tbuckley/cabot-search huggingface dataset:
Time to Treatment Intensification After Monotherapy Failure and Its Association With Subsequent Glycemic Control Among 93,515 Patients With Type 2 Diabetes
Authors: Urvi Desai, Noam Y. Kirson, Jennifer Kim, Kamlesh Khunti, Sarah King, Erich Trieschman, Michael Hellstern, Phillip R. Hunt, Jayanti Mukherjee
Journal: Diabetes Care (2018)

OBJECTIVE The goal of this study was to evaluate the association between the timing of treatment intensification and subsequent glycemic control among patients with type 2 diabetes in whom monotherapy fails. RESEARCH DESIGN AND METHODS This retrospective analysis of the U.K. Clinical Practice Research Datalink database focused on patients with type 2 diabetes and one or more HbA1c measurements ≥7% (≥53 mmol/mol) after ≥3 months of metformin or sulfonylurea monotherapy (first measurement meeting these criteria was taken as the study index date). Baseline (6 months before the index date) characteristics were stratified by time from the index date to intensification (early: &amp;lt;12 months; intermediate: 12 to &amp;lt;24 months; late: 24 to &amp;lt;36 months). Intensification was defined as initiating after the index date one or more noninsulin antidiabetes medication in addition to metformin or a sulfonylurea. Association between time to intensification and subsequent glycemic control (first HbA1c &amp;lt;7% [&amp;lt;53 mmol/mol] after intensification) was evaluated using Kaplan-Meier analyses and Cox proportional hazard models that accounted for baseline differences. RESULTS Of the 93,515 patients who met the study criteria (mean age 60 years; ∼59% male; 80% taking metformin), 23,761 (25%) intensified &amp;lt;12 months after the index date; 11,908 (13%) intensified after 12 to &amp;lt;24 months; and 7,146 (8%) intensified after 24 to &amp;lt;36 months. Patients who intensified treatment ≥36 months after the index date (n = 9,638 [10%]) and those with no evidence of treatment intensification during the observable follow-up period (n = 41,062 [44%]) were not included in further analyses. The median times from intensification to control were 20.0, 24.1, and 25.7 months, respectively, for the early, intermediate, and late intensification cohorts. After adjustment for baseline differences, the likelihood of attaining glycemic control was 22% and 28% lower for patients in the intermediate and late intensification groups, respectively, compared with those intensifying early (P &amp;lt; 0.0001). CONCLUSIONS Earlier treatment intensification is associated with shorter time to subsequent glycemic control, independent of whether patients initiate first-line treatment with metformin or a sulfonylurea.
Abstract P258: Prevalence of Metabolically Healthy Obesity in US Adult Population: NHANES 1999-2014
Authors: Tingting Liu, Changwei Li, Shengxu Li
Journal: Circulation (2018)

Background: Obesity prevalence has been increasing while cardiometabolic mortality has been decreasing. The reasons for this paradox are not fully understood. Aim: To test the hypothesis that the prevalence of metabolically healthy obesity (MHO) in the U.S. adult population increases over time. Methods: The study included 16,459 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2014. MHO was defined as central obesity (waist circumference≥102 cm for men and ≥88 cm for women) without any of the following conditions: elevated levels of blood pressure (&lt;125/85 mm Hg), glucose (&lt;100 mg/dL), and triglycerides (&lt;150 mm/dL), reduced levels of high-density lipoprotein cholesterol (≥40 mg/dL for men and ≥50 mg/dL for women), and any medication use for high cholesterol, hypertension, or diabetes. Results: The prevalence of central obesity increased from 45.17% in 1999-2000 to 56.72% in 2013-2014 (P=0.003). MHO prevalence increased from 4.95% in 1999-2000 to 8.92% in 2013-2014. Among those with central obesity, the proportion of MHO increased from 11.0% in 1999-2000 to 15.7% in 2013-2014. Female gender, a younger age, being Hispanic and non-Hispanic Black, and high education (some college or above) were associated with higher prevalence of MHO. Conclusions: While the prevalence of central obesity in the U.S. population has increased, the prevalence of MHO and the proportion of MHO among those who are centrally obese have also increased since 1999, which may partly contribute to the paradox between increased obesity prevalence and reduced cardiometabolic mortality.
The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models
Authors: Carmen Vicente, Rocco Stirparo, Sofie Demeyer, Charles E. de Bock, Olga Gielen, Mardelle Atkins, Jiekun Yan, Georg Halder, Bassem A. Hassan, Jan Cools
Journal: Journal of Hematology & Oncology (2018)

