tbuckley/cabot-search huggingface dataset:
Proteomic risk markers for coronary heart disease and stroke: validation and mediation of randomized trial hormone therapy effects on these diseases
Authors: Ross L Prentice, Shanshan Zhao, Melissa Johnson, Aaron Aragaki, Judith Hsia, Rebecca D Jackson, Jacques E Rossouw, JoAnn E Manson, Samir M Hanash
Journal: Genome Medicine (2013)

We previously reported mass spectrometry-based proteomic discovery research to identify novel plasma proteins related to the risk of coronary heart disease (CHD) and stroke, and to identify proteins with concentrations affected by the use of postmenopausal hormone therapy. Here we report CHD and stroke risk validation studies for highly ranked proteins, and consider the extent to which protein concentration changes relate to disease risk or provide an explanation for hormone therapy effects on these outcomes. Five proteins potentially associated with CHD (beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), thrombospondin-1(THBS1), complement factor D pre-protein (CFD), and insulin-like growth factor binding protein 1 (IGFBP1)) and five potentially associated with stroke (B2M, IGFBP2, IGFBP4, IGFBP6, and hemopexin (HPX)) had high discovery phase significance level ranking and an available ELISA assay, and were included in case-control validation studies within the Women's Health Initiative (WHI) hormone therapy trials. Protein concentrations, at baseline and 1 year following randomization, were assessed for 358 CHD cases and 362 stroke cases, along with corresponding disease-free controls. Disease association, and mediation of estrogen-alone and estrogen plus progestin effects on CHD and stroke risk, were assessed using logistic regression. B2M, THBS1, and CFD were confirmed (P <0.05) as novel CHD risk markers, and B2M, IGFBP2, and IGFBP4 were confirmed as novel stroke disease risk markers, while the assay for HPX proved to be unreliable. The change from baseline to 1 year in B2M was associated (P <0.05) with subsequent stroke risk, and trended similarly with subsequent CHD risk. Change from baseline to 1 year in IGFBP1 was also associated with CHD risk, and this change provided evidence of hormone therapy effect mediation. Plasma B2M is confirmed to be an informative risk marker for both CHD and stroke. The B2M increase experienced by women during the first year of hormone therapy trial participation conveys cardiovascular disease risk. The increase in IGFBP1 similarly conveys CHD risk, and the magnitude of the IGFBP1 increase following hormone therapy may be a mediator of hormone therapy effects. Plasma THBS1 and CFD are confirmed as CHD risk markers, and plasma IGFBP4 and IGFBP2 are confirmed as stroke risk markers. ClinicalTrials.gov identifier: NCT00000611
Oxidative stress in aldosteronism
Authors: Y SUN, R AHOKAS, S BHATTACHARYA, I GERLING, L CARBONE, K WEBER
Journal: Cardiovascular Research (2006)

Congestive heart failure (CHF) is more than a failing heart and salt-avid state. Also present is a systemic illness which features oxidative stress in diverse tissues, a proinflammatory phenotype, and a wasting of soft tissue and bone. Reactive oxygen and nitrogen species contribute to this illness and the progressive nature of CHF. Aldosteronism, an integral component of the neurohormonal profile found in CHF, plays a permissive role in leading to an altered redox state. Because of augmented urinary and fecal excretion of Ca2+ and Mg2+ and consequent decline in plasma-ionized [Ca2+]o and [Mg2+]o that accompanies aldosteronism, parathyroid glands release parathyroid hormone (PTH) in an attempt to restore Ca2+ and Mg2+ homeostasis; this includes bone resorption. However, PTH-mediated intracellular Ca2+ overloading, considered a Ca2+ paradox, leads to oxidative stress. This can be prevented by: spironolactone, an aldosterone receptor antagonist that rescues urinary and fecal cation losses; parathyroidectomy; amlodipine, a Ca2+ channel blocker; N-acetylcysteine, an antioxidant. In addition to the role played by aldosteronism in the appearance of secondary hyperparathyroidism is the chronic use of a loop diuretic, which further enhances urinary Ca2+ and Mg2+ excretion, and reduced Ca2+ stores associated with hypovitaminosis D. This broader perspective of CHF and the ever increasing clinical relevance of divalent cations and oxidative stress raise the question of their potential management with macro- and micronutrients. An emerging body of evidence suggests the nutritional management of CHF offers an approach that will be complementary to today's pharmaceutical-based strategies.
Keratitis, ichthyosis and deafness syndrome with development of multiple hair follicle tumours
Authors: K-H. Kim, J-S. Kim, Y-J. Piao, Y-C. Kim, K-B. Shur, J-H. Lee, J-K. Park
Journal: British Journal of Dermatology (2002)

