tbuckley/cabot-search huggingface dataset:
Oxidative stress in pancreatic alpha and beta cells as a selection criterion for biocompatible biomaterials
Authors: Mireille M.J.P.E. Sthijns, Marlon J. Jetten, Sami G. Mohammed, Sandra M.H. Claessen, Rick H.W. de Vries, Adam Stell, Denise F.A. de Bont, Marten A. Engelse, Didem Mumcuoglu, Clemens A. van Blitterswijk, Patricia Y.W. Dankers, Eelco J.P. de Koning, Aart A. van Apeldoorn, Vanessa L.S. LaPointe
Journal: Biomaterials (2020)

The clinical success rate of islet transplantation, namely independence from insulin injections, is limited by factors that lead to graft failure, including inflammation, acute ischemia, acute phase response, and insufficient vascularization. The ischemia and insufficient vascularization both lead to high levels of oxidative stress, which are further aggravated by islet encapsulation, inflammation, and undesirable cell-biomaterial interactions. To identify biomaterials that would not further increase damaging oxidative stress levels and that are also suitable for manufacturing a beta cell encapsulation device, we studied five clinically approved polymers for their effect on oxidative stress and islet (alpha and beta cell) function. We found that 300 poly(ethylene oxide terephthalate) 55/poly(butylene terephthalate) 45 (PEOT/PBT300) was more resistant to breakage and more elastic than other biomaterials, which is important for its immunoprotective function. In addition, it did not induce oxidative stress or reduce viability in the MIN6 beta cell line, and even promoted protective endogenous antioxidant expression over 7 days. Importantly, PEOT/PBT300 is one of the biomaterials we studied that did not interfere with insulin secretion in human islets.
Gustave Roussy Immune Score based on a three-category risk assessment scale serves as a novel and effective prognostic indicator for surgically resectable early-stage non-small-cell lung cancer: A propensity score matching retrospective cohort study
Authors: Shuang-Jiang Li, Liang Zhao, Hong-Yu Wang, Hai-Ning Zhou, Juan Ju, Heng Du, Guo-Wei Che
Journal: International Journal of Surgery (2020)
68Ga-FAPI-04 Accumulation in Myocardial Infarction in a Patient With Neuroendocrine Carcinoma
Authors: Wenjia Zhu, Fan Guo, Yawen Wang, Haiyan Ding, Li Huo
Journal: Clinical Nuclear Medicine (2020)

Abstract We present a case of a 64-year-old man with neuroendocrine carcinoma. Incidental findings were demonstrated on 68 Ga-FAPI-04 PET/CT in the inferior wall of left ventricle. A diagnosis of old myocardial infarction was made based on typical electrocardiogram change. Our case suggests that 68 Ga-FAPI PET/CT, as a noninvasive method to reflect fibroblast activation, is potentially feasible for assessment of cardiac remodeling after myocardial infarction in a clinical setting.
TCT CONNECT-329 Impact of Transcatheter Mitral Valve Repair With the MitraClip on 30-Day Renal Function and 2-Year Outcomes: The COAPT Trial
Authors: Nirat Beohar, Gorav Ailawadi, Lak Kotinkaduwa, Bjorn Redfors, Zixuan Zhang, L. Garrison Morgan, Esteban Escolar, Saibal Kar, Scott Lim, Jacob Mishell, Brian Whisenant, William Abraham, JoAnn Lindenfeld, Michael Mack, Gregg Stone
Journal: Journal of the American College of Cardiology (2020)
TCT-394 Late Outcomes After Transcatheter Aortic Valve Replacement With a Mechanically Expanded Versus Self-Expandable Valve: Final 5-Year Results From the REPRISE III Randomized Trial
Authors: Michael Reardon, Vivek Rajagopal, Raj Makkar, Tanvir Bajwa, Neal Kleiman, Axel Linke, Dean Kereiakes, Paul Underwood, Dominic Allocco, David Rizik
Journal: Journal of the American College of Cardiology (2021)
TCT CONNECT-23 Impact of Gender on Long-Term Prognosis in Acute ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention: Analysis of 10-Year All-Comers Registry
Authors: Belen Cid Alvarez, Maria Juskova, Pablo Tasende Rey, Belen Alvarez, Eva González Babarro, Jose Maria Garcia Acuna, Rosa Maria Agra Bermejo, Pedro Rigueiro, Jose Ramon González-Juanatey, Ramiro Trillo
Journal: Journal of the American College of Cardiology (2020)
Hepatobiliary acid-base homeostasis: Insights from analogous secretory epithelia
Authors: David C. Trampert, Stan F.J. van de Graaf, Aldo Jongejan, Ronald P.J. Oude Elferink, Ulrich Beuers
Journal: Journal of Hepatology (2020)

