tbuckley/cabot-search huggingface dataset:
The RNA binding protein human antigen R is a gatekeeper of liver homeostasis
Authors: Pallavi Subramanian, Sofia Gargani, Alessandra Palladini, Margarita Chatzimike, Michal Grzybek, Mirko Peitzsch, Anastasios D. Papanastasiou, Iryna Pyrina, Vasileios Ntafis, Bettina Gercken, Mathias Lesche, Andreas Petzold, Anupam Sinha, Marina Nati, Veera Raghavan Thangapandi, Ioannis Kourtzelis, Margarita Andreadou, Anke Witt, Andreas Dahl, Ralph Burkhardt, Robert Haase, António Miguel de Jesus Domingues, Ian Henry, Nicola Zamboni, Peter Mirtschink, Kyoung‐Jin Chung, Jochen Hampe, Ünal Coskun, Dimitris L. Kontoyiannis, Triantafyllos Chavakis
Journal: Hepatology (2021)

NAFLD is initiated by steatosis and can progress through fibrosis and cirrhosis to HCC. The RNA binding protein human antigen R (HuR) controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte HuR in NAFLD development and progression to fibrosis and HCC.Hepatocyte-specific, HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or an NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis, and HCC development were studied by histology, flow cytometry, quantitative PCR, and RNA sequencing. The liver lipidome was characterized by lipidomics analysis, and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation sequencing. Hepatocyte-specific, HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition compared to control HuR-sufficient mice. On an NAFLD-inducing diet, hepatocyte-specific HuR deficiency resulted in exacerbated inflammation, fibrosis, and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics, and RNA immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady state, a triglyceride signature resembling that of NAFLD livers. Moreover, up-regulation of secreted phosphoprotein 1 expression mediated, at least partially, fibrosis development in hepatocyte-specific HuR deficiency on an NAFLD-inducing diet, as shown by experiments using antibody blockade of osteopontin.HuR is a gatekeeper of liver homeostasis, preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.
Coronary Artery Anomalies
Authors: Francesco Gentile, Vincenzo Castiglione, Raffaele De Caterina
Journal: Circulation (2021)

