tbuckley/cabot-search huggingface dataset:
Intestinal Metabolites Are Profoundly Altered in the Context of HLA–B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis
Authors: Mark Asquith, Sean Davin, Patrick Stauffer, Claire Michell, Cathleen Janowitz, Phoebe Lin, Joe Ensign‐Lewis, Jason M. Kinchen, Dennis R. Koop, James T. Rosenbaum
Journal: Arthritis & Rheumatology (2017)

HLA-B27-associated spondyloarthritides are associated with an altered intestinal microbiota and bowel inflammation. We undertook this study to identify HLA-B27-dependent changes in both host and microbial metabolites in the HLA-B27/β2 -microglobulin (β2 m)-transgenic rat and to determine whether microbiota-derived metabolites could impact disease in this major model of spondyloarthritis.Cecal contents were collected from Fischer 344 33-3 HLA-B27/β2 m-transgenic rats and wild-type controls at 6 weeks (before disease) and 16 weeks (with active bowel inflammation). Metabolomic profiling was performed by high-throughput gas and liquid chromatography-based mass spectrometry. HLA-B27/β2 m-transgenic rats were treated with the microbial metabolites propionate or butyrate in drinking water for 10 weeks, and disease activity was subsequently assessed.Our screen identified 582 metabolites, of which more than half were significantly altered by HLA-B27 expression at 16 weeks. Both microbial and host metabolites were altered, with multiple pathways affected, including those for amino acid, carbohydrate, xenobiotic, and medium-chain fatty acid metabolism. Differences were even observed at 6 weeks, with up-regulation of histidine, tyrosine, spermidine, N-acetylmuramate, and glycerate in HLA-B27/β2 m-transgenic rats. Administration of the short-chain fatty acid propionate significantly attenuated HLA-B27-associated inflammatory disease, although this was not associated with increased FoxP3+ T cell induction or with altered expression of the immunomodulatory cytokines interleukin-10 (IL-10) or IL-33 or of the tight junction protein zonula occludens 1. HLA-B27 expression was also associated with altered host expression of messenger RNA for the microbial metabolite receptors free fatty acid receptor 2 (FFAR2), FFAR3, and niacin receptor 1.HLA-B27 expression profoundly impacts the intestinal metabolome, with changes evident in rats even at age 6 weeks. Critically, we demonstrate that a microbial metabolite, propionate, attenuates development of HLA-B27-associated inflammatory disease. These and other microbiota-derived bioactive mediators may provide novel treatment modalities in HLA-B27-associated spondyloarthritides.
Reducing doxorubicin cardiotoxicity in rats with mammary tumors by dantrolene.
Authors: Valentina K Todorova, Yihong Jiang-Cao Kaufmann, Asangi R Kumarapeli, Eric R Siegel, Aaron Owen, Julia H Aronson, Issam Makhoul, Jeanne Wei, Sue A Theus, Suzanne Klimberg
Journal: Journal of Clinical Oncology (2017)

