tbuckley/cabot-search huggingface dataset:
Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics
Authors: Joshua Rowland, Artur Akbarov, James Eales, Xiaoguang Xu, John P. Dormer, Hui Guo, Matthew Denniff, Xiao Jiang, Parisa Ranjzad, Alicja Nazgiewicz, Priscilla Ribeiro Prestes, Andrzej Antczak, Monika Szulinska, Ingrid A. Wise, Ewa Zukowska-Szczechowska, Pawel Bogdanski, Adrian S. Woolf, Nilesh J. Samani, Fadi J. Charchar, Maciej Tomaszewski
Journal: Kidney International (2019)

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
Sixty seconds on . . . waiting times
Authors: Nigel Hawkes
Journal: BMJ (2019)

This year the traditional lament has fallen silent. There’s even been some positive mood music from NHS England, claiming in its weekly reports that the system is working well.

December 2018 wasn’t bad, to be fair: bed occupancy, emergency department waiting times, and ambulance handover delays were all better than in December 2017.

I am. But, since then, …
Phase I study of nivolumab (Nivo) + <i>nab</i>-paclitaxel (<i>nab</i>-P) + gemcitabine (Gem) in advanced pancreatic cancer (APC).
Authors: Zev A. Wainberg, Howard S. Hochster, Edward Jae-Hoon Kim, Ben George, Aparna Kalyan, E. Gabriela Chiorean, David Michael Waterhouse, Martin Gutierrez, Aparna Raj Parikh, Rishi Jain, Daniel R. Carrizosa, Hatem Hussein Soliman, Rafia Bhore, Sibabrata Banerjee, Larry Lyons, Chrystal Ursula Louis, Teng Jin Ong, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2019)

298 Background: Chemotherapy may work synergistically with immune checkpoint inhibitors by increasing tumor antigen exposure. This 2-part phase I study assessed safety and efficacy of Nivo + nab-P + Gem in APC. Methods: Treatment-naive patients (pts) with APC (locally advanced or metastatic) received nab-P 125 mg/m 2 + Gem 1000 mg/m 2 on d 1, 8, and 15 + Nivo 3 mg/kg on d 1 and 15 of each 28-d cycle until disease progression (PD), unacceptable toxicity, or withdrawal. Pts could continue Nivo alone beyond initial PD. Part 1 assessed dose-limiting toxicities (DLTs) and determined the recommended Part 2 dose; Part 2 (expansion phase) further assessed safety. The primary endpoints were DLTs (Part 1) and safety and tolerability (Parts 1 and 2). Key secondary endpoints were response rates, progression-free survival (PFS), and overall survival (OS). Results: As of July 13, 2018, 50 pts with APC were treated: 6 in Part 1; 44 in Part 2. The median age was 67.5 years; 56% were male; 62% had an ECOG PS 1. Of 40 pts with available data, 12 (24%) had ≥ 1% and 6 (12%) had ≥ 5% PD-L1 expression at baseline (data missing for 10 pts). The median follow-up was 11.3 mo. In Part 1, 1 DLT (hepatitis, as evidenced by grade 3 elevated liver function tests; suspected to be related to nab-P + Gem) was reported. In Parts 1 and 2, 48 pts (96%) had ≥ 1 grade 3/4 TEAE; 7 (14%) discontinued treatment due to a TEAE. Most common (&gt; 10%) grade 3/4 TEAEs of special interest were anemia (36%), neutropenia (36%), gastrointestinal events (24%), hepatic toxicity (22%), peripheral neuropathy (16%), thrombocytopenia (12%), and colitis (12%). One grade 5 TEAE, respiratory failure (most likely pneumonitis), was reported. The table shows treatment responses. Of 7 pts (14%) who continued Nivo beyond initial PD, 4 achieved disease control. The median PFS was 5.5 mo (6-mo PFS rate, 47%). The median OS was 9.9 mo (6-mo OS rate, 73%). Conclusions: Combining Nivo with nab-P + Gem is feasible in pts with APC: 1 DLT was reported, and no unexpected safety signals were detected. Clinical trial information: NCT02309177. [Table: see text]
Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape
Authors: Xianjie Jiang, Jie Wang, Xiangying Deng, Fang Xiong, Junshang Ge, Bo Xiang, Xu Wu, Jian Ma, Ming Zhou, Xiaoling Li, Yong Li, Guiyuan Li, Wei Xiong, Can Guo, Zhaoyang Zeng
Journal: Molecular Cancer (2019)