The CNOT3 protein is a subunit of the CCR4-NOT complex, which is involved in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL). Here, we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, and other members of the CCR4-NOT complex. Our data show that knockdown of Not3, the structural components Not1/Not2, and the deadenylases twin/Pop2 all result in increased tumor formation. In addition, overexpression of Not3 could reduce tumor formation. Not3 downregulation has a mild but broad effect on gene expression and leads to increased levels of genes involved in DNA replication and ribosome biogenesis. CycB upregulation also contributes to the Not3 tumor phenotype. Similar findings were obtained in human T-ALL cell lines, pointing out the conserved function of Not3. Together, our data establish a critical role for Not3 and the entire CCR4-NOT complex as tumor suppressor.
Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes
Authors: Trevor M Penning, Phumvadee Wangtrakuldee, Richard J Auchus
Journal: Endocrine Reviews (2018)

Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C enzymes acting as 3-ketosteroid, 17-ketosteroid, and 20-ketosteroid reductases are involved in the prereceptor regulation of ligands for the androgen, estrogen, and progesterone receptors and are considered drug targets to treat steroid hormone-dependent malignancies and endocrine disorders. In contrast, AKR1D1 is the only known steroid 5β-reductase and is essential for bile-acid biosynthesis, the generation of ligands for the farnesoid X receptor, and the 5β-dihydrosteroids that have their own biological activity. In this review we discuss the crystal structures of these AKRs, their kinetic and catalytic mechanisms, AKR genomics (gene expression, splice variants, polymorphic variants, and inherited genetic deficiencies), distribution in steroid target tissues, roles in steroid hormone action and disease, and inhibitor design.
Pathogenetic Characteristics of Mesenchymal Stem Cells in Hidradenitis Suppurativa
Authors: Anna Campanati, Monia Orciani, Giulia Sorgentoni, Veronica Consales, Annamaria Offidani, Roberto Di Primio
Journal: JAMA Dermatology (2018)

<h3>Importance</h3> Hidradenitis suppurativa (HS) is a disease of the terminal hair follicle in apocrine gland–enriched skin areas, where immunobiology dysregulation of mesenchymal stem cells (MSCs) may have a key role. <h3>Objective</h3> To investigate the MSC profile in patients with HS and in healthy controls. <h3>Design, Setting, and Participants</h3> In this prospective case-control study, patients with HS were recruited from the Dermatological Clinic at the Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy. Biopsy specimens were analyzed at the Histology Section of the Department of Clinical and Molecular Sciences. Participants included 11 patients with HS and 9 healthy controls, who were recruited into the study between January 20, 2015, and September 20, 2016, and underwent punch biopsy from axillary skin. None of the participants had received any antibiotics (systemic or topical therapy) within almost 12 weeks before the study. <h3>Main Outcomes and Measures</h3> The immunophenotypic profile of MSCs was characterized following the minimal criteria established by the International Society for Cellular Therapy for the identification of MSCs. Levels of 12 cytokines belonging to helper T-cell subtypes 1, 2, and 17 pathways were examined on the secretome of isolated cells by enzyme-linked immunoabsorbent assay. <h3>Results</h3> Skin MSCs were characterized in 11 patients with HS (8 women and 3 men; mean [SD] age, 35.8 [7.9] years) and 9 healthy controls (7 women and 2 men; mean [SD] age, 36.7 [6.9] years). The healthy controls were matched with patients with HS for body mass index. Mesenchymal stem cells isolated from patients with HS (HS-MSCs) and from healthy controls (C-MSCs) met the International Society for Cellular Therapy minimal criteria. Compared with C-MSCs, cytokine analyses of HS-MSCs revealed statistically significant overexpression of interleukin (IL) 6 (median [interquartile range {IQR}], 8765.00 [7659.00-9123.00] vs 2849.00 [2609.00-3001.00] pg/mL;<i>P</i> = .008), IL-10 (median [IQR], 29.46 [26.35-35.79] vs 21.36 [19.89-23.33] pg/mL;<i>P</i> = .004), IL-12 (median [IQR], 15.25 [13.27-16.25] vs 11.89 [10.73-12.33] pg/mL;<i>P</i> = .03), IL-17A (median [IQR], 15.24 [13.23-17.24] vs 11.24 [10.28-11.95] pg/mL;<i>P</i> = .008), tumor necrosis factor (median [IQR], 42.54 [42.20-43.94] vs 32.55 [31.78-33.28] pg/mL;<i>P</i> = .004), transforming growth factor β1 (median [IQR], 1728.00 [1535.00-1979.00] vs 500.80 [465.00-634.50] pg/mL;<i>P</i> = .004), and interferon γ (median [IQR], 11.49 [10.71-12.35] vs 9.45 [9.29-10.01] pg/mL;<i>P</i> = .005). <h3>Conclusions and Relevance</h3> Mesenchymal stem cells isolated from the skin of patients with HS seem to be activated toward an inflammatory status. The imbalance between proinflammatory and anti-inflammatory activities of MSCs favors the hypothesis of their pathogenic involvement in HS.
Abstract P130: Patterns of Change in Step Count During the First 12 Months of a Weight Loss Intervention: A Group-based Trajectory Analysis
Authors: Christopher C Imes, Yaguang Zheng, Hu Lu, Dara D Mendez, Rachel W Goode, Meghan Mattos, Qianheng Ma, Ran Sun, Yang Yu, Cynthia A Danford, Susan M Sereika, Lora E Burke
Journal: Circulation (2016)

