tbuckley/cabot-search huggingface dataset:
Keratin 23 Is a Peroxisome Proliferator‐Activated Receptor Alpha–Dependent, MYC‐Amplified Oncogene That Promotes Hepatocyte Proliferation
Authors: Donghwan Kim, Chad N. Brocker, Shogo Takahashi, Tomoki Yagai, Taehyeong Kim, Guomin Xie, Hua Wang, Aijuan Qu, Frank J. Gonzalez
Journal: Hepatology (2019)

Chronic activation of the nuclear receptor peroxisome proliferator–activated receptor alpha (PPARA) promotes MYC‐linked hepatocellular carcinoma (HCC) in mice. Recent studies have shown that MYC can function as an amplifier of transcription where MYC does not act as an “on‐off” switch for gene expression but rather accelerates transcription rates at active promoters by stimulating transcript elongation. Considering the possibility that MYC may amplify the expression of PPARA target genes to potentiate cell proliferation and liver cancer, gene expression was analyzed from livers of wild‐type and liver‐specific Myc knockout ( Myc ΔHep ) mice treated with the PPARA agonist pirinixic acid. A subset of PPARA target genes was amplified in the presence of MYC, including keratin 23 ( Krt23 ). The induction of Krt23 was significantly attenuated in Myc ΔHep mice and completely abolished in Ppara ‐null mice. Reporter gene assays and chromatin immunoprecipitation confirmed direct binding of both PPARA and MYC to sites within the Krt23 promoter. Forced expression of KRT23 in primary hepatocytes induced cell cycle–related genes. These data indicate that PPARA activation elevates MYC expression, which in turn potentiates the expression of select PPARA target genes involved in cell proliferation. Finally, KRT23 protein is highly elevated in human HCCs. Conclusion: These results revealed that MYC‐mediated transcriptional potentiation of select PPARA target genes, such as Krt23 , may remove rate‐limiting constraints on hepatocyte growth and proliferation leading to liver cancer.
Real world usage of gemcitabine and nabpaclitaxel in older adults with metastatic pancreatic cancer: A single institution experience.
Authors: Arthur Winer, Elizabeth A. Handorf, Lavanya Nagappan, Aryeh Blumenreich, Farhana Chowdhury, Namrata Vijayvergia, Efrat Dotan
Journal: Journal of Clinical Oncology (2019)

358 Background: The median age at diagnosis for metastatic pancreatic cancer (mPC) is 72. Gemcitabine and Nab-Paclitaxel (GA) is often the preferred chemo regimen in this population due to presumed reduced toxicity compared with FOLFIRINOX. While the traditional GA schedule (TDS) includes treatment on days 1, 8, and 15 of a 28-day cycle, it can cause side effects and patients often require dose reductions. There is data for a modified dosing schedule (MDS) treating only on day 1 and 15. Therefore, we retrospectively analyzed our older adults treated with GA using the TDS versus the MDS and compared tolerability and outcomes between the two groups. Methods: We identified pts with mPC &gt;64 y/o treated with GA at Fox Chase Cancer Center between 1/2010 - 7/2018 and collected their demographic, disease and treatment information. We analyzed discrete variables using Fisher’s exact test and continuous variables using Wilcoxon tests. Overall survival (OS) was analyzed by the Kaplan-Meier method and Cox proportional hazards regression. Results: Fifty-six pts were identified with a median age at diagnosis of 71 (range: 64-90) and 67.8% with metastatic disease at presentation. 57% received GA in the first line. 44% were treated with TDS while 56% received a MDS; an older median age was seen in the MDS group (73 vs 69 y/o, p&lt;0.001). Up front dose reductions of GA were seen in 24% in the TDS vs 48% in MDS, and they were more common with nab-paclitaxel (26% in MDS vs 10% in TDS) than with gemcitabine (two pts in TDS vs one pt in MDS). Of pts who began with TDS only 11 (19% of all pts) were able to tolerate it without adjustment throughout treatment; 14 (25%) transitioned to the MDS. More pts suffered grade ≥3 toxicity with the TDS vs. MDS (68% vs. 51%; p=0.27) and more required a dose reduction (TDS 72% vs. MDS 48%; p=0.1). 58% required an additional GA dose reduction over the course of treatment. Median OS among GA treated pts in the front line (n=32) was not significantly different (MDS: 11.7 mo vs. TDS: 13 mo; p=0.1). Conclusions: These results demonstrate tolerability and similar efficacy of the GA MDS among older adults with mPC. Given the limited sample size, further studies are required to help establish the appropriate therapy for older patients.
Cytomegalovirus Reactivation in Haploidentical Blood or Marrow Transplant (BMT) Using Post-Transplant Cyclophosphamide (PTCy) Is Associated with Higher Non-Relapse-Related Mortality, Despite Rarity of Disease
Authors: Maria Veronica Dioverti, Chiung-Yu Huang, Megan Morales, Na Lu, Willa Cochran, Douglas Gladstone, Darin Ostrander, Robin Avery, Richard J. Jones, Richard F Ambinder, Kieren Marr
Journal: Blood (2018)
Generation of a Unique Cohort of Hemophilia A Dogs Tolerant to Human FVIII for Evaluating the Safety and Efficacy of AAV Delivery of Wild Type and Variant Human FVIII
Authors: Giang N. Nguyen, Lauren Wimsey, Elizabeth Merricks, Katherine P. Ponder, Timothy C. Nichols, Denise E. Sabatino
Journal: Blood (2018)
Induction of Donor-Specific Immune Tolerance with Clinical MIC Cell Infusion — a Phase I Study (TOL-1)
Authors: Christian Morath, Anita Schmitt, Christian Kleist, Volker Daniel, Gerhard Opelz, Caner Süsal, Florian Kälble, Claudia Sommerer, Lei Wang, Angela Hückelhoven, Arianeb Mehrabi, Uta Merle, Luiza Pego da Silva, Carsten Müller-Tidow, Martin Zeier, Matthias Schaier, Michael Schmitt, Peter Terness
Journal: Blood (2018)
Use, Temporal Trends, and Outcomes of Endovascular Therapy After Interhospital Transfer in the United States
Authors: Shreyansh Shah, Ying Xian, Shubin Sheng, Kori S. Zachrison, Jeffrey L. Saver, Kevin N. Sheth, Gregg C. Fonarow, Lee H. Schwamm, Eric E. Smith
Journal: Circulation (2019)

