tbuckley/cabot-search huggingface dataset:
Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice
Authors: Matthew R. Alexander, Christopher W. Moehle, Jason L. Johnson, Zhengyu Yang, Jae K. Lee, Christopher L. Jackson, Gary K. Owens
Journal: Journal of Clinical Investigation (2011)

Clinical complications of atherosclerosis arise primarily as a result of luminal obstruction due to atherosclerotic plaque growth, with inadequate outward vessel remodeling and plaque destabilization leading to rupture. IL-1 is a proinflammatory cytokine that promotes atherogenesis in animal models, but its role in plaque destabilization and outward vessel remodeling is unclear. The studies presented herein show that advanced atherosclerotic plaques in mice lacking both IL-1 receptor type I and apolipoprotein E (Il1r1–/–Apoe–/– mice) unexpectedly exhibited multiple features of plaque instability as compared with those of Il1r1+/+Apoe–/– mice. These features included reduced plaque SMC content and coverage, reduced plaque collagen content, and increased intraplaque hemorrhage. In addition, the brachiocephalic arteries of Il1r1–/–Apoe–/– mice exhibited no difference in plaque size, but reduced vessel area and lumen size relative to controls, demonstrating a reduction in outward vessel remodeling. Interestingly, expression of MMP3 was dramatically reduced within the plaque and vessel wall of Il1r1–/–Apoe–/– mice, and Mmp3–/–Apoe–/– mice showed defective outward vessel remodeling compared with controls. In addition, MMP3 was required for IL-1–induced SMC invasion of Matrigel in vitro. Taken together, these results show that IL-1 signaling plays a surprising dual protective role in advanced atherosclerosis by promoting outward vessel remodeling and enhancing features of plaque stability, at least in part through MMP3-dependent mechanisms.
Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer
Authors: Elvira Avilla, Valentina Guarino, Carla Visciano, Federica Liotti, Maria Svelto, GnanaPrakasam Krishnamoorthy, Renato Franco, Rosa Marina Melillo
Journal: Cancer Research (2011)

Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer.
Transformation of human kidney proximal tubule cells by ras-containing retroviruses. Implications for tumor progression.
Authors: D M Nanus, S A Ebrahim, N H Bander, F X Real, L M Pfeffer, J R Shapiro, A P Albino
Journal: The Journal of Experimental Medicine (1989)

Normal human kidney proximal tubule cells into which a ras oncogene was inserted undergo a series of transformation-related alterations that are characteristic of renal carcinomas. These include changes in morphology, growth potential, anchorage dependence, antigen expression, growth factor production, and chromosomal stability. Further, there are spontaneous progressive alterations in vitro in the karyotype and antigenic profile of the transformed cells. Cytogenetic analyses suggest that alterations of chromosome 21 may play an early and pivotal role in the development of transformed proximal tubule cells.
Drug-Induced Extrapyramidal Symptoms and Their Relations to Clinical Efficacy
Authors: CHING-PIAO CHIEN, ALBERTO DIMASCIO
Journal: American Journal of Psychiatry (1967)

Various theories have been proposed relating classes of drug-induced extrapyramidal symptoms to the therapeutic actions of these drugs. But contradictory conclusions have been drawn from basically similar sets of observations; the literature on the topic is fraught with confusion and equivocal results. The authors suggest reasons for the past confusion and urge that future studies be designed with adequate controls and methodological sophistication.
Pulmonary rehabilitation in chronic respiratory insufficiency. 5. Home mechanical ventilation.
Authors: J F Muir
Journal: Thorax (1993)

