tbuckley/cabot-search huggingface dataset:
An extracellular vesicle-related gene expression signature identifies high-risk patients in medulloblastoma
Authors: Thomas K Albert, Marta Interlandi, Martin Sill, Monika Graf, Natalia Moreno, Kerstin Menck, Astrid Rohlmann, Viktoria Melcher, Sonja Korbanka, Gerd Meyer zu Hörste, Tobias Lautwein, Michael C Frühwald, Christian F Krebs, Dörthe Holdhof, Melanie Schoof, Annalen Bleckmann, Markus Missler, Martin Dugas, Ulrich Schüller, Natalie Jäger, Stefan M Pfister, Kornelius Kerl
Journal: Neuro-Oncology (2020)

Abstract Background Medulloblastoma (MB) is a malignant brain tumor in childhood. It comprises 4 subgroups with different clinical behaviors. The aim of this study was to characterize the transcriptomic landscape of MB, both at the level of individual tumors as well as in large patient cohorts. Methods We used a combination of single-cell transcriptomics, cell culture models and biophysical methods such as nanoparticle tracking analysis and electron microscopy to investigate intercellular communication in the MB tumor niche. Results Tumor cells of the sonic hedgehog (SHH)–MB subgroup show a differentiation blockade. These cells undergo extensive metabolic reprogramming. The gene expression profiles of individual tumor cells show a partial convergence with those of tumor-associated glial and immune cells. One possible cause is the transfer of extracellular vesicles (EVs) between cells in the tumor niche. We were able to detect EVs in co-culture models of MB tumor cells and oligodendrocytes. We also identified a gene expression signature, EVS, which shows overlap with the proteome profile of large oncosomes from prostate cancer cells. This signature is also present in MB patient samples. A high EVS expression is one common characteristic of tumors that occur in high-risk patients from different MB subgroups or subtypes. Conclusions With EVS, our study uncovered a novel gene expression signature that has a high prognostic significance across MB subgroups.
Multicentre randomised controlled trial on virtual chromoendoscopy in the detection of neoplasia during colitis surveillance high-definition colonoscopy (the VIRTUOSO trial)
Authors: Kesavan Kandiah, Sharmila Subramaniam, Sreedhari Thayalasekaran, Fergus JQ Chedgy, Gaius Longcroft-Wheaton, Carole Fogg, James F Brown, Samuel CL Smith, Marietta Iacucci, Pradeep Bhandari
Journal: Gut (2020)

Longstanding colonic IBD increases the risk of developing colorectal cancer. The utility of chromoendoscopy with standard-definition white light technology has been established. However, the use of high-definition virtual chromoendoscopy (HDV) in colitis surveillance remains undefined.
Association between <i>Brachyspira</i> and irritable bowel syndrome with diarrhoea
Authors: Karolina S Jabbar, Brendan Dolan, Lisbeth Eklund, Catharina Wising, Anna Ermund, Åsa Johansson, Hans Törnblom, Magnus Simren, Gunnar C Hansson
Journal: Gut (2020)

Objective The incidence of IBS increases following enteric infections, suggesting a causative role for microbial imbalance. However, analyses of faecal microbiota have not demonstrated consistent alterations. Here, we used metaproteomics to investigate potential associations between mucus-resident microbiota and IBS symptoms. Design Mucus samples were prospectively collected from sigmoid colon biopsies from patients with IBS and healthy volunteers, and their microbial protein composition analysed by mass spectrometry. Observations were verified by immunofluorescence, electron microscopy and real-time PCR, further confirmed in a second cohort, and correlated with comprehensive profiling of clinical characteristics and mucosal immune responses. Results Metaproteomic analysis of colon mucus samples identified peptides from potentially pathogenic Brachyspira species in a subset of patients with IBS. Using multiple diagnostic methods, mucosal Brachyspira colonisation was detected in a total of 19/62 (31%) patients with IBS from two prospective cohorts, versus 0/31 healthy volunteers (p&lt;0.001). The prevalence of Brachyspira colonisation in IBS with diarrhoea (IBS-D) was 40% in both cohorts (p=0.02 and p=0.006 vs controls). Brachyspira attachment to the colonocyte apical membrane was observed in 20% of patients with IBS and associated with accelerated oro-anal transit, mild mucosal inflammation, mast cell activation and alterations of molecular pathways linked to bacterial uptake and ion–fluid homeostasis. Metronidazole treatment paradoxically promoted Brachyspira relocation into goblet cell secretory granules—possibly representing a novel bacterial strategy to evade antibiotics. Conclusion Mucosal Brachyspira colonisation was significantly more common in IBS and associated with distinctive clinical, histological and molecular characteristics. Our observations suggest a role for Brachyspira in the pathogenesis of IBS, particularly IBS-D.
Microarray identification of molecular markers of cisplatin resistance in human ovarian carcinomas
Authors: Timothy C. Cheng, Gerald Manorek, Goli Samimi, Chuck C. Berry, Stephen B. Howell
Journal: Cancer Research (2004)