e12013 Background: Doxorubicin (DOX), widely used in breast cancer, is known for its cardiotoxicity. Preventing DOX-cardiotoxicity without affecting its antitumor efficacy has not been successful. DOX-cardiotoxicity results from oxidative stress that increases intracellular calcium levels by promoting the release of Ca2+ from sarcoplasmic reticulum (SR) and impairing Ca 2+ clearance in cardiomyocytes. Dantrolene (DNT), a postsynaptic muscle relaxant inhibits the release of Ca 2+ from SR by inhibiting the ryanodine receptor (RYR). The aim of this study was to examine the effect of DNT on cardiotoxicity and anti-tumor efficacy of DOX in a rat model of breast cancer. Methods: Female F344 rats with implanted MatBIII breast cancer cells were randomized into 3 groups of 12 rats/group and were treated as follows: “DOX” group was injected i.p. with DOX 2x week for 3 weeks (cumulative dose 12 mg/kg); “DNT” group received daily DNT (5mg/kg/day) by oral gavage; and “DOX+DNT” group was treated with DOX 2x week for 3 weeks and daily DNT (5mg/kg). The presence of cardiac alterations was examined by echocardiography before and after the experiment. Body weight, tumor size and volume were measured at sacrifice. H&amp;E stainings of the hearts and tumors was examined. Blood glutathione (GSH) levels were determined. Results: Mortality in the groups of rats treated with DOX alone, DNT+DOX and DNT was 40%, 16% and 0%, respectively. Histopathologic analysis of hearts of the surviving rats showed reduced DOX induced cardiotoxicity in the group treated with DOX+DNT as shown by reduced interstitial edema, cytoplasmic vacuolization and myofibrilar dysruption, compared to DOX only treated hearts. DNT significantly increased cardiac output and stroke volume, and improved the decline of left ventricle ejection fraction (LVEF) induced by DOX by 50%. Also, reduced breast tumor volumes with increased tumor necrosis was observed in rats treated with DOX+DNT compared to DOX alone. Rats treated with DNT lost less body weight and had a higher blood GSH levels. Conclusions: These data indicate that DNT is able to provide protection against DOX cardiotoxicity while maintaining its antitumor efficacy. Further preclinical studies are needed to determine the optimal dosing of DNT.
Erratum: Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+T cells
Authors: M L Lesniewski, P Haviernik, R P Weitzel, S Kadereit, M M Kozik, L R Fanning, Y C Yang, Y Hegerfeldt, M R Finney, M Z Ratajczak, N Greco, P Paul, J Maciejewski, M J Laughlin
Journal: Leukemia (2008)
Doctor convicted of manslaughter is suspended from register for a year
Authors: Clare Dyer
Journal: BMJ (2017)

A hospital doctor who was convicted of manslaughter by gross negligence in the treatment of a 6 year old boy who died from sepsis and heart attack has been suspended for 12 months by a medical practitioners’ tribunal.

Hadiza Bawa-Garba was a senior specialist registrar in paediatrics at Leicester Royal Infirmary in February 2011 when Jack Adcock, who had Down’s Syndrome, was admitted with diarrhoea, vomiting, and difficult breathing.

Bawa-Garba initially diagnosed gastroenteritis and ordered a fluid bolus, chest radiography, and blood tests. But she did not review the x ray pictures or the blood test results for hours after they became available and failed to appreciate the import of the blood results when she finally …
Single Nucleotide Polymorphisms (SNPs) Associated with Cognitive Impairment in Patients Treated with Hematopoietic Cell Transplantation (HCT): A Longitudinal Study
Authors: Noha Sharafeldin, Alysia Bosworth, Yanjun Chen, Sunita K Patel, Purnima Singh, Xuexia Wang, Emily Morse, Molly Mather, Can-Lan Sun, Liton F. Francisco, Stephen J. Forman, F. Lennie Wong, Smita Bhatia
Journal: Blood (2016)
Abstract 12926: New Use of Low-dose Aspirin is Not Associated With a Significantly Increased Risk of Intracranial Bleeds: Results From a Population-based Nested Case-control Study in the United Kingdom
Authors: Luis Garcia Rodriguez, David Gaist, Montse Soriano-Gabarró, Lucia Cea Soriano
Journal: Circulation (2016)

Introduction: Low-dose aspirin protects against ischemic cardio- and cerebrovascular disease (CVD/CeVD) and colorectal cancer yet may be associated with a small increased risk of intracranial bleeds (ICB). Aim: To quantify the risk of ICB associated with new use of low-dose aspirin for CVD/CeVD prevention using The Health Improvement Network in the UK. Methods: From a source population aged 40-84 years from 2000-2012 and free of previous low-dose aspirin use, a cohort of new users of low-dose aspirin (75-300 mg; N=199,049) was identified. Each member was matched to a person free of low-dose aspirin on that day by age, sex and primary care practitioner visits in the previous year. Cohorts (mean age at entry, 59.6 years) were followed for up to 14 years (median 5.4 years) to identify incident cases of ICB, with validation by manual review of patient records and/or linkage to hospitalization data. Nested case-control analysis was conducted using cases from both cohorts. To account for changes in aspirin exposure over time, an ‘as-treated’ analysis was used. Controls (n=10,000) were frequency-matched to cases by age, sex and calendar year. Two definitions of current use were used for low-dose aspirin: use on i) 0-7 days or ii) 0-365 days before the index date (ICB date for cases, random date for controls). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression overall and stratified by CVD/CeVD status at study entry (primary or secondary prevention populations). Results: A total of 1635 incident cases of ICB were identified. As shown in the Table, compared with never use, current use of low-dose aspirin was not associated with a significant increase risk of ICB among the primary or secondary CVD/CeVD prevention populations, or any ICB subtype. For current use, no significant changes in ICB risk were seen between doses of 75mg, 150mg and 300mg. Conclusions: New use of low-dose aspirin does not significantly increase the risk of any type of ICB.
Abstract 6117: Significance of Flow Aliasing in the Proximal Left Coronary Artery on Transthoracic Color Doppler Echocardiography in Patients with Unstable Angina
Authors: Hideki Okayama, Kazuhisa Nishimura, Makoto Saito, Katsuji Inoue, Akiyoshi Ogimoto, Tomoaki Ohtsuka, Toyofumi Yoshii, Go Hiasa, Takumi Sumimoto, Junichi Funada, Jitsuo Higaki
Journal: Circulation (2008)