<h3>Abstract</h3> <h3>Rationale</h3> Activins are inflammatory and tissue-repair-related members of the TGFβ-superfamily that have been implicated in the pathogenesis of several immuno-inflammatory disorders including sepsis/acute respiratory distress syndrome (ARDS). We hypothesized that they might be of particular relevance to COVID-19 pathophysiology. <h3>Objectives</h3> To assess the involvement of the Activin-Follistatin-axis in COVID-19 pathophysiology. <h3>Methods</h3> Levels of Activins -A, -B and their physiological inhibitor Follistatin, were retrospectively analyzed in 314 serum samples from 117 COVID-19 patients derived from two independent centers and compared with common demographic, clinical and laboratory parameters. Optimal-scaling with ridge-regression was used to screen variables and establish a prediction model. <h3>Main Results</h3> The Activin/Follistatin-axis was significantly deregulated during the course of COVID-19 and was independently associated with severity and in-hospital mortality. FACT-CLINYCoD, a novel disease scoring system, adding one point for each of Follistatin &gt;6235 pg/ml, Activin-A &gt;591 pg/ml, Activin-B &gt;249 pg/ml, CRP &gt;10.3 mg/dL, LDH &gt;427 U/L, Intensive Care Unit (ICU) admission, Neutrophil/Lymphocyte-Ratio &gt;5.6, Years of Age &gt;61, Comorbidities &gt;1 and D-dimers &gt;1097 ng/ml, efficiently predicted and monitored fatal outcome independently of multiplicity and timing of sampling (AUC: 0.951±0.032, p&lt;10<sup>-6</sup>). Validation in 35 samples derived from a third hospital indicated comparable AUC (0.958±0.086, p=0.032). <h3>Conclusion</h3> This study unravels the link between Activin/Folistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that copes with the dynamic and heterogeneous nature of COCVID-19, predicts disease outcome and supports clinical decision making. Prospective large-scale validation of this calculator, as well as investigation of the mechanisms linking Activin/Folistatin-axis to COVID-19 pathogenesis is warranted.
Predictors of Bleeding and Time Dependence of Association of Bleeding With Mortality
Authors: Willibald Hochholzer, Stephen D. Wiviott, Elliott M. Antman, Charles F. Contant, Jianping Guo, Robert P. Giugliano, Anthony J. Dalby, Gilles Montalescot, Eugene Braunwald
Journal: Circulation (2011)