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.
Abstract 15552: Interferon Regulatory Factors 3 and 7 Regulate Vein Graft Remodeling via Tumor Necrosis Factor Induced Macrophage Accumulation
Authors: Karin H Simons, Margreet R de Vries, Erna A Peters, Jaap F Hamming, J. W Jukema, Paul H Quax
Journal: Circulation (2016)

Introduction: Vein grafts are used to bypass atherosclerotic lesions; however, patency rates of these grafts are poor. Inflammation driven by toll like receptors (TLRs) is a major cause of vein gra...
NRF2 Activation in Cancer: From DNA to Protein
Authors: Erica W. Cloer, Dennis Goldfarb, Travis P. Schrank, Bernard E. Weissman, Michael B. Major
Journal: Cancer Research (2019)

Abstract The Cancer Genome Atlas catalogued alterations in the Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2–related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across 226 studies, with significant enrichment in lung and upper airway cancers. These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming. Almost universally, NRF2 activity strongly associates with poor patient prognosis and chemo- and radioresistance. Yet to date, FDA-approved drugs targeting NRF2 activity in cancer have not been realized. Here, we review various mechanisms that contribute to NRF2 activation in cancer, organized around the central dogma of molecular biology (i) at the DNA level with genomic and epigenetic alterations, (ii) at the RNA level including differential mRNA splicing and stability, and (iii) at the protein level comprising altered posttranslational modifications and protein–protein interactions. Ultimately, defining and understanding the mechanisms responsible for NRF2 activation in cancer may lead to novel targets for therapeutic intervention.
Cancer statistics for African Americans, 2019
Authors: Carol E. DeSantis, Kimberly D. Miller, Ann Goding Sauer, Ahmedin Jemal, Rebecca L. Siegel
Journal: CA A Cancer Journal for Clinicians (2019)

In the United States, African American/black individuals bear a disproportionate share of the cancer burden, having the highest death rate and the lowest survival rate of any racial or ethnic group for most cancers. To monitor progress in reducing these inequalities, every 3 years the American Cancer Society provides the estimated number of new cancer cases and deaths for blacks in the United States and the most recent data on cancer incidence, mortality, survival, screening, and risk factors using data from the National Cancer Institute, the North American Association of Central Cancer Registries, and the National Center for Health Statistics. In 2019, approximately 202,260 new cases of cancer and 73,030 cancer deaths are expected to occur among blacks in the United States. During 2006 through 2015, the overall cancer incidence rate decreased faster in black men than in white men (2.4% vs 1.7% per year), largely due to the more rapid decline in lung cancer. In contrast, the overall cancer incidence rate was stable in black women (compared with a slight increase in white women), reflecting increasing rates for cancers of the breast, uterine corpus, and pancreas juxtaposed with declining trends for cancers of the lung and colorectum. Overall cancer death rates declined faster in blacks than whites among both males (2.6% vs 1.6% per year) and females (1.5% vs 1.3% per year), largely driven by greater declines for cancers of the lung, colorectum, and prostate. Consequently, the excess risk of overall cancer death in blacks compared with whites dropped from 47% in 1990 to 19% in 2016 in men and from 19% in 1990 to 13% in 2016 in women. Moreover, the black-white cancer disparity has been nearly eliminated in men <50 years and women ≥70 years. Twenty-five years of continuous declines in the cancer death rate among black individuals translates to more than 462,000 fewer cancer deaths. Continued progress in reducing disparities will require expanding access to high-quality prevention, early detection, and treatment for all Americans.
Abstract 18704: Composition Dependence of the Clot Stabilizing Potential of Transfusion Plasmas
Authors: Thomas Orfeo, Matthew Gissel, Maria Cristina Bravo, Mark Fung, Kathleen Brummel-Ziedins
Journal: Circulation (2016)

