian, Yuqi Wang, Jiaoying Wang, Jie Li, Yaping Li, Zhiwen Zhang
Journal: Advanced Healthcare Materials (2021)

Abstract The dense and heterogeneous physical network of the extracellular matrix (ECM) in tumors represents a formidable barrier that limits intratumor drug delivery and the therapeutic efficacy of many anticancer therapies. Here, the two major nanomedicine strategies to circumvent intratumor ECM barriers: regulating the physiochemical properties of nanomedicines and remodeling the components and structure of the ECM are summarized. Nanomedicines can be rationally regulated by optimizing physiochemical properties or designed with biomimetic features to promote ECM permeation capability. Meanwhile, they can also be designed to remodel the ECM by modulating signaling pathways or destroying the components and architecture of the ECM via chemical, biological, or physical treatments. These efforts produce profound improvements in intratumor drug delivery and anticancer efficacy. Moreover, to aid in their anticancer efficacy, feasible approaches for improving ECM‐circumventing nanomedicines are proposed.
TCT-180 IMPROVE Hand Study—Similar Occurrence of Upper-Extremity Dysfunction Following Slender 5-F Versus 6-F Transradial Percutaneous Coronary Intervention
Authors: Elena Cheung, Marco Alings, Carlo Holtzer, Marcel Kofflard, J.H. Coert, A.J.J. IJsselmuiden
Journal: Journal of the American College of Cardiology (2021)
Efficacy and Safety of Fitusiran Prophylaxis, an siRNA Therapeutic, in a Multicenter Phase 3 Study (ATLAS-INH) in People with Hemophilia A or B, with Inhibitors (PwHI)
Authors: Guy Young, Alok Srivastava, Kaan Kavakli, Cecil Ross, Jameela Sathar, Huyen Tran, Runhui Wu, Jing Sun, Stacey Poloskey, Zhiying Qui, Salim Kichou, Shauna R. Andersson, Baisong Mei, Savita Rangarajan
Journal: Blood (2021)
External controls to improve on glioblastoma clinical trials
Authors: Annette M Molinaro
Journal: Neuro-Oncology (2021)

Randomized clinical trials (RCTs) are the gold standard for delineating the effect of treatment from bias, the placebo effect, and disease course changes. As such, RCTs are expensive, require a large sample size, and take a long time to complete.1 All three of these are challenging, especially for rare diseases, like glioblastoma (GBM), where RCTs can be deemed unfeasible or unethical.2,3 A common workaround in Phase II trials is to employ a single-arm study design. In a single-arm study, the best scenario is to observe a treatment effect signal; however, this design does not allow quantification of the signal nor assessment of potential biases. Recently, external control data have garnered attention to address the noted limitations of RCTs and single-arm studies.4 External controls refer to a non-randomized control that serves as the reference for interpreting a treatment effect. External controls can also be termed synthetic, concurrent, or historical controls and are selected from data sources (eg, electronic medical records [EMRs], disease registries) external to the study of interest, commonly referred to as real-world data (RWD).5 A second source is historical trials. Several approaches employing external controls to augment controls in RCTs and single-arm studies have been suggested to delineate the treatment effect.1,6
4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells
Authors: Emiliano Roselli, Justin C Boucher, Gongbo Li, Hiroshi Kotani, Kristen Spitler, Kayla Reid, Estelle V Cervantes, Yannick Bulliard, Nhan Tu, Sae Bom Lee, Bin Yu, Frederick L Locke, Marco L Davila
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Co-stimulatory signals regulate the expansion, persistence, and function of chimeric antigen receptor (CAR) T cells. Most studies have focused on the co-stimulatory domains CD28 or 4-1BB. CAR T cell persistence is enhanced by 4-1BB co-stimulation leading to nuclear factor kappa B (NF-κB) signaling, while resistance to exhaustion is enhanced by mutations of the CD28 co-stimulatory domain. Methods We hypothesized that a third-generation CAR containing 4-1BB and CD28 with only PYAP signaling motif (mut06) would provide beneficial aspects of both. We designed CD19-specific CAR T cells with either 4-1BB or mut06 together with the combination of both and evaluated their immune-phenotype, cytokine secretion, real-time cytotoxic ability and polyfunctionality against CD19-expressing cells. We analyzed lymphocyte-specific protein tyrosine kinase (LCK) recruitment by the different constructs by immunoblotting. We further determined their ability to control growth of Raji cells in NOD scid gamma (NSG) mice. We also engineered bi-specific CARs against CD20/CD19 combining 4-1BB and mut06 and performed repeated in vitro antigenic stimulation experiments to evaluate their expansion, memory phenotype and phenotypic (PD1 + CD39 + ) and functional exhaustion. Bi-specific CAR T cells were transferred into Raji or Nalm6-bearing mice to study their ability to eradicate CD20/CD19-expressing tumors. Results Co-stimulatory domains combining 4-1BB and mut06 confers CAR T cells with an increased central memory phenotype, expansion, and LCK recruitment to the CAR. This enhanced function was dependent on the positioning of the two co-stimulatory domains. A bi-specific CAR targeting CD20/CD19, incorporating 4-1BB and mut06 co-stimulation, showed enhanced antigen-dependent in vitro expansion with lower exhaustion-associated markers. Bi-specific CAR T cells exhibited improved in vivo antitumor activity with increased persistence and decreased exhaustion. Conclusion These results demonstrate that co-stimulation combining 4-1BB with an optimized form of CD28 is a valid approach to optimize CAR T cell function. Cells with both mono-specific and bi-specific versions of this design showed enhanced in vitro and in vivo features such as expansion, persistence and resistance to exhaustion. Our observations validate the approach and justify clinical studies to test the efficacy and safety of this CAR in patients.
Black patients with COVID-19 had increased risk for 30-d mortality, PE, and other adverse outcomes vs. White patients
Authors: Paul I. Musey, Benton R. Hunter
Journal: Annals of Internal Medicine (2021)