The balance between benefit (ischemia protection) and risk (bleeding) is a key consideration in choosing the intensity of antiplatelet therapy for patients with acute coronary syndromes. The goals of this analysis were to identify baseline characteristics that independently predict bleeding and to determine how bleeding events impact the subsequent mortality in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel--Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38).Multivariable Cox regression analyses adjusted for treatment, baseline, and procedural variables were used to determine the predictors for serious (TIMI major or minor) bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the bleed. From the 13 420 patients with acute coronary syndromes included in this analysis, 534 (4.0%) experienced a serious bleeding event. Variables with the highest strength of association with risk of serious bleeding were female sex, use of a glycoprotein IIb/IIIa inhibitor, duration of intervention, age, assignment to prasugrel, regional characteristics, admission diagnosis of ST-elevation myocardial infarction, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. Serious bleeding was associated with a significantly increased adjusted hazard ratio of 5.84 (95% confidence interval 4.11 to 8.29) for mortality. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event.The major predictors of serious bleeding were a combination of patient and procedural characteristics and antiplatelet therapies. Although serious bleeding was strongly associated with mortality within the first month of the bleeding event, this association was not significant beyond 40 days.http://www.clinicaltrial.gov. Unique identifier NCT00097591.
A Genome-Wide Scan of Pulmonary Function Measures in the National Heart, Lung, and Blood Institute Family Heart Study
Authors: Jemma B. Wilk, Anita L. DeStefano, Donna K. Arnett, Stephen S. Rich, Luc Djousse, Robert O. Crapo, Mark F. Leppert, Michael A. Province, L. Adrienne Cupples, Daniel J. Gottlieb, Richard H. Myers
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Spirometric measures of pulmonary function exhibited high heritability in the National Heart, Lung, and Blood Institute Family Heart Study. A genome scan of FEV1, FVC, and the ratio of FEV1/FVC was performed to identify chromosomal regions influencing these measures. The pulmonary traits were adjusted through multiple linear regression techniques for the effects of age, age2, body mass index, height, smoking status, and pack-years of smoking. The distribution of FEV1/FVC was transformed to account for nonnormality, and standardized residuals were used as the quantitative trait for variance component linkage analysis in GENEHUNTER (Whitehead Institute, Cambridge, MA). The genome scan identified regions on chromosomes 4 and 18 with logarithm of the odds favoring linkage (LOD) scores above 2.5, and these two chromosomes were further evaluated by incorporating additional marker genotyping. The FEV1/FVC ratio was linked to chromosome 4 around 28 centimorgans (cM; D4S1511) with a LOD score of 3.5, and the transformed ratio was linked to the same region with a LOD of 2.0. FEV1 and FVC were suggestively linked to regions on chromosome 18 with multipoint LOD scores of 2.4 for FEV1 and 1.5 for FVC at 31 cM (D18S843) and a LOD of 2.9 for FVC at 79 cM (D18S858).
Deletion of LCE3C_LCE3B is associated with rheumatoid arthritis and systemic lupus erythematosus in the Chinese Han population
Authors: X. Lu, J. Guo, X. Zhou, R. Li, X. Liu, Y. Zhao, B. Zhu, X. Liu, J. Xu, P. Zhu, X. Wu, J. He, X. Liu, H. Zhang, Z. Li
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> The deletion of <i>LCE3C_LCE3B</i> confers susceptibility to psoriasis and rheumatoid arthritis (RA) in Caucasians. The aim of this study was to investigate the variant involvement in RA in the Chinese Han population and to further explore its potential role in the susceptibility to systemic lupus erythematosus (SLE). <h3>Methods</h3> <i>LCE3C_LCE3B</i>-<i>del</i> was genotyped in 898 patients with RA and 681 healthy controls. Two single nucleotide polymorphisms (SNPs, rs4112788 and rs4085613) in strong linkage disequilibrium with <i>LCE3C_LCE3B</i>-<i>del</i> were then genotyped in patients with RA (n=1222), SLE (n=870) and healthy controls (n=1031). <h3>Results</h3> The deletion of <i>LCE3C_LCE3B</i> and SNPs rs4112788 and rs4085613 showed an association with RA (allele analysis: p=7.72×10<sup>−4</sup>, OR 1.28, 95% CI 1.11 to 1.47; p=6.39×10<sup>−4</sup>, OR 1.23, 95% CI 1.09 to 1.38; and p=5.38×10<sup>−4</sup>, OR 1.23, 95% CI 1.10 to 1.39, respectively). The two SNPs were also significantly associated with SLE (allele analysis: p=7.68×10<sup>−3</sup>, OR 1.19, 95% CI 1.05 to 1.36 and p=5.30×10<sup>−3</sup>, OR 1.20, 95% CI 1.06 to 1.37). <h3>Conclusions</h3> This study provides evidence for an association between <i>LCE3C_LCE3B</i>-<i>del</i> and RA in non-Caucasian populations, and SNPs rs4112788 and rs4085613 tagging <i>LCE3C_LCE3B</i>-<i>del</i> were novel susceptibility factors for SLE.
A Mammaglobin-A Targeting Agent for Noninvasive Detection of Breast Cancer Metastasis in Lymph Nodes
Authors: Narges K. Tafreshi, Steven A. Enkemann, Marilyn M. Bui, Mark C. Lloyd, Dominique Abrahams, Amanda S. Huynh, Jongphil Kim, Stephen R. Grobmyer, W. Bradford Carter, Josef Vagner, Robert J. Gillies, David L. Morse
Journal: Cancer Research (2010)

Pathologic axillary lymph node (ALN) status is an important prognostic factor for staging breast cancer. Currently, status is determined by histopathology following surgical excision of sentinel lymph node(s), which is an invasive, time consuming, and costly procedure with potential morbidity to the patient. Here, we describe an imaging platform for noninvasive assessment of ALN status, eliminating the need for surgical examination of patients to rule out nodal involvement. A targeted imaging probe (MamAb-680) was developed by conjugation of a mammaglobin-A-specific monoclonal antibody to a near-infrared fluorescent dye. Using DNA and tissue microarray, mammaglobin-A was validated as a cell-surface target that is expressed in ALN-positive patient samples but is not expressed in normal lymph nodes. In vivo selectivity was determined by i.v. injection of MamAb-680 into mice with mammaglobin-A-positive and -negative mammary fat pad (MFP) tumors; and by peritumoral MFP injection of the targeted imaging probe in mice with spontaneous ALN metastases. Fluorescence imaging showed that probe was only retained in positive tumors and metastases. As few as 1,000 cells that endogenously express mammaglobin-A were detected in ALN, indicating high sensitivity of this method. Translation of this approach offers considerable potential as a noninvasive clinical strategy to stage breast cancer.
Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy
Authors: Naoko Honma, Rie Horii, Takuji Iwase, Shigehira Saji, Mamoun Younes, Kaiyo Takubo, Masaaki Matsuura, Yoshinori Ito, Futoshi Akiyama, Goi Sakamoto
Journal: Journal of Clinical Oncology (2008)