Coronary artery anomalies (CAAs) are a group of congenital conditions characterized by abnormal origin or course of any of the 3 main epicardial coronary arteries. Although CAAs have been identified as a common underlying condition in young athletes with sudden cardiac death, the widespread use of invasive and noninvasive coronary imaging has led to increased recognition of CAAs among adults. CAAS are often discovered as an incidental finding during the diagnostic workup for ischemic heart disease. The clinical correlates and prognostic implication of CAAs remain poorly understood in this context, and guideline-recommended therapeutic choices are supported by a low level of scientific evidence. Several studies have examined whether assessment of CAA-related myocardial ischemia can improve risk stratification in these patients, suggesting that multimodality imaging and functional tests may be key in the management of CAAs. The aim of this review is to outline definitions, classification, and epidemiology of the most relevant CAAs, highlighting recent advances and the potential impact of multimodality evaluation, and to discuss current therapeutic opportunities.
P16.11 Vitamin C levels and the hypoxic pathway in human glioma tissues
Authors: E R Burgess, R L I Crake, E Phillips, H R Morrin, J A Royds, M C M Vissers, B A Robinson, G U Dachs
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Gliomas are the most common brain cancer and survival is poor, with 11–15 months for high-grade glioblastoma patients, despite treatment. Gliomas are hypoxic tumours, which increases with tumour grade. Under hypoxia, the transcription factor hypoxia inducible factor-1 (HIF) accumulates and upregulates expression of genes involved in tumour development and progression. HIF-1 levels and activity are controlled by HIF hydroxylases which target HIF-1α for degradation and prevent co-activation. HIF hydroxylases are part of the 2-oxoglutarate (2-OG)-dependent dioxygenase enzyme family, that require 2-OG and oxygen as substrates and ascorbate and iron as co-factors. The role of ascorbate in regulating the hypoxic pathway in cancer is of interest, with previous research showing reduced HIF pathway activity with increasing tumour ascorbate levels. Brain tissue has one of the highest ascorbate levels in the body, and is one of the last to become depleted under deficiency, indicating an important role for ascorbate in this tissue. One previous study has analysed ascorbate levels in 11 human glioblastoma patients, and showed lower ascorbate in tumour tissue compared to normal brain tissue. There have been no studies investigating the relationship between ascorbate levels and the hypoxic pathway in human glioma tissues. MATERIAL AND METHODS Human glioma tissues (n = 39), obtained from the Cancer Society Tissue Bank Christchurch (ethics approval H19/163), were processed for ascorbate and hypoxic pathway proteins (HIF-1α, CA-IX, BNIP3, HKII, GLUT1 and VEGF). Ascorbate levels were quantified by HPLC-ED, and proteins were measured by Western blotting and ELISA. Spearman’s correlations were used to identify relationships between ascorbate and HIF pathway proteins. RESULTS Of the samples, 64% were GBM. Ascorbate was significantly lower in GBM compared to low-grade gliomas (p = 0.04). VEGF was significantly higher in GBM compared to astrocytomas (p = 0.01). Increased tumour ascorbate was associated with lower VEGF and CA-IX proteins. HIF-1α and BNIP3 protein were positively associated, and VEGF was positively associated with HKII and CA-IX. VEGF inversely associated with BNIP3, and CA-IX inversely associated with HKII. The hypoxic pathway score (calculated from protein levels of members of the hypoxic pathway) was reduced in tumours with higher ascorbate but this did not reach significance (p = 0.2). CONCLUSION This is the first study to show that ascorbate levels were reduced in high-grade gliomas compared to low-grade. Some members of the hypoxic pathway were associated with ascorbate levels. The overall hypoxic pathway score did not significantly correlate with ascorbate and increased numbers of samples are required to confirm any associations. Other variables, such as IDH-1 mutation status of the tumours may affect the correlation and will be analysed next.
Swabs by emergency responders (SWABBER): Enhancing care beyond the cancer center during the COVID-19 pandemic.
Authors: Olivia S. Allen, Mark Liu, Kevin Munjal, Rex Lomboy, Aarti Sonia Bhardwaj, Alma Abdallah, Natalie Massenburg, Shawn Casadiego, Cardinale B. Smith
Journal: Journal of Clinical Oncology (2021)

97 Background: The COVID-19 pandemic caused sudden changes in healthcare delivery, and new policies were rapidly implemented to ensure safety for patients and staff. However, COVID-19 testing requirements presented a barrier for many patients. Outdoor testing in New York City became less feasible during colder months, and oncology patients have additional concerns, such as limited mobility and immunosuppression. To address these barriers, we created an in-home COVID-19 testing program through a partnership between Community Paramedicine and Oncology: SWABBER (SWABS by Emergency Responders). We evaluated patient use of and satisfaction with SWABBER. Methods: SWABBER began in September 2020 as an interdisciplinary initiative to offer in-home, asymptomatic COVID-19 PCR testing for patients on active treatment in an effort to provide more coordinated care and improve patient experience. Tests were performed prior to the first day of each treatment cycle at no cost to patients. Randomly selected patients completed a brief survey about their experiences with the program, with questions on a seven-point Likert scale. Sociodemographic data was collected from the EMR, and we used a chi-square test to identify differences in patient use of SWABBER by race. Results: From September 8, 2020–April 1, 2021, we saw 7,204 patients for infusion, of whom 993 (14%) participated in SWABBER. The cohort of all patients receiving treatment was 45% White, 19% Black, 6% Asian, 29% Other, and 1% Unknown race. The SWABBER cohort was 36% White, 21% Black, 12% Asian, 29% Other, and 1% Unknown race. There was a significant difference in patient race between these two groups (P &lt; 0.00001), with more Black and Asian patients in SWABBER compared to all patients receiving treatment. A total of 406 (41%) SWABBER patients completed the patient experience survey. The mean scores for overall experience and likelihood of recommending the program were 6.9, with standard deviations of 0.56 and 0.44, respectively. Conclusions: SWABBER enabled us to deliver care directly to patients’ homes, mitigating COVID-19 exposure while promoting accessible care and providing an increased benefit for minority patients. Through SWABBER, we achieved near-perfect patient experience ratings, reduced the burden of testing, created a safer environment for patients and staff, and kept cancer care on track. Future work will evaluate ways to maintain elevated patient experience and continue striving for inclusive care beyond the pandemic.[Table: see text]
Perspectives on the Treatment of Malignant Pleural Mesothelioma
Authors: Sam M. Janes, Doraid Alrifai, Dean A. Fennell
Journal: New England Journal of Medicine (2021)

