tbuckley/cabot-search huggingface dataset:
Higher serum levels of short-chain fatty acids are associated with non-progression to arthritis in individuals at increased risk of RA
Authors: Klara Martinsson, Kerstin Dürholz, Georg Schett, Mario M Zaiss, Alf Kastbom
Journal: Annals of the Rheumatic Diseases (2021)

Transition from the autoimmune to the clinical phase of rheumatoid arthritis (RA) is a critical step that is yet insufficiently understood. Identification of factors that facilitate the progression from this prodromal RA at-risk state to clinical RA may open new possibilities for preventive interventions. In this context, nutritional factors may be critical. Short-chain fatty acids (SCFAs) are intestinal microbial metabolites that result from nutritional fibre digestion and exert immune regulatory properties.1 SCFAs have shown to effectively inhibit the onset of experimental arthritis.2 Furthermore, serum butyrate levels decrease shortly before the onset of arthritis.2 Whether SCFA levels may play a role in the transition from the autoimmune to the clinical phase of RA in humans, however, has not been studied to date.

To address this concept, we measured serum SCFA levels in a prospective cohort of 82 individuals with an increased risk to develop RA.3 At inclusion, these individuals were positive for anti-citrullinated protein antibodies (ACPA) and had musculoskeletal pain but no clinical signs of arthritis (joint swelling). Baseline characteristics are shown in online supplemental table 1. Following a median follow-up of 72 months, 39 patients (48%) had developed clinical arthritis after a median of 6 months. Baseline serum samples were analysed for SCFA …
Abstract 12110: Low Density Lipoprotein Receptor-Related Protein 1 Levels and Syntax Score in Patients Presenting With ST Elevation Myocardial Infarction
Authors: Mehmet A Agirbasli, furkan bolen, Rabia Korkmaz, Ilkay Kartal, ferruh K isman
Journal: Circulation (2021)

Introduction: Low density lipoprotein receptor-related protein 1 (LRP1) protects against cardiomyocyte death through its ability to promote Akt- and ERK1/2-dependent survival pathways. LRP1 signaling is crucial in promoting cell survival. LRP1 inhibits cell death, and promotes the resolution of the inflammation and scar formation following tissue injury. LRP1 serves as a common receptor that mediates the myocardial cell protective effects of several signaling cascades. The association between LRP1 and severity coronary artery disease (CAD) in the setting of acute injury, such as ST elevation myocardial infarction (STEMI) remains to be elucidated. We measured the soluble LRP1 (sLRP1) levels in patients who presented with STEMI. CAD severity as assessed by SYNTAX score. Methods: We measured sLRP1 levels in 46 patients who presented with STEMI (mean age 61±13.3, M/F=36/10). The SYNTAX score was categorized as low (≤20), and high (&gt;20). The control group (n=60) was selected from outpatients without significant comorbidities (N=60, age 47±14.2, M/F=16/44). Results: Patients with STEMI and high SYNTAX scores display significantly lower sLRP1 levels compared to the group with STEMI and low syntax score and controls (p=0.035 and 0.016, respectively). Median (IQR) sLRP1 levels are 1.90 (0.67), 2.25 (2.56) and 2.26 (1.59) μg/ml, respectively (Figure 1). Conclusions: Previous studies indicate that LRP1 is cardioprotective by the activation of the reperfusion injury salvage kinase pathway after ischemia reperfusion. In this study we observe that sLRP1 decreases with the complexity of CAD in patients with STEMI. Low sLRP1 levels can be a biomarker of complex CAD. Various studies have reported the role of LRP1 in cardiac remodeling after myocardial injury. Future studies are required to estimate the utility of sLRP1 as a diagnostic and prognostic biomarker in STEMI. This work was supported by the Research Fund of Istanbul Medeniyet University (project number 1358).
1. A Direct Comparison of Foamy and Lentiviral Vector Genotoxicity in SCID-Repopulating Cells Shows Foamy Vectors Are Less Prone to Clonal Dominance
Authors: Elizabeth M. Everson, Miles E. Olzsko, David J. Leap, Jonah D. Hocum, Grant D. Trobridge
Journal: Molecular Therapy (2016)