Introduction: Each transfusion unit of fresh frozen plasma (FFP) is produced from an individual blood donor and can vary two to threefold in the concentrations of the procoagulant, anticoagulant, p...
Risk of venous thromboembolism in ankylosing spondylitis: a general population-based study
Authors: Juan Antonio Aviña-Zubieta, Jonathan Chan, Mary De Vera, Eric C Sayre, Hyon Choi, John Esdaile
Journal: Annals of the Rheumatic Diseases (2019)

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis (DVT), can be life threatening. An increased frequency of VTE has been found in inflammatory conditions. To date, evidence assessing whether this risk is also greater in patients with ankylosing spondylitis (AS) is scarce.Using the provincial British Columbia, Canada healthcare database that encompasses all residents within the province, we conducted matched cohort analyses of incident PE, DVT and overall VTE among incident cases of AS and compared them with individuals randomly selected from the general population without AS. We calculated incidence rates (IRs) of VTE and multivariable analyses after adjusting for traditional risk factors using Cox models.Among 7190 incident cases of AS, 35 developed PE and 47 developed DVT. IRs of PE, DVT and overall VTE per 1000 person-years for patients with AS were 0.79, 1.06, 1.56 compared with 0.40, 0.50, 0.77 in the control cohort. Corresponding fully adjusted HRs (95% CI) of PE, DVT and VTE were 1.36 (0.92 to 1.99), 1.62 (1.16 to 2.26) and 1.53 (1.16 to 2.01), respectively. The risks of PE, DVT and VTE were highest in the first year of diagnosis with HR (95% CI) of 2.88 (0.87 to 9.62), 2.20 (0.80 to 6.03) and 2.10 (0.88 to 4.99), respectively.These findings demonstrate an increased risk of VTE in the general AS population. This risk appears the most prominent in the first year after diagnosis.
Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma
Authors: Bradley D. Shields, Brian Koss, Erin M. Taylor, Aaron J. Storey, Kirk L. West, Stephanie D. Byrum, Samuel G. Mackintosh, Rick Edmondson, Fade Mahmoud, Sara C. Shalin, Alan J. Tackett
Journal: Cancer Research (2019)

Abstract Identifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first in vivo evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo. Transplantation of B16.Ecad into Rag1−/− and CD103−/− mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103+ mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin–expressing tumors and suggests therapeutic advancement through amplifying CD103+ immune cell subsets. Significance: These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103+ immune cells as a therapeutic strategy against other E-cadherin–expressing malignancies.
Abstract 17981: Decreased Oscillatory Pattern of Sympathetic Nerve Activity is Associated With Arterial Baroreflex Dysfunction in Chronic Heart Failure Patients
Authors: Edgar Toschi-Dias, Raphaela V Groehs, Ligia M Antunes-Correa, Patrícia F Trevizan, Denise M Lobo, Patrícia Oliveira, Maria Janieire N Alves, Dirceu R Almeida, Carlos Eduardo Negrao, Maria Urbana P Rondon
Journal: Circulation (2015)