Source CitationMetra B, Summer R, Brooks SE, et al. Racial disparities in COVID-19 associated pulmonary embolism: a multicenter cohort study. Thromb Res. 2021;205:84-91. https://pubmed.ncbi.nlm.nih.gov/34274560/AbstractClinical Impact RatingsEmergency Med: Hospitalists: Infectious Disease:
PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity
Authors: Christopher Ronald Funk, Shuhua Wang, Kevin Z. Chen, Alexandra Waller, Aditi Sharma, Claudia L. Edgar, Vikas A. Gupta, Shanmuganathan Chandrakasan, Jaquelyn T. Zoine, Andrew Fedanov, Sunil S. Raikar, Jean L. Koff, Christopher R. Flowers, Silvia Coma, Jonathan A. Pachter, Sruthi Ravindranathan, H. Trent Spencer, Mala Shanmugam, Edmund K. Waller
Journal: Blood (2022)
TCT-342 Percutaneous Coronary Intervention in Patients With Complex Lesion Anatomy: A ReCre8 Subanalysis
Authors: Nicole van Hemert, Michiel Voskuil, Rik Rozemeijer, Adriaan Kraaijeveld, Saskia Rittersma, Geert Leenders, Mera Stein, Peter Frambach, Pim van der Harst, Pierfrancesco Agostoni, Pieter Stella
Journal: Journal of the American College of Cardiology (2021)
Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to <i>TTN</i> mutations
Authors: Andrey Fomin, Anna Gärtner, Lukas Cyganek, Malte Tiburcy, Izabela Tuleta, Luisa Wellers, Lina Folsche, Anastasia J. Hobbach, Marion von Frieling-Salewsky, Andreas Unger, Anna Hucke, Franziska Koser, Astrid Kassner, Katharina Sielemann, Katrin Streckfuß-Bömeke, Gerd Hasenfuss, Alexander Goedel, Karl-Ludwig Laugwitz, Alessandra Moretti, Jan F. Gummert, Cristobal G. dos Remedios, Holger Reinecke, Ralph Knöll, Sebastiaan van Heesch, Norbert Hubner, Wolfram H. Zimmermann, Hendrik Milting, Wolfgang A. Linke
Journal: Science Translational Medicine (2021)

