tbuckley/cabot-search huggingface dataset:
SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota
Authors: Harry Sokol, Vanessa Contreras, Pauline Maisonnasse, Aurore Desmons, Benoit Delache, Valentin Sencio, Arnaud Machelart, Angela Brisebarre, Lydie Humbert, Lucie Deryuter, Emilie Gauliard, Severine Heumel, Dominique Rainteau, Nathalie Dereuddre-Bosquet, Elisabeth Menu, Raphael Ho Tsong Fang, Antonin Lamaziere, Loic Brot, Celine Wahl, Cyriane Oeuvray, Nathalie Rolhion, Sylvie Van Der Werf, Stéphanie Ferreira, Roger Le Grand, François Trottein
Journal: Gut Microbes (2021)

The current pandemic of coronavirus disease (COVID) 2019 constitutes a global public health issue. Regarding the emerging importance of the gut-lung axis in viral respiratory infections, analysis of the gut microbiota's composition and functional activity during a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be instrumental in understanding and controling COVID 19. We used a nonhuman primate model (the macaque), that recapitulates mild COVID-19 symptoms, to analyze the effects of a SARS-CoV-2 infection on dynamic changes of the gut microbiota. 16S rRNA gene profiling and analysis of β diversity indicated significant changes in the composition of the gut microbiota with a peak at 10-13 days post-infection (dpi). Analysis of bacterial abundance correlation networks confirmed disruption of the bacterial community at 10-13 dpi. Some alterations in microbiota persisted after the resolution of the infection until day 26. Some changes in the relative bacterial taxon abundance associated with infectious parameters. Interestingly, the relative abundance of Acinetobacter (Proteobacteria) and some genera of the Ruminococcaceae family (Firmicutes) was positively correlated with the presence of SARS-CoV-2 in the upper respiratory tract. Targeted quantitative metabolomics indicated a drop in short-chain fatty acids (SCFAs) and changes in several bile acids and tryptophan metabolites in infected animals. The relative abundance of several taxa known to be SCFA producers (mostly from the Ruminococcaceae family) was negatively correlated with systemic inflammatory markers while the opposite correlation was seen with several members of the genus Streptococcus. Collectively, SARS-CoV-2 infection in a nonhuman primate is associated with changes in the gut microbiota's composition and functional activity.
Bioevaluation of glucose-modified liposomes as a potential drug delivery system for cancer treatment using 177-Lu radiotracking
Authors: Đorđe Cvjetinović, Željko Prijović, Drina Janković, Magdalena Radović, Marija Mirković, Zorana Milanović, Miloš Mojović, Đani Škalamera, Sanja Vranješ-Đurić
Journal: Journal of Controlled Release (2021)
Abstract PR-01: Real-time, point-of-care pathology diagnosis via embedded deep learning
Authors: Bowen Chen, Max Lu, Jana Lipkova, Faisal Mahmood
Journal: Clinical Cancer Research (2021)

Abstract There is an urgent need for widespread cancer diagnosis in low resource settings, especially in contrast to areas with developed healthcare systems. According to a study in The Lancet, in the U.S. there is one pathologist for every 20,000 individuals, while in Sub-Saharan Africa, there is only one for every million. In addition, current telepathology systems for cancer diagnosis mostly rely on pathologists performing remotely, which is low-throughput and requires more time and resources. With the growth of telepathology, remote diagnosis becomes a viable solution to address the lack of skilled pathologists in developing regions. Here, we present a cost-efficient device that incorporates embedded deep learning to achieve real time, point-of-care diagnosis of whole pathology slides. We achieve this with a low-cost, 3D-printable microscope that uses the Raspberry Pi and camera module to capture high-resolution images of slides. Then, using a weakly-supervised deep-learning model run on the NVIDIA Jetson Nano, the device is able to accurately classify the whole slide without any pixel-level annotations. Furthermore, the model’s attention-based approach to diagnosis allows us to generate human-interpretable heatmaps displaying the regions most influential to the model’s diagnosis. Our device also incorporates a touch screen and batteries to increase accessibility as an easy-to-use and low maintenance device while still maintaining an efficient runtime given the available resources. Overall, we demonstrate that the device is capable of achieving accurate, high-throughput, and interpretable cancer diagnoses in low resource settings. Citation Format: Bowen Chen, Max Lu, Jana Lipkova, Faisal Mahmood. Real-time, point-of-care pathology diagnosis via embedded deep learning [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PR-01.
Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases
Authors: Marika Haderer, Philip Neubert, Eva Rinner, Annika Scholtis, Lucile Broncy, Heidi Gschwendtner, Arne Kandulski, Vlad Pavel, Alexander Mehrl, Christoph Brochhausen, Sophie Schlosser, Karsten Gülow, Claudia Kunst, Martina Müller
Journal: Gut (2021)

