tbuckley/cabot-search huggingface dataset:
Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study
Authors: Laura E. Dichtel, Linda L. Carpenter, Maren Nyer, David Mischoulon, Allison Kimball, Thilo Deckersbach, Darin D. Dougherty, David A. Schoenfeld, Lauren Fisher, Cristina Cusin, Christina Dording, Nhi-Ha Trinh, Paola Pedrelli, Albert Yeung, Amy Farabaugh, George I. Papakostas, Trina Chang, Benjamin G. Shapero, Justin Chen, Paolo Cassano, Emily M. Hahn, Elizabeth M. Rao, Roscoe O. Brady, Ravinder J. Singh, Audrey R. Tyrka, Lawrence H. Price, Maurizio Fava, Karen K. Miller
Journal: American Journal of Psychiatry (2020)

Objective: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21–70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity. Results: The participants’ mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo. Conclusions: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.
Health-Related Quality of Life at 1 Year in the Drepagreffe Trial Comparing Chronic Transfusion to Transplantation in Children with Sickle Cell Anemia and a History of Abnormal Cerebral Velocities
Authors: Francoise Bernaudin, Elise Drain, Jean-Hugues Dalle, Emmanuella Leveille, Regis Peffault De Latour, Valentine Brousse, Catherine Paillard, Isabelle Thuret, Benedicte Neven, Corinne Guitton, Claire Galambrun, Corinne Pondarré, Camille Runel, Charlotte Jubert, Gisele Elana, Florence Missud, Olivier Taieb, Eleonore Petras, Lydia Divialle-Doumdo, Cécile Arnaud, Annie Kamdem, Gérard Socié, Sylvie Chevret
Journal: Blood (2017)
Activation of NF-κB-Inducing Kinase in Islet β Cells Causes β Cell Failure and Diabetes
Authors: Xinzhi Li, Yongsen Wu, Yue Song, Na Ding, Min Lu, Linna Jia, Yujun Zhao, Ming Liu, Zheng Chen
Journal: Molecular Therapy (2020)

Islet β cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the β cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that β cell-specific overexpression of NIK (β-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, β cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H2O2-induced β cell death and also reduces streptozotocin (STZ)-induced β cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, β cell death, and diabetes. In all, this study not only uncovers a role of NIK in β cell failure but also provides a potential therapeutic target for the treatment of diabetes. Islet β cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the β cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that β cell-specific overexpression of NIK (β-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, β cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H2O2-induced β cell death and also reduces streptozotocin (STZ)-induced β cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, β cell death, and diabetes. In all, this study not only uncovers a role of NIK in β cell failure but also provides a potential therapeutic target for the treatment of diabetes.
Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation
Authors: Hyeseung Lee, Robert J. Fenster, S. Sebastian Pineda, Whitney S. Gibbs, Shahin Mohammadi, Jose Davila-Velderrain, Francisco J. Garcia, Martine Therrien, Hailey S. Novis, Fan Gao, Hilary Wilkinson, Thomas Vogt, Manolis Kellis, Matthew J. LaVoie, Myriam Heiman
Journal: Neuron (2020)
Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease
Authors: Erdem Kucukal, Yuncheng Man, Ailis Hill, Shichen Liu, Allison Bode, Ran An, Jaikrishnan Kadambi, Jane A. Little, Umut A. Gurkan
Journal: American Journal of Hematology (2020)

Abstract Sickle cell disease (SCD) is a recessive genetic blood disorder exhibiting abnormal blood rheology. Polymerization of sickle hemoglobin, due to a point mutation in the β‐globin gene of hemoglobin, results in aberrantly adhesive and stiff red blood cells (RBCs). Hemolysis, abnormal RBC adhesion, and abnormal blood rheology together impair endothelial health in people with SCD, which leads to cumulative systemic complications. Here, we describe a microfluidic assay combined with a micro particle image velocimetry technique for the integrated in vitro assessment of whole blood viscosity (WBV) and RBC adhesion. We examined WBV and RBC adhesion to laminin (LN) in microscale flow in whole blood samples from 53 individuals with no hemoglobinopathies (HbAA, N = 10), hemoglobin SC disease (HbSC, N = 14), or homozygous SCD (HbSS, N = 29) with mean WBV of 4.50 cP, 4.08 cP, and 3.73 cP, respectively. We found that WBV correlated with RBC count and hematocrit in subjects with HbSC or HbSS. There was a significant inverse association between WBV and RBC adhesion under both normoxic and physiologically hypoxic (SpO 2 of 83%) tests, in which lower WBV associated with higher RBC adhesion to LN in subjects with HbSS. Low WBV has been found by others to associate with endothelial activation. Altered WBV and abnormal RBC adhesion may synergistically contribute to the endothelial damage and cumulative pathophysiology of SCD. These findings suggest that WBV and RBC adhesion may serve as clinically relevant biomarkers and endpoints in assessing emerging targeted and curative therapies in SCD.
Physical activity and other health-related outcomes after knee injury in youth and young adults (PhD Academy Award)
Authors: Allison M Ezzat
Journal: British Journal of Sports Medicine (2020)

