tbuckley/cabot-search huggingface dataset:
<scp>JAK</scp>/<scp>STAT</scp> Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis
Authors: Trudy McGarry, Carl Orr, Sarah Wade, Monika Biniecka, Siobhan Wade, Lorna Gallagher, Candice Low, Douglas J. Veale, Ursula Fearon
Journal: Arthritis & Rheumatology (2018)

To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA).Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 μM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA whole tissue synovial explants was quantified by ELISAs/MSD multiplex assays, and metabolic markers were quantified by RT-PCR. Finally, RASF invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion/Matrigel outgrowth assays and ELISA.Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASFs and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP production, and the maximal respiratory capacity and the respiratory reserve in RASFs, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK2), glycogen synthase kinase 3α (GSK-3α), lactate dehydrogenase A, and hypoxia-inducible factor 1α. Tofacitinib inhibited the effect of oncostatin M (OSM) on interleukin-6 (IL-6) and monocyte chemotactic protein 1 and reversed the effects of OSM on RASF cellular metabolism. Using RA whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, 3'-phosphoinositide-dependent protein kinase 1, HK2, and GSK-3α, the proinflammatory mediators IL-6, IL-8, IL-1β, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE-2, and RASF outgrowth from synovial explants, RASF invasion, and matrix metalloproteinase 1 activity.This study demonstrates that JAK/STAT signaling mediates the complex interplay between inflammation and cellular metabolism in RA pathogenesis.
3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk
Authors: Hyun Jung Park, Ping Ji, Soyeon Kim, Zheng Xia, Benjamin Rodriguez, Lei Li, Jianzhong Su, Kaifu Chen, Chioniso P. Masamha, David Baillat, Camila R. Fontes-Garfias, Ann-Bin Shyu, Joel R. Neilson, Eric J. Wagner, Wei Li
Journal: Nature Genetics (2018)
Predicting Suicide Attempts and Suicide Deaths Following Outpatient Visits Using Electronic Health Records
Authors: Gregory E. Simon, Eric Johnson, Jean M. Lawrence, Rebecca C. Rossom, Brian Ahmedani, Frances L. Lynch, Arne Beck, Beth Waitzfelder, Rebecca Ziebell, Robert B. Penfold, Susan M. Shortreed
Journal: American Journal of Psychiatry (2018)

The authors sought to develop and validate models using electronic health records to predict suicide attempt and suicide death following an outpatient visit.Across seven health systems, 2,960,929 patients age 13 or older (mean age, 46 years; 62% female) made 10,275,853 specialty mental health visits and 9,685,206 primary care visits with mental health diagnoses between Jan. 1, 2009, and June 30, 2015. Health system records and state death certificate data identified suicide attempts (N=24,133) and suicide deaths (N=1,240) over 90 days following each visit. Potential predictors included 313 demographic and clinical characteristics extracted from records for up to 5 years before each visit: prior suicide attempts, mental health and substance use diagnoses, medical diagnoses, psychiatric medications dispensed, inpatient or emergency department care, and routinely administered depression questionnaires. Logistic regression models predicting suicide attempt and death were developed using penalized LASSO (least absolute shrinkage and selection operator) variable selection in a random sample of 65% of the visits and validated in the remaining 35%.Mental health specialty visits with risk scores in the top 5% accounted for 43% of subsequent suicide attempts and 48% of suicide deaths. Of patients scoring in the top 5%, 5.4% attempted suicide and 0.26% died by suicide within 90 days. C-statistics (equivalent to area under the curve) for prediction of suicide attempt and suicide death were 0.851 (95% CI=0.848, 0.853) and 0.861 (95% CI=0.848, 0.875), respectively. Primary care visits with scores in the top 5% accounted for 48% of subsequent suicide attempts and 43% of suicide deaths. C-statistics for prediction of suicide attempt and suicide death were 0.853 (95% CI=0.849, 0.857) and 0.833 (95% CI=0.813, 0.853), respectively.Prediction models incorporating both health record data and responses to self-report questionnaires substantially outperform existing suicide risk prediction tools.
Evaluation of outcomes over time (1998-2009) of patients (pts) with stage III colon cancer receiving adjuvant FOLFOX: Analysis of 7,230 patients from MOSAIC, C07, C08, N0147, AVANT, and PETACC8 trials in the ACCENT Database.
Authors: Mohamed E. Salem, Jun Yin, Richard M. Goldberg, Levi Pederson, Norman Wolmark, Steven R. Alberts, Julien Taieb, John Marshall, Sara Lonardi, Takayuki Yoshino, Rachel Kerr, Greg Yothers, Axel Grothey, Thierry Andre, Aimery De Gramont, Qian Shi
Journal: Journal of Clinical Oncology (2018)