Background: The use of endovascular therapy (EVT) in patients with acute ischemic stroke who have large vessel occlusion has rapidly increased in the United States following pivotal trials demonstrating its benefit. Information about the contribution of interhospital transfer in improving access to EVT will help organize regional systems of stroke care. Methods: We analyzed trends of transfer-in EVT from a cohort of 1 863 693 patients with ischemic stroke admitted to 2143 Get With The Guidelines-Stroke participating hospitals between January 2012 and December 2017. We further examined the association between arrival mode and in-hospital outcomes by using multivariable logistic regression models. Results: Of the 37 260 patients who received EVT at 639 hospitals during the study period, 42.9% (15 975) arrived at the EVT-providing hospital after interhospital transfer. Transfer-in EVT cases increased from 256 in the first quarter 2012 to 1422 in the fourth quarter 2017, with sharply accelerated increases following the fourth quarter 2014 ( P &lt;0.001 for change in linear trend). Transfer-in patients were younger and more likely to be of white race, to arrive during off-hours, and to be treated at comprehensive stroke centers. Transfer-in patients had significantly longer last-known-well-to-EVT initiation time (median, 289 minutes versus 213 minutes; absolute standardized difference, 67.33) but were more likely to have door-to-EVT initiation time of ≤90 minutes (65.6% versus 23.6%; absolute standardized difference, 93.18). In-hospital outcomes were worse for transfer-in patients undergoing EVT in unadjusted and in risk-adjusted models. Although the difference in in-hospital mortality disappeared after adjusting for delay in EVT initiation (14.7% versus 13.4%; adjusted odds ratio, 1.01; 95% CI, 0.92–1.11), transfer-in patients were still more likely to develop symptomatic intracranial hemorrhage (7.0% versus 5.7%; adjusted odds ratio, 1.15; 95% CI, 1.02–1.29) and less likely to have either independent ambulation at discharge (33.1% versus 37.1%; adjusted odds ratio, 0.87; 95% CI, 0.80–0.95) or to be discharged to home (24.3% versus 29.1%; adjusted odds ratio, 0.82; 95% CI, 0.76–0.88). Conclusions: Interhospital transfer for EVT is increasingly common and is associated with a significant delay in EVT initiation highlighting the need to develop more efficient stroke systems of care. Further evaluation to identify factors that impact EVT outcomes for transfer-in patients is warranted.
556 Identification of two distinct allergenic sites of a rye grass pollen allergen, Lol p IV
Authors: K.S. Jaggi, A.K.M. Ekramoddoullah, F.T. Kisil, J.M.M. Dzuba-Fischer, E.S. Rector, A.H. Sehon
Journal: Journal of Allergy and Clinical Immunology (1988)
ESCMID-EUCIC clinical guidelines on decolonization of multidrug-resistant Gram-negative bacteria carriers
Authors: E. Tacconelli, F. Mazzaferri, A.M. de Smet, D. Bragantini, P. Eggimann, B.D. Huttner, E.J. Kuijper, J.-C. Lucet, N.T. Mutters, M. Sanguinetti, M.J. Schwaber, M. Souli, J. Torre-Cisneros, J.R. Price, J. Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2019)