4465  Cisplatin (DDP) is highly effective for the initial therapy of a variety of human cancers, but resistance emerges quickly during treatment and the mechanisms that mediate resistance remain poorly defined. To identify novel genes that are specific to the resistant phenotype as well as biochemical pathways that might be involved, we used large-scale analysis of gene expression differences between cisplatin sensitive and stably-resistant cell lines using Stanford Microarray Facility cDNA arrays with 43,200 features and ∼25, 593 genes. Dye-swap and lowess normalization were performed to correct for experimental bias. To ensure high confidence in genes identified against a high background of noise, pairwise comparisons were made within 6 pairs of cell lines, and each comparison was independently replicated 6 times. The significance of differences in expression was assessed using Significance Analysis of Microarrays (SAM) (Tusher et al, PNAS 98:5116, 2001). The importance of a large number of replicates was highlighted by the finding that, of the genes that were found to be differentially expressed when all 6 replicates were included in the analysis, an average of 24.8 % would have been missed if only 5 replicates had been used, while 38.3 % would have been missed if only 4 independent RNA samples had been analyzed. The number of genes significantly differentially expressed in each pair of sensitive- and cisplatin-resistant cell lines varied from 486 to 3797. Few genes were consistently differentially expressed in multiple pairs of cell lines. No genes were differentially expressed in all 6 pairs or in 5/6 pairs. In total, 17 genes were differentially up-regulated in 4/6 cell pairs and 2 were down-regulated. A total of 110 genes were up-regulated in at least 3/6 cell pairs, and 58 were down-regulated. Of these genes, many have central roles in the regulation of intracellular redox potential. Analysis of biochemical pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG database) identified a statistically significant overabundance of differentially expressed genes associated with the tyrosine metabolism, benzoate degradation via CoA ligation, butanoate metabolism, cell cycle, glycolysis/gluconeogenesis, citrate cycle, galactose metabolism, fatty acid metabolism, oxidative phosphorylation, beta-alanine metabolism, selenoamino acid metabolism, D-arginine and D-ornithine metabolism, starch and sucrose metabolism and Prion disease. This statistically rigorous approach has identified a set of biochemical pathways not previously suspected of playing a mechanistic role in cisplatin resistance, and has provided guidelines for more precise identification of markers of cisplatin resistance in clinical samples.
米国の白人,ハワイの日系アメリカ人及び日本の日本人におけるCRP及びフィブリノーゲンと無症候性アテローム性動脈硬化症との関係:ERA-JUMP研究
Authors: Nagasawa Shinya, Miura Katsuyuki, Kadowaki Takashi, Kadota Aya, Okamura Tomonori, Nakamura Yasuyuki, Ueshima Hirotsugu, Sekikawa Akira
Journal: Circulation (2009)
Abstract 17211: Targeting Mitogen-Activated Kinase Alleviates Free Heme-Induced Endothelial Barrier Dysfunction and Vascular Leakage in Lungs
Authors: Joel James, Mathews Valuparampil Varghes, Marina zemskova, Olga Rafikova, Ruslan Rafikov
Journal: Circulation (2020)