Many epithelia secrete bicarbonate-rich fluid to generate flow, alter viscosity, control pH and potentially protect luminal and intracellular structures from chemical stress. Bicarbonate is a key component of human bile and impaired biliary bicarbonate secretion is associated with liver damage. Major efforts have been undertaken to gain insight into acid-base homeostasis in cholangiocytes and more can be learned from analogous secretory epithelia. Extrahepatic examples include salivary and pancreatic duct cells, duodenocytes, airway and renal epithelial cells. The cellular machinery involved in acid-base homeostasis includes carbonic anhydrase enzymes, transporters of the solute carrier family, and intra- and extracellular pH sensors. This pH-regulatory system is orchestrated by protein-protein interactions, the establishment of an electrochemical gradient across the plasma membrane and bicarbonate sensing of the intra- and extracellular compartment. In this review, we discuss conserved principles identified in analogous secretory epithelia in the light of current knowledge on cholangiocyte physiology. We present a framework for cholangiocellular acid-base homeostasis supported by expression analysis of publicly available single-cell RNA sequencing datasets from human cholangiocytes, which provide insights into the molecular basis of pH homeostasis and dysregulation in the biliary system.
Hiding in Plain Sight — Somatic Mutation in Human Disease
Authors: Ephrat Levy-Lahad, Mary-Claire King
Journal: New England Journal of Medicine (2020)

Beck et al. define an adult-onset inflammatory disorder that unites multiple clinical conditions with previously different diagnoses or with no diagnosis at all; their findings are now reported in the Journal.1 The VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is defined by genotype, not by clinical phenotype. We agree with the authors that the names of disorders should be based on the responsible gene or pathway. Gene-based nosology best complements the discovery and deployment of genotype-targeted treatments for both inherited and noninherited forms of disease.2 Beck et al. found that myeloid cells in each patient with the VEXAS syndrome . . .
TCT CONNECT-350 Impact of Right Ventricular-Pulmonary Arterial Coupling in Heart Failure Patients With Functional Mitral Regurgitation: Analysis From the COAPT Trial
Authors: Michael Brener, Paul Grayburn, JoAnn Lindenfeld, Daniel Burkhoff, Mengdan Liu, Federico Asch, Diego Medvedofsky, Neil Weissman, Jeroen Bax, William Abraham, Michael Mack, Gregg Stone, Rebecca Hahn
Journal: Journal of the American College of Cardiology (2020)
Dysregulation of glycogen synthase kinase-3β signaling in hepatocellular carcinoma cells
Authors: Christèle Desbois-Mouthon, Marie-José Blivet-Van Eggelpoë, Eléonore Beurel, Mathieu Boissan, Roland Delélo, Axelle Cadoret, Jacqueline Capeau
Journal: Hepatology (2002)