The overarching aim of my PhD dissertation was to understand attitudes and beliefs about physical activity (PA), examine key health outcomes and objectively examine PA in youth and young adults (hereafter referred to as youth). I examined PA (actigraphy) and other physical and psychological health outcomes in the time period after recovery from acute knee injury and before a diagnosis of post-traumatic osteoarthritis (PTOA) in individuals who had sustained a previous intra-articular knee injury.

Traumatic knee injuries are among the most common sport-related injuries sustained by youth and are associated with significant societal and personal burden, including increased risk of future PTOA.1 Much research has focused on return to sport (RTS) after knee injury.2 3 However, despite the key role of PA in prevention of disease, disability and death, there is a paucity of knowledge surrounding PA participation in youth after …
Mumps Cases Disproportionately Affecting Persons Living with HIV Infection and Men Who Have Sex with Men — Chicago, Illinois, 2018
Authors: Tristan D. McPherson, Enrique Ramirez, Madeline Ringness, Peter Ruestow, Mariel Marlow, Marielle J. Fricchione
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

During January 1-March 2, 2018, the number of mumps cases among adults reported to the Chicago Department of Public Health (CDPH) doubled compared with the same period in 2017. In response, CDPH created a supplementary questionnaire to collect additional information on populations affected and potential transmission routes. An epidemiologic analysis of routine and supplementary data, including spatiotemporal analysis, was performed to describe mumps cases reported to CDPH during 2018. A fourfold increase in mumps cases was reported during 2018 compared with 2017, with men who have sex with men (MSM) and persons living with human immunodeficiency virus (HIV) infection disproportionately represented among cases. A spatiotemporal, residential cluster was identified in a 9-square-mile area within six adjacent communities. The majority of persons affected were MSM, and this area was visited by many other persons with mumps diagnoses. Spatiotemporal analyses could be used in real time to identify case clusters to target public health response efforts, including to guide recommendations for additional measles, mumps, and rubella (MMR) vaccine and to identify specific transmission venues.
Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer
Authors: Chengheng Liao, Yang Zhang, Cheng Fan, Laura E. Herring, Juan Liu, Jason W. Locasale, Mamoru Takada, Jin Zhou, Giada Zurlo, Lianxin Hu, Jeremy M. Simon, Travis S. Ptacek, Victor G. Andrianov, Einars Loza, Yan Peng, Huanghe Yang, Charles M. Perou, Qing Zhang
Journal: Cancer Discovery (2020)

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC. SIGNIFICANCE: We provide evidence from unbiased screens that BBOX1 is a potential therapeutic target in TNBC and that genetic knockdown or pharmacologic inhibition of BBOX1 leads to decreased TNBC cell fitness. This study lays the foundation for developing effective BBOX1 inhibitors for treatment of this lethal disease.This article is highlighted in the In This Issue feature, p. 1611.
AB1068 REGULATORY EFFECT OF SHORT-TERM LOW DOSE OF IL-2 RESTORES REGULATORY T CELLS IN IgG4-RELATED DISEASE
Authors: Y. Wu, X. C. Zhao, J. Luo
Journal: Annals of the Rheumatic Diseases (2020)