Introduction: Increased physical activity (PA) along with reduced energy intake are the key components of weight loss treatment. Objective measures of PA are more reliable than self-report and are infrequently used in clinical trials. Pedometers are inexpensive, often imbedded in mobile devices (e.g. smartphones), and provide a good estimate of overall daily PA. Hypotheses: We hypothesized that groups with different patterns of daily step counts would emerge over the 12-month period. Methods: We examined the first 12 months of data from the Self Efficacy Lifestyle Focus Trial during which standard behavioral treatment for weight loss was implemented. Participants were given an Omron HJ-720IT pedometer in the third week of the intervention. Pedometer use was recommended as a way to monitor PA goals, but not required. Mean daily step counts were calculated monthly from pedometer data, with days having zero step counts coded as missing. Group-based trajectory modeling was used to identify distinct classes of trajectories of mean daily step counts. Results: The sample (N=120) was 81.8% female, 73.6% White with mean (±SD) age of 53.9±9.0 years and baseline body mass index of 33.2±3.8 kg/m2. Four trajectory groups were identified: active (≥10000 steps/day; n=14, 11.7%), somewhat active (7500 to 9999 steps/day; n=34, 28.3%), low active (5000 to 7499 steps/day; n=33, 27.5%), and sedentary (&lt;5000 steps/day; n=39, 32.5%). Over 12 months, the active group increased their daily step counts, while the low active and sedentary groups decreased their step counts. Conclusions: Based on our findings, it appeared that study participation, including pedometer use, had little effect on step counts, except in the group that was already active. This suggests that less active individuals may have difficulty initiating activities that increase steps even when using a pedometer. Increased emphasis on simple strategies to increase step count and PA are needed to change sedentary habits.
PU.1 regulates Alzheimer’s disease-associated genes in primary human microglia
Authors: Justin Rustenhoven, Amy M. Smith, Leon C. Smyth, Deidre Jansson, Emma L. Scotter, Molly E. V. Swanson, Miranda Aalderink, Natacha Coppieters, Pritika Narayan, Renee Handley, Chris Overall, Thomas I. H. Park, Patrick Schweder, Peter Heppner, Maurice A. Curtis, Richard L. M. Faull, Mike Dragunow
Journal: Molecular Neurodegeneration (2018)