Heterozygous truncating variants in TTN (TTNtv), the gene coding for titin, cause dilated cardiomyopathy (DCM), but the underlying pathomechanisms are unclear and disease management remains uncertain. Truncated titin proteins have not yet been considered as a contributor to disease development. Here, we studied myocardial tissues from nonfailing donor hearts and 113 patients with end-stage DCM for titin expression and identified a TTNtv in 22 patients with DCM (19.5%). We directly demonstrate titin haploinsufficiency in TTNtv-DCM hearts and the absence of compensatory changes in the alternative titin isoform Cronos. Twenty-one TTNtv-DCM hearts in our cohort showed stable expression of truncated titin proteins. Expression was variable, up to half of the total titin protein pool, and negatively correlated with patient age at heart transplantation. Truncated titin proteins were not detected in sarcomeres but were present in intracellular aggregates, with deregulated ubiquitin-dependent protein quality control. We produced human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs), comparing wild-type controls to cells with a patient-derived, prototypical A-band-TTNtv or a CRISPR-Cas9–generated M-band-TTNtv. TTNtv-hiPSC-CMs showed reduced wild-type titin expression and contained truncated titin proteins whose proportion increased upon inhibition of proteasomal activity. In engineered heart muscle generated from hiPSC-CMs, depressed contractility caused by TTNtv could be reversed by correction of the mutation using CRISPR-Cas9, eliminating truncated titin proteins and raising wild-type titin content. Functional improvement also occurred when wild-type titin protein content was increased by proteasome inhibition. Our findings reveal the major pathomechanisms of TTNtv-DCM and can be exploited for new therapies to treat TTNtv-related cardiomyopathies.
Body Fat Distribution, Cardiometabolic Traits, and Risk of Major Lower-Extremity Arterial Disease in Postmenopausal Women
Authors: Guo-Chong Chen, Rhonda Arthur, Victor Kamensky, Jin Choul Chai, Bing Yu, Aladdin H. Shadyab, Matthew Allison, Yangbo Sun, Nazmus Saquib, Robert A. Wild, Wei Bao, Andrew J. Dannenberg, Thomas E. Rohan, Robert C. Kaplan, Sylvia Wassertheil-Smoller, Qibin Qi
Journal: Diabetes Care (2021)

OBJECTIVE To assess the relationship between body fat distribution and incident lower-extremity arterial disease (LEAD). RESEARCH DESIGN AND METHODS We included 155,925 postmenopausal women with anthropometric measures from the Women’s Health Initiative who had no known LEAD at recruitment. A subset of 10,894 participants had body composition data quantified by DXA. Incident cases of symptomatic LEAD were ascertained and adjudicated through medical record review. RESULTS We identified 1,152 incident cases of LEAD during a median 18.8 years follow-up. After multivariable adjustment and mutual adjustment, waist and hip circumferences were positively and inversely associated with risk of LEAD, respectively (both P-trend &amp;lt; 0.0001). In a subset (n = 22,561) where various cardiometabolic biomarkers were quantified, a similar positive association of waist circumference with risk of LEAD was eliminated after adjustment for diabetes and HOMA of insulin resistance (P-trend = 0.89), whereas hip circumference remained inversely associated with the risk after adjustment for major cardiometabolic traits (P-trend = 0.0031). In the DXA subset, higher trunk fat (P-trend = 0.0081) and higher leg fat (P-trend &amp;lt; 0.0001) were associated with higher and lower risk of LEAD, respectively. Further adjustment for diabetes, dyslipidemia, and blood pressure diminished the association for trunk fat (P-trend = 0.49), yet the inverse association for leg fat persisted (P-trend = 0.0082). CONCLUSIONS Among U.S. postmenopausal women, a positive association of upper-body fat with risk of LEAD appeared to be attributable to traditional risk factors, especially insulin resistance. Lower-body fat was inversely associated with risk of LEAD beyond known risk factors.
TCT-53 Same-Day Discharge Post-Transcatheter Aortic Valve Replacement Using a Standardized Clinical Pathway During the COVID-19 Pandemic: The PROTECT TAVR Study
Authors: Madeleine Barker, Janarthanan Sathananthan, Emily Perdoncin, Patricia Keegan, Chandan Devireddy, Kendra Grubb, Andrei Pop, Jeremiah Depta, Devesh Rai, Mark Spence, Jonathan Mailey, Douglas Muir, Mark Russo, Alexis Okoh, Meghan Smith, Masud Rana, Sandra Lauck, John Webb, David Wood
Journal: Journal of the American College of Cardiology (2021)
Precision diagnostics in lymphomas – Recent developments and future directions
Authors: Larry Mansouri, Birna Thorvaldsdottir, Stamatia Laidou, Kostas Stamatopoulos, Richard Rosenquist
Journal: Seminars in Cancer Biology (2021)