Objective Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP. Design Since BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing Escherichia coli ( E. coli ) and Proteus mirabilis ( P. mirabilis ) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects. Results SBP-derived E. coli and P. mirabilis led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin. Conclusion Patients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.
Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin‐resistant forms of obesity and type 2 diabetes mellitus
Authors: Mini P. Sajan, Barbara C. Hansen, Mildred Acevedo‐Duncan, Mark S. Kindy, Denise R. Cooper, Robert V. Farese
Journal: MedComm (2021)

Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin-angiotensin-adrenal axis, thus increasing vasoconstriction, sodium retention, and cardiovascular risk; and in liver, hyperinsulinemia increases lipogenesis, obesity, hepatosteatosis, hyperlipidemia, and cardiovascular risk. In summary, increases in hepatic aPKC are critically required for development of DIO/MetS/T2DM and its adverse sequelae, and therapeutic approaches that limit hepatic aPKC may be particularly effective.
Impact of primary tumor location, histology, and host factors on objective response to immune checkpoint inhibitors in metastatic urothelial carcinoma.
Authors: Scott Dawsey, Mohammad Siddique Khan, Nathan Radakovich, Wei Wei, Omar Y. Mian, Moshe Chaim Ornstein, Timothy D. Gilligan, Shilpa Gupta
Journal: Journal of Clinical Oncology (2021)

493 Background: Factors affecting response to immune checkpoint inhibitor (ICI) are poorly understood in metastatic urothelial carcinoma (mUC). While tumor PD-L1 status is often used as a biomarker, it is not always predictive and ICI also benefits patients (pts) with PD-L1 negative tumors. Therefore, we sought to study the effect of some host and disease-related variables like gender, ethnicity, body mass index (BMI), platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ration (NLR) on objective responses in pts with mUC treated with ICI. Methods: We performed a retrospective analysis of adult pts with mUC who received ≥2 cycles of ICI (pembrolizumab or atezolizumab) at the Cleveland Clinic from 2015 to 2020. Tumor and host-related factors evaluated are listed in the table below. We focused on meaningful treatment response, so only partial response (PR) and complete response (CR) were included as responders, while stable disease (SD) and progressive disease (PD) were counted as non-responders. Analysis was carried out with Fisher’s exact test and Wilcoxon rank sum test as applicable. Results: A total of 124 pts with mUC that received ICI were included. Gender did not correlate with response (p&gt;0.99) or duration of response (p=0.37). Ethnicity did not correlation with response (p=0.78) or duration of response (p=0.24). Histology (UC, mixed variant histology or non UC) did not correlate with response (p=0.13) or duration of response (p=0.87). Location of primary malignancy (upper tract versus lower tract) did not correlate with response (p&gt;0.99) or duration of response (p=0.36). BMI (p=0.23), PLR (p=0.9), and NLR (p=0.9) did not correlate with objective response. Conclusions: In our single center experience of pts with mUC treated with ICI, host factors (gender, ethnicity, histology, BMI, NLR, PLR) and location of primary tumor did not correlate with treatment response or duration of response. Although there were few African Americans represented in this study as commonly seen for minority representation, it is encouraging that no significant differences in responses were observed. The role of BMI and gender in response to ICI treatment in mUC was not observed. While there are limitations of a retrospective analysis, our study warrants investigation into predictive factors of response to ICI in mUC. Ongoing work integrating radiomics and pathomics will further our understanding and develop potential predictive biomarkers of response to ICI in mUC. [Table: see text]
Hydroxychloroquine modulates immunological pathways activated by RNA:DNA hybrids in Aicardi–Goutières syndrome patients carrying RNASEH2 mutations
Authors: Jessica Garau, Daisy Sproviero, Francesca Dragoni, Elisa Piscianz, Carolina Santonicola, Davide Tonduti, Stephana Carelli, Alessandra Tesser, Gian Vincenzo Zuccotti, Alberto Tommasini, Simona Orcesi, Orietta Pansarasa, Cristina Cereda
Journal: Cellular and Molecular Immunology (2021)