Summary We report multiple occurrences of various kinds of tumours that originate from hair follicles in a patient diagnosed with KID (keratitis, ichthyosis, deafness) syndrome. These tumours are diagnosed as: (i) trichilemmal cysts in early lesions; (ii) proliferating trichilemmal tumours in moderate duration lesions; and (iii) malignant proliferating trichilemmal tumours in advanced lesions that are thought to progress from benign trichilemmal lesions. This three‐step process raises the hypothesis of a multihit model that could account for the frequent development of tumours in KID patients.
A Novel FoxM1-Caveolin Signaling Pathway Promotes Pancreatic Cancer Invasion and Metastasis
Authors: Chen Huang, Zhengjun Qiu, Liwei Wang, Zhihai Peng, Zhiliang Jia, Craig D. Logsdon, Xiangdong Le, Daoyan Wei, Suyun Huang, Keping Xie
Journal: Cancer Research (2011)

Abstract Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its precise functional roles and regulation remain unclear. In this study, we determined the oncogenic function of Cav-1 in preclinical models of pancreatic cancer and in human tissue specimens. Cav-1 expression levels correlated with metastatic potential and epithelial–mesenchymal transition (EMT) in both mouse and human pancreatic cancer cells. Elevated levels in cells promoted EMT, migration, invasion, and metastasis in animal models, whereas RNA interference (RNAi)-mediated knockdown inhibited these processes. We determined that levels of Cav-1 and the Forkhead transcription factor FoxM1 correlated directly in pancreatic cancer cells and tumor tissues. Enforced expression of FoxM1 increased Cav-1 levels, whereas RNAi-mediated knockdown of FoxM1 had the opposite effect. FoxM1 directly bound to the promoter region of Cav-1 gene and positively transactivated its activity. Collectively, our findings defined Cav-1 as an important downstream oncogenic target of FoxM1, suggesting that dysregulated signaling of this novel FoxM1-Cav-1 pathway promotes pancreatic cancer development and progression. Cancer Res; 72(3); 655–65. ©2011 AACR.
Preventing sexually transmitted infections: back to basics
Authors: Anne Rompalo
Journal: Journal of Clinical Investigation (2011)

Sexually transmitted infections (STIs) have plagued humans for millennia and can result in chronic disease, pregnancy complications, infertility, and even death. Recent technological advances have led to a better understanding of the causative agents for these infections as well as aspects of their pathogenesis that might represent novel therapeutic targets. The articles in this Review Series provide excellent updates on the recent advances in understanding of the pathogenesis of some very important and persistent STIs and discuss the importance of considering each pathogen in the broader context of the environment of the individual who it infects.
Early Detection of Chronic Pulmonary Allograft Dysfunction by Exhaled Biomarkers
Authors: Alain Van Muylem, Christiane Knoop, Marc Estenne
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Early detection of bronchiolitis obliterans syndrome (BOS) is important because therapies are more likely to be effective if employed early in the disease process.To compare the performance of exhaled NO and CO (which reflect airway inflammation) and the slope of the alveolar plateau for helium (which reflects heterogeneity of ventilation distribution) for detection of BOS stages 0-p and 1.Recipients of bilateral (n=64) and single (n=1) lung grafts were prospectively monitored for 1,249 days; the helium slope was derived from single-breath washouts and exhaled NO and CO were measured by chemiluminescence on 933 occasions.At the end of follow-up, 9 patients were in stage 0-p and 16 patients were in BOS stage 1 or higher; 21 patients had at least one measurement made in BOS stage 0-p. All markers increased in BOS stage 0-p, but only the helium slope increased in BOS stage 1. The helium slope had better sensitivity for detection of stages 0-p and 1 than either exhaled NO or CO, but considering exhaled NO and CO together improved their sensitivity; the best sensitivity was found with the three markers in combination. The biomarkers had high negative predictive values, but low specificity and positive predictive values.After lung transplantation, (1) the helium slope and exhaled NO, but also exhaled CO, increase in BOS stage 0-p, (2) the helium slope has better sensitivity than exhaled NO and CO for the detection of BOS stages 0-p and 1, and (3) exhaled biomarkers have high negative predictive values, but low specificity and positive predictive values.
Ca <sup>2+</sup> Sparks and Waves in Canine Purkinje Cells
Authors: Bruno D. Stuyvers, Wen Dun, Scot Matkovich, Vincenzo Sorrentino, Penelope A. Boyden, Henk E.D.J. ter Keurs
Journal: Circulation Research (2005)

