tbuckley/cabot-search huggingface dataset:
Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice
Authors: Kenichi Ishizawa, Qin Wang, Jinping Li, Ning Xu, Yoshikazu Nemoto, Chikayuki Morimoto, Wataru Fujii, Yoshifuru Tamura, Yoshihide Fujigaki, Kazuhisa Tsukamoto, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Patients with type 2 diabetes often exhibit salt-sensitive hypertension, but the mechanisms underlying this association remain unclear. One potential link, Kelch-like 3 (KLHL3), regulates BP by targeting the serine/threonine kinases with-no-lysines (WNKs) for degradation, thereby modulating activity of the NaCl cotransporter (NCC). The authors previously found that phosphorylation at serine 433 (S433) in KLHL3 downregulates KLHL3 activity. In this study, they show that protein kinase C–mediated phosphorylation of KLHL3 at S433 inactivates KLHL3 and increases NCC activity in db/db diabetic mice, and they show that an inhibitor of a sodium glucose cotransporter 2 (SGLT2), ipragliflozin, ameliorates this effect. These data indicate a previously unrecognized pathway by which dysregulated glucose metabolism stimulates renal salt reabsorption and provide insights into the mechanism for SGLT2 inhibitors’ cardiorenal protective effect. Background Mechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption via NaCl cotransporter (NCC). Methods We used the db/db diabetes mouse model to explore KLHL3′s role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells. Results We observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3 S433-P ). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3 S433-P and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3 S433-P levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC’s causal role in KLHL3 S433-P and NCC induction. Conclusions Dysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.
The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis
Authors: Michael P. Madaio, Istvan Czikora, Nino Kvirkvelia, Malgorzata McMenamin, Qiang Yue, Ting Liu, Haroldo A. Toque, Supriya Sridhar, Katherine Covington, Rabei Alaisami, Paul M. O’Connor, Robert W. Caldwell, Jian-Kang Chen, Matthias Clauss, Michael W. Brands, Douglas C. Eaton, Maritza J. Romero, Rudolf Lucas
Journal: Kidney International (2019)
A Dangerous Detour
Authors: David D. Berg, James Kirshenbaum, Elizabeth Gay, Anand Vaidya, Joseph Loscalzo
Journal: New England Journal of Medicine (2019)

A 26-year-old woman with T-cell acute lymphoblastic leukemia who was receiving consolidation chemotherapy through an indwelling central venous catheter presented with progressive dyspnea. The patient had reported the dyspnea to her oncologist 1 month earlier. Computed tomographic angiography of the chest was performed at that time and revealed multiple emboli . . .
“Incentive hope” and the nature of impulsivity in low-socioeconomic-status individuals
Authors: Francesca Walsh, Erik Cheries, Youngbin Kwak
Journal: Behavioral and Brain Sciences (2019)

Abstract Low-income environments have been associated with greater levels of impulsive behavior, which contribute to the higher debt and obesity rates that further perpetuate current wealth and health disparities. In this commentary, we describe how this might be explained by an appeal to “incentive hope” and the motivational drive toward consumption triggered by the future uncertainty these groups face.
Abstract 16606: 30-day and 2-year Prognostic Information of Total Atheroma Volume, Segment Stenosis Score, and Traditional Coronary Artery Stenosis Assessment by CT Angiography - Results From the CORE320 International Study
Authors: Armin Arbab-Zadeh, Tiago Magalhaes, Satoru Kishi, Carlos Rochitte, Marcus Y Chen, Klaus F Kofoed, Marc Dewey, Richard T George, Hiroyuki Niinuma, Kakuya Kitagawa, Matthew Matheson, Andrea Vavere, Julie M Miller, Frank Rybicki, Christopher Cox, Marcelo Di Carli, Melvin E Clouse, Jeffrey Brinker, Joao Lima
Journal: Circulation (2015)