Introduction: Several studies confirm that free heme in circulation due to hemolysis causes endothelial barrier dysfunction. We recently demonstrated that hemolysis-induced vascular leakage with barrier dysfunction was a contributory factor to the development of pulmonary hypertension (PH). However, the precise molecular mechanisms involved in the pathology of heme induced barrier disruption still remains to be elucidated. Hypothesis: Previous studies by us showed that free heme activated the p38/MAPK pathway. Therefore, we hypothesized that targeting mitogen-activated protein kinase kinase 3 (MKK3) a key regulator of this pathway would alleviate heme induced vascular leakage. Methods: Barrier dysfunction in human micro-vascular endothelial cells (HLMVEC) was monitored using noninvasive electrical impedance and immunostaining. We used an MKK3 knockout mouse model to assess the efficacy of targeting the p38/MAPK pathway. Results: We found a rapid drop in the HLMVEC barrier integrity with heme, in a dose dependent manner (p&lt;0.05). Investigating the barrier proteins showed that heme significantly affected the tight junction proteins, zona occludens-1, claudin1, and claudin5 (p&lt;0.05). We also found the p38MAPK/HSP27 pathway, involved in regulating the endothelial cytoskeleton remodeling, to be significantly altered with heme treatment, both in the HLMVEC and mice (p&lt;0.05). However, heme treated mice showed no significant change in E-selectin, ICAM1 and VCAM1, indicating that the primary rapid target of heme was the p38/MAPK pathway and not the inflammatory pathways. Finally, injecting mice with heme-FITC-dextran and then following its release into the lungs demonstrated that the MKK3 KO significantly prevented heme induced vascular leakage (p&lt;0.05). Conclusion: We demonstrate that heme induces a rapid barrier dysfunction by disruption of endothelial barrier proteins via the p38/MAPK pathway. Also, knocking out MKK3, a crucial regulator of the p38/MAPK pathway significantly decreased heme induced vascular leakage, a contributory factor to PH. Taken together, our results show that targeting the MKK3/p38MAPK axis represents a decisive treatment strategy in alleviating heme induced barrier dysfunction in cardiovascular diseases.
Abstract 15817: Transcatheter Closure of Paramitral Leaks: Use of the Agilis™ Nxt Steerable Sheath to Aid Device Placement
Authors: Neha Ahluwalia, Robert Pass, Barry a Love
Journal: Circulation (2020)

Introduction: Paramitral leak (PML) has been reported in 5-17% of patients after surgical prosthetic mitral valve replacements. Transcatheter closure of PML has emerged as a Class IIa alternative to surgical repair by the AHA/ACC. Reaching all areas around the mitral annulus for device delivery from a transseptal approach can be difficult. We describe our center’s experience utilizing a transseptal approach with use of a steerable sheath and real-time 3D echo to facilitate closure. Methods: Retrospective review of cases of transcatheter PML repair from 9/09 to 2/19 at Mount Sinai Medical Center. Results: 32 patients underwent 43 catheterizations for PML closure (see Table 1). Indications for PML repair were CHF in (78%) and hemolysis (22%). 25/32 were bioprosthetic valves and the rest mechanical (7/32; table). PML’s could be crossed in 41/43 attempts (95%). Location of leaks/devices demonstrated in Figure 1. The median number of devices placed at one cath was 1 (range 1-3) and the most commonly used device was the Amplatzer muscular VSD device (64/71devices; 90%). 9/32 (28%) required an additional cath to complete PML closure. At last cath, clinical PML closure was achieved in 26/32 (81%) pts attempted. 3/32 (9%) had hemolysis from residual PML after closure and required surgical mitral valve replacement. Aside from failed attempts or those requiring repeat cath, there were no serious complications. Conclusions: Use of the Agilis™ NxT Steerable Sheath allowed closure of the majority of PML encountered. Success rates were high though a large percentage required additional caths to achieve success. Serious complications were uncommon.
Abstract 15371: Risk of Early Recurrent Myocardial Infarction After Index Myocardial Infarction Stratified by Index Treatment Strategy
Authors: Raunak Nair, Michael Johnson, Kathleen A Kravitz, Jeevanantham Rajeswaran, Moses Anabila, Eugene H Blackstone, Venu Menon, A Michael M Lincoff, Samir R Kapadia, Umesh N Khot
Journal: Circulation (2020)