The clinicopathologic importance of a second estrogen receptor (ER), ER-beta, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-beta assay, probably because of the lack of standardized methodology, the presence of several ER-beta isotypes (ER-beta1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-beta status provides clinically useful information over what is already provided by the traditional ER-alpha/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues.Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti-ER-beta antibodies that detect ER-beta1-3 (ER-betaN), ER-beta1, and ER-betacx (ER-beta2).Positive staining for ER-betaN or ER-beta1 was associated with significantly better survival. By contrast, ER-betacx status did not influence survival. In multivariate analysis, ER-beta1 status emerged as an independent predictor of recurrence and mortality. ER-beta1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-beta1 positivity was associated with significantly better survival in patients with ER-alpha-negative/PR-negative or ER-alpha-negative/PR-negative/human epidermal growth factor receptor 2-negative (triple-negative) tumors, which are widely believed to be hormone unresponsive, have poor prognosis, and require chemotherapy.Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.
PKCα expression is a marker for breast cancer aggressiveness
Authors: Gry Kalstad Lønne, Louise Cornmark, Iris Omanovic Zahirovic, Göran Landberg, Karin Jirström, Christer Larsson
Journal: Molecular Cancer (2010)

Abstract Background Protein kinase C (PKC) isoforms are potential targets for breast cancer therapy. This study was designed to evaluate which PKC isoforms might be optimal targets for different breast cancer subtypes. Results In two cohorts of primary breast cancers, PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. Cell line studies demonstrated that PKCα levels are high in MDA-MB-231 and absent in T47D cells which proliferated slower than other cell lines. Furthermore, PKCα silencing reduced proliferation of MDA-MB-231 cells. PKCα inhibition or downregulation also reduced cell migration in vitro . Conclusions PKCα is a marker for poor prognosis of breast cancer and correlates to and is important for cell functions associated with breast cancer progression.
Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood
Authors: Jocelyn Charlton, Richard D Williams, Mark Weeks, Neil J Sebire, Sergey Popov, Gordan Vujanic, William Mifsud, Marisa Alcaide-German, Lee M Butcher, Stephan Beck, Kathy Pritchard-Jones
Journal: Genome biology (2014)

Wilms tumor is the most common pediatric renal malignancy and there is a clinical need for a molecular biomarker to assess treatment response and predict relapse. The known mutated genes in this tumor type show low mutation frequencies, whereas aberrant methylation at 11p15 is by far the most common aberration. We therefore analyzed the epigenome, rather than the genome, to identify ubiquitous tumor-specific biomarkers. Methylome analysis of matched normal kidney and Wilms tumor identifies 309 preliminary methylation variable positions which we translate into three differentially methylated regions (DMR) for use as tumor-specific biomarkers. Using two novel algorithms we show that these three DMRs are not confounded by cell type composition. We further show that these DMRs are not methylated in embryonic blastema but are intermediately methylated in Wilms tumor precursor lesions. We validate the biomarker DMRs using two independent sample sets of normal kidney and Wilms tumor and seven Wilms tumor histological subtypes, achieving 100% and 98% correct classification, respectively. As proof-of-principle for clinical utility, we successfully use biomarker DMR-2 in a pilot analysis of cell-free circulating DNA to monitor tumor response during treatment in ten patients. These findings define the most common methylated regions in Wilms tumor known to date which are not associated with their embryonic origin or precursor stage. We show that this tumor-specific methylated DNA is released into the blood circulation where it can be detected non-invasively showing potential for clinical utility.
Serotonin Transporter Gene (SLC6A4) Promoter Polymorphisms and the Susceptibility to Posttraumatic Stress Disorder in the General Population
Authors: Hans Jörgen Grabe, Carsten Spitzer, Christian Schwahn, Agnes Marcinek, Antje Frahnow, Sven Barnow, Michael Lucht, Harald Jürgen Freyberger, Ulrich John, Henri Wallaschofski, Henry Völzke, Dieter Rosskopf
Journal: American Journal of Psychiatry (2009)

