tbuckley/cabot-search huggingface dataset:
Increased Membrane Expression of Proteinase 3 during Neutrophil Adhesion in the Presence of Anti–Proteinase 3 Antibodies
Authors: Soumeya Brachemi, Agnès Mambole, Fadi Fakhouri, Luc Mouthon, Loïc Guillevin, Philippe Lesavre, Lise Halbwachs-Mecarelli
Journal: Journal of the American Society of Nephrology (2007)

We investigated membrane proteinase 3 (mPR3) expression during TNF-alpha-induced adhesion of neutrophils in the presence of anti-PR3 antibodies, a situation occurring during anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis. Three increasing levels of mPR3 expression were observed on the mPR3(+) neutrophil subset after stepwise cell activation. TNF-alpha activation without adhesion, TNF-alpha-induced adhesion, and adhesion in the presence of anti-PR3 mAb or human anti-PR3 ANCA resulted, respectively, in a two-, seven-, and 24-fold increase of mPR3 levels. In plasma, anti-PR3 antibodies poorly recognized suspended neutrophils, whereas they bound to mPR3 on adherent cells. mPR3 upregulation was also triggered by IL-8, formyl-methionyl-leucyl-phenylalanine (fMLP), and neutrophil adhesion to activated human umbilical vein endothelial cells. It involved beta2 integrins and Fcgamma receptor, because it was prevented by anti-CD18 antibodies and was not observed with anti-PR3 F(ab')(2). Furthermore, it was specific to anti-PR3 mAb, and no mPR3 upregulation was observed with anti-myeloperoxidase or anti-HLA-ABC mAb. Newly expressed mPR3 molecules, after TNF-induced adhesion, were mobilized from secretory vesicles (CD35(+)) and secondary granules (CD11b(+)). The adhesion- and antibody-dependent upregulations of mPR3 expression occurred with little azurophilic granule degranulation, no sign of apoptosis, and no further CD177 upregulation. In conclusion, this study describes an amplifying loop in polymorphonuclear neutrophil activation process, whereby ANCA are involved in the membrane expression of their own antigen during cell adhesion. This could explain the restriction of ANCA-associated vasculitis to small vessels, the main site of neutrophil adhesion.
Symposium: reproduction in baboons. Secretory proteins of the baboon (Papio anubis) endometrium: regulation during the menstrual cycle and early pregnancy
Authors: A. Fazleabas
Journal: Human Reproduction Update (1997)

The biological function of uterine endometrial secretory proteins in the primate remain to be elucidated. In general, during the luteal phase and under progesterone dominance, the glandular epithelial cells synthesize and secrete a number of proteins. Of these, placental protein 14 (PP14; now referred to as glycodelin) and insulin-like growth factor binding protein-1 (IGFBP-1) are the best characterized. Although induced by progesterone, their synthesis increases exponentially during pregnancy. In the baboon, glycodelin is immunolocalized to the mid functionalis and basal glands between days 10 and 12 post-ovulation. In response to either exogenous or blastocyst-secreted chorionic gonadotrophin, glandular synthesis increases markedly and remains elevated up to days 18-25 of pregnancy. The decrease in glycodelin in the endometrium is associated with glandular regression during the first third of pregnancy. In contrast, IGFBP-1 is only observed in the deep basal glands during the luteal phase. Following the establishment of pregnancy, IGFBP-1 synthesis switches from glandular to stromal and is correlated with the process of decidualization. IGFBP-1 synthesis continues to increase throughout gestation. We propose that glycodelin may have immunosuppressive properties and that IGFBP-1 may regulate trophoblast migration within the uterine endometrium. Key words: baboon/glycodelin/IGFBP-1/placental protein 14/pregnancy
Differential Regulation of Protease Activated Receptor-1 and Tissue Plasminogen Activator Expression by Shear Stress in Vascular Smooth Muscle Cells
Authors: Maria Papadaki, Johannes Ruef, Kytai Truong Nguyen, Fengzhi Li, Cam Patterson, Suzanne G. Eskin, Larry V. McIntire, Marschall S. Runge
Journal: Circulation Research (1998)