Introduction: Among abundant information on coronary artery disease (CAD) features by CT angiography (CTA), total atheroma volume and segment stenosis score (SSS) have recently shown promise for clinical utility. Methods: We followed 379 patients with suspected or known CAD enrolled in the CORE320 study for 2 years after 320-detector row CT coronary angiography. CT images were analyzed for semi-automatically derived total % atheroma volume (total atherosclerotic burden/vessel volume analyzed) and SSS in addition to traditional stenosis assessment (≥50%). Outcome variables were 1) 30-day revascularization and 2) major adverse cardiac events (MACE) after 2 years follow up. Events included cardiac death, myocardial infarction, hospitalization for acute chest pain or heart failure, arrhythmia, and revascularization. Area under the curve (AUC) and Kaplan-Meyer analysis were used to compare risk prediction and survival analysis according to CT CAD characteristics. Results: Thirty-day revascularization was most accurately predicted by CT stenosis assessment (AUC 75, confidence interval [CI] 71-80) vs. % atheroma volume (70 [65-74] and CTA SSS (67 [62-72]) (p=0.007). Prediction of MACE (45 late revascularizations, 5 myocardial infarctions, 1 cardiac death, 8 hospitalizations for chest pain or congestive heart failure, and 1 arrhythmia) was similar for % atheroma volume (64 [71 for patients without history of CAD]) and CTA stenosis assessment (65 [70]) but risk discrimination using common criteria trended favorably for % atheroma volume (FIGURE). Accuracy was low for CTA SSS (58 [62]). Conclusions: Semi-automated assessment of % total atheroma volume by CTA performs similarly to standard stenosis assessment for predicting short and long term event rates, especially revascularization, in patients with suspected CAD and holds promise for more nuanced risk discrimination. In contrast, CTA segment stenosis score performed only modestly in our analysis.
Low risk pragmatic trials do not always require participants’ informed consent
Authors: Rafael Dal-Ré, Cristina Avendaño-Solà, Brigitte Bloechl-Daum, Anthonius de Boer, Stefan Eriksson, Uwe Fuhr, Søren Holm, Stefan K James, Robert J Mentz, Emilio Perucca, Frits R Rosendaal, Shaun Treweek
Journal: BMJ (2019)

Clinical trial regulations should remove unnecessary obstacles for the conduct of pragmatic trials assessing the comparative effectiveness of medicines posing no or minimal risk to participants, say <b>Rafael Dal-Ré and colleagues</b>
Improving CKD-Specific Patient-Reported Measures of Health-Related Quality of Life
Authors: John E. Ware, Michelle M. Richardson, Klemens B. Meyer, Barbara Gandek
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Monitoring patient-reported outcomes to capture CKD’s effects on health-related quality of life (QOL) is important for population health and individual care. Current measures such as the Kidney Disease Quality of Life-36 (KDQOL-36) do not incorporate some proven measurement advances, and measures incorporating such advances are rarely compared with current methods. The authors evaluated the validity of a new approach to CKD-specific QOL measurement that comprehensively represents CKD-specific QOL, yields a single summary QOL impact score, and generally requires only 1 minute. Across CKD stages 3–5, dialysis, and transplant patients, results favored the new approach over the KDQOL-36 in comparisons of validity, including responsiveness (sensitivity to clinical change), across multiple clinical tests. Computerized adaptive test versions of the new approach were more efficient than static versions. Background Patient-reported outcome measures that are more practical and clinically useful are needed for patients with CKD. We compared a new CKD-specific quality-of-life impact scale (CKD-QOL) with currently used measures. Methods Patients ( n =485) in different treatment groups (nondialysis stages 3–5, on dialysis, or post-transplant) completed the kidney-specific CKD-QOL and Kidney Disease Quality of Life-36 (KDQOL-36) forms and the generic SF-12 Health Survey at baseline and 3 months. New items summarizing quality of life (QOL) impact attributed to CKD across six QOL domains yielded single impact scores from a six-item static (fixed-length) form and from computerized adaptive tests (CATs) with three to six items. Validity tests compared the CKD-QOL, KDQOL-36 (Burden, Effects, and Symptoms/Problems subscales), and generic SF-12 measures across groups in four tests of clinical status and clinician assessment of change (CKD-specific tests), and number of comorbidities. ANOVA was used to test for group mean differences, variances in each measure explained by groups, and relative validity (RV) in comparison with the referent KDQOL-36 Burden subscale. Results KDQOL-36 and CKD-QOL measures generally discriminated better than generic SF-12v2 measures. The pattern of variances across CKD-specific tests comparing validity favored CKD-QOL two-fold over KDQOL-36. Two RV test results confirmed CKD-QOL improvements over the referent KDQOL scale. Results for static and CAT CKD-QOL forms were similar. SF-12 Physical and KDQOL-36 Symptoms scores worsened with increasing comorbid condition counts. Conclusions Overall, compared with the KDQOL-36, the new approach to summarizing CKD-specific QOL impact performed better across multiple tests of validity. CAT surveys were more efficient than static surveys.
Beyond “incentive hope”: Information sampling and learning under reward uncertainty
Authors: Maya Zhe Wang, Benjamin Y. Hayden
Journal: Behavioral and Brain Sciences (2019)

