tbuckley/cabot-search huggingface dataset:
Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke
Authors: Bruce C.V. Campbell, Peter J. Mitchell, Leonid Churilov, Nawaf Yassi, Timothy J. Kleinig, Richard J. Dowling, Bernard Yan, Steven J. Bush, Helen M. Dewey, Vincent Thijs, Rebecca Scroop, Marion Simpson, Mark Brooks, Hamed Asadi, Teddy Y. Wu, Darshan G. Shah, Tissa Wijeratne, Timothy Ang, Ferdinand Miteff, Christopher R. Levi, Edrich Rodrigues, Henry Zhao, Patrick Salvaris, Carlos Garcia-Esperon, Peter Bailey, Henry Rice, Laetitia de Villiers, Helen Brown, Kendal Redmond, David Leggett, John N. Fink, Wayne Collecutt, Andrew A. Wong, Claire Muller, Alan Coulthard, Ken Mitchell, John Clouston, Kate Mahady, Deborah Field, Henry Ma, Thanh G. Phan, Winston Chong, Ronil V. Chandra, Lee-Anne Slater, Martin Krause, Timothy J. Harrington, Kenneth C. Faulder, Brendan S. Steinfort, Christopher F. Bladin, Gagan Sharma, Patricia M. Desmond, Mark W. Parsons, Geoffrey A. Donnan, Stephen M. Davis
Journal: New England Journal of Medicine (2018)

Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion.
Neutral Theory and Rapidly Evolving Viral Pathogens
Authors: Simon D W Frost, Brittany Rife Magalis, Sergei L Kosakovsky Pond
Journal: Molecular Biology and Evolution (2018)

The evolution of viral pathogens is shaped by strong selective forces that are exerted during jumps to new hosts, confrontations with host immune responses and antiviral drugs, and numerous other processes. However, while undeniably strong and frequent, adaptive evolution is largely confined to small parts of information-packed viral genomes, and the majority of observed variation is effectively neutral. The predictions and implications of the neutral theory have proven immensely useful in this context, with applications spanning understanding within-host population structure, tracing the origins and spread of viral pathogens, predicting evolutionary dynamics, and modeling the emergence of drug resistance. We highlight the multiple ways in which the neutral theory has had an impact, which has been accelerated in the age of high-throughput, high-resolution genomics.
Lowering the upper limit of serum alanine aminotransferase levels may detect significant liver disease in the elderly
Authors: H. Schmilovitz-Weiss, R. Gingold-Belfer, A. Gossman, N. Issa, D. Boltin, Y. Beloosesky, N. Koren-Morag, J. Meyerovitch, A. Weiss
Journal: Journal of Hepatology (2018)
Akkermansia spp. mediates protection from obesity-associated NAFLD development in germ free mice following intestinal microbiota transplantation from high fat diet and quercetin treated donors
Authors: D. Porras, E. Nistal, S. Martínez-Flórez, J.L. Olcoz-Goni, R. Jover, F. Jorquera, J. González-Gállego, M.-V. Garcia-Mediavilla, S. Sánchez-Campos
Journal: Journal of Hepatology (2018)
Abstract 16918: Activation Mapping of Idiopathic Ventricular Ectopy- Characterization of a Threshold Value Predicting Successful Catheter Ablation
Authors: Michele Murphy, Augustus Mealor, Will Camnitz, Andrew Darby, Rohit Malhotra, Kenneth Bilchick, Pamela Mason, John Ferguson, Michael Mangrum
Journal: Circulation (2016)

Background:  Catheter ablation of ventricular ectopy is performed with increasing frequency. Activation mapping to locate the earliest presystolic electrogram (EGM) is the most accurate method to identify the optimal ablation site. Despite this, activation mapping of ventricular ectopy has not been systematically reviewed in a large series, and the optimal activation time predicting successful ablation has not previously been determined. The goal of this study is to determine the local presystolic activation time most predictive of successful ablation.   Methods and Results:  We retrospectively reviewed 100 consecutive successful endocardial PVC ablations for idiopathic ventricular ectopy and analyzed the local activation time at each successful and unsuccessful ablation site. A total of 560 ablation lesions were reviewed. Activation time was calculated as the difference between the earliest peak of the local bipolar EGM and onset of the reference surface QRS complex. Acute success was defined as complete elimination of the target PVC during the procedure with no recurrence at 30 days by ECG and follow-up Holter. A local activation time 30 ms presystolic best predicted success with a sensitivity of 80%, specificity 80%, and an area under the ROC curve of 0.906 (p   45 ms presystolic was 100% specific for successful ablation.   Conclusion:  In our experience, a local presystolic activation time of 30 ms is the threshold value most predictive of successful PVC ablation. Our review is the first to systematically characterize an activation time predicting success with idiopathic PVC ablation in a large cohort.
Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress
Authors: Jaime N. Guzman, Ema Ilijic, Ben Yang, Javier Sanchez-Padilla, David Wokosin, Dan Galtieri, Jyothisri Kondapalli, Paul T. Schumacker, D. James Surmeier
Journal: Journal of Clinical Investigation (2018)

