tbuckley/cabot-search huggingface dataset:
Aggravation of asthmatic inflammation by chlorine exposure via innate lymphoid cells and CD11c<sup>intermediate</sup> macrophages
Authors: Ji‐Su Shim, Hyun‐Seung Lee, Da‐Eun Park, Ji Won Lee, Boram Bae, Yuna Chang, Jihyun Kim, Hye Young Kim, Hye‐Ryun Kang
Journal: Allergy (2019)

Chlorine is widely used in daily life as disinfectant. However, chronic exposure to chlorine products aggravates allergic TH 2 inflammation and airway hyperresponsiveness (AHR). Innate lymphoid cells (ILCs) in airways contribute to the inception of asthma in association with virus infection, pollution, and excess of nutrient, but it is not known whether chronic chlorine exposure can activate innate immune cells. The aim of this study was to evaluate the impact of chlorine inhalation on the innate immunity such as ILCs and macrophages in relation with the development of asthma by using murine ovalbumin (OVA) sensitization/challenge model.Six-week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low-dose chlorine exposure by inhalation of naturally vaporized gas of 5% sodium hypochlorite solution. AHR, airway inflammatory cells, from BALF and the population of ILCs and macrophages in the lung were evaluated.The mice exposed to chlorine with OVA (Cl + OVA group) showed enhanced AHR and eosinophilic inflammation compared to OVA-treated mice (OVA group). The population of TH 2 cells, ILC2s, and ILC3s increased in Cl + OVA group compared with OVA group. CD11cint macrophages also remarkably increased in Cl + OVA group compared with OVA group. The deletion of macrophages by clodronate resulted in reduction of ILC2s and ILC3s population which was restored by adoptive transfer of CD11cint macrophages.Chronic chlorine inhalation contributes to the exacerbation of airway inflammation in asthmatic airway by mobilizing pro-inflammatory macrophage into the lung as well as stimulating group 2 and 3 ILCs.
A small molecule inhibitor against kinase domain of mammalian target of rapamycin (mTOR) causes autophagic cell death in glioblastoma
Authors: Weiming Xu, Rene Bissonette, Kimberly Fultz, Mercedes Delgado, Sophie Perrin-Ninkovic, Patrick Papa, Jennifer Riggs, John Sapienza, Ronald Albers, Branden Lee, Roy Harris, Deborah Mortensen, Sabita Sankar
Journal: Cancer Research (2008)

3365  Background: Autophagy is a process of intracellular bulk degradation whereby cellular proteins, organelles and cytoplasmic components are engulfed in double membrane forming autophagic vesicles, and delivered to the lysosomal system for subsequent degradation. Autophagy is regulated by phosphotidylinositol-3-kinases (PI3K) and mammalian target of rapamycin (mTOR) pathways. Activation of mTOR kinase has been shown to down-regulate autophagy process. Previous data indicated that autophagy could be induced by rapamycin as well as mTOR small interfering RNA (siRNA). Silencing of mTOR with siRNA augmented the cytotoxicity of rapamycin in glioblastoma, indicating that autophagy was a primary mediator of the anti-tumor effect of rapamycin rather than a protective response. The goals of this study were to determine whether a small molecule inhibitor against the kinase domain of mTOR would cause autophagic cell death. The secondary objective is to develop a high content screen assay for autophagy detection.  Methods: U-87 MG glioblastoma cells were treated with an mTOR specific kinase inhibitor. Inactivation of both mTOR complexes (TOR1 and TOR2) was evaluated by measuring phosphorylation of S6 Ser 235/236 and AKT Ser473 in cell lysates at indicated times. Autophagy was detected by fluorescent dye monodansylcadaverine (MDC) and acridine orange (AO) and confirmed by high content imaging assay with polyclonal antibody against LC3 (microtubule-associated protein 1 light chain 3), a specific biomarker for autophagy. The cleaved LC3-II protein was measured by western immunoblotting. Cell proliferation was measured by Alamar blue after 72 hours of treatment.  Results: Upon treatment of U-87 MG cells with mTOR kinase inhibitor for 48 hours, massive autophagy formation was observed in U-87 MG glioblastoma. Using high content imaging assay (Cellomics), the spots in the cytoplasm representing autophagic vesicles were increased in a dose-dependent manner. This correlated with an anti-proliferative effect. We also identified other compounds within the same series that possess a similar effect.  Conclusion:We demonstrate that an mTOR kinase inhibitor results in significant autophagic cell death in glioblastoma which correlates with the anti-proliferative effect suggesting the blockage of mTOR kinase activity initiates type II programmed cell death.
Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update
Authors: Shannon M. Dunlay, Michael M. Givertz, David Aguilar, Larry A. Allen, Michael Chan, Akshay S. Desai, Anita Deswal, Victoria Vaughan Dickson, Mikhail N. Kosiborod, Carolyn L. Lekavich, Rozalina G. McCoy, Robert J. Mentz, Ileana L. Piña
Journal: Circulation (2019)

Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research.
Collider bias (aka sample selection bias) in observational studies: why the effects of hyperandrogenism in elite women’s sport are likely underestimated
Authors: Nicolai Topstad Borgen
Journal: British Journal of Sports Medicine (2019)

The medical condition of hyperandrogenism has entered common parlance because the International Association of Athletics Federation (IAAF) decided to ban women with the condition from competing against women who have 'normal' levels of testosterone (see box 1).This paper argues that the two articles substantiating the IAAF's regulation 1 2 fail to prove that elevated levels of natural testosterone are causally linked to better sporting performance.By studying elite athletes both papers induce a collider stratification bias that attenuates the competitive advantage of testosterone -a little-known bias that often plagues studies of highly selective samples.Box 1 Background  In April 2018, IAAF introduced a new eligibility regulation for female athletes, requiring women with Differences of Sexual Development to reduce their blood testosterone levels to below 5 nmol per litre. IAAF builds its case on two articles in BJSM from 2017, by authors with declared connections to IAAF, suggesting that testosterone levels in female athletes are positively correlated with athletic performance 1 2 .Several studies have criticized this research 3-6 , highlighting the lack of correlation analysis 4 , the focus on free testosterone 4 , and the problem of type I error in statistical tests 3 , all of which the authors of the original articles have attempted to address 7 .There has also been calls to retract the study because of serious flaws in the data 8 . The regulation was challenged in the Court of Arbitration for Sport by Caster Semenya, 800m Olympic and world champion.The ruling upheld the regulation, amidst further disagreement between medical professional bodies. CausalityDo elevated levels of natural testosterone cause women to run faster or throw further?And if sohow much faster or further?The size of the competitive advantage of testosterone is a causal research question.Yet, the two key papers in BJSM 1 2 have neither sufficiently discussed the challenges related to casual inference with observational data nor used methods that allows for causal interpretation of the results.Consequently, the two studies reveal that elite female athletes
Opposing roles of Akt1 and Akt2 in the Rac/PAK pathway
Authors: Guolei Zhou, Sun Sik Bae, Kanav Bhatheja, David F. Tucker, Morris J. Birnbaum, Jeffrey M. Field
Journal: Cancer Research (2006)

