tbuckley/cabot-search huggingface dataset:
Identification of a new citrullinated epitope on filaggrin for the early diagnosis of rheumatoid arthritis
Authors: E Szarka, F Babos, A Magyar, F Hudecz, G Nagy, G Sarmay
Journal: Annals of the Rheumatic Diseases (2010)

Anti-citrullinated protein antibodies (ACPA) are sensitive and specific markers for diagnosis and prognosis in rheumatoid arthritis (RA). Citrullination is a post-translational modification of arginine by deimination, induced by peptidylarginine deiminase. It is a physiologically occurring phenomena during apoptosis, inflammation or keratinisation. Citrullination has been observed in different synovial proteins, including fibrinogen, vimentin and collagen. Antibodies specific for cyclic citrullinated filaggrin peptides (CCP) were detected in RA sera and anti-CCP positivity is widely used for diagnostic purposes. However, to determine …
HDL Cholesterol and Protective Factors in Atherosclerosis
Authors: Gerd Assmann, Antonio M. Gotto
Journal: Circulation (2004)

A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol Education Program guidelines. However, HDL-C should be considered as part of the patient’s overall profile of established risk factors in determining treatment strategies.
Molecular Genetics of Colorectal Cancer
Authors: Eric R. Fearon
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes-most prominently the APC, KRAS, and p53 genes-are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.
RNAi-mediated inhibition of presenilin 2 inhibits glioma cell growth and invasion and is involved in the regulation of Nrg1/ErbB signaling
Authors: Bei Liu, Liang Wang, Liang-Liang Shen, Ming-Zhi Shen, Xiao-Dong Guo, Tao Wang, Qin-Chuan Liang, Chao Wang, Jun Zheng, Yi Li, Lin-Tao Jia, Hua Zhang, Guo-Dong Gao
Journal: Neuro-Oncology (2012)

Gliomas are the leading cause of death among adults with primary brain malignancies. Treatment for malignant gliomas remains limited, and targeted therapies have been incompletely explored. In this study, we found that the protein expression of presenilin 2 (PS2) was significantly increased in glioma tissues, at least partially because of promoter demethylation. We further evaluated the biological functions of PS2 in U251 glioma cell proliferation, migration, invasion, and tumor growth in vivo by specific inhibition of PS2 using short hairpin RNA (shRNA). We found that PS2 depletion inhibited glioma cell growth as the result of inhibited proliferation and induced apoptosis. PS2 depletion also decreased the invasive capability of glioma cells and anchorage-independent colony formation in soft agar. Moreover, suppression of PS2 expression significantly impaired the growth of glioma xenografts in nude mice. Finally, the decrease in glioma cell growth caused by PS2 depletion seems to involve Nrg1/ErbB signaling. In summary, our data highlight the use of RNA interference (RNAi) as a tool to better understand the molecular basis of PS2 in glioma progression and to uncover new targets for the treatment of glioma.
Reproductive and Sexual Function After Platinum-Based Chemotherapy in Long-Term Ovarian Germ Cell Tumor Survivors: A Gynecologic Oncology Group Study
Authors: David M. Gershenson, Anna M. Miller, Victoria L. Champion, Patrick O. Monahan, Qianqian Zhao, David Cella, Stephen D. Williams
Journal: Journal of Clinical Oncology (2007)

To compare malignant ovarian germ cell tumor survivors with a matched control group of females on menstrual and reproductive outcomes, sexual functioning, and dyadic adjustment.Eligible patients met the following criteria: (1) history of malignant ovarian germ cell tumor; (2) treatment with surgery plus platinum-based chemotherapy; (3) age at least 18 years and continuously disease-free with minimum follow-up of 2 years; (4) capability of completing questionnaire and telephone interview; and (5) completion of written informed consent. The control group was drawn from acquaintances recommended by survivors and matched for age, race, and education. Scales with established reliability and validity were used to measure quality-of-life concepts of sexual functioning and social networks.One hundred thirty-two survivors and 137 controls completed the study. Of 132 survivors, 71 (53.8%) had fertility-sparing surgery. Of fertile survivors, 62 (87.3%) reported still having menstrual periods. Twenty-four survivors reported 37 offspring after cancer treatment. Compared with controls, survivors had significantly greater reproductive concerns (P < .0001), less sexual pleasure (P = .003), and lower scores on the total Sexual Activity Scale Score (P = .001). However, survivors had better dyadic consensus (P = .004), dyadic satisfaction (P = .005), and dyadic cohesion (P = .014).Women who had fertility-sparing surgery were very likely to retain menstrual function and fertility after chemotherapy. Although there is some increase in gynecologic symptoms and diminution in sexual pleasure, survivors tended to have stronger, more positive relationships with significant others.
MMP12 and reduced risk of COPD
Authors: A. Pillai
Journal: Thorax (2010)