The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass - demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.
Non-alcoholic fatty liver disease and relative risk of incident steatohepatitis, cirrhosis and hepatocellular carcinoma events in four European primary care databases
Authors: M. Alexander, K. Loomis, N. Dhalwani, J. van der Lei, T. Duarte-Salles, D. Prieto-Alhambra, D. Ansell, A. Pasqua, F. Lapi, P. Rijnbeek, M. Mosseveld, D. Waterworth, N. Sattar, W. Alazawi, S. Kendrick
Journal: Journal of Hepatology (2018)
Probiotics drive gut microbiome triggering emotional brain signatures
Authors: Deepika Bagga, Johanna Louise Reichert, Karl Koschutnig, Christoph Stefan Aigner, Peter Holzer, Kaisa Koskinen, Christine Moissl-Eichinger, Veronika Schöpf
Journal: Gut Microbes (2018)

Experimental manipulation of the gut microbiome was found to modify emotional and cognitive behavior, neurotransmitter expression and brain function in rodents, but corresponding human data remain scarce. The present double-blind, placebo-controlled randomised study aimed at investigating the effects of 4 weeks' probiotic administration on behavior, brain function and gut microbial composition in healthy volunteers. Forty-five healthy participants divided equally into three groups (probiotic, placebo and no intervention) underwent functional MRI (emotional decision-making and emotional recognition memory tasks). In addition, stool samples were collected to investigate the gut microbial composition. Probiotic administration for 4 weeks was associated with changes in brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in gut microbiome profile. Microbiome composition mirrored self-reported behavioral measures and memory performance. This is the first study reporting a distinct influence of probiotic administration at behavioral, neural, and microbiome levels at the same time in healthy volunteers. The findings provide a basis for future investigations into the role of the gut microbiota and potential therapeutic application of probiotics.
Abstract 21333: Persistent Decreased Survival in Diabetic Subjects With HFrEF Despite Advances in Therapy
Authors: Masoor Kamalesh, Tarek Ajam, Srikant Devaraj, Samer Ajam
Journal: Circulation (2017)

Background: With the advancement in diabetic management throughout the years, this study aimed to compare the effect of diabetes mellitus on mortality in patients with heart failure with reduced ejection fraction (HFrEF). Methods: The VA’s databases were queried to identify all patients diagnosed with HFrEF from 2007 to 2015. A total of 61,400 diabetic patients were matched to as many non-diabetic patients using propensity score matching with replacement. To estimate the impact of diabetic patients on overall mortality of HFrEF patients, the Cox proportional hazard model was used on the matched sample and adjusted for patient characteristics. Results: From the overall sample of 114,010 patients with HFrEF, 61,400 (54%) had diabetes mellitus. On the matched sample, after adjusting for patient characteristics such as age, sex, high beta blocker dose, heart rate quartile, carvedilol, metoprolol, comorbidities, and medications, we found that the diabetic patients were associated with a higher overall mortality compared to non-diabetic patients (HR: 1.50, 95% CI: 1.48-1.53, p&lt;0.001). Conclusions: Diabetic HFrEF patients have a higher risk of mortality than non-diabetic HFrEF patients despite controlling for beta blocker dose, medications and comorbidities.
Role of <scp>ADAMTS</scp> ‐12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor
Authors: Jian‐lu Wei, Wenyu Fu, Aubryanna Hettinghouse, Wen‐jun He, Kenneth E. Lipson, Chuan‐ju Liu
Journal: Arthritis & Rheumatology (2018)

