tbuckley/cabot-search huggingface dataset:
Perinatal Marijuana Use and the Developing Child
Authors: Lauren M. Jansson, Chloe J. Jordan, Martha L. Velez
Journal: JAMA (2018)

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The exerkine apelin reverses age-associated sarcopenia
Authors: Claire Vinel, Laura Lukjanenko, Aurelie Batut, Simon Deleruyelle, Jean-Philippe Pradère, Sophie Le Gonidec, Alizée Dortignac, Nancy Geoffre, Ophelie Pereira, Sonia Karaz, Umji Lee, Mylène Camus, Karima Chaoui, Etienne Mouisel, Anne Bigot, Vincent Mouly, Mathieu Vigneau, Allan F. Pagano, Angèle Chopard, Fabien Pillard, Sophie Guyonnet, Matteo Cesari, Odile Burlet-Schiltz, Marco Pahor, Jerome N. Feige, Bruno Vellas, Philippe Valet, Cedric Dray
Journal: Nature Medicine (2018)
Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models
Authors: Alex McCampbell, Tracy Cole, Amy J. Wegener, Giulio S. Tomassy, Amy Setnicka, Brandon J. Farley, Kathleen M. Schoch, Mariah L. Hoye, Mark Shabsovich, Linhong Sun, Yi Luo, Mingdi Zhang, Sai Thankamony, David W. Salzman, Merit Cudkowicz, Danielle L. Graham, C. Frank Bennett, Holly B. Kordasiewicz, Eric E. Swayze, Timothy M. Miller
Journal: Journal of Clinical Investigation (2018)

Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy.
Implications of the 2017 ACC/AHA Hypertension Guideline for Public Health in Nepal
Authors: David A. Watkins
Journal: JAMA Network Open (2018)

Gulam Muhammed Al Kibria, MBBS, MSPH; Krystal Swasey, MPH; Angela KC, MSPH; Mohammadhassan Mirbolouk, MD; Muhammad Nazmus Sakib, MBBS; Atia Sharmeen, MBBS; Mahmuda Jahan Chadni, MBBS, MSc; Kristen A. Stafford, MPH, PhD
Expression of vitamin D receptor in naevi and melanoma
Authors: C. del Puerto, C. Navarrete-Dechent, M. Molgó, C.A. Camargo, A. Borzutzky, S. González
Journal: British Journal of Dermatology (2018)

Deficiency of vitamin D is associated with an increased risk of cancer. Although its importance in malignant melanoma is debated, vitamin D does appear to suppress the growth of the non‐melanoma skin tumours basal cell carcinoma and squamous cell carcinoma. This study from Santiago, Chile, and Boston, USA, looked at whether the vitamin D receptor in melanoma cells was lost in comparison with mole cells. Both are formed from cells called melanocytes; the difference is that the melanocytes are malignant in melanoma, benign in moles. Melanoma samples were taken from 54 patients and compared with 55 samples of moles from patients with no history of melanoma or abnormal (“dysplastic”) moles. The melanoma samples were looked at down the microscope and classified according to standard measures such as thickness, depth of invasion into the skin, ulceration, etc. They were specially stained to show up the vitamin D receptor. The intensity of staining, and the numbers of cells that showed vitamin D receptor in both the nucleus and cytoplasm, were assessed. There was significant loss of the vitamin D receptor in the cytoplasm, though not the nucleus, of melanoma cells in comparison to mole cells. This was associated with the thickness and staging of the melanoma in the skin: the thicker the tumour, the more vitamin D receptor was lost. Similar findings have been reported in carcinomas of the prostate, stomach and pancreas. The degree of loss of vitamin D receptor may help decide which patients might benefit from taking vitamin D.
Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study
Authors: Samuele Cortese, Shihua Sun, Junhua Zhang, Esha Sharma, Zheng Chang, Ralf Kuja-Halkola, Catarina Almqvist, Henrik Larsson, Stephen V Faraone
Journal: The Lancet Psychiatry (2018)
Predictive Value of the High-Sensitivity Troponin T Assay and the Simplified Pulmonary Embolism Severity Index in Hemodynamically Stable Patients With Acute Pulmonary Embolism
Authors: MareikeLankeit, DavidJiménez, MaciejKostrubiec, ClaudiaDellas, GerdHasenfuss, PiotrPruszczyk, StavrosKonstantinides
Journal: Circulation (2011)