There are currently no published guidelines in the UK for what constitutes adequate training in bronchoscopy, or how best to assess competence.The data presented here clearly demonstrate different speeds at which people learn new tasks, even when we consider operators highly experienced in similar procedural techniques.With the ever-expanding number and complexity of bronchoscopic procedures (and of medical procedures in general), there is a need to formulate adequate assess-ment tools for trainee development, and we propose cusum analysis as one such tool.However, accurate and appropriate standards of practice must be determined prior to assessment to ensure correct identification of those who are underperforming.
Abstract 3450: Internalization and recycling of RET receptor tyrosine kinase isoforms
Authors: Mathieu Joseph François Crupi, Douglas S. Richardson, Lois M. Mulligan
Journal: Cancer Research (2014)

Abstract The RET (REarranged in Transfection) receptor tyrosine kinase is crucial for the normal development of the kidneys and enteric nervous system, as well as the regulation of neural-crest cell behaviours, including migration, proliferation, differentiation and survival. RET is also a potent contributor to clinically challenging cancers. Activating mutations in RET can lead to multiple endocrine neoplasia type 2, a cancer syndrome characterized by medullary thyroid carcinoma. Increased activation of wildtype RET receptors has been linked to aggressive breast cancers, and enhanced invasion and perineural spread in pancreatic carcinoma. Two distinct isoforms of the growth factor receptor arise through alternative splicing of the 3’ exons, and are termed RET9 and RET51 to denote the number of amino acids in each C-terminal tail. These isoforms induce unique transphosphorylation patterns on intracellular tyrosine residues, differentially bind downstream signalling proteins, and possess different intrinsic abilities to cause cellular transformation. Here, we explore the differential subcellular localization and trafficking of the two isoforms in human cell line models to better understand RET-mediated cancers. We have observed that RET51 is efficiently matured and localized to the cell membrane, while immature RET9 matures more slowly, leading to lower relative expression on the plasma membrane. Subsequent to RET activation, both isoforms at the cell surface are internalized through AP2-adaptor interactions and the clathrin coated-pit pathway into endosomes. Although RET51 is internalized more rapidly than RET9, a portion of RET51 molecules recycles back to the plasma membrane, maintaining high expression levels at the cell surface. We have shown that RET51 interacts with the sorting protein GGA3, which may allow the long isoform to travel back to the cell surface. Recycling prevents efficient degradation of RET51, allowing for prolonged downstream signaling relative to RET9. Since RET51 has a longer residency time in an endosomal compartment, where sustained Erk1/2 signaling promotes mitogenesis, this may in part explain the greater transforming potential of RET51. Together, our data suggest that differences in RET isoform subcellular localization and trafficking would lead to differences in signal transduction and may in part explain the functional differences observed between RET isoforms. Citation Format: Mathieu Joseph François Crupi, Douglas S. Richardson, Lois M. Mulligan. Internalization and recycling of RET receptor tyrosine kinase isoforms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3450. doi:10.1158/1538-7445.AM2014-3450
New tool aims to unlock the secrets of engaging patients
Authors: A. O'Dowd
Journal: BMJ (2010)

A tool is being launched that will allow doctors to access hundreds of pieces of research into how to engage patients and the public in health care.

Using the online tool, doctors will be able to discover the lessons learnt from global research into areas including patient experience, health literacy, shared decisions to choose appropriate treatment, self management, health promotion, and public engagement.

The Invest in Engagement tool analyses and presents the results of 280 research reviews, claiming to be the best available evidence from around the world. It was commissioned by the Department of Health and produced by health research think tank the Picker Institute Europe.