Hematopoietic stem cell (HSC) gene therapy has immense potential for numerous diseases including primary immunodeficiencies. However, in some SCID-X1 patients treated with gammaretroviral vectors, leukemia occurred as a result of vector mediated genotoxicity. Lentiviral vectors are less genotoxic than gammaretroviral vectors and have become the retroviral vector of choice in HSC clinical trials. Foamy retroviral vectors have a promising integration profile and are less prone to read-through transcription when directly compared to gammaretroviral or lentiviral vectors. Here we directly compared the safety and efficacy of foamy vectors to lentiviral vectors in human cord blood CD34+ repopulating cells in immunodeficient mice (NSG). To increase their genotoxic potential, foamy and lentiviral vectors with identical transgene cassettes that utilized a known genotoxic spleen focus forming virus promoter were used. Our rationale was that in order to compare the relative safety of these two vector systems in normal human CD34+ cells, within the relatively short time span of repopulating cells in mice, a highly genotoxic promoter would be the best way to elicit differences in genotoxicity. Both foamy and lentiviral vectors resulted in efficient marking in vivo with 12.2% of peripheral blood human CD45+ cells expressing EGFP for foamy vectors, and 9.6% for lentiviral vectors at 19 weeks after transplantation. A total of 837 foamy vector and 423 lentiviral vector unique integration sites were recovered in human SCID repopulating cells 19 weeks after transplantation. Foamy vector proviruses were observed less often within genes (40%) than lentiviral vectors (74%), and were also observed less often within proto-oncogenes (6.6%) than lentiviral vectors (9.7%). Analysis of clonality in repopulating cells within individual mice showed that the foamy vector group was more polyclonal with fewer dominant clones (2/6 mice) than in the lentiviral vector group (8/8 mice) (Figure 1). Dominant clones were defined as a single integration site having over 20% of captures. Five of the thirteen dominant clones from the lentiviral group had integrations near known proto-oncogenes (Table 1) but in the foamy vector group, none of the three dominant clones had a known proto-oncogene near the integration site. In summary, in a direct comparison in human CD34+ SCID repopulating cells, foamy vectors resulted in fewer dominant clones and more polyclonal repopulation than lentiviral vectors. Our data further supports the relative safety of foamy vectors for HSC gene therapy.
Abstract 12671: Trend in Incidence and Mortality of Cardiac Amyloidosis Among Patients With Acute Myocardial Infarction
Authors: Mohammed M Uddin, Tanveer Mir, Eskara Pervez, Daniel Deneve, Hamza Tahir, Anirudh Damughatla, Lakshmi Guduguntla, Saba Zafar, Chadi Alraies, Mujeeb Sheikh
Journal: Circulation (2021)