It has been reported that upstream components of the insulin-like growth factor (IGF) signaling axis could be overexpressed during hepatocarcinogenesis in humans and rodents. However, the signal transduction pathways activated downstream have been poorly studied. Here, we examined whether glycogen synthase kinase-3β (GSK-3β) could be a target in human hepatoma cell lines and transgenic ASV mice with hepatic expression of the SV40 large T antigen. In HuH7, Mahlavu, and Hep3B cells, basal levels of GSK-3β Ser9 phosphorylation were strongly elevated, indicating that GSK-3β was inhibited. GSK-3β phosphorylation was insensitive to exogenous IGFs and was blocked with an IGF-1 receptorneutralizing antibody in Mahlavu and Hep3B cells. By using LY294002 and ML-9, which act as phosphatidylinositol 3-kinase (PI3-K) and Akt inhibitors, respectively, we showed that GSK-3β phosphorylation required P13-K activation in both cell lines whereas downstream Akt activation was required only in Mahlavu cells. However, in the 2 cell lines, GSK-3β Ser9 phosphorylation was controlled by protein kinase C (PKC)ξ because it was blocked by an inhibitory PKCξ peptide. The blockage of GSK-3β phosphorylation markedly inhibited glycogen synthesis and decreased β-catenin expression. In addition, the overexpression of a constitutively active GSK-3β reduced AP-1-mediated gene transcription in Hep3B cells. Finally, we observed that reexpression of IGF-2 in tumoral livers from ASV mice was associated with a marked phosphorylation of GSK-3β. In conclusion, our results identify GSK-3β as a molecular target of the constitutive activation of the IGF axis in in vitro and in vivo models of hepatocarcinogenesis. Persistent phosphorylation of GSK-3β could be critical for regulation of glycogen metabolism and cell growth in hepatoma cells. (Hepatology2002;36:1528-1536).
THU0023 Antigen independent generation of immuno-modulatory th2 cells is regulated by map kinase activation and il-4
Authors: A Skapenko, PE Lipsky, JR Kalden, H Schulze-Koops
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Evidence suggests that human autoimmune diseases might be driven by pro-inflammatory Th1 cells whereas immuno-modulatory Th2 cells are rarely found. The mechanisms regulating Th2 cell differentiation from resting human T cells, however, are not completely characterised. <h3>Objectives</h3> To delineate the mechanisms controlling Th2 differentiation, we defined optimal Th2 inducing conditions in human naive and memory CD4<sup>pos</sup> T cells <i>in vitro</i> and investigated activation of intracellular signalling pathways and their individual role in Th2 differentiation. <h3>Methods</h3> A cell culture system was employed that permitted Th2 cell differentiation after short term priming. The phenotype of freshly isolated and primed T cells was determined by cytometric analysis of intracellular cytokines. Activation of intracellular signalling pathways was assessed by western blot analysis or kinase activity assays. <h3>Results</h3> In the absence of TCR ligation, stimulation of CD28 induced Th2 differentiation from purified CD4<sup>pos</sup> peripheral blood memory but not from cord blood naive T cells. Co-stimulation via CD28 and the TCR, on the other hand, enhanced Th2 cell differentiation from naive T cells but suppressed it from memory T cells. Comparison of naive and memory T cell responses to CD28 stimulation, therefore, revealed critical signals facilitating Th2 cell differentiation. CD28 engagement initiated IL-4 gene transcription and activation of p38 MAP kinase in memory T cells but not in naive cells. By contrast, PI3-kinase and JNK/SAPK pathways were activated in both subsets. Whereas IL-4 had a synergistic effect with anti-CD28 on the generation of Th2 cells in memory T cells, it was not sufficient to complement CD28 signals in naive T cells. T cell differentiation in the presence of specific inhibitors to IL-4, the MAP kinases and PI3-kinase revealed that TCR independent, CD28 mediated Th2 differentiation is critically dependent on IL-4 stimulation and the activation of the MAP kinases p38 and ERK1/2. Whereas CD28 signals directly activated IL-4 and p38 in memory T cells, ERK phosphorylation required indirect stimulation by IL-2. <h3>Conclusion</h3> The results indicate that generation of Th2 effectors requires coordinate signalling via the CD28 and IL-2 pathways. The mechanisms regulating Th2 cell differentiation might provide valuable tools for therapeutic modulation of chronic autoimmunity.
Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer
Authors: Aranzazu Fernandez-Martinez, Ian E. Krop, David W. Hillman, Mei-Yin Polley, Joel S. Parker, Lucas Huebner, Katherine A. Hoadley, Jonathan Shepherd, Sara Tolaney, N. Lynn Henry, Chau Dang, Lyndsay Harris, Donald Berry, Olwen Hahn, Clifford Hudis, Eric Winer, Ann Partridge, Charles M. Perou, Lisa A. Carey
Journal: Journal of Clinical Oncology (2020)

CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
TCT CONNECT-21 Revascularization in Very Elderly Patients With Baseline Renal Dysfunction Presenting With Acute Myocardial Infarction
Authors: Derek Phan, Ara Rostomian, Ming-Sum Lee, Naing Moore, Prakash Mansukhani, Vicken Aharonian, Somjot Brar, Ray Zadegan
Journal: Journal of the American College of Cardiology (2020)
Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity
Authors: Bangxing Hong, Valerie Chapa, Uksha Saini, Puneet Modgil, David E. Cohn, Guangan He, Zahid H. Siddik, Anil K. Sood, Yuanqing Yan, Karuppaiyah Selvendiran, Guangsheng Pei, Zhongming Zhao, Ji Young Yoo, Balveen Kaur
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. Experimental Design: Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models (n = 9–10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of antitumor immune response (n = 3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition in vivo. Results: Gene Ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV)-related pathways in infected cells (FDR = 2.97E-57). Mechanistically, we identified reduced expression of transporters expressed on EV implicated in cisplatin efflux. The increased cisplatin retention led to increased cisplatin–DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS–STING pathway with a significant activation of innate immune cells and translated to an increase in antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy. Conclusions: To our knowledge, this is the first report to show HSV-induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.
Application of Artificial Intelligence for the Diagnosis and Treatment of Liver Diseases
Authors: Joseph C. Ahn, Alistair Connell, Douglas A. Simonetto, Cian Hughes, Vijay H. Shah
Journal: Hepatology (2020)