Information seeking, especially when motivated by strategic learning and intrinsic curiosity, could render the new mechanism "incentive hope" proposed by Anselme &amp; Güntürkün sufficient, but not necessary to explain how reward uncertainty promotes reward seeking and consumption. Naturalistic and foraging-like tasks can help parse motivational processes that bridge learning and foraging behaviors and identify their neural underpinnings.
HSR19-086: Healthcare Costs and Resource Utilization Associated With Adverse Events Among Hairy Cell Leukemia Patients Treated With Purine Nucleoside Analogs
Authors: Narendranath Epperla, Melissa Pavilack, Temitope Olufade, Richa Bashyal, Teng Huang, Huseyin Yuce, Leslie Andritsos
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Purine nucleoside analogs (PNAs) are highly effective for first-line treatment of hairy cell leukemia (HCL). In clinical trials of single PNAs, several adverse events (AEs) were reported; however, little is known regarding the costs and healthcare resource utilization (HRU) resulting from AEs in HCL patients (pts) treated with PNAs in non-clinical trial settings. Objective: Determine the costs and HRU of high incident and clinically important AEs associated with PNA therapy in HCL pts in the Truven MarketScan database. Methods: Adults (aged ≥18 years) with ≥2 HCL diagnosis codes ≥30 days apart during January 1, 2006–December 31, 2015 were included. Pts had ≥1 prescription claim for a PNA (cladribine or pentostatin ± rituximab) after HCL diagnosis date. First PNA claim date was defined as the index date. Pts had continuous health plan enrollment for ≥6 months at baseline and ≥12-months follow-up with no PNA in the baseline period. Pts were placed into cohorts based on the occurrence of myelosuppression (MSPN) and opportunistic infections (OI) as these were highest incident and clinically important AEs observed. Generalized linear models were used to compare outcomes during the 12-month follow-up. Results: Of the 219 pts with no history of MSPN, 101 developed MSPN (incidence [I]: 461 per 1000 pt-years) and of 619 pts with no history of OI, 26 developed OI (I: 42 per 1000 pt-years). Demographics were similar between pts with and without MSPN and OI. Pts who developed OI or MSPN had significantly higher inpatient admissions and costs (Table 1). Conclusions: PNA-treated HCL pts who developed MSPN or OI incurred higher HRU than those who did not develop either condition. This indicates the need for new therapeutic strategies to reduce HCL-treatment-associated toxicities.
CRISPR-Mediated Loss of Immunoglobulin Heavy Chain in Multiple Myeloma Cell Line Results in Metabolic Pathway Alterations
Authors: Denise K Walters, Renee C Tschumper, Dominique B Hoelzinger, Sophia J Quinton, Xiaojian Shi, Haiwei Gu, Diane F Jelinek
Journal: Blood (2018)
Food security and obesity: Can passerine foraging behavior inform explanations for human weight gain?
Authors: Ursula Pool
Journal: Behavioral and Brain Sciences (2019)

Abstract Commonly used measures of human food insecurity differ categorically from measures determining food security in other species. In addition, human foraging behaviors may have arisen in a divergent evolutionary context from nonhuman foraging. Hence, a theoretical framework based on food insecurity and fat storage in nonhumans may not be appropriate for explaining associations between human food insecurity and obesity.
Abstract MP30: Longitudinal Tracking of Obesity From Childhood and Adolescence Into Adulthood: The International Childhood Cardiovascular Cohort (i3C) Consortium
Authors: Justin R Ryder, Alan R Sinaiko, David R Jacobs, Tian Hu, Trudy Burns, Jessica G Woo, Elaine M Urbina, Lydia Bazzano, Alison Venn, Terrence Dwyer, Markus Juonalla, Olli Raitakari, Ronald Prineas, Julia Steinberger
Journal: Circulation (2018)