We have investigated the subcellular spontaneous Ca2+ events in canine Purkinje cells using laser scanning confocal microscopy. Three types of Ca2+ transient were found: (1) nonpropagating Ca2+ transients that originate directly under the sarcolemma and lead to (2) small Ca2+ wavelets in a region limited to 6-microm depth under the sarcolemma causing (3) large Ca2+ waves that travel throughout the cell (CWWs). Immunocytochemical studies revealed 3 layers of Ca2+ channels: (1) channels associated with type 1 IP3 receptors (IP3R1) and type 3 ryanodine receptors (RyR3) are prominent directly under the sarcolemma; (2) type 2 ryanodine receptors (RyR2s) are present throughout the cell but virtually absent in a layer between 2 and 4 microm below the sarcolemma (Sub-SL); (3) type 3 ryanodine receptors (RyR3) is the dominant Ca2+ release channel in the Sub-SL. Simulations of both nonpropagating and propagating transients show that the generators of Ca2+ wavelets differ from those of the CWWs with the threshold of the former being less than that of the latter. Thus, Purkinje cells contain a functional and structural Ca2+ system responsible for the mechanism that translates Ca2+ release occurring directly under the sarcolemma into rapid Ca2+ release in the Sub-SL, which then initiates large-amplitude long lasting Ca2+ releases underlying CWWs. The sequence of spontaneous diastolic Ca2+ transients that starts directly under the sarcolemma and leads to Ca2+ wavelets and CWWs is important because CWWs have been shown to cause nondriven electrical activity.
Obesity hypoventilation syndrome: does the current definition need revisiting?
Authors: Nicholas Hart, Swapna Mandal, Ari Manuel, Babak Mokhlesi, Jean-Louis Pépin, Amanda Piper, John R Stradling
Journal: Thorax (2013)

Obesity hypoventilation syndrome (OHS) has been conventionally (and to some extent arbitrarily) defined by the combination of obesity (body mass index (BMI) >30 kg/m2), daytime hypercapnia (arterial partial pressure of carbon dioxide (PaCO2) ≥45 mm Hg or 6 kPa) during wakefulness, and usually (but not always) the presence of ‘sleep disordered breathing’, such as obstructive sleep apnoea, rapid eye movement sleep hypoventilation or both.1 The survival curve for untreated OHS is significantly reduced compared with the non-obese,2 and so early identification and treatment for these patients is likely to be beneficial. Little is currently known about the true prevalence of OHS in ambulatory obese individuals, with estimates range from 0.3–0.4% of the general population,3 to around 30% of hospitalised patients with a BMI >35 kg/m …
Sudden Death Related to Toxicity in a Patient on Capecitabine and Irinotecan Plus Bevacizumab Intake: Pharmacogenetic Implications
Authors: Laetitia Dahan, Joseph Ciccolini, Alexandre Evrard, Litaty Mbatchi, Jack Tibbitts, Pauline Ries, Emmanuelle Norguet, Cedric Mercier, Athanassios Iliadis, L'Houcine Ouafik, Bruno Lacarelle, Jean-Francois Seitz
Journal: Journal of Clinical Oncology (2011)
Nonsurgical Management of Urinary Incontinence in Women: A Clinical Practice Guideline From the American College of Physicians
Authors: Amir Qaseem, Paul Dallas, Mary Ann Forciea, Melissa Starkey, Thomas D. Denberg, Paul Shekelle
Journal: Annals of Internal Medicine (2014)