Modern medical care produces large volumes of multimodal patient data, which many clinicians struggle to process and synthesize into actionable knowledge. In recent years, artificial intelligence (AI) has emerged as an effective tool in this regard. The field of hepatology is no exception, with a growing number of studies published that apply AI techniques to the diagnosis and treatment of liver diseases. These have included machine-learning algorithms (such as regression models, Bayesian networks, and support vector machines) to predict disease progression, the presence of complications, and mortality; deep-learning algorithms to enable rapid, automated interpretation of radiologic and pathologic images; and natural-language processing to extract clinically meaningful concepts from vast quantities of unstructured data in electronic health records. This review article will provide a comprehensive overview of hepatology-focused AI research, discuss some of the barriers to clinical implementation and adoption, and suggest future directions for the field.
TCT CONNECT-39 Long-Term Outcomes After Drug-Eluting Stent Implantation in Thrombotic Lesions: An Individual Patient-Data Pooled Analysis of 8 Randomized Controlled Trials
Authors: Mayank Yadav, Gary Mintz, Sorin Brener, Zhipeng Zhou, Bjorn Redfors, Mahesh Madhavan, Pieter Smits, Clemens von Birgelen, Patrick Serruys, Martin Leon, Gregg Stone
Journal: Journal of the American College of Cardiology (2020)
Abstract P120: Prevalence of Psychiatric Disorders and In-Hospital Recovery Among Women with Stress Cardiomyopathy
Authors: Elena Salmoirago-Blotcher, Mark O’Connor, Robert Goldberg, Sybil Crawford, Joseph Bouchard, Timothy Fitzgibbons, Keith Medeiros, Dennis Tighe, Ira Ockene, Gerard Aurigemma
Journal: Circulation (2013)

Background Stress cardiomyopathy (SC) is a reversible condition mimicking acute myocardial infarction usually affecting postmenopausal women and often triggered by emotional or physical stress. The...
Neuromuscular block monitoring by smartphone application (i-TOF© system): an observational pilot study
Authors: Lorenzo Schiavoni, Giuseppe Pascarella, Stefania Grande, Felice Eugenio Agrò
Journal: npj Digital Medicine (2020)

Abstract Neuromuscular block monitoring is recommended by international guidelines to improve myorelaxation during surgery and reduce the risk of postoperative residual curarization. We conducted a pilot study to verify the efficacy of i-TOF, a wireless neuromuscular monitoring device connectable to a smartphone, comparing it with TOF WATCH SX. We enrolled 53 patients who underwent general anesthesia. For each patient, we recorded by both devices, in different time intervals, train-of-four (TOF) count/ratio after induction to general anesthesia (TI0–TI3) and during recovery (TR0–TR3). Moreover, post-tetanic count (PTC) was evaluated during deep neuromuscular block (TP0–TP2). We noticed no significant differences between the devices in recorded mean values of TOF ratio, TOF count, and PTC analyzed at time intervals for every phase of general anesthesia, although the i-TOF tends to an underestimation compared to TOF WATCH SX. For each patient, data sessions were successfully recorded by a smartphone. This aspect could be relevant for clinicians in order to have a stored proof of good clinical practice to be added on anesthesiologist records. By our results, i-TOF demonstrates a comparable efficacy to TOF WATCH SX, suggesting that it could be a proven alternative to standard devices for neuromuscular block monitoring. Further studies are needed to confirm our findings.
CCA-Addition Gone Wild: Unusual Occurrence and Phylogeny of Four Different tRNA Nucleotidyltransferases in <i>Acanthamoeba castellanii</i>
Authors: Lieselotte Erber, Heike Betat, Mario Mörl
Journal: Molecular Biology and Evolution (2020)

Abstract tRNAs are important players in the protein synthesis machinery, where they act as adapter molecules for translating the mRNA codons into the corresponding amino acid sequence. In a series of highly conserved maturation steps, the primary transcripts are converted into mature tRNAs. In the amoebozoan Acanthamoeba castellanii, a highly unusual evolution of some of these processing steps was identified that are based on unconventional RNA polymerase activities. In this context, we investigated the synthesis of the 3′-terminal CCA-end that is added posttranscriptionally by a specialized polymerase, the tRNA nucleotidyltransferase (CCA-adding enzyme). The majority of eukaryotic organisms carry only a single gene for a CCA-adding enzyme that acts on both the cytosolic and the mitochondrial tRNA pool. In a bioinformatic analysis of the genome of this organism, we identified a surprising multitude of genes for enzymes that contain the active site signature of eukaryotic/eubacterial tRNA nucleotidyltransferases. In vitro activity analyses of these enzymes revealed that two proteins represent bona fide CCA-adding enzymes, one of them carrying an N-terminal sequence corresponding to a putative mitochondrial target signal. The other enzymes have restricted activities and represent CC- and A-adding enzymes, respectively. The A-adding enzyme is of particular interest, as its sequence is closely related to corresponding enzymes from Proteobacteria, indicating a horizontal gene transfer. Interestingly, this unusual diversity of nucleotidyltransferase genes is not restricted to Acanthamoeba castellanii but is also present in other members of the Acanthamoeba genus, indicating an ancient evolutionary trait.