It has been reported that ADAMTS-12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS-12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS-12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis.The collagen-induced arthritis (CIA) model was established in ADAMTS-12-deficient mice and their control littermates to determine the role of ADAMTS-12 in vivo. Micro-computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme-linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein-protein interaction assays were performed to detect the interactions of ADAMTS-12 and its various deletion mutants with connective tissue growth factor (CTGF).Deficiency of ADAMTS-12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS-12 caused enhanced osteoclastogenesis. In vitro and in vivo protein-protein interaction assays demonstrated that ADAMTS-12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS-12. In addition, deletion of ADAMTS-12 enhanced, while overexpression of ADMATS-12 reduced, CTGF-mediated inflammation. Furthermore, ADAMTS-12 regulation of inflammation was largely lost in CTGF-deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS-12-deficient CIA mouse model.This study provides evidence that ADAMTS-12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover.
Non-alcoholic steatohepatitis impairs Kupffercell-mediated immune tolerance in the mouse liver
Authors: L.A. Orci, C. Toso, K. Mario, F. Slits, V. Delaune, G. Oldani, C. Gonelle-Gispert, L. Rubbia-Brandt, S. Lacotte
Journal: Journal of Hepatology (2018)
Unfinished Business: Evolution of the MHC and the Adaptive Immune System of Jawed Vertebrates
Authors: Jim Kaufman
Journal: Annual Review of Immunology (2018)

The major histocompatibility complex (MHC) is a large genetic region with many genes, including the highly polymorphic classical class I and II genes that play crucial roles in adaptive as well as innate immune responses. The organization of the MHC varies enormously among jawed vertebrates, but class I and II genes have not been found in other animals. How did the MHC arise, and are there underlying principles that can help us to understand the evolution of the MHC? This review considers what it means to be an MHC and the potential importance of genome-wide duplication, gene linkage, and gene coevolution for the emergence and evolution of an adaptive immune system. Then it considers what the original antigen-specific receptor and MHC molecule might have looked like, how peptide binding might have evolved, and finally the importance of adaptive immunity in general.
Multicenter Prospective Phase II Trial of Neoadjuvant Dose-Dense Gemcitabine Plus Cisplatin in Patients With Muscle-Invasive Bladder Cancer
Authors: Gopa Iyer, Arjun V. Balar, Matthew I. Milowsky, Bernard H. Bochner, Guido Dalbagni, S. Machele Donat, Harry W. Herr, William C. Huang, Samir S. Taneja, Michael Woods, Irina Ostrovnaya, Hikmat Al-Ahmadie, Maria E. Arcila, Jamie C. Riches, Andreas Meier, Caitlin Bourque, Maha Shady, Helen Won, Tracy L. Rose, William Y. Kim, Brooke E. Kania, Mariel E. Boyd, Catharine K. Cipolla, Ashley M. Regazzi, Daniela Delbeau, Asia S. McCoy, Hebert Alberto Vargas, Michael F. Berger, David B. Solit, Jonathan E. Rosenberg, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2018)

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m 2 on day 1 and cisplatin 35 mg/m 2 on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non–muscle-invasive disease (&lt; pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to &lt; pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for &lt; pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.
Genetic unrelatedness of co-occurring pancreatic adenocarcinomas and IPMNs challenges current views of clinical management
Authors: Aldo Scarpa, Francisco X Real, Claudio Luchini
Journal: Gut (2018)

Intraductal papillary mucinous neoplasms (IPMNs) represent the most common cystic preinvasive lesion in the pancreas, which can progress to invasive pancreatic ductal adenocarcinoma (PDAC). Patients with radiological findings consistent with IPMN are strictly monitored with imaging techniques, and surgical resection is recommended in case of clinical and/or radiological ‘high-risk stigmata’ or ‘worrisome features’.1 2 Recent research has suggested the potential role of molecular analysis of cyst fluid to discriminate IPMNs from other types of pancreatic cysts and from invasive lesions.3–6 

Notably, recent evidences pointed out the presence of a so-called ‘field effect’ of pancreatic carcinogenesis. This concept indicates the occurrence of seemingly unrelated patches of non-neoplastic cells that may be partly shared with a tumour lesion.7 Therefore, within the pancreas not only a preinvasive lesion is at risk of progression to malignancy but independent preinvasive and invasive lesions may develop as well. In other words, the ‘field effect’ might separately predispose to both preinvasive and invasive lesions. Along this line, Pea and colleagues, sequenced DNA from a cohort of IPMNs and PDAC from the same patients, showing that a significant proportion of the recurrent cancers was likely independent from the primary resected IPMNs.8 