Microglia play critical roles in the brain during homeostasis and pathological conditions. Understanding the molecular events underpinning microglial functions and activation states will further enable us to target these cells for the treatment of neurological disorders. The transcription factor PU.1 is critical in the development of myeloid cells and a major regulator of microglial gene expression. In the brain, PU.1 is specifically expressed in microglia and recent evidence from genome-wide association studies suggests that reductions in PU.1 contribute to a delayed onset of Alzheimer’s disease (AD), possibly through limiting neuroinflammatory responses. To investigate how PU.1 contributes to immune activation in human microglia, microarray analysis was performed on primary human mixed glial cultures subjected to siRNA-mediated knockdown of PU.1. Microarray hits were confirmed by qRT-PCR and immunocytochemistry in both mixed glial cultures and isolated microglia following PU.1 knockdown. To identify attenuators of PU.1 expression in microglia, high throughput drug screening was undertaken using a compound library containing FDA-approved drugs. NanoString and immunohistochemistry was utilised to investigate the expression of PU.1 itself and PU.1-regulated mediators in primary human brain tissue derived from neurologically normal and clinically and pathologically confirmed cases of AD. Bioinformatic analysis of gene expression upon PU.1 silencing in mixed glial cultures revealed a network of modified AD-associated microglial genes involved in the innate and adaptive immune systems, particularly those involved in antigen presentation and phagocytosis. These gene changes were confirmed using isolated microglial cultures. Utilising high throughput screening of FDA-approved compounds in mixed glial cultures we identified the histone deacetylase inhibitor vorinostat as an effective attenuator of PU.1 expression in human microglia. Further characterisation of vorinostat in isolated microglial cultures revealed gene and protein changes partially recapitulating those seen following siRNA-mediated PU.1 knockdown. Lastly, we demonstrate that several of these PU.1-regulated genes are expressed by microglia in the human AD brain in situ. Collectively, these results suggest that attenuating PU.1 may be a valid therapeutic approach to limit microglial-mediated inflammatory responses in AD and demonstrate utility of vorinostat for this purpose.
Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries
Authors: Federico Moccetti, Eran Brown, Aris Xie, William Packwood, Yue Qi, Zaverio Ruggeri, Weihui Shentu, Junmei Chen, Jose A. López, Jonathan R. Lindner
Journal: Journal of the American College of Cardiology (2018)
Development of a novel target module redirecting UniCAR T cells to Sialyl Tn-expressing tumor cells
Authors: L. R. Loureiro, A. Feldmann, R. Bergmann, S. Koristka, N. Berndt, C. Arndt, J. Pietzsch, C. Novo, P. Videira, M. Bachmann
Journal: Blood Cancer Journal (2018)
Abstract 16458: Paracrine Crosstalk Between Paltelets And Vascular Endothelial Cell is Mediated via MicroRNAs
Authors: Seema Dangwal, Bernd Stratmann, Claudia Bang, Diethelm Tschoepe, Thomas Thum
Journal: Circulation (2015)

Majority of extracellular miRNAs constituting plasma miRNA pool are released by platelets. This study investigated the miRNA signature of leukocyte depleted platelets (LDP) isolated from T2DM or healthy subjects and explored the mechanism of miRNA mediated vascular crosstalk. LDPs, obtained by leukocyte filtration of platelet rich plasma (PRP), were isolated from blood withdrawn from 6 T2DM patients (male, age: 54.8±7.6 yrs; HbA1c: 8.9±0.6%; BMI: 30.9±2.8kg/m2) and 10 healthy volunteers (male, age: 49.2±6.8yrs; HbA1c: 5.3±0.2%; BMI: 26.6±3.8kg/m2). Total RNA isolated from diabetic or healthy LDPs was subjected to PCR based miRNA profiling. Matrigel capillary formation and genomic BrdU incorporation were measured as readouts of angiogenesis and cell proliferation respectively. Cellular metabolic activities were measured by WST-1 assay. Student t-test was applied to compare groups and p&lt;0.05 considered significant. Total 735 (97%) miRNAs were detected (threshold&lt; 29 Ct) in all LDPs. Levels of 19.5% miRNAs were decreased in T2DM platelets, whereas 7.5% miRNAs showed increase at 2-50 fold cutoff value. Compared to healthy LDPs (n=10), decreased levels of 14 highly platelet enriched miRNAs candidates including miR-21 and miR-22 were confirmed by RTPCR validation of individual T2DM LDPs irrespective of aspirin intake or presence of coronary heart disease (n=11). Thrombin stimulation of washed healthy platelets increased miRNA release into cell supernatant and confocal microscopy confirmed the cellular uptake of platelet released micro-particles into human coronary artery endothelial cells within 2-24h. In addition, endothelial overexpression of miR-21 or miR-22 decreased cell proliferation and metabolic activity, whereas miR-22 also attenuated capillary formation capacity. MiR-21 and miR-22 modulation inversely regulated expression of cell-cycle regulator gene CDK-6 at mRNA and protein levels. Diabetic platelets show distinct miRNA signature compared to healthy platelets and lower levels of miRNAs in diabetic platelets may represent their active secretion during diabetes. Released miRNAs may mediate crosstalk with vascular cells by influencing cellular gene expression and function upon their uptake.
Targeting Endothelial Erk1/2-Akt Axis as a Regeneration Strategy to Bypass Fibrosis during Chronic Liver Injury in Mice
Authors: Yuanxiang Lao, Yanyan Li, Ping Zhang, Qianqian Shao, Weiran Lin, Bintao Qiu, Yongzhuang Lv, Lichun Tang, Shishuai Su, Hongyu Zhang, Chunyan Tian, Aihua Sun, Handong Wei, Pumin Zhang, Yan Wu, Ying Jiang, Fuchu He
Journal: Molecular Therapy (2018)