Background: Noninvasive coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) has been validated and utilized at the bedside. However, because this method requires pharmaceutical provocation, it has some risk especially for patients suspected of acute coronary syndrome. Color aliasing of coronary flow on TTDE in the short axis (SAX) view at the aortic root level suggests that flow acceleration produced by stenosis is occasionally observed during screening in patients with chest pain. The aim of this study was to investigate the clinical significance of flow aliasing on TTDE in the SAX view at the aortic root in patients with unstable angina. Methods: Patients (n=104) with unstable angina were evaluated. Proximal left coronary flow was sought in the SAX view at the aortic root level under color Doppler guidance at a color velocity range of ±19 cm/sec. When detected coronary flow showed color aliasing, the color velocity range was gradually raised until color aliasing nearly disappeared. Then, the color baseline was shifted until color flow showed isovelocity. AHA segment 6 on the coronary angiogram obtained within 24 hours was defined as the proximal left anterior descending artery (LAD). Results: Color aliasing was observed in 49 of 104 patients. In 14 of these 49 patients, there was significant stenosis (≥50% luminal reduction) in the left main coronary artery (LMCA) and 25 had significant stenosis in the proximal LAD. In patients with flow aliasing, a cut-off value of isovelocity ≥33.0 cm/sec predicted significant coronary stenosis with a sensitivity of 90%, specificity of 80%, positive predictive value of 95%, and negative predictive value of 67%. In all 104 patients, the cut-off value predicted significant coronary stenosis with a sensitivity of 60%, specificity of 96%, positive predictive value of 95%, and negative predictive value of 66%. Conclusion: Detection of flow aliasing by TTDE in the SAX view is a promising method for noninvasive diagnosis of LMCA and proximal LAD stenosis. This method may be useful for expeditious risk stratification and decision making in patients with unstable angina.
Obesity and rates of clinical remission and low MRI inflammation in rheumatoid arthritis
Authors: Michael D George, Mikkel Østergaard, Philip G Conaghan, Paul Emery, Daniel G Baker, Joshua F Baker
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> Obesity has been proposed as a risk factor for refractory rheumatoid arthritis (RA). We evaluated the impact of obesity on achieving clinical and imaging definitions of low disease activity. <h3>Methods</h3> This study evaluated 470 patients with RA from GO-BEFORE and GO-FORWARD randomised clinical trials. Included patients had blinded clinical disease activity measures and MRI at baseline, 24 and 52 weeks. Synovitis, osteitis and total inflammation scores were determined using the RA MRI scoring system. Multivariable logistic regression analyses compared odds of achieving Disease Activity Score using 28 joints and C-reactive protein (DAS28-CRP) remission, low component measures, or low MRI inflammation measures at 24 weeks in patients with obesity versus no obesity. <h3>Results</h3> At 24 weeks, patients with obesity were significantly less likely to achieve DAS28(CRP) remission (OR 0.47; 95% CI 0.24 to 0.92, p=0.03). In contrast, patients with obesity had similar odds of achieving low synovitis (OR 0.94; 95% CI 0.51 to 1.72, p=0.84) and inflammation scores (OR 1.16; 95% CI 0.61 to 2.22, p=0.64) and greater odds of achieving low osteitis scores (OR 2.06; 95% CI 1.10 to 3.84, p=0.02) versus normal weight patients. <h3>Conclusions</h3> Patients with RA and obesity have lower rates of DAS28 remission but similar rates of low MRI activity compared with patients without obesity, suggesting that obesity and its associated comorbidities can bias clinical disease activity measures. <h3>Trial registration number</h3> NCT00361335 and NCT00264550; Post-results.
Detection of Head and Neck Cancer in Surgical Specimens Using Quantitative Hyperspectral Imaging
Authors: Guolan Lu, James V. Little, Xu Wang, Hongzheng Zhang, Mihir R. Patel, Christopher C. Griffith, Mark W. El-Deiry, Amy Y. Chen, Baowei Fei
Journal: Clinical Cancer Research (2017)