724 Background: Adjuvant FOLFOX is the standard of care for pts with stage III colon cancer and a platform to test new agents. Improvements in supportive care and development of newer treatments for metastatic disease impact the overall outcome of pts treated with adjuvant therapy. We examined the trend of disease-free survival (DFS), survival after recurrence (SAR), and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of colon cancer pts enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated by adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T/N stage, tumor sidedness and histologic grade. Results: In total, 7,230 pts (stage II [n = 1122]; stage III [n = 6,108]) were identified; 32% and 68% were treated in the old and new era, respectively. Stage III pts enrolled in the new era were significantly younger, more likely to have T4/N2 disease, higher tumor grade, and left-sided tumors. After adjusting for pt characteristics, no difference in DFS was seen over time. However prolonged SAR and OS were observed in pts treated in the new era (Table). 5yr OS increased from 76% to 80% over time. Median SAR improved from 14.8 to 26.4 months. Conclusions: Stage III colon cancer pts who received adjuvant FOLFOX experienced significant improvements in SAR and OS—but not DFS—over time. In view of the improvements in OS and nearly doubled SAR, the optimal duration of OS follow-up to evaluate the benefits of adjuvant therapy (currently 5 years) should be reassessed, and ACCENT investigators are planning to conduct these additional analyses using their large pooled-trial database. [Table: see text]
Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells
Authors: Shengzhi Liu, Yao Fan, Andy Chen, Aydin Jalali, Kazumasa Minami, Kazuhiko Ogawa, Harikrishna Nakshatri, Bai-Yan Li, Hiroki Yokota
Journal: Cancer Research (2018)

Abstract While bone is a frequent target of breast cancer–associated metastasis, little is known about the effects of tumor–bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, fluphenazine and trifluoperazine, on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of fluphenazine and trifluoperazine downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of fluphenazine and trifluoperazine on tumor growth, tumor–osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor–osteocyte interactions strengthen dopamine receptor–mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment. Significance: These findings provide novel insight into the cellular cross-talk in the bone microevironment and the effects of dopamine modulators on mammary tumor cells and osteocytes. Cancer Res; 78(14); 3865–76. ©2018 AACR.
Abstract 17388: Cardiac MRI Derived Forward Stroke Energy is a Better Index of Left Ventricular Pump Function over Ejection Fraction in Mitral Regurgitation
Authors: Kanika Kalra, Muralidhar Padala
Journal: Circulation (2015)