Genetics is an integral part of the clinical diagnostics of lymphomas that improves disease subclassification and patient risk-stratification. With the introduction of high-throughput sequencing technologies, a rapid, in-depth portrayal of the genomic landscape in major lymphoma entities was achieved. Whilst a few lymphoma entities were characterized by a predominant gene mutation (e.g. Waldenström's macroglobulinemia and hairy cell leukemia), the vast majority demonstrated a very diverse genetic landscape with a high number of recurrent gene mutations (e.g. chronic lymphocytic leukemia and diffuse large B cell lymphoma), indeed reflecting the great clinical heterogeneity among lymphomas. These studies have allowed better understanding of the ontogeny and evolution of different lymphomas, while also identifying new genetic markers that can complement lymphoma diagnostics and improve prognostication. However, despite these efforts, there is still a limited number of gene mutations with predictive impact that can guide treatment selection. In this review, we will highlight clinically relevant diagnostic, prognostic and predictive markers in lymphomas that are used today in routine diagnostics. We will also discuss how comprehensive genomic characterization using broad sequencing panels, allowing for the simultaneous detection of different types of genetic aberrations, may aid future development of precision diagnostics in lymphomas. This may in turn pave the way for the implementation of tailored precision therapy strategies at the individual patient level.
Clinical progress and advanced research of red blood cells based drug delivery system
Authors: Yichen Li, Faisal Raza, Yuhao Liu, Yiqi Wei, Ruonan Rong, Mengyuan Zheng, Weien Yuan, Jing Su, Mingfeng Qiu, Y. Li, F. Raza, Y. Liu, Y. Wei, R. Rong, M. Zheng, W. Yuan, J. Su, M. Qiu
Journal: Biomaterials (2021)
Prioritise allergies with better training for doctors and a national tsar, says report
Authors: Adrian O’Dowd
Journal: BMJ (2021)

A national focus is needed on the potential dangers of allergies, including the appointment of a national clinical leader for allergy and better training for doctors on dealing with the issue.

These are the conclusions of a report1 from the All Party Parliamentary Group for Allergy, published on 27 October in conjunction with the National Allergy Strategy Group.

Around a third of people, more than 20 million in the UK, have an allergy related disorder, and the new report calls for an influential “national clinical director for allergy” to be appointed to implement a new national strategy aimed at helping people affected by allergic disease.

Foods, drugs, and insect stings can cause fatal and near fatal reactions, and such incidents have been increasing …
Disparities in Use of Video Telemedicine Among Patients With Limited English Proficiency During the COVID-19 Pandemic
Authors: Loretta Hsueh, Jie Huang, Andrea K. Millman, Anjali Gopalan, Rahul K. Parikh, Silvia Teran, Mary E. Reed
Journal: JAMA Network Open (2021)

This cross-sectional study assesses whether having limited English proficiency was associated with lower video use compared with telephone use, especially among patients without prior video visit experience, during the COVID-19 pandemic.
Biomarkers for Myocardial Infarction Type Discrimination—The Key Might Be in the Time Course of the Disease
Authors: Ahmad Hayek, Francois Derimay, Thomas Bochaton
Journal: JAMA Cardiology (2021)

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