Liver sinusoidal endothelial cells (LSECs) have great capacity for liver regeneration, and this capacity can easily switch to profibrotic phenotype, which is still poorly understood. In this study, we elucidated a potential target in LSECs for regenerative treatment that can bypass fibrosis during chronic liver injury. Proregenerative LSECs can be transformed to profibrotic phenotype after 4 weeks of carbon tetrachloride administration or 10 days of bile duct ligation. This phenotypic alternation of LSECs was mediated by extracellular regulated protein kinases 1 and 2 (Erk1/2)-Akt axis switch in LSECs during chronic liver injury; Erk1/2 was normally associated with maintenance of the LSEC proregenerative phenotype, inhibiting hepatic stellate cell (HSC) activation and promoting tissue repair by enhancing nitric oxide (NO)/reactive oxygen species (ROS) ratio and increasing expression of hepatic growth factor (HGF) and Wingless-type MMTV integration site family member 2 (Wnt2). Alternatively, Akt induced LSEC profibrotic phenotype, which mainly stimulated HSC activation and concomitant senescence by reducing NO/ROS ratio and decreasing HGF/Wnt2 expression. LSEC-targeted adenovirus or drug particle to promote Erk1/2 activity can alleviate liver fibrosis, accelerate fibrosis resolution, and enhance liver regeneration. This study demonstrated that the Erk1/2-Akt axis acted as a switch to regulate the proregenerative and profibrotic phenotypes of LSECs, and targeted therapy promoted liver regeneration while bypassing fibrosis, providing clues for a more effective treatment of liver diseases.
External validation of computed tomography decision rules for minor head injury: prospective, multicentre cohort study in the Netherlands
Authors: Kelly A Foks, Crispijn L van den Brand, Hester F Lingsma, Joukje van der Naalt, Bram Jacobs, Eline de Jong, Hugo F den Boogert, Özcan Sir, Peter Patka, Suzanne Polinder, Menno I Gaakeer, Charlotte E Schutte, Kim E Jie, Huib F Visee, Myriam G M Hunink, Eef Reijners, Meriam Braaksma, Guus G Schoonman, Ewout W Steyerberg, Korné Jellema, Diederik W J Dippel
Journal: BMJ (2018)

Abstract Objective To externally validate four commonly used rules in computed tomography (CT) for minor head injury. Design Prospective, multicentre cohort study. Setting Three university and six non-university hospitals in the Netherlands. Participants Consecutive adult patients aged 16 years and over who presented with minor head injury at the emergency department with a Glasgow coma scale score of 13-15 between March 2015 and December 2016. Main outcome measures The primary outcome was any intracranial traumatic finding on CT; the secondary outcome was a potential neurosurgical lesion on CT, which was defined as an intracranial traumatic finding on CT that could lead to a neurosurgical intervention or death. The sensitivity, specificity, and clinical usefulness (defined as net proportional benefit, a weighted sum of true positive classifications) of the four CT decision rules. The rules included the CT in head injury patients (CHIP) rule, New Orleans criteria (NOC), Canadian CT head rule (CCHR), and National Institute for Health and Care Excellence (NICE) guideline for head injury. Results For the primary analysis, only six centres that included patients with and without CT were selected. Of 4557 eligible patients who presented with minor head injury, 3742 (82%) received a CT scan; 384 (8%) had a intracranial traumatic finding on CT, and 74 (2%) had a potential neurosurgical lesion. The sensitivity for any intracranial traumatic finding on CT ranged from 73% (NICE) to 99% (NOC); specificity ranged from 4% (NOC) to 61% (NICE). Sensitivity for a potential neurosurgical lesion ranged between 85% (NICE) and 100% (NOC); specificity from 4% (NOC) to 59% (NICE). Clinical usefulness depended on thresholds for performing CT scanning: the NOC rule was preferable at a low threshold, the NICE rule was preferable at a higher threshold, whereas the CHIP rule was preferable for an intermediate threshold. Conclusions Application of the CHIP, NOC, CCHR, or NICE decision rules can lead to a wide variation in CT scanning among patients with minor head injury, resulting in many unnecessary CT scans and some missed intracranial traumatic findings. Until an existing decision rule has been updated, any of the four rules can be used for patients presenting minor head injuries at the emergency department. Use of the CHIP rule is recommended because it leads to a substantial reduction in CT scans while missing few potential neurosurgical lesions.