Obesity in childhood and adolescence tracks into adulthood. However, limited longitudinal data exist on variation in tracking in relation to pediatric development periods, race, and gender. The study objective was to relate adult (age&gt;30) weight status to that in childhood (3-11, mean 8.5 yrs; adult 36.6 yrs; N=4,511) and adolescence (12-17, mean 14 yrs; adult 39.9 yrs; N=7,215) from seven i3C cohorts. Overall tracking of BMI into adulthood was highly significant (p&lt;0.0001) and similar from childhood and adolescence. Almost all obese children (74.3%) and adolescents (81.6%) became obese adults, and few obese children (6.5%) or adolescents (4.2%) became normal-weight adults. Overweight children and adolescents also were more likely to become obese adults (60.7% and 65.2%, respectively), and few became normal weight (11.7% and 6.6%). Normal weight children and adolescents tended to remain normal weight into adulthood (43% and 40.3%), but 22.7% of both normal-weight children and adolescents became obese. Patterns differed by race and gender (both p&lt;0.001). Obese adolescent females had the highest persistence of obesity in adulthood (84.2%), followed by obese adolescent males (79.3%), obese male children (78.1%) and obese female children (70.6%). Normal weight male and female children and adolescents had a similar low prevalence of obesity as adults (22-23%), but females were more likely than males to remain normal weight from childhood (51.2% and 33.1%) and adolescence (48.7% and 30.6%). Tracking by race (see Table) showed that blacks had greater risk of adult obesity regardless of childhood or adolescent weight category. The results show that: 1) almost all obese and most overweight children and adolescents became obese adults; 2) one-fifth of white normal weight children and adolescents became obese adults; 3) even normal weight black children and adolescents are at significant risk of becoming obese adults. These data strongly suggest the need for early intervention to prevent adult obesity-related morbidity.
KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer
Authors: Wenting Liao, Michael J. Overman, Adam T. Boutin, Xiaoying Shang, Di Zhao, Prasenjit Dey, Jiexi Li, Guocan Wang, Zhengdao Lan, Jun Li, Ming Tang, Shan Jiang, Xingdi Ma, Peiwen Chen, Riham Katkhuda, Krittiya Korphaisarn, Deepavali Chakravarti, Andrew Chang, Denise J. Spring, Qing Chang, Jianhua Zhang, Dipen M. Maru, Dean Y. Maeda, John A. Zebala, Scott Kopetz, Y. Alan Wang, Ronald A. DePinho
Journal: Cancer Cell (2019)
Long Noncoding RNA MALAT1 Regulates Cancer Glucose Metabolism by Enhancing mTOR-Mediated Translation of TCF7L2
Authors: Pushkar Malakar, Ilan Stein, Amijai Saragovi, Roni Winkler, Noam Stern-Ginossar, Michael Berger, Eli Pikarsky, Rotem Karni
Journal: Cancer Research (2019)