3533  p21-activated kinases(PAKs) are effectors of the small GTPases Rac and Cdc42 which modulate a range of biological activities, including cytoskeletal dynamics, proliferation, transformation, and survival. Its role in the regulation of cytoskeletal dynamics enables PAK to function in morphology, motility, polarity, neurogenesis, angiogenesis and cancer metastasis. The Akt/Protein Kinase B family is widely studied for its role in insulin signaling and cell survival. The family consists of three isoforms: Akt1, Akt2 and Akt3. Recent studies with knockout mice revealed that Akt1 is primarily involved in cell survival while Akt2 is primarily involved in insulin signaling. Thus, emerging evidence suggests that the Akt isoforms have distinct biological roles. We have previously revealed a connection between Akt and PAK (1), finding that Akt1 phosphorylates Pak1 at serine 21 and releases the Nck adaptor protein (2). In this study, we utilized Mouse Embyro Fibroblast (MEF) cell lines derived from Akt1 or Akt2 Knock Out (KO) mice to study the interaction between Akt and PAK1. When stimulated with the growth factor PDGF, Akt2 KO cells displayed a dramatic increase in dorsal ruffles, a cytoskeletal phenotype associated with increased cell motility. The Akt2 KO cells also had elevated PAK and Rac activities. In Akt2 knockouts there was also an increased association of Nck with PAK. The phenotypes in the Akt2 KO cells were Akt2 specific as reexpression of Akt2 in the Akt2 KO cells rescued the elevated Pak and Rac activity as well as the dorsal ruffling. Active Akt2 but not active Akt1 inhibited PAK activity in a kinase assays. In addition, PAK formed a complex with Akt2 in a transfection system. These data reveal an unexpected functional link between Akt2 and PAK, suggesting a model whereby Akt2 inactivates PAK by binding to it without phosphorylating it. Akt2 may also inhibit Pak by competing with the Nck binding region on PAK. In conclusion, Akt1 and Akt2 have opposing roles in PAK signaling. While Akt1 modestly stimulates PAK activity and phosphorylates serine 21, Akt2 binds and inhibits Pak. 1. Tang, Y., H. Zhou, A. Chen, R. N. Pittman, and J. Field. 2000. The Akt proto-oncogene links Ras to Pak and cell survival signals. J. Biol. Chem. 275:9106-9109. 2. Zhou, G. L., Y. Zhuo, C. C. King, B. H. Fryer, G. M. Bokoch, and J. Field. 2003. Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Mol Cell Biol 23:8058-69.
Risk of Zika microcephaly correlates with features of maternal antibodies
Authors: Davide F. Robbiani, Priscilla C. Olsen, Federico Costa, Qiao Wang, Thiago Y. Oliveira, Nivison Nery, Adeolu Aromolaran, Mateus S. do Rosário, Gielson A. Sacramento, Jaqueline S. Cruz, Ricardo Khouri, Elsio A. Wunder, Adriana Mattos, Bruno de Paula Freitas, Manoel Sarno, Gracinda Archanjo, Dina Daltro, Gustavo B.S. Carvalho, Kleber Pimentel, Isadora C. de Siqueira, João R.M. de Almeida, Daniele F. Henriques, Juliana A. Lima, Pedro F.C. Vasconcelos, Dennis Schaefer-Babajew, Stephanie A. Azzopardi, Leonia Bozzacco, Anna Gazumyan, Rubens Belfort, Ana P. Alcântara, Gustavo Carvalho, Licia Moreira, Katiaci Araujo, Mitermayer G. Reis, Rebekah I. Keesler, Lark L. Coffey, Jennifer Tisoncik-Go, Michael Gale, Lakshmi Rajagopal, Kristina M. Adams Waldorf, Dawn M. Dudley, Heather A. Simmons, Andres Mejia, David H. O’Connor, Rosemary J. Steinbach, Nicole Haese, Jessica Smith, Anne Lewis, Lois Colgin, Victoria Roberts, Antonio Frias, Meredith Kelleher, Alec Hirsch, Daniel N. Streblow, Charles M. Rice, Margaret R. MacDonald, Antonio R.P. de Almeida, Koen K.A. Van Rompay, Albert I. Ko, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2019)

Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015–2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P &amp;lt; 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.
Targeting the Fn14-Rac1 signaling pathway in invasive glioma cells
Authors: Matthew Ennis, Wendy McDonough, Brock Armstrong, Marc Symons, Bodour Salhia, Jeffrey Winkles, Michael Berens, Nhan Tran
Journal: Cancer Research (2008)