Background—The new, high-sensitivity troponin T (hsTnT) assay may improve risk stratification of normotensive patients with acute pulmonary embolism (PE). We externally validated the prognostic value of hsTnT, and of the simplified Pulmonary Embolism Severity Index (sPESI), in a large multicenter cohort. Methods and Results—We prospectively examined 526 normotensive patients with acute PE; of those, 31 (5.9%) had an adverse 30-day outcome. The predefined hsTnT cutoff value of 14 pg/mL was associated with a high prognostic sensitivity and negative predictive value, comparable to those of the sPESI. Both hsTnT ≥14 pg/mL (OR, 4.97 [95% CI, 1.71–14.43]; P=0.003) and sPESI ≥1 point(s) (OR, 9.51 [2.24–40.29]; P=0.002) emerged, besides renal insufficiency (OR, 2.97 [1.42–6.22]; P=0.004), as predictors of early death or complications; in a multivariable model, they remained independent predictors of outcome (P=0.044 and 0.012, respectively). A total of 127 patients (24.1%) were identified as low risk by a sPESI o...
Neoadjuvant Chemotherapy Reinforces Antitumour T cell Response in Urothelial Urinary Bladder Cancer
Authors: David Krantz, Ciputra Adijaya Hartana, Malin E. Winerdal, Markus Johansson, Farhood Alamdari, Tomasz Jakubczyk, Ylva Huge, Firas Aljabery, Karin Palmqvist, A. Ali Zirakzadeh, Benny Holmström, Katrine Riklund, Amir Sherif, Ola Winqvist
Journal: European Urology (2018)
Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis
Authors: Tamer B. Shabaneh, Aleksey K. Molodtsov, Shannon M. Steinberg, Peisheng Zhang, Gretel M. Torres, Gadisti A. Mohamed, Andrea Boni, Tyler J. Curiel, Christina V. Angeles, Mary Jo Turk
Journal: Cancer Research (2018)

Regulatory T cells (Treg) are critical mediators of immunosuppression in established tumors, although little is known about their role in restraining immunosurveillance during tumorigenesis. Here, we employ an inducible autochthonous model of melanoma to investigate the earliest Treg and CD8 effector T-cell responses during oncogene-driven tumorigenesis. Induction of oncogenic BRAFV600E and loss of Pten in melanocytes led to localized accumulation of FoxP3+ Tregs, but not CD8 T cells, within 1 week of detectable increases in melanocyte differentiation antigen expression. Melanoma tumorigenesis elicited early expansion of shared tumor/self-antigen-specific, thymically derived Tregs in draining lymph nodes, and induced their subsequent recruitment to sites of tumorigenesis in the skin. Lymph node egress of tumor-activated Tregs was required for their C-C chemokine receptor 4 (Ccr4)-dependent homing to nascent tumor sites. Notably, BRAFV600E signaling controlled expression of Ccr4-cognate chemokines and governed recruitment of Tregs to tumor-induced skin sites. BRAFV600E expression alone in melanocytes resulted in nevus formation and associated Treg recruitment, indicating that BRAFV600E signaling is sufficient to recruit Tregs. Treg depletion liberated immunosurveillance, evidenced by CD8 T-cell responses against the tumor/self-antigen gp100, which was concurrent with the formation of microscopic neoplasia. These studies establish a novel role for BRAFV600E as a tumor cell-intrinsic mediator of immune evasion and underscore the critical early role of Treg-mediated suppression during autochthonous tumorigenesis.Significance: This work provides new insights into the mechanisms by which oncogenic pathways impact immune regulation in the nascent tumor microenvironment. Cancer Res; 78(17); 5038-49. ©2018 AACR.
Associations between Living Near Water and Risk of Mortality among Urban Canadians
Authors: Dan L. Crouse, Adele Balram, Perry Hystad, Lauren Pinault, Matilda van den Bosch, Hong Chen, Daniel Rainham, Errol M. Thomson, Christopher H. Close, Aaron van Donkelaar, Randall V. Martin, Richard Ménard, Alain Robichaud, Paul J. Villeneuve
Journal: Environmental Health Perspectives (2018)