Most mesotheliomas originate in the pleura and are due to asbestos exposure. The incidence is decreasing somewhat with asbestos remediation, but mortality remains high in part because of late diagnosis and treatment resistance. Pemetrexed–cisplatin and immune checkpoint inhibitors modestly extend survival.
Where Should Orphaned and Separated Children and Adolescents Live: Comparing Institutionalized- and Family-Based Venues in Kenya
Authors: Sten H. Vermund
Journal: JAMA Network Open (2021)

Paula Braitstein, PhD, MA, MSc; Allison DeLong, MSc; David Ayuku, PhD; Mary Ott, MD, MPH; Lukoye Atwoli, MBChB, PhD; Omar Galárraga, PhD; Edwin Sang, MSc; Joseph Hogan, PhD
Methionine-free diet duration for optimal restriction in association with cystemustine treatment: A Phase I clinical trial.
Authors: Emilie Thivat, Xavier Durando, Eric Cellarier, Marie-Chantal Farges, Aicha Demidem, Hervé Curé, Jean-Claude Madelmont, Marie-Paule Vasson, Philippe Chollet
Journal: Cancer Research (2004)

3741  The growth of human and animal tumors with in vitro and in vivo models has been shown to be inhibited by dietary methionine (MET) restriction. Furthermore, cytostatic drugs (Fluoropyrimidines, nitrosoureas, platinoids,..) in association with MET restriction presented with a substantial improvement of their therapeutic index. Particularly, MET deprivation potentiated the effect of cystemustine treatment in B16 melanoma bearing mice (Cellarier et al, 2003. Cancer Treat Rev; 29, 489–499). On the basis of these experimental results, we initiated a phase I clinical trial of dietary MET restriction in association with cystemustine treatment for adults with recurrent gliomas or metastatic melanomas. This trial had for objective to determine the optimal methionine-free diet duration and the feasibility of this schedule associated to cystemustine delivery. Eight patients received bimonthly cycles of exclusive MET-free synthetic diet, which allowed testing randomly 4 periods of 1, 2, 3 or 4 consecutive regime days. Cystemustine (60 mg/m2) was given every 2 weeks at noon of the last day of each MET-free diet. Nutritional status was evaluated by physical examination and PINI, BMI determinations before and after diet. During each day of the experimental period, daily fasting (8 AM) and feeding (12 AM) concentrations of plasma methionine were measured. This MET-free diet coupled with cytemustine did not have a deleterious effect on nutritional status of patients. Moreover, myelosuppression remained moderate and no WHO grade III or IV hematologic toxicity was observed. Methionine concentrations after night fasting were not decreased in response to diet. Conversely, feeding methionine concentrations were reduced by dietary MET restriction level from 23.1 ± 1.2 μM to 11.6 ± 1.0 μM after one day of diet, represented by a decline of 48 ± 5 %. The optimal plasmatic depletion in Met was obtained at 1st day of regimen and the increase in duration did not increase the percentage of depletion. The absence of cumulative effect between 1 and 4 days of regimen could be linked to endogenous production of MET, increased protein catabolism and release from peripheral tissues during fasting state as evaluated by fasting MET plasmatic level. We intend to realize a phase II clinical trial to evaluate the putatively increased response rate of cystemustine with a 1 or 2 days dietary MET restriction.
Treatment for Alzheimer Disease—Sex and Gender Effects Need to Be Explicitly Analyzed and Reported in Clinical Trials
Authors: Janice B. Schwartz, Sandra Weintraub
Journal: JAMA Network Open (2021)