Background: Sympathetic activation and arterial baroreflex (ABR) dysfunction typify chronic heart failure (CHF). In addition, decreased oscillatory pattern of muscle sympathetic nerve activity (MSNA, LF MSNA /HF MSNA ) seems to contribute to sympathetic exacerbation in patients with CHF. Unknown is whether the LF MSNA /HF MSNA is associated with ABR dysfunction in CHF patients. To answer this question, we investigated the association between gain, latency and coupling of ABR function and LF MSNA /HF MSNA in CHF patients. Methods and Results: Forty-three CHF patients, Functional Class II to III, NYHA, ejection fraction ≤40% were allocated into two groups according to the level of LF MSNA /HF MSNA index: 1) Higher LF MSNA /HF MSNA (n=21, 52±2 years) and 2) Lower LF MSNA /HF MSNA (n=22, 54±1 years). Blood pressure (BP, oscillometric beat-to-beat basis) and MSNA (microneurography technique) were recorded during 10 min at rest. Spectral and cross-spectral analyses of BP and MSNA variabilities were conducted to assess the LF MSNA /HF MSNA and the gain, latency and coupling between BP and MSNA of ABR function. Etiology, ejection fraction, gain and latency of ABR function were similar between groups. However, the patients with lower LF MSNA /HF MSNA had increased MSNA bursts frequency (53±2vs. 39±3 bursts/min, P&lt;0.01) and total activity (180±15 vs. 126±17 a.u, P=0.03) compared to the patients with higher LF MSNA /HF MSNA . In contrast, the patients with lower LF MSNA /HF MSNA had reduced coupling of ABR function (69±3 vs. 80±2 %, P&lt;0.01). Further analysis showed a significant association between the coupling of ABR function and LF MSNA /HF MSNA (R=0.36, P=0.02). Conclusions: There is an inverse association between the LF MSNA /HF MSNA index and sympathetic nerve activity. In addition, there is a direct association between the LF MSNA /HF MSNA index and the coupling of ABR, which suggests that the ABR dysfunction explains, at least in part, the augmented sympathetic nerve activity in CHF patients.
Abstract 18230: Very Low Rates of LDL Goal Attainment in Real Clinical Setting: Interim Results of a Nation-wide Registry of Familial Hypercholesterolemia in Turkey (A-HIT 2)
Authors: Meral Kayikcioglu, Lale Tokgozoglu, Volkan Dogan, Ceyhun Ceyhan, Abdullah Tuncez, Merih Kutlu, Ersel Onrat, Gokhan Alici, Mehmet Akbulut, Ahmet Celik, Tayfun Sahin, Alper Sonmez, Oner Ozdogan, Ahmet Temizhan, Salih Kilic, Fahri Bayram, Tevfik Sabuncu, Fatma Yilmaz Coskun, Muge Ildizli, Emre Durakoglugil, Mehmet Birhan Yilmaz, Aytul Belgi Yildirim
Journal: Circulation (2017)

Introduction: Familial hypercholesterolemia (FH) is a common genetic disease of high levels of cholesterol leading to premature atherosclerosis. Attainment of LDL-goals with lipid-lowering is the m...
Alpha-1 Antitrypsin improves engraftment in a rat model of hepatocyte transplantation through inhibition of the innate immune system
Authors: Charlotte A. Lee, Anil Dhawan, Ragai R. Mitry, Sharon Lehec, Valeria Iansante, Raquel Fernandez-Dacosta, Celine Filippi, Anil Chandrashekran, Muhammed Yuksel, Yun Ma, Maria Koulmanda, Terry Strom, Emer Fitzpatrick
Journal: Hepatology (2017)
Actions in Support of Newborn Screening for Critical Congenital Heart Disease — United States, 2011–2018
Authors: Jill Glidewell, Scott D. Grosse, Tiffany Riehle-Colarusso, Nelangi Pinto, Jeff Hudson, Rachel Daskalov, Amy Gaviglio, Erin Darby, Sikha Singh, Marci Sontag
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In 2011, the U.S. Department of Health and Human Services added critical congenital heart disease (CCHD), which occurs in two of every 1,000 births, to the list of conditions recommended to states for universal newborn screening (1). Without early detection, infants with CCHD are at risk for substantial morbidity and death in the first weeks and months of life (2). Based on 2007-2013 data, deaths from CCHD and other cardiac causes in infants aged <6 months significantly declined in infants born in eight states after they had fully implemented mandated newborn CCHD screening policies by June 2013 (3). CDC collaborated with the American Academy of Pediatrics (AAP) and the Association of Public Health Laboratories' Newborn Screening Technical Assistance and Evaluation Program (NewSTEPs) to update a 2015 report (4) on states' actions toward adopting and implementing policies supporting CCHD newborn screening. In 2018, all 50 states and the District of Columbia (DC) had implemented CCHD screening policies, and, with one exception, all states mandated that screening be done (California mandates that screening be offered). However, not all states had data systems in place for tracking all screening results and outcomes. Ongoing evaluation activities, which rely on screening data, could help identify program improvement opportunities and monitor the impact of early identification of CCHD.
Abstract B41: Modeling bone development and cancer predisposition in Diamond Blackfan anemia (DBA)
Authors: Jimmy Hom, Brian Dulmovits, Luanne Peters, Adrianna Vlachos, Jeffrey M. Lipton, Lionel Blanc
Journal: Cancer Research (2018)