Background: Increasing evidence suggests that residential exposures to natural environments, such as green spaces, are associated with many health benefits. Only a single study has examined the potential link between living near water and mortality. Objective: We sought to examine whether residential proximity to large, natural water features (e.g., lakes, rivers, coasts, "blue space") was associated with cause-specific mortality. Methods: Our study is based on a population-based cohort of nonimmigrant adults living in the 30 largest Canadian cities [i.e., the 2001 Canadian Census Health and Environment Cohort) (CanCHEC)]. Subjects were drawn from the mandatory 2001 Statistics Canada long-form census, who were linked to the Canadian mortality database and to annual income-tax filings, through 2011. We estimated associations between living within 250m of blue space and deaths from several common causes of death. We adjusted models for many personal and contextual covariates, as well as for exposures to residential greenness and ambient air pollution. Results: Our cohort included approximately 1.3 million subjects at baseline, 106,180 of whom died from nonaccidental causes during follow-up. We found significant, reduced risks of mortality in the range of 12–17% associated with living within 250m of water in comparison with living farther away, among all causes of death examined, except with external/accidental causes. Protective effects were found to be higher among women and all older adults than among other subjects, and protective effects were found to be highest against deaths from stroke and respiratory-related causes. Conclusions: Our findings suggest that living near blue spaces in urban areas has important benefits to health, but further work is needed to better understand the drivers of this association. https://doi.org/10.1289/EHP3397
HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Black Men Who Have Sex with Men — Non–Health Care Facilities, 20 Southern U.S. Jurisdictions, 2016
Authors: Mariette Marano, Renee Stein, Wei Song, Deesha Patel, Nicole Taylor-Aidoo, Songli Xu, Lamont Scales
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Identifying HIV-infected persons who are unaware of their human immunodeficiency virus (HIV) infection status, linking them to care, and reducing health disparities are important national HIV prevention goals (1). Gay, bisexual, and other men who have sex with men (collectively referred to as MSM) accounted for 70% of HIV infection diagnoses in the United States in 2016, despite representing only 2% of the population (2,3). African American or black (black) MSM accounted for 38% of all new diagnoses of HIV infection among MSM (2). Nearly two thirds (63%) of all U.S. black MSM with diagnosed HIV infection reside in the southern United States (2), making targeted HIV prevention activities for black MSM in this region critical. Analysis of CDC-funded HIV testing data for black MSM submitted by 20 health departments in the southern United States in 2016 revealed that although black MSM received 6% of the HIV tests provided, they accounted for 36% of the new diagnoses in non-health care facilities. Among those who received new diagnoses, 67% were linked to HIV medical care within 90 days of diagnosis, which is below the 2020 national goal of linking at least 85% of persons with newly diagnosed HIV infection to care within 30 days (1). Black MSM in the southern United States are the group most affected by HIV, but only a small percentage of CDC tests in the southern United States are provided to this group. Increasing awareness of HIV status through HIV testing, especially among black MSM in the southern United States, is essential for reducing the risk for transmission and addressing disparities. HIV testing programs in the southern United States can reach more black MSM by conducting targeted risk-based testing in non-health care settings and by routine screening in agencies that also provide health care services to black MSM.
Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration
Authors: Ayman Oweida, Mohammad K. Hararah, Andy Phan, David Binder, Shilpa Bhatia, Shelby Lennon, Sanjana Bukkapatnam, Benjamin Van Court, Nomin Uyanga, Laurel Darragh, Hyun Min Kim, David Raben, Aik Choon Tan, Lynn Heasley, Eric Clambey, Raphael Nemenoff, Sana D. Karam
Journal: Clinical Cancer Research (2018)