Background: Little known about the roles of peripheral immune cell subsets in IgG4-related disease (IgG4-RD). Objectives: The aim of our study was to analyze the role of low-dose interleukin-2 (ld-IL2) on these cells in IgG4-RD. Methods: The percentage and absolute counts of lymphocyte subpopulations [CD3+ (T cells), CD4+, CD8+, CD19+ (B cells) and CD16+CD56+ (NK cells)] and CD4+T cell subsets (Th1, Th2, Th17, regulatory T (Treg)) using single platform flow cytometry in 25 IgG4-RD patients which were admitted and treated, as well as 24 healthy controls (HCs). Among IgG4-RD patients, 19 patients given only conventional treatments while 5 patients were were not only given conventional treatments but also received ld-IL2 (0.5 million IU/day) for 5 days. Results: We found that the absolute counts of T, CD4+T and Th1 cells were increased in the peripheral immune cells of IgG4-RD patients when compared with HCs. Meanwhile, the percentage of B, Th2, Th17 and Treg cells demonstrated significantly decreased. The ratio of Th1/Th2 and Th1/Treg in IgG4-RD patients were higher than that in HCs. After IL-2 administration, the absolute numbers of Treg cells increased dramatically, furthermore, the proportion of Treg cells had a trend towards higher values compared with those before treatment. Conversely, the ratio of Th2/Treg was downward. There were no any significant differences in the above subsets between before and after conventional treatments. Conclusion: Our findings support that the reduction of Treg cells in IgG4-RD patients, as well as ld-IL2 combined with conventional treatments were able to restore the Treg cells. References: [1]Akiyama M, Sasaki T, Kaneko Y, et al. Serum soluble interleukin-2 receptor is a useful biomarker for disease activity but not for differential diagnosis in IgG4-related disease and primary Sjögren’s syndrome adults from a defined population. Clin Exp Rheumatol, 2018. [2]Zhang SX, Wang J, Sun HH et al. Circulating regulatory T cells were absolutely decreased in dermatomyositis/polymyositis patients and restored by low-dose IL-2. Ann Rheum Dis, 2019. Disclosure of Interests: None declared
Abstract 13991: Foregone and Delayed Medical Care is Associated With Increased Health Care Costs and Utilization Among Heart Failure Patients in the United States
Authors: Alexander W Thomas, Javier Valero-Elizondo, Rohan Khera, Haider J Warraich, Harlan M Krumholz, Khurram Nasir, Nihar R Desai
Journal: Circulation (2019)

Introduction: Heart failure (HF) is a leading cause of morbidity and mortality with health care expenditures projected to increase 3-fold from 2012 to 2030. The proportion of patients with HF who f...
Immune Responses in 101HEMB01, a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with Severe Hemophilia B
Authors: Roberto Calcedo, Leticia Kuri-Cervantes, Hui Peng, Qiuyue Qin, Surina Boyd, Mark Schneider, Matt Hewitt, Michael Betts, James Wilson
Journal: Blood (2017)
Abstract #3749: Omega-3 polyunsaturated fatty acids suppress cell invasion, tumorigenicity, angiogenesis, and metastasis by inhibition of MMPs/VEGF through NF-kB and AP-1 signal in breast cancer
Authors: Kyu Lim, Eun-Jin Yun, Kyoung-Sub Song, Hae-Duck Park, Jong-Seok Kim, Eul-Soon Shin, Chang Han, Tong Wu, Jing X Kang, Jong-Il Park, Gi-Ryang Kweon, Wan-Hee Yoon, Byung-Doo Hwang
Journal: Cancer Research (2009)

Omega-3 polyunsaturated fatty acids (\#969;3-PUFAs) are known to inhibit cancer cells proliferation in animal models and cell lines; in contrast, \#969;6-PUFAs promote the growth of cancer cells. However, the molecular mechanisms remain to be further understood. This study was designed to investigate action mechanisms of \#969;3-PUFAs, especially docosahexaenoic acid (DHA), on inhibition of invasion, tumorigenicity, angiogenesis and metastasis in breast cancer. DHA suppressed motility and invasion of MDA-MB-231 cells in a dose-dependent manner; in contrast, AA has no effect. In gelatin embedded zymography, activities of MMP-2 and MMP-9 were decreased by DHA treatment and the levels of their mRNA were also decreased in dose-dependent manner. MMP-2 and MMP-9 promoter activity were inhibited after DHA treatment. The levels of VEGF protein and its promoter activity were inhibited by DHA treatment. AA- and PGE2-induced VEGF promoter activity was also inhibited by DHA pretreatment. The level of NF-kB protein and binding activities of NF-\#954;B and AP-1 were decreased by DHA treatment. DHA inhibited NF-kB and Cox-2 reporter activities and PGE2-dependent increases of their promoter activities were also inhibited by DHA pretreatment. When mouse breast cancer E0771 cells were implanted into Fat1 mice (Fat1 transgenic mice express a Caenorhabditis elegans \#969;3-desaturase converting \#969;6- to \#969;3-PUFAs endigenously.), tumor size and volume were significantly reduced in Fat1 transgenic mice compared with wild mice. In immunohistochemical analysis of tumors of Fat1 mice, apoptotic cells were markedly increased and angiogenesis significantly was reduced, compared with wild mice tumor. Binding activites of NF-kB and AP-1 were decreased in Fat1 mice tumors. When E0771 cells were injected through tail vein, lung metastasis of breast cancer cells was significantly inhibited in Fat1 transgenic mice. These findings suggest that \#969;3-PUFAs may inhibit tumor invasion, tumorigenicity, angiogenesis, and metastasis by decrease of MMPs activities and VEGF level via reduction of NF-kB and AP-1 in breast cancer. Thus, utilization of \#969;3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human breast cancer. [This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2007-521-E00014), Yihang Scholarship Foundation of Chungnam National University Medical School, and Dr. Park\#8217;s Breast Clinic, Korea].  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3749.
Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With <i>FLT3</i>–Internal Tandem Duplication Mutation (SORMAIN)
Authors: Andreas Burchert, Gesine Bug, Lea V. Fritz, Jürgen Finke, Matthias Stelljes, Christoph Röllig, Ellen Wollmer, Ralph Wäsch, Martin Bornhäuser, Tobias Berg, Fabian Lang, Gerhard Ehninger, Hubert Serve, Robert Zeiser, Eva-Maria Wagner, Nicolaus Kröger, Christine Wolschke, Michael Schleuning, Katharina S. Götze, Christoph Schmid, Martina Crysandt, Eva Eßeling, Dominik Wolf, Ying Wang, Alexandra Böhm, Christian Thiede, Torsten Haferlach, Christian Michel, Wolfgang Bethge, Thomas Wündisch, Christian Brandts, Susanne Harnisch, Michael Wittenberg, Heinz-Gert Hoeffkes, Susanne Rospleszcz, Alexander Burchardt, Andreas Neubauer, Markus Brugger, Konstantin Strauch, Carmen Schade-Brittinger, Stephan K. Metzelder
Journal: Journal of Clinical Oncology (2020)