Background: Literature regarding recent trends, outcomes of cardiac amyloidosis (CA) in acute myocardial infarction (AMI) are limited. Objective: To study coronary interventions, trends in mortality outcomes among patients with AMI and CA. Methods: Data from the national readmissions database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the United States, representing more than 95% of the national population were analyzed for hospitalizations visits for CA among AMI. A Linear p-trend was used to assess the trends. Results: Out of the total 4,016,407 adult patients (mean age 68.9 ± 13.8 years, 40.4% females) with AMI, 4,252 (0.11%) had CA. CA was significant positive predictor for mortality in AMI patients (OR 1.3, p &lt;0.001). CA patients had higher rates of complications including 375 (8.8%) VTVF, 1,343 (31.6%) AF, 320 (7.9%) conduction block, 335 (8.1%) cardiogenic shock, 1,146 (27%) and 1,536 (36.1%) AHFPEF and AHFREF, respectively. CA patients had significantly fewer cardiovascular interventions when compared to non-CA patients. Among the total of 363,668 deaths in AMI, 717 (16.9%) had associated CA. PCI had no association with mortality on coarsened exact matching of baseline characteristics (OR 0.37, p&lt;0.02) among CA patients. Sensitivity analysis of STEMI patients had similar results. The trends for incidence and mortality of CA in AMI remained steady over the study years (linear p-trends 0.3164 and 0.7624, respectively). Conclusion: CA is a rare pathology associated with significant complications and mortality. Coronary interventions had no significant mortality benefits. Thus, more research will be needed for the management of high-risk patients. Keywords: Acute Myocardial Infarction (AMI), Cardiac Amyloidosis (CA), epidemiology; predictors; mortality; complications; risk factors; readmissions.
Checklist for Evaluation of Image-Based Artificial Intelligence Reports in Dermatology
Authors: Roxana Daneshjou, Catarina Barata, Brigid Betz-Stablein, M. Emre Celebi, Noel Codella, Marc Combalia, Pascale Guitera, David Gutman, Allan Halpern, Brian Helba, Harald Kittler, Kivanc Kose, Konstantinos Liopyris, Josep Malvehy, Han Seung Seog, H. Peter Soyer, Eric R. Tkaczyk, Philipp Tschandl, Veronica Rotemberg
Journal: JAMA Dermatology (2021)

The use of artificial intelligence (AI) is accelerating in all aspects of medicine and has the potential to transform clinical care and dermatology workflows. However, to develop image-based algorithms for dermatology applications, comprehensive criteria establishing development and performance evaluation standards are required to ensure product fairness, reliability, and safety.
Daratumumab, Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: Pooled Analysis of Octans and Alcyone
Authors: Jian Hou, Weijun Fu, Soo-Mee Bang, Honghui Huang, Kihyun Kim, Wei Li, Gang An, Je-Jung Lee, Zhen Cai, Jie Jin, Yafei Wang, CS Chim, Paula Rodriguez-Otero, Meletios A. Dimopoulos, Tomoaki Fujisaki, Jae Hoon Lee, Susan Wroblewski, Robin Carson, Ming Qi, Jianping Wang, Yang Song, Bin Jia, Xue Yang, Wenyu Liu, Yunan Li, Renyi Zhang, Jianxiang Wang
Journal: Blood (2021)
Abstract 14135: Impact of Increasing Left Ventricular and Left Atrial Size on Echocardiographic Measurements in Patients With Non-Ischemic Cardiomyopathy
Authors: Mustafa Turkmani, Gui Ting Liu, Tom K Wang, Donna Salam, Wai Hong W Tang, Brian P Griffin, Scott D Flamm, Deborah H Kwon
Journal: Circulation (2021)