Purpose: Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance.Experimental Design: Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti-PD-L1 or anti-TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody.Results: We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory.Conclusions: These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. Clin Cancer Res; 24(21); 5368-80. ©2018 AACR.
Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer
Authors: Seung Tae Kim, Razvan Cristescu, Adam J. Bass, Kyoung-Mee Kim, Justin I. Odegaard, Kyung Kim, Xiao Qiao Liu, Xinwei Sher, Hun Jung, Mijin Lee, Sujin Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Mingew Choi, AmirAli Talasaz, Peter Soonmo Kang, Jonathan Cheng, Andrey Loboda, Jeeyun Lee, Won Ki Kang
Journal: Nature Medicine (2018)
Dysregulated iron metabolism in polycythemia vera: etiology and consequences
Authors: Yelena Z. Ginzburg, Maria Feola, Eran Zimran, Judit Varkonyi, Tomas Ganz, Ronald Hoffman
Journal: Leukemia (2018)

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.
Countercurrent Exchange of Heat in the Dog Kidney
Authors: AsbjöRNRöED, Knutaukland
Journal: Circulation Research (1969)

The mechanisms of renal heat clearance were studied in anesthetized dogs by recording renal venous and cortical temperatures during step changes of arterial blood temperature induced by infusion of 0.9% saline of room temperature into the renal artery. The venous thermodilution curves were well described by a three-exponential function with average rate constants: k1 = 10.4 min-1, k2 = 2.2 min-1, and k3 = 0.59 min-1, and intercepts at 34%, 44%, and 22%, respectively. The various components were interpreted as follows: The slow component mainly represents heat conduction from inner medullary and perirenal tissue as shown by extrarenal temperature recording and by calculating the heat distribution volume. Local cortical recordings showed that cortex is not a homogeneous compartment, and k2 reflects an average cortical heat clearance, k1 is much higher than blood flow per gram of tissue in any kidney region and results from heat exchange between intrarenal arteries and veins. The arteriovenous diffusion of h...
Abstract 12936: Hepatic Steatosis and Cardiometabolic Risk in Rural India: A Prospective Cohort Study
Authors: Aferdita Spahillari, Anamitra Barik, Ravi V Shah, Venkatesh L Murthy, Ranendra Das, Rajesh K Rai, Kaushik Das, Amal Santra, Jaba Ranjan Hembram, Dilip Bhattacharya, Saumya Das, Abhijit Chowdhury
Journal: Circulation (2016)

Background: While liver fat is linked to metabolic disease in first-world environments, its prevalence and impact in rural locations are less clear. We aimed to measure the association between liver fat, cardiometabolic profiles and subclinical cardiovascular disease (CVD) in a large rural Indian cohort. Hypothesis: We hypothesized that despite lower BMI, the presence of liver fat would be related to cardiometabolic risk and subclinical CVD. Methods: In 4691 individuals in the Birbhum Population Project (BPP) in West Bengal, India, we performed liver ultrasonography, carotid ultrasound and biochemical and clinical profiling. We assessed the association of liver fat with risk factors (dysglycemia, dyslipidemia, hypertension) and subclinical CVD (by carotid intimal-medial thickness) in models adjusted for age, sex, income, education, BMI, waist circumference, smoking, blood pressure and glucose. Results: Rural Indians exhibited a higher visceral adiposity index and pro-atherogenic dyslipidemia at a lower BMI than Americans. Individuals with any degree of liver fat by ultrasound had a greater probability of dysglycemia (adjusted odds ratio OR=1.67, 95%CI 1.31-2.12, P&lt;0.0001) and pro-atherogenic dyslipidemia (OR=1.33, 95% CI 1.07-1.63, P=0.009), but not hypertension. We observed a positive association between liver fat and carotid intimal-medial thickness (CIMT) in an unadjusted model (β=0.02, P=0.0001), which was extinguished after adjustment for cardiometabolic risk factors. Conclusion: In a large population of rural Indians, presence of liver fat was associated with prevalent cardiometabolic risk and subclinical CVD at lower BMIs relative to multi-ethnic Americans, though the association with subclinical CVD was extinguished after adjustment. These results underscore the emerging relevance of hepatic steatosis in the developing world, and suggest efforts to target this accessible phenotype for cardiometabolic risk prevention.