ScopeThe aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all settings.MethodsThese evidence-based guidelines were produced after a systematic review of published studies on decolonization interventions targeting the following MDR-GNB: third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE), carbapenem-resistant Enterobacteriaceae (CRE), aminoglycoside-resistant Enterobacteriaceae (AGRE), fluoroquinolone-resistant Enterobacteriaceae (FQRE), extremely drug-resistant Pseudomonas aeruginosa (XDRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), cotrimoxazole-resistant Stenotrophomonas maltophilia (CRSM), colistin-resistant Gram-negative organisms (CoRGNB), and pan-drug-resistant Gram-negative organisms (PDRGNB). The recommendations are grouped by MDR-GNB species. Faecal microbiota transplantation has been discussed separately. Four types of outcomes were evaluated for each target MDR-GNB:(a) microbiological outcomes (carriage and eradication rates) at treatment end and at specific post-treatment time-points; (b) clinical outcomes (attributable and all-cause mortality and infection incidence) at the same time-points and length of hospital stay; (c) epidemiological outcomes (acquisition incidence, transmission and outbreaks); and (d) adverse events of decolonization (including resistance development). The level of evidence for and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached through a nominal-group technique for the final list of recommendations.RecommendationsThe panel does not recommend routine decolonization of 3GCephRE and CRE carriers. Evidence is currently insufficient to provide recommendations for or against any intervention in patients colonized with AGRE, CoRGNB, CRAB, CRSM, FQRE, PDRGNB and XDRPA. On the basis of the limited evidence of increased risk of CRE infections in immunocompromised carriers, the panel suggests designing high-quality prospective clinical studies to assess the risk of CRE infections in immunocompromised patients. These trials should include monitoring of development of resistance to decolonizing agents during treatment using stool cultures and antimicrobial susceptibility results according to the EUCAST clinical breakpoints.
Cost and effectiveness of genetic testing in metastatic colorectal cancer (mCRC) at Montefiore Medical Center (MMC).
Authors: Nadia Ashai, Matthew Stuart, Devika Rao, Mateo Mejia Saldarriaga, Wei Zhang, Renee Huang, Rahul Narang, Jennifer W. Chuy, Andreas Kaubisch, Sanjay Goel, Balazs Halmos, Lakshmi Rajdev
Journal: Journal of Clinical Oncology (2019)

643 Background: Upfront testing for MSI, and mutations in KRAS, NRAS, and BRAF is recommended. The most cost-effective way of obtaining this information remains unclear. We examined cost of broad next generation sequencing (NGS), in comparison to hotspot (HT) and individual target (IT) testing in patients with mCRC with Medicare (MC) and commercial insurance (CI) at MMC. As a surrogate of effectiveness, we hypothesize that patients with NGS are more likely to enroll in clinical trials. Methods: Cost of individual and hotspot tests were derived from known reimbursement rates with insurances affiliated with MMC. Due to ongoing changes in current procedural terminology for NGS, we used known reimbursement amounts from our patients. We applied these costs to a model population of 1,000,000 people. We then evaluated clinical trial enrollment of patients who had either NGS or hotspot/individual testing. Results: MC costs for IT, HT, NGS testing were $1,504, $752, and $4,680 respectively. CI costs were $1,910, $814, $2,366 for IT, HT, and NGS testing respectively. When applied to our model population, NGS cost $914,604 and $1,131,016 more than individual and hot spot testing respectively for MC patients, and $21,432 and $72,924 more for CI patients. Analysis of effectiveness included 136 patients, wherein 8% of those with NGS (n = 5/61) were enrolled in clinical trials as a result of testing compared to 1% of those with HT/IT (n = 1/75). Conclusions: Broad spectrum NGS costs more than individual or hot spot testing in mCRC. However, patients with NGS testing were more likely to be enrolled in clinical trials, suggesting the need for studies to further evaluate ideal testing modality. [Table: see text]
Effect of High-Intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia
Authors: Kari Nytrøen, Katrine Rolid, Arne Kristian Andreassen, Marianne Yardley, Einar Gude, Dag Olav Dahle, Elisabeth Bjørkelund, Anne Relbo Authen, Ingelin Grov, Julia Philip Wigh, Christian Have Dall, Finn Gustafsson, Kristjan Karason, Lars Gullestad
Journal: Circulation (2019)