Introduction: Mitral regurgitation (MR) into the low impedance left atrium (LA) enables a pop off valve effect and enables a false low end-diastolic volume and increased ejection fraction (EF). EF in these patients seems falsely high even though their ventricular contraction seems impaired, thus better indices that represent ventricular contraction are required in this lesion. Hypothesis: In this study we sought to investigate if forward stroke energy (FSE), which represents the forward kinetic energy of the blood through the aortic valve is a better indicator of ventricular contraction than EF. Methods: Phase-contrast MRI was performed in patients with MR (n=63; Mild MR =23; Moderate-severe MR=40), at the aortic and mitral valve planes, to compute the transvalvular through-plane flow. EF was measured as ((end-diastolic volume- end systolic volume)/end-diastolic volume), and FSE as (forward aortic stroke volume X mean arterial pressure). LV contractility was computed as the dynamic myocardial wall thickening over the cardiac cycle. Results: Regional peak wall thickening was significantly reduced in the moderate-severe MR groups - equatorial sector (5.9±0.6mm vs. 4.3±0.4mm, p=0.02) and apical sector (6.4±0.5mm vs. 4.5±0.3mm, p=0.003), indicating LV dysfunction with higher MR severity. EF did not capture this difference in LV contraction between the groups (50.1±3.7% vs. 48.3±3.2%, p=0.72). However, FSE demonstrated a significant difference between the two groups and a significant negative correlation (6527±483 mmHg.mL vs. 4895±282 mmHg.mL, p=0.002, r(MRfraction)=-0.42, p=0.0007). Conclusions: Forward stroke energy may better capture reduced myocardial contractility in the setting of MR, than EF - the current clinical gold standard.
Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency
Authors: Mukil Natarajan, Amy P. Hsu, Michael A. Weinreich, Yuan Zhang, Julie E. Niemela, John A. Butman, Stefania Pittaluga, Janyce Sugui, Amanda L. Collar, Jean K. Lim, Tirdad Zangeneh, Tara Carr, Andrew J. Oler, Morgan Similuk, Lindsey B. Rosen, Jigar V. Desai, Alexandra F. Freeman, Steven M. Holland, Kyung J. Kwon-Chung, Joshua D. Milner, Michail S. Lionakis
Journal: Journal of Allergy and Clinical Immunology (2018)
Moral externalization and normativity: The errors of our ways
Authors: P Kyle Stanford
Journal: Behavioral and Brain Sciences (2018)

Abstract I respond to the many thoughtful suggestions and concerns of my commentators on a wide variety of questions. These include whether moral norms form a unified category, whether they have a distinctive phenomenology, and/or whether moral normativity is a cultural construct; whether moral externalization is necessary for correlated interaction or human prosociality; precisely how such externalization generates correlated interactions among prosocial agents; and whether there are any convincing alternative explanations for it.
GPIbα is required for platelet-mediated hepatic thrombopoietin generation
Authors: Miao Xu, June Li, Miguel Antonio Dias Neves, Guangheng Zhu, Naadiya Carrim, Ruoying Yu, Sahil Gupta, John Marshall, Ori Rotstein, Jun Peng, Ming Hou, Shinji Kunishima, Jerry Ware, Donald R. Branch, Alan H. Lazarus, Zaverio M. Ruggeri, John Freedman, Heyu Ni
Journal: Blood (2018)
Outcomes after endoscopic resection of large laterally spreading lesions of the papilla and conventional ampullary adenomas are equivalent
Authors: Amir Klein, Zhengyan Qi, Farzan Bahin, Halim Awadie, Dhruv Nayyar, Michael Ma, Rogier Voermans, Stephen Williams, Eric Lee, Michael Bourke
Journal: Endoscopy (2018)