Purpose: This study intends to investigate the feasibility of using hyperspectral imaging (HSI) to detect and delineate cancers in fresh, surgical specimens of patients with head and neck cancers.Experimental Design: A clinical study was conducted in order to collect and image fresh, surgical specimens from patients (N = 36) with head and neck cancers undergoing surgical resection. A set of machine-learning tools were developed to quantify hyperspectral images of the resected tissue in order to detect and delineate cancerous regions which were validated by histopathologic diagnosis. More than two million reflectance spectral signatures were obtained by HSI and analyzed using machine-learning methods. The detection results of HSI were compared with autofluorescence imaging and fluorescence imaging of two vital-dyes of the same specimens.Results: Quantitative HSI differentiated cancerous tissue from normal tissue in ex vivo surgical specimens with a sensitivity and specificity of 91% and 91%, respectively, and which was more accurate than autofluorescence imaging (P < 0.05) or fluorescence imaging of 2-NBDG (P < 0.05) and proflavine (P < 0.05). The proposed quantification tools also generated cancer probability maps with the tumor border demarcated and which could provide real-time guidance for surgeons regarding optimal tumor resection.Conclusions: This study highlights the feasibility of using quantitative HSI as a diagnostic tool to delineate the cancer boundaries in surgical specimens, and which could be translated into the clinic application with the hope of improving clinical outcomes in the future. Clin Cancer Res; 23(18); 5426-36. ©2017 AACR.
Cardiometabolic correlates of sleep disordered breathing in Andean highlanders
Authors: Luu V. Pham, Catherine H. Miele, Noah G. Schwartz, Rafael S. Arias, Adi Rattner, Robert H. Gilman, J. Jaime Miranda, Vsevolod Y. Polotsky, William Checkley, Alan R. Schwartz
Journal: European Respiratory Journal (2017)

Associations between sleep disordered breathing (SDB) and cardiometabolic outcomes have not been examined in highlanders. We performed nocturnal polygraphy in Peruvian highlanders (3825 m). Multivariable linear regression models examined associations between SDB metrics and haemoglobin, glucose tolerance (haemoglobin A1c (HbA1c)), fasting glucose, homeostatic model-based assessments of insulin resistance and β-cell function (HOMA-IR and HOMA-β, respectively), blood pressure, and lipids, while adjusting for age, sex, body mass index (BMI) and wake oxygenation. Participants (n=187; 91 men) were (median (interquartile range)) 52 (45–62) years old, and had a BMI of 27.0 (24.3–29.5) kg·m −2 and 87% (85–88%) oxyhaemoglobin (arterial oxygen) saturation during wakefulness. In fully adjusted models, worsening nocturnal hypoxaemia was associated with haemoglobin elevations in men (p=0.03), independent of wake oxygenation and apnoea–hypopnoea index (AHI), whereas worsening wake oxygenation was associated with haemoglobin elevations in older women (p=0.02). In contrast, AHI was independently associated with HbA1c elevations (p&lt;0.05). In single-variable models, nocturnal hypoxaemia was associated with higher HbA1c, HOMA-IR and HOMA-β (p&lt;0.001, p=0.02 and p=0.04, respectively), whereas AHI was associated with HOMA-IR, systolic blood pressure and triglyceride elevations (p=0.02, p=0.01 and p&lt;0.01, respectively). These associations were not significant in fully adjusted models. In highlanders, nocturnal hypoxaemia and sleep apnoea were associated with distinct cardiometabolic outcomes, conferring differential risk for excessive erythrocytosis and glucose intolerance, respectively.
A prospective analysis of individual body fat depots and risk of developing cancer: Insights from the Dallas heart study.
Authors: Arjun Gupta, Ambarish Pandey, Colby Ayers, Muhammad S Beg, Susan G Lakoski, Gloria L Vega, Scott M Grundy, David H. Johnson, Ian J Neeland
Journal: Journal of Clinical Oncology (2016)