Abstract —Recent studies have demonstrated that vascular smooth muscle cells are responsive to changes in their local hemodynamic environment. The effects of shear stress on the expression of human protease activated receptor-1 (PAR-1) and tissue plasminogen activator (tPA) mRNA and protein were investigated in human aortic smooth muscle cells (HASMCs). Under conditions of low shear stress (5 dyn/cm 2 ), PAR-1 mRNA expression was increased transiently at 2 hours compared with stationary control values, whereas at high shear stress (25 dyn/cm 2 ), mRNA expression was decreased (to 29% of stationary control; P &lt;0.05) at all examined time points (2 to 24 hours). mRNA half-life studies showed that this response was not due to increased mRNA instability. tPA mRNA expression was decreased (to 10% of stationary control; P &lt;0.05) by low shear stress after 12 hours of exposure and was increased (to 250% of stationary control; P &lt;0.05) after 24 hours at high shear stress. The same trends in PAR-1 mRNA levels were observed in rat smooth muscle cells, indicating that the effects of shear stress on human PAR-1 were not species-specific. Flow cytometry and ELISA techniques using rat smooth muscle cells and HASMCs, respectively, provided evidence that shear stress exerted similar effects on cell surface–associated PAR-1 and tPA protein released into the conditioned media. The decrease in PAR-1 mRNA and protein had functional consequences for HASMCs, such as inhibition of [Ca 2+ ] mobilization in response to thrombin stimulation. These data indicate that human PAR-1 and tPA gene expression are regulated differentially by shear stress, in a pattern consistent with their putative roles in several arterial vascular pathologies.
Effects of Weight Loss, Weight Cycling, and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program
Authors: Linda M. Delahanty, Qing Pan, Kathleen A. Jablonski, Vanita R. Aroda, Karol E. Watson, George A. Bray, Steven E. Kahn, Jose C. Florez, Leigh Perreault, Paul W. Franks
Journal: Diabetes Care (2014)

This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors.This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years.Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = -0.57 mg/dL per kg, 95% CI -0.66, -0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0-6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits.Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.
Normal Induction but Attenuated Progression of Germinal Center Responses in BAFF and BAFF-R Signaling–Deficient Mice
Authors: Ziaur SM. Rahman, Sambasiva P. Rao, Susan L. Kalled, Tim Manser
Journal: The Journal of Experimental Medicine (2003)

The factors regulating germinal center (GC) B cell fate are poorly understood. Recent studies have defined a crucial role for the B cell–activating factor belonging to TNF family (BAFF; also called BLyS) in promoting primary B cell survival and development. A role for this cytokine in antigen-driven B cell responses has been suggested but current data in this regard are limited. A BAFF receptor expressed by B cells (BAFF-R/BR3) is defective in A/WySnJ mice which exhibit a phenotype similar to BAFF-deficient (BAFF−/−) animals. Here, we show that although GC responses can be efficiently induced in both A/WySnJ and BAFF−/− mice, these responses are not sustained. In BAFF−/− mice, this response is rapidly attenuated and accompanied by perturbed follicular dendritic cell development and immune complex trapping. In contrast, analysis of the A/WySnJ GC response revealed a B cell autonomous proliferative defect associated with reduced or undetectable Ki67 nuclear proliferation antigen expression by GC B cells at all stages of the response. These data demonstrate a multifaceted role for the BAFF pathway in regulating GC progression.
Diastolic Heart Failure — A Common and Lethal Condition by Any Name
Authors: Gerard P. Aurigemma
Journal: New England Journal of Medicine (2006)

This issue of the Journal contains two provocative contributions to the literature on heart failure. Owan et al.1 describe the epidemiologic outcomes and survival rates among patients with heart failure who were admitted to the Mayo Clinic Hospitals for the disease from 1987 through 2001, extending results published in 19982; Bhatia et al.3 review the shorter-term outcomes among patients hospitalized for heart failure in the province of Ontario over a two-year period, beginning in April 1999. Both groups of investigators subdivided their patients according to the level of ejection fraction. They then compared the characteristics and clinical courses of . . .
Cardiac tamponade. A clinical or an echocardiographic diagnosis?
Authors: N O Fowler
Journal: Circulation (1993)

In most patients, cardiac tamponade should be diagnosed by a clinical examination that shows elevated systemic venous pressure, tachycardia, dyspnea, and paradoxical arterial pulse. Systemic blood pressure may be normal, decreased, or even elevated. The diagnosis is confirmed by echocardiographic demonstration of moderately large or large circumferential pericardial effusion and in most instances, of right atrial compression, abnormal respiratory variation in right and left ventricular dimensions, and in tricuspid and mitral valve flow velocities. Pulsus paradoxus may be absent with left ventricular dysfunction, atrial septal defect, regional tamponade, and positive-pressure breathing. Systemic venous pressure may be normal with localized tamponade of the left atrium or ventricle. Patients with moderately large or large pericardial effusions may have echocardiographic evidence of right atrial compression without clinical signs of elevated venous pressure or pulsus paradoxus. The majority of these patients have mild or moderate tamponade and if not subjected to pericardial drainage, should be observed closely. In some of these patients, when the etiology is known and the disease can be treated effectively with medication, e.g., nonsteroidal anti-inflammatory agents or adrenal corticosteroids in Dressler's syndrome or relapsing pericarditis, pericardial drainage may not be necessary.
The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood–Brain Barrier in Glioblastoma
Authors: Jenny L. Pokorny, David Calligaris, Shiv K. Gupta, Dennis O. Iyekegbe, Dustin Mueller, Katrina K. Bakken, Brett L. Carlson, Mark A. Schroeder, Debra L. Evans, Zhenkun Lou, Paul A. Decker, Jeanette E. Eckel-Passow, Vincenzo Pucci, Bennett Ma, Stuart D. Shumway, William F. Elmquist, Nathalie Y.R. Agar, Jann N. Sarkaria
Journal: Clinical Cancer Research (2015)

Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide.In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging.GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 >300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors.Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM.
S-Nitrosothiol Signaling in Respiratory Biology
Authors: Benjamin Gaston, David Singel, Allan Doctor, Jonathan S. Stamler
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Genetic and biochemical data demonstrate a pivotal role for S-nitrosothiols (SNOs) in mediating the actions of nitric oxide synthases (NOSs). SNOs serve to convey NO bioactivity and to regulate protein function. This understanding is of immediate interest to the pulmonary clinical and research communities. This article reviews the following: (1) biochemical and cellular evidence that SNOs in amino acids, peptides, and proteins elicit NOS-dependent signaling in the respiratory system and (2) studies that link SNO signaling to pulmonary medicine. SNO-mediated signaling is involved in the regulation of minute ventilation, ventilation-perfusion matching, pulmonary arterial pressure, basal airway tone, and respiratory and peripheral muscle function. Derangements in SNO signaling are implicated in many disorders relevant to pulmonary and critical care medicine, including apnea, hypoxemia, pulmonary hypertension, asthma, cystic fibrosis, pneumonia, and septic shock.
Nocturnal temperature controlled laminar airflow for treating atopic asthma: a randomised controlled trial
Authors: Robert J Boyle, Christophe Pedroletti, Magnus Wickman, Leif Bjermer, Erkka Valovirta, Ronald Dahl, Andrea Von Berg, Olof Zetterström, John O Warner
Journal: Thorax (2011)

<h3>Objective</h3> To determine whether environmental control using nocturnal temperature controlled laminar airflow (TLA) treatment could improve the quality of life of patients with persistent atopic asthma. <h3>Design</h3> Randomised, double-blind, placebo-controlled, parallel-group trial. <h3>Setting</h3> Nineteen European asthma clinics. <h3>Participants</h3> 312 patients aged 7–70 with inadequately controlled persistent atopic asthma. <h3>Main outcome measure</h3> Proportion of patients with an increase of ≥0.5 points in asthma quality of life score after 1 year of treatment. <h3>Results</h3> TLA devices were successfully installed in the bedrooms of 282 (90%) patients included in the primary efficacy analysis. There was a difference in treatment response rate between active (143 of 189, 76%) and placebo (56 of 92, 61%) groups, difference 14.8% (95% CI 3.1 to 26.5, p=0.02).3 In patients aged ≥12, on whom the study was powered, the difference in response rate was similar-active 106 of 143 (74%), placebo 42 of 70 (60%), difference 14.1% (0.6 to 27.7, p=0.059). There was a difference between groups in fractional exhaled nitric oxide change of −7.1 ppb (−13.6 to −0.7, p=0.03). Active treatment was associated with less increase in cat-specific IgE than placebo. There was no difference in adverse event rates between treatment groups. <h3>Conclusion</h3> Inhalant exposure reduction with TLA improves quality of life, airway inflammation and systemic allergy in patients with persistent atopic asthma. TLA may be a treatment option for patients with inadequately controlled persistent atopic asthma. <h3>Trial registration number</h3> Clinical Trials NCT00986323.
Lithium: a key to the genetics of bipolar disorder
Authors: Cristiana Cruceanu, Martin Alda, Gustavo Turecki
Journal: Genome Medicine (2009)