Background: Echocardiography is the primary imaging modality for assessment of patients with non-ischemic cardiomyopathy (NICM), but it is known to underestimate cardiac magnetic resonance (CMR) measurements of LV volumes. We sought to assess the impact of increasing left ventricular end-diastolic volume index (LVEDVi) and left atrial volume index (LAVi) on the accuracy of echocardiographic measurements, when compared to CMR. Methods: NICM patients undergoing CMR between 4/4/2001-12/29/2017 with echocardiography measurements that were obtained within 90 days were retrospectively recorded. Bland Altman analysis and Pearson’s correlation were performed to compare echocardiographic and CMR assessment. Multivariable logistic regression analysis was also performed to predict Echo bias &gt; 50cc/m2 for LVEDVi. Results: Echocardiographic and CMR measurements of LVEDVi and LAVI were obtained in 390 and 400 patients, respectively. Figure 1 illustrates the Bland Altman and Pearson’s correlation of echo vs CMR measurements of LVEDVi and LAVi. While echo and CMR LVEDVi and LAVi were significantly correlated (r=0.762 and 0.605, respectively), there was significant increase in echocardiographic underestimation as the LVEDVi and LAVi as the left ventricle and left atrium increased in size. Multivariable logistic regression analysis is presented in Figure 1. There was a trend toward increased error in women (p=0.076), but age and BME were not significantly associated with increased echo underestimation. Increasing LVEDVi was the strongest predictor of echo underestimation (p&lt;0.0001). Conclusion: Echo underestimation of LV and LA size in patients with NICM increases as the LV and LA size increases. Increased error in echocardiographic measurements may have significant clinical impact in regards to prognosis and procedural therapeutic management strategies.
Ascorbate Deficiency Is Associated with Severity of Cytokine Release Syndrome Following Therapy with Chimeric Antigen Receptor T-Cells
Authors: Ankit Kansagra, Dheepthi P. Ramasamy, Aishwarya Sannareddy, Qing Ding, Alexa Wilden, Cedric B. Robinson, Helen Stephens, Fatma Kalkan, Larry D. Anderson, Farrukh T. Awan, Robert H. Collins, Gurbakhash Kaur, Yazan F. Madanat, Prapti Patel, Syed M Rizvi, Praveen Ramakrishnan, John Sweetenham, Madhuri Vusirikala, Michalis Agathocleous, Stephen Chung
Journal: Blood (2021)
Attitudes towards COVID-19 mitigation measures implemented at St Mark's Bowel Cancer Screening Centre: a cross-sectional analysis of survey data from an ethnically diverse region in London
Authors: Andrew Prentice, Ghalial Kayal, Sarah Marshall, Christian von Wagner, Robert S Kerrison
Journal: The Lancet (2021)

BackgroundNegative attitudes towards, and experiences with, health services can negatively affect attendance at diagnostic investigation. Since services resumed in June, 2020 (ie, following the first months of the COVID-19 pandemic), several new procedures to reduce COVID-19 transmission have been implemented, but the extent to which these measures are acceptable to patients has not yet been examined. We aimed to assess patient attitudes towards the measures implemented within St Mark's Bowel Cancer Screening Centre, St Mark's Hospital, Harrow, UK.MethodsWe surveyed patients who underwent colonoscopy after their procedure and asked a series of questions using the five-point Likert scales. Factor analysis was used to group questions into mutually exclusive groups, with three factors were subsequently identified: attitudes towards measures to reduce hospital-based COVID-19 transmission (factor 1; five items), attitudes towards precolonoscopy COVID-19 swabbing (factor 2; two items), and attitudes towards protective clothing (factor 3; two items). Scales ranged from five to 25 for factor 1 and two to ten for factors 2 and 3 (with higher scores representing more positive attitudes). Descriptive statistics were used to calculate means, whereas linear regression was used to test associations between participant demographics, COVID-19 anxiety, and bowel cancer anxiety with attitudinal factors. Participation in the study was voluntary and consent was obtained from all participants.FindingsOf the 408 patients invited, 288 patients (71%) who underwent colonoscopy between July 1, 2020, and May 1, 2021, were surveyed. Participants were predominantly men (n=182; 63%) and of White (n=167; 58%) or South Asian ethnicity (n=59; 20%; the mean age of all participants was 66·52 years [SD 5·29]). The mean score was 23·12 for factor 1, 7·60 for factor 2, and 8·15 for factor 3. South Asian adults were less positive towards measures to reduce COVID-19 transmission (factor 1; 23·04) than White adults (23·18; β coefficient 0·31; p=0·035). COVID-19 anxiety was the only predictor of attitudes towards protective clothing (factor 3), with higher COVID-19 anxiety being associated with more positive attitudes towards protective clothing (0·25; p=0·037).InterpretationAttitudes towards COVID-19 prevention measures were highly positive. Future service evaluation should focus on reassuring South Asian patients of measures to reduce hospital-related infection (eg, through information provision). South Asian patients are more likely to be diagnosed at a later stage, so reducing barriers to diagnosis to prevent COVID-19 from widening inequalities in cancer even further is imperative.FundingThis study was funded by St Mark's Bowel Cancer Screening Centre. RSK is supported by a Cancer Research UK Population Research Fellowship (C68512/A28209).
STEM-03. Oct4/Sox2 DRIVE AN IMMUNOSUPPRESSIVE GSC PHENOTYPE BY INDUCING T-REG EFFECTOR GENES VIA TGFBR2 SIGNALING
Authors: Amanda Johnson, Jack Korleski, John Laterra, Hernando Lopez-Bertoni
Journal: Neuro-Oncology (2021)