Aicardi-Goutières syndrome (AGS) is a rare genetic disease caused by mutations in nine genes that are all involved in nucleic acid metabolism or sensing. 1,2The three RNASEH2 subunits represent the most frequently mutated genes in AGS patients, 1,3 and mutations in RNASEH2 subunits lead to the accumulation of endogenous RNA:DNA hybrids that may trigger an interferon-αmediated immune response 4 through the activation of pattern recognition receptors (PRRs). 5PRRs perform surveillance on extracellular, endosomal, and cytosolic compartments to identify signs of infection: endogenous nucleic acids that are inappropriately cleared may enter and accumulate in the cytoplasm, driving inflammation and autoimmune diseases. 6This accumulation may be the cause of the clinical autoimmune phenotype of AGS patients carrying RNASEH2 mutations.A proven effective cure for AGS has not been discovered, and targeting these two pathways may lead to a treatment that improves patients' immunological symptoms.Hydroxychloroquine (HCQ) interferes with normal antigen processing and presentation and is widely used in the clinical treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. 7HCQ is also a wellknown inhibitor of autophagy that prevents the degradation of autolysosomes.This drug inhibits acidification and maturation of endosomes and increases the pH in lysosomes, resulting in the inhibition of their main functions, such as downstream cell signaling through TLRs. 7Therefore, the aim of our work was to investigate whether HCQ is able to modulate the abnormal inflammatory response driven by RNA:DNA hybrids.Considering the noteworthy difficulties in obtaining primary cells from children affected by this rare disease, we used immortalized lymphoblastoid cell lines (LCLs): one from a patient carrying the RNASEH2A p.R108W + p.F230L mutations, one from a patient carrying the RNASEH2B p.A177T mutation and one from a healthy control.We investigated the presence of RNA:DNA hybrids using the S9.6 antibody and flow cytometry.Quantification of the mean S9.6 fluorescence revealed a significant increase in RNA:DNA hybrids only in the RNASEH2B-mutant LCL (Fig. S1A).RNA:DNA hybrids were primarily localized in the cytoplasm in all three cell
Abstract LT005: Tumor-intrinsic gain of function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment that promotes resistance to immunotherapy
Authors: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi
Journal: Cancer Research (2021)