PURPOSE Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene ( FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD–positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD–positive AML.
Detection rate and treatment gap for atrial fibrillation identified through screening in community health centers in China (AF-CATCH): A prospective multicenter study
Authors: Yi Chen, Qi-Fang Huang, Chang-Sheng Sheng, Wei Zhang, Shuai Shao, Dian Wang, Yi-Bang Cheng, Ying Wang, Qian-Hui Guo, Dong-Yan Zhang, Yan Li, Nicole Lowres, Ben Freedman, Ji-Guang Wang
Journal: PLoS Medicine (2020)

Background Atrial fibrillation (AF) is underdiagnosed and especially undertreated in China. We aimed to investigate the prevalence of unknown and untreated AF in community residents (≥65 years old) and to determine whether an education intervention could improve oral anticoagulant (OAC) prescription. Methods and findings We performed a single–time point screening for AF with a handheld single-lead electrocardiography (ECG) in Chinese residents (≥65 years old) in 5 community health centers in Shanghai from April to September 2017. Disease education and advice on referral to specialist clinics for OAC treatment were provided to all patients with actionable AF (newly detected or undertreated known AF) at the time of screening, and education was reinforced at 1 month. Follow-up occurred at 12 months. In total, 4,531 participants were screened (response rate 94.7%, mean age 71.6 ± 6.3 years, 44% male). Overall AF prevalence was 4.0% (known AF 3.5% [n = 161], new AF 0.5% [n = 22]). The 183 patients with AF were older (p < 0.001), taller (p = 0.02), and more likely to be male (p = 0.01), and they had a higher prevalence of cardiovascular disease than those without AF (p < 0.001). In total, 85% (155/183) of patients were recommended for OAC treatment by the established guidelines (CHA2DS2-VASc ≥ 2 for men; ≥ 3 for women). OAC prescription rate for known AF was 20% (28/138), and actionable AF constituted 2.8% of all those screened. At the 12-month follow-up in 103 patients (81% complete), despite disease education and advice on specialist referral, only 17 attended specialist clinics, and 4 were prescribed OAC. Of those not attending specialist clinics, 71 chose instead to attend community health centers or secondary hospital clinics, with none prescribed OAC, and 15 had no review. Of the 17 patients with new AF and a class 1 recommendation for OAC, only 3 attended a specialist clinic, and none were prescribed OAC. Of the 28 AF patients taking OAC at baseline, OAC was no longer taken in 4. Ischemic stroke (n = 2) or death (n = 3) occurred in 5/126 (4%), with none receiving OAC. As screening was performed at a single time point, some paroxysmal AF cases may have been missed; thus, the rate of new AF may be underestimated. Conclusions We demonstrated a noticeable gap in AF detection and treatment in community-based elderly Chinese: actionable AF constituted a high proportion of those screened. Disease education and advice on specialist referral are insufficient to close the gap. Before more frequent or intensive screening for unknown AF could be recommended in China, greater efforts must be made to increase appropriate OAC therapy in known AF to prevent AF-related stroke.