Abstract Solid malignancies, including GBM, contain small subsets of cells that display stem-like properties (i.e. glioma stem cells or GSCs) and act as key determinants of therapeutic resistance and tumor recurrence. Mechanisms of GSC immune escape are considered fundamental to clinical GBM growth and recurrence. GBM cells escape antitumor immunity by modifying the tumor microenvironment by secreting immune-suppressive factors and recruiting anti-inflammatory/pro-oncogenic cells (e.g. T-regulatory cells, M2-like macrophages). However, whether subsets of GSCs can mimic T-reg-like functions by expressing proteins associated with T-reg immune-suppression remains unknown. Single-cell RNA sequencing analysis of GBM neurospheres revealed a previously unrecognized Oct4/Sox2high/FOXP3- cell subpopulation with high expression of TGFb1, CD39, CD73, PD-L1, and Galectin-1, a gene expression fingerprint typically associated with T-reg cells and their immune suppressive functions within the tumor microenvironment. Bioinformatics analysis of public databases shows that the above-mentioned genes are enriched in the mesenchymal GBM subtype and highly correlated with CD44 and TGFb type II receptor (TGFBR2) expression in both clinical GBM and primary GSCs. Mechanistically, Oct4 and Sox2 were found to directly induce TGFBR2 transcription concurrent with chromatin architectural changes (i.e. heterochromatin-to-euchromatin transition) involving the TGFBR2 gene. Transgenic TGFBR2 expression increased neurosphere cell growth capacity, upregulated expression of T-reg-like effector genes and enriched for CD44+ GSCs. Functionally, neurospheres expressing transgenic Oct4/Sox2 or transgenic TGFBR2 possess increased immunosuppressive capacity, and pharmacological inhibition of TGFBR2 depleted CD44+ GSCs and reduced immunosuppression in Jurkat cell co-cultures. Taken together, we show that reprogramming events initiated by Oct4 and Sox2 induce a CD44+/FOX3P- GSC cell subset with a T-reg-like immunosuppressive transcriptional profile via a TGFBR2-dependent mechanism. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies.
Population level physical activity before and during the first national COVID-19 lockdown: A nationally representative repeat cross-sectional study of 5 years of Active Lives data in England
Authors: Tessa Strain, Stephen J. Sharp, Andrew Spiers, Helen Price, Ciara Williams, Carol Fraser, Søren Brage, Katrien Wijndaele, Paul Kelly
Journal: The Lancet Regional Health - Europe (2021)