Introduction: Survivors of Myocardial Infarction (MI) remain at increased risk for another cardiovascular event. The purpose of our study was to assess the role of index treatment strategy in developing early recurrent MI after acute MI. Methods: We analyzed all cases of MI at a single quaternary care medical center from January 1 st , 2010 to January 1 st , 2017, and identified all cases of recurrent MI within 90 days of index MI. Early recurrent MI cases were further stratified depending on the treatment strategy for index MI. Reinfarctions were also stratified according to the time of readmission into early (0-30 days after discharge) and late (30-90 days after discharge) time periods. Results: We identified 6,626 patients admitted with an acute MI and 168 cases of recurrent MI within 90 days of discharge. Among the index MI patients, 4354 (66%) patients underwent revascularization whereas 2272 (34%) underwent medical management. An unadjusted comparison of the risk of readmission among the 3 different revascularization strategies showed that the CABG group appeared to have the lowest risk of readmission with a recurrent MI, and there was no significant difference in the late risk of readmission between PCI and CABG groups (P=0.8). The medically managed group had the highest late risk of readmission with a recurrent MI. Conclusions: The risk of readmission with a recurrent MI is higher in patients who undergo medical management for index MI. Aiming to improve the standard of care in these patients should be the focal point of interest to curb these reinfarctions.
Abstract 15006: Serotonin Transporter (SERT) Knockout Leads to Increased Myocardial and Mitral Valvular Fibrosis in a Murine Model
Authors: Alex D'Angelo, Estibaliz Castillero, Robert LEVY, Giovanni Ferrari
Journal: Circulation (2020)

Introduction: Heart valve disease attributed to serotonin (5HT) has been observed with 5HT-secreting carcinoid tumors and with the diet drug, Dexfenfluoramine, a 5HT transporter (SLC6A4, also known as SERT) inhibitor and 5HT receptor (HTR) 2B agonist. 5HT/SLC6A4 mechanisms had not been investigated in mitral valve (MV) regurgitation. SLC6A4 internalizes 5HT, limiting HTR signaling. Selective 5HT reuptake inhibitor (SSRI) antidepressants target SLC6A4 to increase 5HT. We showed that SLC6A4 reduction in human MV influences MV regurgitation through enhanced HTR signaling. We further investigate the cardiac impact of SLC6A4 deficiency in a SERT -/- mouse reported to have cardiac abnormalities. Hypothesis: Absence of SERT leads to increased myocardial and MV fibrosis. Methods: SERT -/- and wild type (WT) C57BL/6J mice underwent echocardiography at 8 and 16 weeks (w) of age (N=5 / group). Collagen staining was performed with Masson’s trichrome. Markers of myocardial fibrosis α-smooth muscle actin (αSMA) and collagen type1, alpha 1 (COL1A1) were measured by PCR. Results: 8w and 16w SERT -/- mice showed increased epicardial fibrosis and MV sub-valvular fibrosis, particularly at leaflet attachment points, and in 16w SERT -/- mice MV leaflet fibrosis was also present. At 8w, posterior ventricular wall thickness was greater in SERT -/- mice vs. WT, both in systole (1.30 ± 0.09mm vs. 1.61 ± 0.2mm, p=0.003) and diastole (0.78 ± 0.11mm vs. 1.22 ± 0.29mm, p=0.001). At 16 w, ventricular dimensions were larger in SERT -/- mice vs. WT at end-systole (2.29 ± 0.54mm vs. 3.0 ± 0.47mm, p=0.008) and end-diastole (3.48 ± 0.45mm vs. 4.07 ± 0.35, p=0.006). Fractional shortening was reduced in 16w SERT -/- mice vs. WT (35.20 ± 7.66 vs. 26.74 ± 6.14, p=0.017) and vs. 8w SERT -/- mice (38.85 ± 4.57 vs. 26.74 ± 6.14, p=0.002). PCR showed increased fibrosis markers αSMA and COL1A1 in SERT -/- mice (8w and 16w) vs. WT (all p&lt;0.05). Conclusions: SERT -/- mice show pathologic structural changes and fibrosis in both myocardium and MV, corresponding to functional differences that worsen with age. As inhibition of SLC6A4, combined with active HTR2A/B signaling would hypothetically increase MV remodeling and regurgitation, these animals could be ideal to test 5HT pharmacology.
Mutational landscape influences immunotherapy outcomes among patients with non-small-cell lung cancer with human leukocyte antigen supertype B44
Authors: Amy L. Cummings, Jaklin Gukasyan, Henry Y. Lu, Tristan Grogan, Gemalene Sunga, Charlene M. Fares, Nicholas Hornstein, Jesse Zaretsky, James Carroll, Benjamin Bachrach, Wisdom O. Akingbemi, Debory Li, Zorawar Noor, Aaron Lisberg, Jonathan W. Goldman, David Elashoff, Alex A. T. Bui, Antoni Ribas, Steven M. Dubinett, Maura Rossetti, Edward B. Garon
Journal: Nature Cancer (2020)
Abstract 13783: Disease Modeling Doxorubicin-induced Cardiotoxicity Using Human Induced Pluripotent Stem Cells-derived Cardiomyocytes From Healthy and Type 2 Diabetic Patients
Authors: Tarun Pant, Shailendera Narayan, Ranjan Dash, Balaraman Kalyanaraman, Zeljko J Bosnjak
Journal: Circulation (2020)