Julie Martinkova, MD; Frances-Catherine Quevenco, PhD; Helene Karcher, PhD; Alberto Ferrari, PhD; Else Charlotte Sandset, MD, PhD; Cassandra Szoeke, PhD, MBBS; Jakub Hort, MD, PhD; Reinhold Schmidt, MD; Antonella Santuccione Chadha, MD, PhD; Maria Teresa Ferretti, PhD
Selection of Neoadjuvant Treatment Arms in Trials of Patients With Squamous Cell Cancer of the Esophagus
Authors: Nikolaos A. Trikalinos, Clifford G. Robinson, Haeseong Park
Journal: JAMA Surgery (2021)

To the Editor We read with interest the article by Wang et al1 in JAMA Surgery. We congratulate the authors on undertaking a large, randomized study in a unique population; however, we wanted to bring up some concerns regarding the study rationale and results.
Outcomes of Care by Hospitalists
Authors: James S. Goodwin
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
The mucin protein MUCL1 regulates melanogenesis and melanoma genes in a manner dependent on threonine content*
Authors: J. Kim, H. Choi
Journal: British Journal of Dermatology (2021)

Background The regulation of melanogenesis has been investigated as a long-held aim for pharmaceutical manipulations with denotations for malignancy of melanoma. Mucins have a protective function in epithelial organs; however, in the most outer organ, the skin, the role of mucins has not been studied enough. Objectives Our initial hypothesis developed from the identification of correlations between pigmentation and expressions of skin mucins, particularly those existing in skin tissue. We aimed to investigate the action of mucins in human melanocytic cells. Materials and methods The expression of mucin proteins in human skin was investigated using microarray data from the Human Protein Atlas consortium (HPA) and the Genotype-Tissue Expression consortium (GTEx) database. Mucin expression was measured at RNA and protein levels in melanoma cells. The findings were further validated and confirmed by analysis of independent experiments. Results We found that the several mucin proteins showed expression in human skin cells and among these, mucin-like protein 1 (MUCL1) showed the highest expression and also clear negative correlation with melanogenesis in epidermal melanocytes. We confirmed the correlations between melanogenesis and MUCL1 by revealing negative correlations in melanocytes with different melanin production, resulting from increased composition of threonine, mucin-conforming amino acid, and increased autophagy-related forkhead-box O signalling. Furthermore, threonine itself affects melanogenesis and metastatic activity in melanoma cells. Conclusions We identified a significant association between MUCL1 and threonine with melanogenesis and metastasis-related genes in melanoma cells. Our results define a novel mechanism of mucin regulation, suggesting diagnostic and preventive roles of MUCL1 in cutaneous melanoma.
Changes in Treatment of Patients with Incident ESKD during the Novel Coronavirus Disease 2019 Pandemic
Authors: James B. Wetmore, Kirsten L. Johansen, Jiannong Liu, Yi Peng, David T. Gilbertson, Eric D. Weinhandl
Journal: Journal of the American Society of Nephrology (2021)

The COVID-19 pandemic caused major disruptions to care for patients with advanced CKD.
Poloxamer 188 vs Placebo for Painful Vaso-occlusive Episodes in Children and Adults With Sickle Cell Disease—Reply
Authors: James F. Casella, Shari S. Kronsberg, Rebecca T. Gorney
Journal: JAMA (2021)

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Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming
Authors: Samantha M Morrissey, Fan Zhang, Chuanlin Ding, Diego Elias Montoya-Durango, Xiaoling Hu, Chenghui Yang, Zhen Wang, Fang Yuan, Matthew Fox, Huang-Ge Zhang, Haixun Guo, David Tieri, Maiying Kong, Corey T Watson, Robert A Mitchell, Xiang Zhang, Kelly M McMasters, Jian Huang, Jun Yan
Journal: Cell Metabolism (2021)