To limit the spread of COVID-19 in March 2020, the population of England was instructed to stay home, leaving only for essential shopping, health-care, work, or exercise. The impact on population activity behaviours is not clear. We describe changes in duration and types of activity undertaken by adults ≥16 years in England between March and May 2016-19 and 2020, by socio-demographic strata.
CSIG-17. IMMUNE MODULATORY ROLE OF TYPE I INTERFERON IN SYNGENEIC MOUSE GLIOMA MODELS
Authors: Evelina Blomberg, Manuela Silginer, Michael Weller
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is characterized by a poor prognosis and a challenging phenotype for drug development. Although multimodal treatment, including surgery, radio- and chemotherapy is applied, the overall survival remains just above one year. Numerous clinical trials have studied targeted therapies against commonly deregulated pathways, but an efficient targeted drug is yet to be discovered. Likewise, immunotherapy has not been shown to be active. A subset of glioma tumor cells demonstrates stem-like properties; these cells are commonly referred to as glioma initiating cells (GIC). These types of cells are pluripotent and can by definition initiate and recapitulate glioma growth in experimental animals in vivo. Furthermore, these cells are often resistant to conventional therapies. Interferon β (IFN-β) is an immunomodulatory molecule with anti-cancer properties. We have previously shown that IFN-β greatly reduces sphere-formation capability of GIC. It was also confirmed that IFN-β sensitized resistant GIC to irradiation or the chemotherapeutic agent, temozolomide (TMZ). IFN-β treatment significantly prolonged survival in a xenograft model with GIC cells. In the current project, we want to use syngeneic mouse models to study the immunomodulatory effects of type I IFNs. Preliminary results indicate that abrogation of IFN signalling in tumor cells by CRISPR/Cas9 technology prolonged survival in mice only in cell lines which have substantial baseline autocrine IFN signalling. On the contrary, we did not observe a difference in survival when wild-type tumor cells were implanted in either IFNAR1 deficient or proficient hosts. Flow cytometry analysis will elucidate changes in immune cell recruitment and infiltration upon IFN signalling disruption. Moreover, we explore different treatments in combination with IFN-β as there are indications that TMZ or radiotherapy can have synergistic effects with stimulation of interferon type I signalling.
Optimizing an effective combination of the new microtubule-targeting agent lisavanbulin with standard-of-care therapy for glioblastoma in patient-derived xenograft preclinical models
Authors: Alain Charest
Journal: Neuro-Oncology (2021)

Optimizing an effective combination of the new microtubule-targeting agent lisavanbulin with standard-of-care therapy for glioblastoma in patientderived xenograft preclinical models
Abstract 10616: HIV Infection and the Risk of Heart Failure Hospitalization and Mortality: A Systematic Review and Meta-Analysis of Cohort Studies
Authors: Frank Qian, Xuezhixing Zhang, Han-Zhu Qian, Raza Alvi, Sebhat Erqou, Yuqing Chen, Xianhong Li, Honghong Wang, Tomas Neilan, Markella V Zanni, Sten Vermund, Frank Qian
Journal: Circulation (2021)

Introduction: Incidence of heart failure (HF) is increased among individuals living with human immunodeficiency virus (HIV). Whether HIV adversely affects hospitalization and mortality rates among patients with diagnosed HF has not been systematically evaluated. Hypothesis: We hypothesized that HIV infection would increase the risk of hospitalization and all-cause mortality rates in patients with HF, independent of established risk factors. Methods: We performed a systematic search of PubMed, EMBASE, Cochrane Library and Web of Science through March 7 th , 2021 for cohort studies conducted in adult patients (age≥18 years) with diagnosed HF and ascertainment of HIV infection at baseline. Outcomes assessed include all-cause mortality, HF-associated hospitalization, and all-cause hospitalization. All studies included multivariable adjustments for demographics, cardiovascular risk factors, and comorbidities. Pooled hazard ratio (HR) and 95% confidence intervals (CI) were calculated using a random-effects model. Results: We identified 7 studies consisting of 10,363 HF patients living with HIV and 48,933 HIV negative HF controls. HF patients with HIV had a higher risk of all-cause mortality compared to HIV-negative HF patients, HR (95% CI): 1.20 (1.14, 1.25), I 2 =0%. Similarly, HIV infection was associated with increased risks of both HF-associated hospitalization and all-cause hospitalization, with HR (95% CI) of 1.31 (1.03, 1.65) and 1.27 (1.12, 1.44), respectively; though significant heterogeneity was observed for both of these outcomes, I 2 =80% and 62%, respectively. Conclusions: HIV infection was independently associated with increased risk of all-cause mortality and both HF-associated and all-cause hospitalizations among individuals with HF. Our data may have important implications for HF management in this high-risk population.