Objective: There has been debate whether polymorphisms within the serotonin transporter-linked polymorphic region (5-HTTLPR) moderate susceptibility to posttraumatic stress disorder (PTSD). The authors investigated 5-HTTLPR genotypes and their interaction with the number of traumatic events in the prediction of PTSD in a general population sample. Method: Analyses were based on data from 3,045 subjects who participated in the Study of Health in Pomerania. All participants were assessed with the PTSD module of the Structured Clinical Interview for DSM–IV. The short (S)/long (L) polymorphism of 5-HTTLPR (rs4795541) and the A-G polymorphism (rs25531) were genotyped. Results: Among the participants, 1,663 had been exposed to at least one traumatic event, and 67 (4.0%) developed PTSD. Among those who had experienced less than three traumatic events, the lifetime prevalence of PTSD was 2.6%, 3.5%, and 4.3% for those with zero, one, and two L A alleles, respectively, but the lifetime prevalence was 0%, 7.3%, and 19.6%, respectively, among those with three or more traumatic experiences. This finding suggests that there is an additive excess risk for frequent trauma in the L A /L A genotype, which was confirmed by the relative excess risk due to interaction (RERI). In allelic analysis, RERI was 3.3. Thus, the odds ratio for PTSD in L A allele carriers exposed to three or more traumas was 3.3 times higher as a result of the interaction between PTSD and the L A allele. Conclusions: An additive gene-environment interaction with the high expression L A allele of 5-HTTLPR and frequent trauma in PTSD was found. The attributable proportion indicated that more than 60% of all L A allele carriers who were exposed to three or more traumas developed PTSD as a result of an interaction between genotype and exposure.
Coping with heat stress during match-play tennis: Does an individualised hydration regimen enhance performance and recovery?
Authors: Julien D Périard, Sebastien Racinais, Wade L Knez, Christopher P Herrera, Ryan J Christian, Olivier Girard
Journal: British Journal of Sports Medicine (2014)

To determine whether an individualised hydration regimen reduces thermal, physiological and perceptual strain during match-play tennis in the heat, and minimises alterations in neuromuscular function and physical performance postmatch and into recovery.10 men undertook two matches for an effective playing time (ball in play) of 20 min (∼113 min) in ∼37°C and ∼33% RH conditions. Participants consumed fluids ad libitum during the first match (HOT) and followed a hydration regimen (HYD) in the second match based on undertaking play euhydrated, standardising sodium intake and minimising body mass losses.HYD improved prematch urine specific gravity (1.013±0.006 vs 1.021±0.009 g/mL; p<0.05). Body mass losses (∼0.3%), fluid intake (∼2 L/h) and sweat rates (∼1.6 L/h) were similar between conditions. Core temperature was higher during the first 10 min of effective play in HOT (p<0.05), but increased similarly (∼39.3°C) on match completion. Heart rate was higher (∼11 bpm) throughout HOT (p<0.001). Thermal sensation was higher during the first 7.5 min of effective play in HOT (p<0.05). Postmatch knee extensor and plantar flexor strength losses, along with reductions in 15 m sprint time and repeated-sprint ability (p<0.05), were similar in both conditions, and were restored within 24 h.Both the hydration regimen and ad libitum fluid consumption allowed for minimal body mass losses (<1%). However, undertaking match-play in a euhydrated state attenuated thermal, physiological and perceptual strain. Maximal voluntary strength in the lower limbs and repeated-sprint ability deteriorated similarly in both conditions, but were restored within 24 h.