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the nonsurgical management of urinary incontinence (UI) in women.This guideline is based on published English-language literature on nonsurgical management of UI in women from 1990 through December 2013 that was identified using MEDLINE, the Cochrane Library, Scirus, and Google Scholar. The outcomes evaluated for this guideline include continence, improvement in UI, quality of life, adverse effects, and discontinuation due to adverse effects. It grades the evidence and recommendations by using ACP's guideline grading system. The target audience is all clinicians, and the target patient population is all women with UI.ACP recommends first-line treatment with pelvic floor muscle training in women with stress UI. (Grade: strong recommendation, high-quality evidence).ACP recommends bladder training in women with urgency UI. (Grade: strong recommendation, moderate-quality evidence).ACP recommends pelvic floor muscle training with bladder training in women with mixed UI. (Grade: strong recommendation, moderate-quality evidence).ACP recommends against treatment with systemic pharmacologic therapy for stress UI. (Grade: strong recommendation, low-quality evidence).ACP recommends pharmacologic treatment in women with urgency UI if bladder training was unsuccessful. Clinicians should base the choice of pharmacologic agents on tolerability, adverse effect profile, ease of use, and cost of medication. (Grade: strong recommendation, high-quality evidence).ACP recommends weight loss and exercise for obese women with UI. (Grade: strong recommendation, moderate-quality evidence).
No neurochemical evidence for brain injury caused by heading in soccer
Authors: H. Zetterberg, M. Jonsson, A. Rasulzada, C. Popa, E. Styrud, M. A. Hietala, L. Rosengren, A. Wallin, K. Blennow
Journal: British Journal of Sports Medicine (2007)

Background: The possible injurious effect to the brain of heading in soccer is a matter of discussion. Objective: To determine whether standardised headings in soccer are associated with increased levels of biochemical markers for neuronal injury in cerebrospinal fluid (CSF) and serum. Methods: 23 male amateur soccer players took part in a heading training session involving heading a ball kicked from a distance of 30 m at least 10 m forward. Ten players performed 10 and 13 players performed 20 approved headings. The players underwent lumbar puncture and serum sampling 7–10 days after the headings. The study also included 10 healthy male non-athletic control subjects. CSF was analysed for neurofilament light protein, total tau, glial fibrillary acidic protein, S-100B and albumin concentrations. Serum was analysed for S-100B and albumin. Results: None of the biomarker levels were abnormal and there were no significant differences between any of the three groups, except for a slightly increased CSF S-100B concentration in controls compared with headers. Biomarker levels did not correlate with the number of headings performed. Conclusion: Repeated low-severity head impacts due to heading in soccer are not associated with any neurochemical signs of injury to the brain.
Phase I Trial of Weekly Gemcitabine and Concurrent Radiotherapy in Patients With Inoperable Non-Small-Cell Lung Cancer
Authors: Lucio Trodella, Pierluigi Granone, Salvatore Valente, Adriana Turriziani, Giuseppe Macis, Giuseppe M. Corbo, Stefano Margaritora, Alfredo Cesario, Rolando M. D’Angelillo, Gina Gualano, Sara Ramella, Domenico Galetta, Numa Cellini
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To report the evidence of a phase I trial planned to determine the maximum-tolerated dose (MTD) and related toxicity of weekly gemcitabine (GEM) and concurrent radiotherapy in patients with non–small-cell lung cancer (NSCLC). In addition, the response to treatment was evaluated and reported. PATIENTS AND METHODS: Thirty-six patients with histologically confirmed NSCLC deemed unresectable because of advanced stage were observed and treated according to a combined chemoradiation protocol with GEM as chemotherapeutic agent. GEM was given weekly for 5 consecutive weeks as a 30-minute intravenous infusion concurrent with radiotherapy (1.8 Gy/d; total dose, 50.4 Gy). The initial dose was 100 mg/m2. Pulmonary, esophageal, cardiac, hematologic, and skin toxicities were assessed. The dose of GEM was increased by 50 mg/m2 up to a dose of 250 mg/m2; an additional increase by 25 mg/m2 up to the MTD was planned and realized. Three patients were enrolled for each dose level. RESULTS: Dose-limiting toxicity was...
Impact of chronic liver disease in intensive care unit acquired pneumonia: a prospective study
Authors: Marta Di Pasquale, Mariano Esperatti, Ernesto Crisafulli, Miquel Ferrer, Gianluigi Li Bassi, Mariano Rinaudo, Angels Escorsell, Javier Fernandez, Antoni Mas, Francesco Blasi, Antoni Torres
Journal: Intensive Care Medicine (2013)
Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β
Authors: Polakit Teekakirikul, Seda Eminaga, Okan Toka, Ronny Alcalai, Libin Wang, Hiroko Wakimoto, Matthew Nayor, Tetsuo Konno, Joshua M. Gorham, Cordula M. Wolf, Jae B. Kim, Joachim P. Schmitt, Jefferey D. Molkentin, Russell A. Norris, Andrew M. Tager, Stanley R. Hoffman, Roger R. Markwald, Christine E. Seidman, Jonathan G. Seidman
Journal: Journal of Clinical Investigation (2010)

Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β–neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.
Interferon-γ–Dependent Infiltration of Human T Cells into Neuroblastoma Tumors<i>In vivo</i>
Authors: Gregor S.D. Reid, Xiaochuan Shan, Christina M. Coughlin, Wiem Lassoued, Bruce R. Pawel, Leonard H. Wexler, Carol J. Thiele, Maria Tsokos, Jack L. Pinkus, Geraldine S. Pinkus, Stephan A. Grupp, Robert H. Vonderheide
Journal: Clinical Cancer Research (2009)

To investigate the impact of interferon-gamma-mediated upregulation of major histocompatibility complex class I expression on tumor-specific T-cell cytotoxicity and T-cell trafficking into neuroblastoma tumors in vivo.Restoration of major histocompatibility complex class I expression by interferon-gamma treatment enhances killing of neuroblastoma cells. To understand the potential of this approach in vivo, we developed a novel model of neuroblastoma in which NOD/scid/IL2R gamma(null) immunodeficient mice are engrafted with both human T cells and tumor cells.Here, we show enhanced killing of neuroblastoma cells by patient-derived, tumor-specific T cells in vitro. In addition, interferon-gamma treatment in vivo induces efficient upregulation of major histocompatibility complex class I expression on neuroblastoma tumor cells, and this is accompanied by significantly enhanced infiltration of T cells into the tumor. In a pilot clinical trial in patients with high-risk neuroblastoma, we similarly observed augmented T-cell trafficking into neuroblastoma nests in tumor biopsy specimens obtained from patients after 5 days of systemic interferon-gamma therapy.Interferon-gamma overcomes critical obstacles to the killing of human neuroblastoma cells by specific T cells. Together, these findings provide a rationale for the further testing of interferon-gamma as an approach for improving the efficacy of T cell-based therapies for neuroblastoma and other major histocompatibility complex class I-deficient malignancies. In addition, we describe a model that may expedite the preclinical screening of approaches aimed at augmenting T-cell trafficking into human tumors.
Hapten reactive inducer T cells. II. Evidence that a secreted form of the T cell receptor induces antibody production.
Authors: R H Dekruyff, C Clayberger, H Cantor
Journal: The Journal of Experimental Medicine (1983)

The biologic activity of molecules synthesized and secreted by hapten-specific inducer T cells was examined. After activation, a single inducer clone secretes both antigen-specific inducer peptides as well as nonspecific factors. The nonspecific factors augment the in vitro response of B cells to sheep erythrocytes (SRBC) and Type 2 T-independent antigens. The antigen-specific molecules (ABM) induce plaque-forming cell (PFC) responses in cultures containing ABM, B cells, and antigen that links the epitope recognized by ABM with the B cell epitope. Induction of B cells by ABM is limited to B cells expressing the same I-A allele as the source of the ABM and this reflects binding by ABM to I-A products on B lymphocytes. The data reported here strongly support the view that inducer cells can activate at least some B cells by secretion of a modified form of the T cell surface receptor.