Since the 1950s, lithium salts have been the main line of treatment for bipolar disorder (BD), both as a prophylactic and as an episodic treatment agent. Like many psychiatric conditions, BD is genetically and phenotypically heterogeneous, but evidence suggests that individuals who respond well to lithium treatment have more homogeneous clinical and molecular profiles. Response to lithium seems to cluster in families and can be used as a predictor for recurrence of BD symptoms. While molecular studies have provided important information about possible genes involved in BD predisposition or in lithium response, neither the mechanism of action of this drug nor the genetic profile of bipolar disorder is, as yet, completely understood.
A Five-Gene and Corresponding Protein Signature for Stage-I Lung Adenocarcinoma Prognosis
Authors: Humam Kadara, Carmen Behrens, Ping Yuan, Luisa Solis, Diane Liu, Xuemin Gu, John D. Minna, J. Jack Lee, Edward Kim, Waun-Ki Hong, Ignacio I. Wistuba, Reuben Lotan
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Identification of effective markers for outcome is expected to improve the clinical management of non–small cell lung cancer (NSCLC). Here, we assessed in NSCLC the prognostic efficacy of genes, which we had previously found to be differentially expressed in an in vitro model of human lung carcinogenesis. Experimental Design: Prediction algorithms and risk-score models were applied to the expression of the genes in publicly available NSCLC expression data sets. The prognostic capacity of the immunohistochemical expression of proteins encoded by these genes was also tested using formalin-fixed paraffin-embedded (FFPE) tissue specimens from 156 lung adenocarcinomas and 79 squamous cell carcinomas (SCCs). Results: The survival of all-stages (P &amp;lt; 0.001, HR = 2.0) or stage-I (P &amp;lt; 0.001, HR = 2.84) adenocarcinoma patients that expressed the five-gene in vitro lung carcinogenesis model (FILM) signature was significantly poorer than that of patients who did not. No survival differences were observed between SCCs predicted to express or lack FILM signature. Moreover, all stages (P &amp;lt; 0.001, HR = 1.95) or stage-I (P = 0.001, HR = 2.6) adenocarcinoma patients predicted to be at high risk by FILM transcript exhibited significantly worse survival than patients at low risk. Furthermore, the corresponding protein signature was associated with poor survival (all stages, P &amp;lt; 0.001, HR = 3.6; stage-I, P &amp;lt; 0.001, HR = 3.5; stage-IB, P &amp;lt; 0.001, HR = 4.6) and mortality risk (all stages, P = 0.001, HR = 4.0; stage-I, P = 0.01, HR = 3.4; stage-IB, P &amp;lt; 0.001, HR = 7.2) in lung adenocarcinoma patients. Conclusions: Our findings highlight a gene and corresponding protein signature with effective capacity for identification of stage-I lung adenocarcinoma patients with poor prognosis that are likely to benefit from adjuvant therapy. Clin Cancer Res; 17(6); 1490–501. ©2010 AACR.
The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma
Authors: Stefania Gimelli, Silvana Beri, Harry A Drabkin, Claudio Gambini, Andrea Gregorio, Patrizia Fiorio, Orsetta Zuffardi, Robert M Gemmill, Roberto Giorda, Giorgio Gimelli
Journal: Molecular Cancer (2009)

RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22) in a proposita with dysgerminoma. The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes TRC8 and TSN was tested both on dysgerminoma and in the proposita and her father. The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR) involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. TRC8 was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary. TRC8 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells. A role for TRC8 in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of TRC8 is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA.
Aberrant Promoter Hypermethylation of the <b> <i>Death-Associated Protein Kinase</i> </b> Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens
Authors: Leah C. Pulling, Brian R. Vuillemenot, Julie A. Hutt, Theodora R. Devereux, Steven A. Belinsky
Journal: Cancer Research (2004)

Abstract Loss of expression of the death-associated protein (DAP)-kinase gene by aberrant promoter methylation may play an important role in cancer development and progression. The purpose of this investigation was to determine the commonality for inactivation of the DAP-kinase gene in adenocarcinomas induced in mice by chronic exposure to mainstream cigarette smoke, the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate, and the occupational carcinogen methylene chloride. The timing for inactivation was also determined in alveolar hyperplasias that arise in lung cancer induced in the A/J mouse by NNK. The DAP-kinase gene was not expressed in three of five NNK-induced lung tumor-derived cell lines or in a spontaneously arising lung tumor-derived cell line. Treatment with 5-aza-2′-deoxycytidine restored expression; dense methylation throughout the DAP-kinase CpG island detected by bisulfite sequencing supported methylation as the inactivating event in these cell lines. Methylation-specific PCR detected inactivation of the DAP-kinase gene in 43% of tumors associated with cigarette smoke, a frequency similar to those reported in human non-small cell lung cancer. In addition, DAP-kinase methylation was detected in 52%, 60%, and 50% of tumors associated with NNK, vinyl carbamate, and methylene chloride, respectively. Methylation was observed at similar prevalence in both NNK-induced hyperplasias and adenocarcinomas (46% versus 52%), suggesting that inactivation of this gene is one pathway for tumor development in the mouse lung. Bisulfite sequencing of both premalignant and malignant lesions revealed dense methylation, substantiating that this gene is functionally inactivated at the earliest histological stages of adenocarcinoma development. This study is the first to use a murine model of cigarette smoke-induced lung cancer and demonstrate commonality for inactivation by promoter hypermethylation of a gene implicated in the development of this disease in humans.