One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
MORTALITY REDUCTION IN PATIENTS TREATED WITH LONG-TERM INTENSIVE LIPID THERAPY: 20-YEAR FOLLOW-UP OF THE FAMILIAR ATHEROSCLEROSIS TREATMENT STUDY- OBSERVATIONAL STUDY
Authors: Xue Qiao Zhao, Joseph Davis, Daniel Isquith, Alice Dowdy, Suzanne Boltz, Moni Neradilek, B. Greg Brown
Journal: Journal of the American College of Cardiology (2014)
PTCH1-GLI1 Fusion–Positive Ovarian Tumor: Report of a Unique Case With Response to Tyrosine Kinase Inhibitor Pazopanib
Authors: Rofieda R. Alwaqfi, Megan I. Samuelson, Natalya N. Guseva, Michelle Ouyang, Aaron D. Bossler, Deqin Ma
Journal: Journal of the National Comprehensive Cancer Network (2021)

Recurrent GLI1 gene fusions have been recently described in a subset of soft tissue tumors showing a distinct monotonous epithelioid morphology with a rich capillary network and frequent S100 protein expression. Three different fusion partners-ACTB, MALAT1, and PTCH1-have been reported with the PTCH1-GLI1 fusion from 2 patients only, both with head and neck tumors. Herein, we report for the first time a PTCH1-GLI1 fusion in a primary ovarian tumor from a female patient aged 54 years who presented with a 21-cm right ovarian mass and mesenteric metastasis. The tumor was diagnosed as "favor malignant melanoma" based on histologic examination and extensive immunohistochemistry studies. The patient received 4 cycles of pembrolizumab and 2 cycles of trabectedin but developed multiple metastases. A next-generation sequencing-based assay detected a PTCH1-GLI1 fusion, which led to a revised pathologic diagnosis and a change of the patient's management. The patient was switched to the tyrosine kinase inhibitor (TKI) pazopanib to target the sonic hedgehog pathway. Her disease was stable 49 months post TKI therapy. Our case report is the first to show that a tumor with GLI1 oncogenic activation was sensitive to a TKI. The morphologic and immunohistochemistry similarities of our patient's tumor to other recently described tumors harboring GLI1 fusions suggest that these tumors may all belong to the same entity of GLI1 fusion-positive neoplasms and may be treated similarly.
Inflammation during the life cycle of the atherosclerotic plaque
Authors: Peter Libby
Journal: Cardiovascular Research (2021)

Abstract Inflammation orchestrates each stage of the life cycle of atherosclerotic plaques. Indeed, inflammatory mediators likely link many traditional and emerging risk factors with atherogenesis. Atheroma initiation involves endothelial activation with recruitment of leucocytes to the arterial intima, where they interact with lipoproteins or their derivatives that have accumulated in this layer. The prolonged and usually clinically silent progression of atherosclerosis involves periods of smouldering inflammation, punctuated by episodes of acute activation that may arise from inflammatory mediators released from sites of extravascular injury or infection or from subclinical disruptions of the plaque. Smooth muscle cells and infiltrating leucocytes can proliferate but also undergo various forms of cell death that typically lead to formation of a lipid-rich ‘necrotic’ core within the evolving intimal lesion. Extracellular matrix synthesized by smooth muscle cells can form a fibrous cap that overlies the lesion’s core. Thus, during progression of atheroma, cells not only procreate but perish. Inflammatory mediators participate in both processes. The ultimate clinical complication of atherosclerotic plaques involves disruption that provokes thrombosis, either by fracture of the plaque’s fibrous cap or superficial erosion. The consequent clots can cause acute ischaemic syndromes if they embarrass perfusion. Incorporation of the thrombi can promote plaque healing and progressive intimal thickening that can aggravate stenosis and further limit downstream blood flow. Inflammatory mediators regulate many aspects of both plaque disruption and healing process. Thus, inflammatory processes contribute to all phases of the life cycle of atherosclerotic plaques, and represent ripe targets for mitigating the disease.