1995  Genetic alterations in malignant gliomas affect cell proliferation and cell cycle control, and are currently the targets of most chemotherapeutic agents. However, the efficacy of treating advanced glial tumors with adjuvant therapies remains largely unsuccessful due to the inability to effectively target invading cells. We have been investigating whether the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) regulate glioma cell invasive activity. In a previous report, we demonstrated that Fn14 expression was elevated in glioblastoma multiforme (GBM) specimens and also up-regulated in migrating glioma cells in vitro and invading cells in vivo. Moreover, Fn14-induced glioma invasion is dependent on the small GTPase Rac1. Rac1 is a ubiquitous signaling protein operating in many normal tissues; consequently, therapeutic targeting of this protein would likely have toxic effects on normal cells. It is possible that targeting key regulators of Rac1 may be a more effective and specific therapy toward invading glioma cells. In this study, we found that Ect2, a guanine nucleotide exchange factor (GEF) for Rho family GTPases, including Rac1 and Cdc42, is overexpressed in GBM, and that overexpression of Ect2 correlates directly with tumor grade and inversely with patient survival. Our data shows that Ect2 regulates Rac1 activation downstream of Fn14. Depletion of Ect2 by siRNA duplexes abrogates Fn14-induced Rac1 activation and subsequently glioma cell migration. We also found that TWEAK stimulates the activation of Cdc42 and that this is mediated by Ect2. Interestingly, depletion of Cdc42 expression impairs TWEAK-induced Rac1 activation and also results in a significant reduction of glioma cell migration in vitro. This suggests that Cdc42 is, in part, important for Rac1 activation downstream of the TWEAK-Fn14 signaling pathway and argues for the presence of other Rac-GEF(s) being involved in the Fn14-Rac1 signaling axis. Thus, therapy designed to interfere with the function of specific Fn14 signaling elements is likely to target invasive glioblastoma cells.
Ligand dependent induction of phospho-serine 294 in the hinge region of estrogen receptor alpha within human breast cancer cells
Authors: David Britton, Jason Held, Gary Scott, Birgit Schilling, Christian Atsriku, Michael Baldwin, Bradford Gibson, Christopher Benz
Journal: Cancer Research (2008)

5458  Activated estrogen receptor (ERα) plays a critical role in normal mammary gland physiology as well as in breast cancer development, where it also serves as a major target for breast cancer therapeutics. Serine (S) phosphorylation within the 67 kDa receptor protein is known to contribute significantly to ERα activation by orchestrating its nuclear translocation and the recruitment of transcriptional co-regulators to DNA-bound receptor. Since biochemical methods for detection of S phosphorylation are severely limited, we employed mass spectrometry (MS) to identify and semi-quantitate novel S phosphorylation sites within endogenously expressed ERα from control and growth stimulated human breast cancer cells (MCF7). ERα immunoprecipitated from cultured MCF7 cells was proteolytically digested, and the resulting peptides were MS analyzed using nano-LC-ESI-MS/MS (Q-STAR, MDS Sciex) and vMALDI-MSn (FinniganTM LTQTM, Thermo-Electron). S phosphorylation changes in ERα peptides were semi-quantitated using an ion trap instrument (4000 QTRAP, ABI/MDS Sciex) operated in multiple reaction monitoring (MRM) mode. Trypsin digests yielded 75% peptide coverage of the ERα hinge region (D domain residues Q280 to K309), leading to identification of a novel phospho-S site, pS294. Comparison of pS294 levels relative to induction of known ERα phospho-S sites revealed an 11-fold increase in pS294 relative to a 10-fold increase in pS167 and a 6-fold increase in pS154 following estradiol (10 nM, 30 min) stimulation. In contrast, EGF (50 ng/ml, 10 min) stimulation produced no detectable induction of pS294 but increased pS167 20-fold and pS154 3-fold. The novel observation of significant ERα pS294 induction following estradiol but not EGF stimulation of MCF7 cells suggests that the hinge region actively participates within the ERα activation function 2a (AF2a) domain to selectively recruit co-regulators in response to ligands like estradiol, but not in response to ligand-independent ERα activators like EGF.
Arsenic trioxide (ATO) and temozolomide (TMZ) together with radiation therapy (RT) shows synergistic cytotoxicity in human glioma cell lines
Authors: Shikha Gaur, Jana Portnow, Timothy Synold
Journal: Cancer Research (2007)