Reprogrammed glucose metabolism of enhanced aerobic glycolysis (or the Warburg effect) is known as a hallmark of cancer. The roles of long noncoding RNAs (lncRNA) in regulating cancer metabolism at the level of both glycolysis and gluconeogenesis are mostly unknown. We previously showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acts as a proto-oncogene in hepatocellular carcinoma (HCC). Here, we investigated the role of MALAT1 in regulating cancer glucose metabolism. MALAT1 upregulated the expression of glycolytic genes and downregulated gluconeogenic enzymes by enhancing the translation of the metabolic transcription factor TCF7L2. MALAT1-enhanced TCF7L2 translation was mediated by upregulation of SRSF1 and activation of the mTORC1-4EBP1 axis. Pharmacological or genetic inhibition of mTOR and Raptor or expression of a hypophosphorylated mutant version of eIF4E-binding protein (4EBP1) resulted in decreased expression of TCF7L2. MALAT1 expression regulated TCF7L2 mRNA association with heavy polysomes, probably through the TCF7L2 5'-untranslated region (UTR), as determined by polysome fractionation and 5'UTR-reporter assays. Knockdown of TCF7L2 in MALAT1-overexpressing cells and HCC cell lines affected their metabolism and abolished their tumorigenic potential, suggesting that the effects of MALAT1 on glucose metabolism are essential for its oncogenic activity. Taken together, our findings suggest that MALAT1 contributes to HCC development and tumor progression by reprogramming tumor glucose metabolism. SIGNIFICANCE: These findings show that lncRNA MALAT1 contributes to HCC development by regulating cancer glucose metabolism, enhancing glycolysis, and inhibiting gluconeogenesis via elevated translation of the transcription factor TCF7L2.
High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: a systematic review and meta-analysis
Authors: B. Rochwerg, D. Granton, D. X. Wang, Y. Helviz, S. Einav, J. P. Frat, A. Mekontso-Dessap, A. Schreiber, E. Azoulay, A. Mercat, A. Demoule, V. Lemiale, A. Pesenti, E. D. Riviello, T. Mauri, J. Mancebo, L. Brochard, K. Burns
Journal: Intensive Care Medicine (2019)
Complex social ecology needs complex machineries of foraging
Authors: Toshiya Matsushima, Hidetoshi Amita, Yukiko Ogura
Journal: Behavioral and Brain Sciences (2019)

Uncertainty is caused not only by environmental changes, but also by social interference resulting from competition over food resources. Actually, foraging effort is socially facilitated, which, however, does not require incentive control by the dopamine system; Zajonc's "drive" theory is thus questionable. Instead, social adjustments may be pre-embedded in the limbic network responsible for decisions of appropriate effort-cost investment.
Adverse Events Associated With Immune Checkpoint Inhibitors
Authors: Kenar D. Jhaveri, Rimda Wanchoo
Journal: JAMA (2019)

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Targeted Next-Generation Sequencing of TP53, BIRC3, NOTCH1, SF3B1, and ATM Identifies a Significant Proportion of Lower-Risk Chronic Lymphocytic Leukemia with Unfavorable Prognostic Indicators
Authors: Brian Kwok, Aine Yung, Prashanti Reddy, Yin Xu, Alex Chan, Derek Lyle
Journal: Blood (2018)
Evaluation of bioenergetic and mitochondrial function in liver transplantation
Authors: Rui Miguel Martins, João Soeiro Teodoro, Emanuel Furtado, Anabela Pinto Rolo, Carlos Marques Palmeira, José Guilherme Tralhão
Journal: Clinical and Molecular Hepatology (2019)

We measured changes in mitochondrial function and bioenergetics that occur during ischemia/ reperfusion in fresh liver samples of patients undergoing liver transplantation. These variations correlated with markers of liver function and clinical outcome. Ischemia/reperfusion injury related to liver transplantation affects mitochondrial function and bioenergetics. Experimental studies were conducted to identify the role of bioenergetics and mitochondrial dysfunction. To the best of our knowledge, no investigation of these two factors' impacts on liver transplantation has been performed.This was a prospective study of 28 patients who underwent liver transplantation. We measured parameters of mitochondrial function and bioenergetics in biopsies performed during the procedure.We observed a statistically significant reduction in mitochondrial membrane potential, an increase in lag phase, and decreases in mitochondrial respiration and adenosine triphosphate content (P<0.010). Higher postoperative aminotransferase peaks correlated with worse mitochondrial function; mitochondrial respiration correlated with arterial lactate (P<0.010).There is a relationship between mitochondrial function and ischemia/reperfusion injury. The future use of these clinical markers as prognostic factors may allow early identification of post-transplant liver failure and may indicate the need to perform a new transplant.
Abstract 19617: A Stepwise Approach Using Bolus Isoproterenol Followed by Epinephrine Injection to Induce Infrequent Intraprocedural Premature Ventricular Complexes
Authors: Shinoda Yasutoshi, Yuki Komatsu, Kentaro Yoshida, Akihiko Nogami, Kazutaka Aonuma
Journal: Circulation (2017)

Introduction: Radiofrequency catheter ablation is a widely accepted therapy for idiopathic premature ventricular complexes (PVCs). However, paucity of clinical PVCs at the beginning of procedure ma...