Abstract Background Endoscopic resection of ampullary adenomas is a safe and effective alternative to surgical resection. A subgroup of patients have large laterally spreading lesions of the papilla Vateri (LSL-P), which are frequently managed surgically. Data on endoscopic resection of LSL-P are limited and long-term outcomes are unknown. The aim of this study was to compare the outcomes of endoscopic resection of LSL-P with those of standard ampullary adenomas. Methods A retrospective analysis of a prospectively collected and maintained database was conducted. LSL-P was defined as extension of the lesion ≥ 10 mm from the edge of the ampullary mound. Piecemeal endoscopic mucosal resection of the laterally spreading component was followed by resection of the ampulla. Patient, lesion, and procedural data, as well as results of endoscopic follow-up, were collected. Results 125 lesions were resected. Complete endoscopic resection was achieved in 97.6 % at the index procedure (median lesion size 20 mm, interquartile range [IQR] 13 – 30 mm). Compared with ampullary adenomas, LSL-Ps were significantly larger (median 35 mm vs. 15 mm), contained a higher rate of advanced pathology (38.6 % vs. 18.5 %), and had higher rates of intraprocedural bleeding (50 % vs. 24.7 %) and delayed bleeding (25.0 % vs. 12.3 %). Both groups had similar rates of histologically proven recurrence at first surveillance (16.4 % vs. 17.9 %). Median follow-up for the entire cohort was 18.5 months. For patients with at least two surveillance endoscopies (n = 68; median follow-up 29 months, IQR 18 – 48 months), 95.6 % were clear of disease and considered cured. Conclusions LSL-P can be resected endoscopically with comparable outcomes to standard ampullectomy, albeit with a higher risk of bleeding. Endoscopic treatment should be considered as an alternative to surgical resection, even for large LSL-P.
Quaternary ammonium-induced multidrug tolerant Streptococcus mutans persisters elevate cariogenic virulence in vitro
Authors: Ya-Ling Jiang, Wei Qiu, Xue-Dong Zhou, Hao Li, Jun-Zhuo Lu, Hockin HK Xu, Xian Peng, Ming-Yun Li, Ming-Ye Feng, Lei Cheng, Biao Ren
Journal: International Journal of Oral Science (2017)

Dental caries are the most prevalent chronic infections in the oral cavity, and Streptococcus mutans acts as the main cariogenic bacterial species. Antibacterial quaternary ammonium compounds (QAs) have been developed to preveFnt or treat dental caries. However, there is no report on the tolerance of S. mutans to QAs. In this study, we investigated the development of S. mutans persistence induced by a novel dental caries defensive agent, dimethylaminododecyl methacrylate (DMADDM), for the first time. Typical biphasic killing kinetics for persisters were observed in both S. mutans planktonic and biofilm cultures challenged by DMADDM at concentrations of 20 and 200 μg·mL-1, respectively. The persisters tolerated six other antibiotics with different antibacterial mechanisms, while only daptomycin and vancomycin could slightly reduce the persister numbers in planktonic cultures. The distribution of persisters in DMADDM-treated biofilms was similar to that in the untreated control, except that the total biomass and biofilm height were significantly reduced. A higher exopolysaccharides (EPS):bacteria ratio was observed in DMADDM-treated biofilms. Persisters in biofilms significantly upregulated gtf gene expression, indicating an increase in the bacteria's ability to produce EPS and an elevated capability of cariogenic virulence. Carbon source metabolism was significantly reduced, as related metabolic genes were all downregulated in persisters. Concentrations of 0.1 mM, 1 mM and 10 mM of extra glucose significantly reduced the number of persisters both in planktonic and biofilm conditions. The formation of non-inheritable and multidrug tolerant persisters induced by DMADDM suggested that drug tolerance and new persistent eradication strategies should be considered for oral antibacterial agents.
UK government vows to adopt stringent WHO clean air targets
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The UK government has published a draft plan for its upcoming clean air strategy, which includes a target to reduce particulate matter emissions by 46% by 2030.

The draft strategy,1 published for consultation by the Department for Environment, Food, and Rural Affairs on 22 May, outlines a set of policies and targets for improving future air quality and reducing people’s exposure to air pollution.