4765  BACKGROUND: ATO is effective in the treatment of acute promyelocytic leukemia, but its role in the management of solid tumors has yet to be defined. TMZ with and without RT is the standard of care for patients with newly-diagnosed glioblastoma multiforme (GBM). ATO potentiates the effects of RT in preclinical models. We investigated the cytotoxicity of ATO and TMZ together and in combination with RT in U251T (p53 mutant), T98G (p53 mutant) and U87MG (p53 wild type) glioma cells.METHODS:U251T, U87MG and T98G cells in log phase growth were treated simultaneously with ATO (0.05-10 µM) and/or TMZ (0.05-1000 µM) for 24 hours or sequentially by the following schedules: ATO for 18 hours followed by TMZ for 6 hours or the reverse sequence.For RT experiments, cells were treated with 0-10 Gy of ionizing radiation using a Cesium-137 source. Following RT and/or drug treatment, cells were replated onto 1.5 cm tissue culture dishes in triplicate and incubated at 37oC for 8 to 10 days to form colonies. Colonies of more than 40 cells each were counted and the IC50 values and combination indices (CI) were derived using Calcusyn software (Biosoft, Cambridge, UK). Each combination was repeated in triplicate. RESULTS: The mean single agent IC50’s for ATO, TMZ, and RT were 1.10±0.28 µM, 1.88±0.91µM, and 2.62±0.23 Gy, respectively in U251T cells, 0.80±0.10 µM, 0.80±0.10 µM, and 4.62±0.58 Gy, respectively in U87MG cells and 4.5±0.53 µM, 600±3.0 µM, and 5.0±0.36 Gy, respectively in T98G cells. The CI’s for the various combinations demonstrated additive to synergistic effects in each of the cell lines, with the triple agent combination showing the greatest synergy in all three lines.  CONCLUSIONS: RT followed by sequential ATO and TMZ demonstrated synergistic cytotoxicity in both p53 mutant and wildtype glioma cells. A phase I/II trial of this combination therapy in patients with newly diagnosed GBM is ongoing. This study was supported by CA01727.
Epinephrine Auto-Injectors for Anaphylaxis
Journal: JAMA (2017)

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Radiographic Honeycombing and Altered Lung Microbiota in Patients with Idiopathic Pulmonary Fibrosis
Authors: Robert P. Dickson, Gary B. Huffnagle, Kevin R. Flaherty, Eric S. White, Fernando J. Martinez, John R. Erb-Downward, Bethany B. Moore, David N. O’Dwyer
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Abstract 20416: Ttc39b Deficiency Has a Beneficial Role on Cholesterol and Triglyceride Absorption in Enterocytes
Authors: Masahiro Koseki, Joanne Hsieh, Emi Yakushiji, Carrie Welch, Jahangir Iqbal, Mahmood M Hussain, Alan R Tall, Yasushi Sakata, Shizuya Yamashita
Journal: Circulation (2014)

Background: TTC39B , encoding tetratricopeptide repeat domain 39B, was identified in genome wide association studies (GWAS) as a novel gene influencing HDL-cholesterol (HDL-C) levels. Since Ttc39b had not been previously implicated in lipoprotein metabolism at all and nothing was known about the functions of Ttc39b , we investigated animal models. Method and Results: We have found that on a chow diet there were increases in LXR protein but not mRNA, increased expression of Abca1 mRNA and protein and 22% increased HDL-C levels in Ttc39b -/- mice. Experiments using primary enterocytes isolated from Ttc39b -/- mice revealed that secretion of particles containing apoA-1 increased by approximately twofold. When mice were fed with a high fat/high cholesterol/bile salt diet, primary enterocytes secreted 50% less particles not containing apoA-1, as well as particles containing apoA-1 by twofold. In the cholesterol absorption study by gavaging [ 3 H]-cholesterol total cholesterol absorption were decreased by 50% Ttc39b -/- mice. As a result, hepatic cholesterol and TG after mice were fed with a high fat/high cholesterol/bile salt diet for eighteen week were dramatically decreased in Ttc39b -/- by 42 and 50% respectively. In addition, external oxysterols, such as 7b-hydroxycholesterol and 7-ketocholesterol were also parallel decreased. Conclusion: These studies show that Ttc39b deficiency results in increased LXR primarily in enterocytes, beneficial lipoprotein changes and reduced atherosclerosis. Moreover, Ttc39b -/- mice were protected from fatty liver, indicating that Ttc39b inhibition could be an effective strategy for reducing atherosclerosis and fatty liver.