There is no consensus on how, when, or at what intensity exercise should be performed after heart transplantation (HTx). We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in the maintenance state after HTx, but studies have not investigated HIT effects in the de novo HTx state. We hypothesized that HIT could be introduced early after HTx and that it could lead to clinically meaningful increases in exercise capacity and health-related quality of life.This multicenter, prospective, randomized, controlled trial included 81 patients a mean of 11 weeks (range, 7-16 weeks) after an HTx. Patients were randomized 1:1 to 9 months of either HIT (4×4-minute intervals at 85%-95% of peak effort) or moderate-intensity continuous training (60%-80% of peak effort). The primary outcome was the effect of HIT versus moderate-intensity continuous training on the change in aerobic exercise capacity, assessed as the peak oxygen consumption (Vo2peak). Secondary outcomes included tolerability, safety, adverse events, isokinetic muscular strength, body composition, health-related quality of life, left ventricular function, hemodynamics, endothelial function, and biomarkers.From baseline to follow-up, 96% of patients completed the study. There were no serious exercise-related adverse events. The population comprised 73% men, and the mean±SD age was 49±13 years. At the 1-year follow-up, the HIT group demonstrated greater improvements than the moderate-intensity continuous training group; the groups showed significantly different changes in the Vo2peak (mean difference between groups, 1.8 mL·kg-1·min-1), the anaerobic threshold (0.28 L/min), the peak expiratory flow (11%), and the extensor muscle exercise capacity (464 J). The 1.8-mL·kg-1·min-1 difference was equal to ≈0.5 metabolic equivalents, which is regarded as clinically meaningful and relevant. Health-related quality of life was similar between the groups, as indicated by results from the Short Form-36 (version 2), Hospital Anxiety and Depression Scale, and a visual analog scale.We demonstrated that HIT was a safe, efficient exercise method in de novo HTx recipients. HIT, compared with moderate-intensity continuous training, resulted in a clinically significantly greater change in exercise capacity based on the Vo2peak values (25% versus 15%), anaerobic threshold, peak expiratory flow, and muscular exercise capacity.URL: https://www.clinicaltrials.gov . Unique identifier NCT01796379.
Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems
Authors: Nicolas Michalski, Christine Petit
Journal: Annual Review of Neuroscience (2019)

The genetic approach, based on the study of inherited forms of deafness, has proven to be particularly effective for deciphering the molecular mechanisms underlying the development of the peripheral auditory system, the cochlea and its afferent auditory neurons, and how this system extracts the physical parameters of sound. Although this genetic dissection has provided little information about the central auditory system, scattered data suggest that some genes may have a critical role in both the peripheral and central auditory systems. Here, we review the genes controlling the development and function of the peripheral and central auditory systems, focusing on those with demonstrated intrinsic roles in both systems and highlighting the current underappreciation of these genes. Their encoded products are diverse, from transcription factors to ion channels, as are their roles in the central auditory system, mostly evaluated in brainstem nuclei. We examine the ontogenetic and evolutionary mechanisms that may underlie their expression at different sites.
CMS subtypes characterized by high TMB shows immunosuppressive microenvironment that implies resistance to immunotherapy.
Authors: Christopher Szeto, Chad Garner, Kevin Kazmierczak, Charles Joseph Vaske, Stephen Charles Benz, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2019)