Key pledges include reducing primary particulate matter (PM2.5) levels in order to halve the number of people living in locations where concentrations of particulate matter …
Abstract P024: Maternal Genotype Accounts for Part of the Relationship Between Maternal Size During Pregnancy and Offspring Metabolic Profile in Adulthood
Authors: Pandora L Wander, Colleen Sitlani, Hagit Hochner, Daniel A Enquobahrie, Thomas Lumley, Orly Manor, Ayala Burger, Bella Savitsky, David S Siscovick, Yechiel Friedlander
Journal: Circulation (2013)

Background:  Maternal pre-pregnancy body-mass index (BMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) in adult offspring. However, whether common maternal genetic variation accounts for the association of pre-pregnancy BMI and GWG with markers of offspring CMR at age 32 is unknown.   Methods and Results:  Using archival and follow-up data from 1249 mother-offspring pairs and 1384 single-nucleotide polymorphisms (SNPs) in 170 candidate genes related to cardiometabolic traits from the Jerusalem Perinatal Study (JPS), we created maternal genetic risk scores using the subset of SNPs that were most predictive of exposure and outcome, and fit linear regression models both with and without genetic terms to examine the association of maternal size before pregnancy and weight gain during pregnancy with offspring CMR, measured by offspring BMI, waist circumference, glucose, insulin, blood pressure, and fasting lipid levels. Offspring with low and high birthweight were oversampled, as were overweight and obese mothers, and analyses used inverse probability weighting to account for this sampling scheme.  In GWG models unadjusted for genetic score compared to adjusted models, the coefficient for the BMI term decreased by 41% (95% CI -81%, -11%) from 0.184 to 0.109 and the coefficient for the WC term decreased by 63% (95% CI -318%, -11%) from 0.259 to 0.096. Significant changes in coefficients were neither seen for the other CMR traits tested nor in corresponding pre-pregnancy BMI models.   Conclusions:  In this analysis, maternal genotype accounts for part of the association between gestational weight gain and body size in adult offspring. A similar genetic contribution was not seen in the association between pregravid size and offspring CMR.
Healthcare Cost and Utilization in Nonalcoholic Fatty Liver Disease: Real‐World Data From a Large U.S. Claims Database
Authors: Alina M. Allen, Holly K. Van Houten, Lindsey R. Sangaralingham, Jayant A. Talwalkar, Rozalina G. McCoy
Journal: Hepatology (2018)

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. The health care burden resulting from the multidisciplinary management of this complex disease is unknown. We assessed the total health care cost and resource utilization associated with a new NAFLD diagnosis, compared with controls with similar comorbidities. We used OptumLabs Data Warehouse, a large national administrative claims database with longitudinal health data of over 100 million individuals enrolled in private and Medicare Advantage health plans. We identified 152,064 adults with a first claim for NAFLD between 2010 and 2014, of which 108,420 were matched 1:1 by age, sex, metabolic comorbidities, length of follow-up, year of diagnosis, race, geographic region, and insurance type to non-NAFLD contemporary controls from the OptumLabs Data Warehouse database. Median follow-up time was 2.6 (range 1-6.5) years. The final study cohort consisted of 216,840 people with median age 55 (range 18-86) years, 53% female, 78% white. The total annual cost of care per NAFLD patient with private insurance was $7,804 (interquartile range [IQR] $3,068-$18,688) for a new diagnosis and $3,789 (IQR $1,176-$10,539) for long-term management. These costs are significantly higher than the total annual costs of $2,298 (IQR $681-$6,580) per matched control with similar metabolic comorbidities but without NAFLD. The largest increases in health care utilization that may account for the increased costs in NAFLD compared with controls are represented by liver biopsies (relative risk [RR] = 55.00, 95% confidence interval [CI] 24.48-123.59), imaging (RR = 3.95, 95% CI 3.77-4.15), and hospitalizations (RR = 1.87, 95% CI 1.73-2.02). Conclusion: The costs associated with the care for NAFLD independent of its metabolic comorbidities are very high, especially at first diagnosis. Research efforts shouldfocus on identification of underlying determinants of use, sources of excess cost, and development of cost-effective diagnostic tests.
The Challenge of Vanquishing HIV for the Next Generation—Facing the Future
Authors: Meagan C. Fitzpatrick, Glenda E. Gray, Alison P. Galvani
Journal: JAMA Pediatrics (2018)

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