Abstract KRASG12D mutations in tumor cells can modify the immune microenvironment of pancreatic ductal adenocarcinoma (PDAC), though the effects of secondary genetic alterations have been unexplored. After oncogenic KRAS, TP53 is the most frequently mutated gene in PDAC, however the immune effects of neomorphic TP53 mutations have not been defined. We sought to evaluate the non-cell-autonomous role of mutant p53 in modulating the immune microenvironment of pancreatic cancer by comparing the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) genetically engineered to express the Trp53R172H gain-of-function mutation to their p53 wildtype control. We found orthotopically implanted tumors derived from KrasG12D;Trp53R172H PDEC had a distinct immune profile in comparison to KrasG12D/+;Trp53+/+ tumors, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of KrasG12D;Trp53R172H PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing KrasG12D;Trp53R172H PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link mutant p53 to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy. Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Tumor-intrinsic gain of function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment that promotes resistance to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT005.
HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling
Authors: Joshua G. Travers, Sara A. Wennersten, Brisa Peña, Rushita A. Bagchi, Harrison E. Smith, Rachel A. Hirsch, Lauren A. Vanderlinden, Ying-Hsi Lin, Evgenia Dobrinskikh, Kimberly M. Demos-Davies, Maria A. Cavasin, Luisa Mestroni, Christian Steinkühler, Charles Y. Lin, Steven R. Houser, Kathleen C. Woulfe, Maggie P.Y. Lam, Timothy A. McKinsey
Journal: Circulation (2021)

Background: Diastolic dysfunction (DD) is associated with the development of heart failure and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. We addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction. Methods: Four weeks after uninephrectomy and implantation with deoxycorticosterone acetate pellets, when DD was clearly evident, 1 cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and end point invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red staining and second harmonic generation microscopy of left ventricle (LV) sections, RNA sequencing of LV mRNA, mass spectrometry–based evaluation of decellularized LV biopsies, and atomic force microscopy determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. Results: HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. In contrast to previous models, myofibril relaxation was unimpaired in uninephrectomy/deoxycorticosterone acetate mice. Furthermore, cardiac fibrosis was not evident in any mouse cohort on the basis of picrosirius red staining or second harmonic generation microscopy. However, mass spectrometry revealed induction in the expression of &gt;100 extracellular matrix proteins in LVs of uninephrectomy/deoxycorticosterone acetate mice, which correlated with profound tissue stiffening based on atomic force microscopy. ITF2357/Givinostat treatment blocked extracellular matrix expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the profibrotic chromatin reader protein BRD4 (bromodomain-containing protein 4) to key gene regulatory elements. Conclusions: These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD and establish blockade of extracellular matrix remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Our data reveal the existence of pathophysiologically relevant covert or hidden cardiac fibrosis that is below the limit of detection of histochemical stains such as picrosirius red, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.
Abstract 2941: Combined Assessment of Coronary Artery Stenosis and Myocardial Ischemia by Rest-Dipyridamole Stress Multidetector Computed Tomography
Authors: Patricia M Carrascosa, Carlos Capuñay, Jorge Carrascosa, Alejandro Deviggiano, Alejandro Goldsmit, Marcelo Bettinotti, Mario J Garcia
Journal: Circulation (2007)

Introduction: MDCT coronary angiography has been evolving as a noninvasive method for the assessment of coronary artery disease (CAD). More recently, It has been demonstrated that MDCT identifies reduced contrast enhancement in ischemic and/or scarred myocardial segments. Objective: to determine the ability of rest-stress multidetector computed tomography (RS-MDCT) to detect myocardial ischemia and to assess the relationship between MDCT myocardial perfusion abnormalities and coronary artery stenosis. Methods: Forty seven patients underwent stress/rest 99mTc sestamibi SPECT and RS-MDCT, using a 16-row detector scanner (Philips Brilliance-16). Myocardial segments were classified by SPECT as normal, ischemic or scarred. SPECT results were then compared with MDCT regional myocardial contrast enhancement. The results of MDCT coronary angiography were also analyzed in 20 patients who underwent invasive catheterization. Results: The presence of a reduction in contrast enhancement at rest by MDCT identified scar by SPECT with 96% sensitivity and 98% specificity. A stress-induced reduction in contrast enhancement by MDCT identified ischemia by SPECT with 77% sensitivity and 99% specificity. The segment-based sensitivity and specificity for the detection of significant stenosis by MDCT were 92% and 98%, respectively. Conclusion: Our results showed that a rest-dipyridamole stress MDCT protocol can identify the presence of myocardial ischemia as well as the severity of coronary artery stenosis in patients with suspected coronary artery disease.