610 Background: Tumor mutational burden (TMB) is emerging as an important biomarker for immune checkpoint therapy (ICT) response. Yet even in the context of high TMB, ICT are likely ineffective in an immuno-suppressed microenvironment. Here we demonstrate that a well-characterized subtype of CRC, CMS2, associated with Wnt pathway activation, is immunosuppressive despite high TMB. Methods: Tumor/normal-paired DNAseq (WGS or WES) and deep RNAseq (∼200x10 6 reads per tumor) was performed on 464 GI tumors from a commercial database. Samples were classified as high TMB if they had &gt; 200 non-synonymous exonic mutations as previously established (Rizvi et al, 2015). Each sample was assigned to one of the colorectal Consensus Molecular subtypes (CMS) based on RNA classification. A curated panel of 109 genes that discriminate between 22 immune subsets was identified. For each of these immune signatures, a database containing 1880 unselected tumors was used to define a distribution of expression. The study samples were then scored for their deviances within such distributions. Significant enrichment was analyzed between immune subsets, CMS types, TMB status, and somatic mutational status. Results: Compared to other subtypes, CMS1 &amp; CMS2 were significantly high-TMB (adj. p &lt; 3.8E-4 &amp; p &lt; 4.7E-3 respectively). Perplexingly, CMS2 had significantly lower expression of 11 well-established checkpoint and TME markers including LAG3 and PDL1 (adj. p 1.5E-2 &amp; 2.9E-9 respectively), while CMS1 (MSI-enriched) expresses selected TME markers more than other subtypes (PDL1 adj. p &lt; 4.0E-6 &amp; LAG3 adj. p &lt; 1.0E-6). As expected, CMS2 tumors were significantly enriched for likely pathogenic variants in the Wnt-associated gene APC (adj. p &lt; 1.3E-8). Immune-deconvolution indicated substantial exclusion of Tem cells from CMS2 tumors, in line with Wnt/b-catenin blockade of TcmàTem maturation for immunoreactivity. Conclusions: The most common subtype of CRC, CMS2 (~37%), is highly immunosuppressive despite high TMB. ICT is only effective in an immunologically active microenvironment. TMB alone as a biomarker likely is insufficient to indicate the effectiveness of immunotherapy.
Abstract 18188: Ito Enhancement Leads to Electromechanically Discordant Alternans and Conduction Block Due Ca-Induced Postrepolarization Refractoriness: Arrhythmogenesis in Brugada Syndrome
Authors: Sufen Wang, Moisés Rodríguez-Mañero, Sergio Ibarra-Cortez, Bahij Kreidieh, Elvin Blanco, Miguel Valderrabano
Journal: Circulation (2017)

Introduction: The mechanisms of arrhtyhmogenesis in Brugada Syndrome (BrS) involve the transient outward current Ito.NS5806 (NS, an Ito activator) has been reported to reproduce BrS. Itois known to modulate electromechanical (EM) coupling. Hypothesis: Ito enhancement leads to arrhythmogenic disruption of EM coupling. Methods: We optically mapped action potential (AP) and Ca2+ transient (Ca) in isolated rabbit hearts using incremental pacing protocols to induce alternans and ventricular tachycardia/fibrillation (VT/VF). Alternans spatial and EM (AP and Ca) phase concordance was assessed. NS5806 (15-45 μM, NS) was used as an Ito activator. Results: At baseline, alternans was induced at pacing cycle length (PCL) of 215±7ms, of which became spatially discordant in 70% and EM discordant in 20% at PCL(128±15ms). NS facilitated the occurrence of alternans at slower PCL (301±12), and made alternans EM discordant from its onset (Figure). Pacing induced VT/VF in 10/13 after NS vs 6/20 at BL (all p <0.05). EM discor...
The association of Native American and European ancestry with Atopy, Asthma and Lung function in Asthma Cases and Controls from Peru
Authors: Ayobami T. Akenroye, Michelle Daya, Karina Romero, Tonya M. Brunetti, Meher Preethi Boorgula, Nicholas M. Rafaels, Kathleen C. Barnes, William Checkley, Nadia Hansel, Rasika A. Mathias
Journal: Journal of Allergy and Clinical Immunology (2019)
Uterine Cancer Concern
Authors: Bridget Kuehn
Journal: JAMA (2019)

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Long-Distance Benefits of Marine Reserves: Myth or Reality?
Authors: Stéphanie Manel, Nicolas Loiseau, Marco Andrello, Katharina Fietz, Raquel Goñi, Aitor Forcada, Philippe Lenfant, Stuart Kininmonth, Concepción Marcos, Virginie Marques, Sandra Mallol, Angel Pérez-Ruzafa, Corinna Breusing, Oscar Puebla, David Mouillot
Journal: Trends in Ecology & Evolution (2019)