Abstract DBA is an inherited bone marrow failure syndrome characterized by pure red cell aplasia, congenital physical anomalies, and cancer predisposition, in particular an increased incidence of osteogenic sarcoma (O:E 42.44). In order to investigate the mechanism of defective bone development and ultimately oncogenesis, we used an in vitro model consisting of mouse embryonic stem cells gene trapped for the Ribosomal Protein 19 gene (Rps19) and developed an in vivo transgenic conditional mouse model with floxed Rps19 alleles and a bone-specific expressing Col1a1-CreER. Using a 23-day stepwise osteoblast differentiation model, haploinsufficient Rps19+/- mouse ES cells did not show differences in the ability to develop into mesodermal progenitors based on qPCR analysis of mesodermal transcription factors, but displayed a decreased ability to produce mature osteoblasts based upon decreased alizarin red staining. In addition, higher levels of the Trp53 protein were found in Rps19+/- mouse ES cells at both the pluripotent and mesodermal stages of differentiation. Further, Rps19+/- mouse ES cells presented with aberrant WNT signaling, as represented by decreased levels of β-catenin early in osteoblast differentiation and rising to higher levels towards late osteoblast differentiation. We assessed the hypothesis of WNT signaling involvement in lineage specification and found that Rps19+/- mouse ES cell-derived osteoblasts show decreased levels of Runx2 and increased levels of Sox9. In the transgenic mouse model, tamoxifen-induced recombination of Rps19 at E15-17 did not show gross morphologic skeletal defects at E20.5 for Rps19fl/+ embryos, although Rps19fl/fl embryos displayed severe skeletal defects through alizarin red and alcian blue staining. In conclusion, haploinsufficient levels of Rps19 found in mice contribute to improper skeletal development and probably reflect the clinical scenario. We plan to utilize these in vitro and in vivo models to provide clues into the mechanism of ribosomal protein haploinsufficiency in tumor development, which may suggest surveillance and treatment strategies. Citation Format: Jimmy Hom, Brian Dulmovits, Luanne Peters, Adrianna Vlachos, Jeffrey M. Lipton, Lionel Blanc. Modeling bone development and cancer predisposition in Diamond Blackfan anemia (DBA) [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B41.
The Role of Donor Selection for a Second Allogeneic Stem Cell Transplantation in Patients with AML Relapsing after a First Transplant; A Study on Behalf of the Acute Leukemia Working Party of EBMT
Authors: Avichai Shimoni, Myriam Labopin, Jürgen Finke, Fabio Ciceri, Eric Deconinck, Nicolaus Kröger, Martin Gramatzki, Matthias Stelljes, Didier Blaise, Friedrich Stoelzel, Patrice Chevallier, Ernst Holler, Nathalie Fegueux, Mohamad Mohty, Arnon Nagler
Journal: Blood (2018)
Abstract 19639: The Pulse Pressure Stress Index: A Simple and Novel Exercise-Based Risk Factor for Adverse Cardiovascular Outcomes. Results From the Henry Ford ExercIse Testing (FIT) Project
Authors: Mahmoud S Al Rifai, John McEvoy, Michael Blaha, Clinton Brawner, Al Mallah Mouaz, Steven Keteyian, Jonathan K Ehrman
Journal: Circulation (2017)

Introduction: Pulse pressure (PP) is directly influenced by cardiac output and, hence, changes with physical activity. To our knowledge, no study has evaluated the prognostic significance of PP res...
Clonal Hematopoiesis in Older Women with Extremely Skewed, Non-Random X-Inactivation Is Associated with Previous Cardiovascular and Cerebrovascular Events
Authors: Emily Marre, Julia Erin Wiedmeier, Zhenzhen Zhang, Hyunjung Lee, Dana Parker, Kelsey Westerlund, Christopher A. Eide, Catherine Kato, Maros Ferencik, Brian J. Druker, Kim-Hien Dao
Journal: Blood (2018)