Introduction: Doxorubicin-Induced Cardiotoxicity (DIC) is one of the most common clinical complications in cancer patients. Patients with diabetes have a higher incidence of breast cancer, and their risks of developing DIC is also higher as compared to healthy patients. The human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) have the unique potential to recapitulate the genetic background and have emerged as a powerful tool for disease modeling and drug screening. Hypothesis: We hypothesized that cardiomyocytes derived from T2 diabetic patients will recapitulate greater sensitivity to DIC as compared to CMs derived from non-diabetic individuals. Methods: The patient specific iPSCs were differentiated into CMs with modifications to enhance cardiomyocyte purity (Fig. 1A, n=4 cell lines in each group). After 30 days from the initial differentiation, CMs were exposed to different concentrations of doxorubicin (DOX) based on the pharmacokinetic characteristics of doxorubicin in humans. The DOX-induced stress on the CMs after 24h and 48h was investigated via the analysis of 1) Cellular LDH release 2) Cellular viability using Alamar Blue assay and 3) CM-markers using real-time PCR. Results: Following the treatment with DOX the (iPSC)-derived cardiomyocytes (CMs) from the diabetic patients were more sensitive as compared to control CMs by: 1) An increase in the LDH release, Fig. 1B, 2) Decrease in the cellular viability, Fig. 1C, and 3) Greater downregulation of cardiac specific structural genes including Troponin T and Troponin I mRNA expression. Conclusions: For the first time, we demonstrate the ability of hiPSC-CMs derived from diabetic individuals to recapitulate greater sensitivity to DOX in vitro , validating this platform for predicting DIC severity in vivo .
Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy
Authors: Hannan Gao, Yue Wu, Jiyun Shi, Xin Zhang, Tianyu Liu, Biao Hu, Bing Jia, Yakun Wan, Zhaofei Liu, Fan Wang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Objectives Strategies to improve the responsiveness of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade therapy remain an essential topic in cancer immunotherapy. In this study, we developed a new radiolabeled nanobody-based imaging probe 99m Tc-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of 99m Tc-MY1523 SPECT/CT imaging. Methods The binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with 99m Tc by a site-specific transpeptidation of Sortase-A, and the biodistribution and single photon emission CT (SPECT)/CT were performed in mice bearing different tumors. We used interferon-γ (IFN-γ) as an intervention means to establish animal models with different levels of PD-L1 expression, then investigated the ability of 99m Tc-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by 99m Tc-MY1523 SPECT/CT were carried out in MC-38, A20, and 4T1 tumor-bearing mouse models, followed by the testing of tumor infiltration T cells. Results MY1523 exhibited a high binding affinity and specificity to PD-L1 and had no competitive binding with the therapeutic antibody. 99m Tc-MY1523 was prepared with high specific activity and radiochemical purity. It was found that tumor PD-L1 expression was dynamically upregulated by IFN-γ intervention in MC-38, A20, and 4T1 tumor-bearing mouse models, as indicated by 99m Tc-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by 99m Tc-MY1523 SPECT/CT imaging significantly enhanced the therapeutic efficacy in all animal models, while the tumor growth was effectively suppressed, and the survival time of mice was evidently prolonged. A correlation between dynamically upregulated PD-L1 expression and improved PD-L1 blockade therapy effectiveness was revealed, and the markedly increased infiltration of effector T cells into tumors was verified after the imaging-guided therapy. Conclusion Our results demonstrated that 99m Tc-MY1523 SPECT/CT allowed a real-time, quantitative and dynamic mapping of PD-L1 expression in vivo, and the imaging-guided PD-L1 blockade immunotherapy significantly enhanced the therapeutic efficacy. This strategy merits translation into clinical practice for the better management of combination therapies with radiotherapy or chemotherapy.