The existence of a field-effect carcinogenesis in the pancreas has also been suggested by the work of Shindo and colleagues, who reported that germ line mutations in PDAC susceptibility genes are commonly identified in patients with pancreatic cancer, even when a family history of cancer is lacking.9 Some of these mutations …
Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology
Authors: Claudia I. Vidal, Eric A. Armbrect, Aleodor A. Andea, Angela K. Bohlke, Nneka I. Comfere, Sarah R. Hughes, Jinah Kim, Jessica A. Kozel, Jason B. Lee, Konstantinos Linos, Brandon R. Litzner, Tricia A. Missall, Roberto A. Novoa, Uma Sundram, Brian L. Swick, M. Yadira Hurley, Murad Alam, Zsolt Argenyi, Lyn M. Duncan, Dirk M. Elston, Patrick O. Emanuel, Tammie Ferringer, Maxwell A. Fung, Gregory A. Hosler, Alexander J. Lazar, Lori Lowe, Jose A. Plaza, Victor G. Prieto, June K. Robinson, Andras Schaffer, Antonio Subtil, Wei-Lien Wang
Journal: Journal of the American Academy of Dermatology (2018)
Identification of a novel regulator for smoothened signaling in human cancers
Authors: Jingwu Xie, Tao Sheng, Xiaoli Zhang
Journal: Cancer Research (2007)

4156    Background:  The hedgehog pathway plays a critical role in embryonic development, tissue polarity and carcinogenesis. It is estimated that activation of this pathway is associated with almost all basal cell carcinomas and in nearly 30% of non-skin cancers. Whereas mutations of human homologue of patched 1 (PTCH1), smoothened (SMO) or suppressor of fused [Su(Fu)] contribute to the development of BCCs and medulloblastomas, whereas elevated expression of the ligands- hedgehog molecules may be responsible for activation of hedgehog signaling in prostate, breast, lung and gastrointestinal cancers. However, the molecular basis for SMO signaling regulation, the essential event in pathway activation, remains unclear. Therefore, identification of novel regulators of SMO will further our understanding of hedgehog-mediated carcinogenesis.   Results:  Through yeast two hybrid screening using SMO as bait, we identified a Smooothened Interacting Protein, SIP. In cultured cells, we showed that SIP co-immunoprecipitated reciprocally with SMO. Using GST pull-down studies, we showed that the cytoplasmic tail of SMO is responsible for the interaction with SIP. We found that stability of SMO protein, but not Gli1 protein, can be enhanced with ectopic expression of SIP in a dose-dependent manner. To demonstrate whether inactivation of SIP is sufficient to inhibit growth of cancer cells with activated hedgehog signaling, we treated cancer cell lines with SIP siRNA or control siRNA and measured DNA synthesis and softagar growth. We found that SIP siRNA inhibited DNA synthesis and softagar growth of PLC/PRF/5 cells, which have activated hedgehog signaling, but had no effects on HepG2 cells, which have no detectable hedgehog signaling.   Conclusion: We have identified a novel regulator of SMO, SIP. We find that SMO interacts with SIP through its c-terminal tail. The protein stability of SMO is enhanced by the presence of SIP. Inactivation of SIP by specific siRNA, just like SMO antagonist cyclopamine, reduced DNA synthesis and cell growth of cancer cells with activated hedgehog signaling. Thus, targeted inhibition of SIP may have significant implications in cancer therapeutics.
Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators
Authors: Charles N. Serhan, Bruce D. Levy
Journal: Journal of Clinical Investigation (2018)

Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies.
Eco-Evolutionary Genomics of Chromosomal Inversions
Authors: Maren Wellenreuther, Louis Bernatchez
Journal: Trends in Ecology & Evolution (2018)

Chromosomal inversions have long fascinated evolutionary biologists due to their suppression of recombination, which can protect co-adapted alleles. Emerging research documents that inversions are commonly linked to spectacular phenotypes and have a pervasive role in eco-evolutionary processes, from mating systems, social organisation, environmental adaptation, and reproductive isolation to speciation. Studies also reveal that inversions are taxonomically widespread, with many being old and large, and that balancing selection is commonly facilitating their maintenance. This challenges the traditional view that the role of balancing selection in maintaining variation is relatively minor. The ubiquitous importance of inversions in ecological and evolutionary processes suggests that structural variation should be better acknowledged and integrated in studies pertaining to the molecular basis of adaptation and speciation.
NAITRE study on the impact of conditional cash transfer on poor pregnancy outcomes in underprivileged women: protocol for a nationwide pragmatic cluster-randomised superiority clinical trial in France
Authors: Marc Bardou, Bruno Crépon, Anne-Claire Bertaux, Aurélie Godard-Marceaux, Astrid Eckman-Lacroix, Elise Thellier, Frédérique Falchier, Philippe Deruelle, Muriel Doret, Xavier Carcopino-Tusoli, Thomas Schmitz, Thiphaine Barjat, Mathieu Morin, Franck Perrotin, Ghada Hatem, Catherine Deneux-Tharaux, Isabelle Fournel, Laurent Laforet, Nicolas Meunier-Beillard, Isabelle Le Ray, Esther Duflo
Journal: BMJ (2017)