1516 Background: Excess adiposity is associated with an increased risk of cancer; however, body mass index (BMI) is an imprecise measure of adiposity-related cancer risk. We examined the association of specific adipose tissue depots with the risk of incident cancer in the Dallas Heart Study (DHS). Methods: Individuals without prevalent cancer in the DHS underwent quantification of adipose tissue depots: visceral (VAT) and abdominal subcutaneous adipose tissue (SAT) and liver fat by MRI, and lower body subcutaneous fat by DXA and were followed for the development of cancer using the Texas Cancer Registry. Multivariable Cox proportional hazards modeling was performed to examine the association between individual fat depots and incident cancer. Results: Among 2,627 participants (median age 43 years; 54% women; 69% nonwhite), 167 (6.4%) developed incident cancer during a median follow-up of 12 years. The most common primary sites were breast (25%) in women and prostate (20%) in men. VAT levels were 2.34 kg in the incident cancer group vs. 2.04 kg among those without an incident cancer (P= 0.002). In multivariable models adjusted for sex, race, smoking, alcohol use and family history of malignancy, each 1-standard deviation increase in VAT was significantly associated with a 25% increased risk of cancer: HR 1.25 (95% CI 1.06- 1.47). However the association was completely attenuated with the addition of age to the model. In contrast, each 1-standard deviation increase in lower body subcutaneous fat was associated with a reduced incidence of cancer; HR 0.93 (95% CI 0.87- 0.98) in the fully adjusted model. No association between SAT or liver fat and cancer was seen. Conclusions: In this study in a young, multiethnic population, adiposity-associated cancer risk was heterogeneous and varied by fat depot: VAT was associated with incident cancer but not independent of age and lower body subcutaneous fat appeared to protect against cancer development. Further studies of the adiposity-cancer relationship are needed to elucidate this relationship and to examine the association with prognosis and response to therapy.
Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors
Authors: Dennis Plenker, Maximilian Riedel, Johannes Brägelmann, Marcel A. Dammert, Rakhee Chauhan, Phillip P. Knowles, Carina Lorenz, Marina Keul, Mike Bührmann, Oliver Pagel, Verena Tischler, Andreas H. Scheel, Daniel Schütte, Yanrui Song, Justina Stark, Florian Mrugalla, Yannic Alber, André Richters, Julian Engel, Frauke Leenders, Johannes M. Heuckmann, Jürgen Wolf, Joachim Diebold, Georg Pall, Martin Peifer, Maarten Aerts, Kris Gevaert, René P. Zahedi, Reinhard Buettner, Kevan M. Shokat, Neil Q. McDonald, Stefan M. Kast, Oliver Gautschi, Roman K. Thomas, Martin L. Sos
Journal: Science Translational Medicine (2017)

An examination of the activity profiles of RET inhibitors suggests potential treatment for RET -rearranged cancers.
Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A<sub>1c</sub> Levels
Authors: Richard M. Bergenstal, Robin L. Gal, Crystal G. Connor, Rose Gubitosi-Klug, Davida Kruger, Beth A. Olson, Steven M. Willi, Grazia Aleppo, Ruth S. Weinstock, Jamie Wood, Michael Rickels, Linda A. DiMeglio, Kathleen E. Bethin, Santica Marcovina, Andreana Tassopoulos, Sooji Lee, Elaine Massaro, Suzan Bzdick, Brian Ichihara, Eileen Markmann, Paul McGuigan, Stephanie Woerner, Michelle Ecker, Roy W. Beck
Journal: Annals of Internal Medicine (2017)

Background: Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin. Objective: To determine whether a racial difference exists in the relationship of mean glucose and HbA1c. Design: Prospective, 12-week observational study. Setting: 10 diabetes centers in the United States. Participants: 104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%. Measurements: Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values. Results: The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons). Limitation: There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals. Conclusion: On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes. Primary Funding Source: Helmsley Charitable Trust.