The institute said the tool would help doctors and …
Wnt Signaling Exerts an Antiproliferative Effect on Adult Cardiac Progenitor Cells Through IGFBP3
Authors: Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Frank Conyers, Michael Bauer, Annette Liao, Jian Guan, Dylan Crapps, Jung-Kyu Han, Hanhua Dong, Ahmad F. Bayomy, Gabriel C. Fine, Karen Westerman, Travis L. Biechele, Randall T. Moon, Thomas Force, Ronglih Liao
Journal: Circulation Research (2011)

Rationale: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear. Objective: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. Methods and Results: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested after injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its antiproliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a after myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury. Conclusions: Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states.
The Expression of the Regulatory T Cell–Specific Forkhead Box Transcription Factor FoxP3 Is Associated with Poor Prognosis in Ovarian Cancer
Authors: Dominik Wolf, Anna M. Wolf, Holger Rumpold, Heidi Fiegl, Alain G. Zeimet, Elisabeth Muller-Holzner, Martina Deibl, Guenther Gastl, Eberhard Gunsilius, Christian Marth
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The forkhead box transcription factor FoxP3 is specifically expressed in T cells with regulatory properties (Treg). Recently, high numbers of Treg were described to be associated with poor survival in different malignancies. The aim of the presented study was determine the prognostic effect of FoxP3 mRNA expression (reflecting the tissue content of Treg) in ovarian carcinoma and its relation with cytokines, such as IFN-γ. Experimental Design: Total RNA was isolated from 99 ovarian carcinoma and from 14 healthy ovarian biopsies. Real-time PCR for FoxP3 was done and correlated with IFN-γ-, CD3-, IRF-1-, SOCS-1-, HER-2-, and iNOS expression as well as patients' outcome. The mRNA data was corroborated by FoxP3 immunohistochemistry. Results: Quantitation of FoxP3 expression identified a patient subgroup (&amp;gt;81th percentile), which is characterized by a significantly worse prognosis in terms of overall survival (27.8 versus 77.3 months, P = 0.0034) and progression-free survival (18 versus 57.5 months; P = 0.0041). FoxP3 expression correlated with IFN-γ, IRF-1, and CD3 expression. High FoxP3 expression represents an independent prognostic factor for overall survival (P = 0.004) and progression-free survival (P = 0.004). Conclusions: High expression levels of FoxP3 might represent a surrogate marker for an immunosuppressive milieu contributing to tumor immune escape. Strategies selectively depleting Treg might improve the antitumor activity of endogenously arising tumor-reactive T cells and immunotherapies using vaccines or antibodies.
The AA Genotype of the Regulatory <i>BCL2</i> Promoter Polymorphism (−938C&amp;gt;A) Is Associated with a Favorable Outcome in Lymph Node–Negative Invasive Breast Cancer Patients
Authors: Hagen S. Bachmann, Friedrich Otterbach, Rainer Callies, Holger Nückel, Maja Bau, Kurt W. Schmid, Winfried Siffert, Rainer Kimmig
Journal: Clinical Cancer Research (2007)

Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities.Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival.Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node-negative breast cancer patients, whereas no genotype effect could be observed in lymph node-positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for cancer-related death in lymph node-negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node-positive but not of lymph node-negative breast cancer patients. In lymph node-negative cases, the (-938C>A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2-expressing carcinomas (P = 0.006).These results suggest the (-938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node-negative breast cancer.
Invariant NKT cells are required for airway inflammation induced by environmental antigens
Authors: Gerhard Wingender, Paul Rogers, Glenda Batzer, Myung Steve Lee, Dong Bai, Bo Pei, Archana Khurana, Mitchell Kronenberg, Anthony A. Horner
Journal: The Journal of Experimental Medicine (2011)

Invariant NKT cells (iNKT cells) are a unique subset of T lymphocytes that rapidly carry out effector functions. In this study, we report that a majority of sterile house dust extracts (HDEs) tested contained antigens capable of activating mouse and human iNKT cells. HDEs had adjuvant-like properties in an ovalbumin (OVA)-induced asthma model, which were dependent on Vα14i NKT cells, as vaccinated animals deficient for iNKT cells displayed significantly attenuated immune responses and airway inflammation. Furthermore, the administration of HDEs together with OVA mutually augmented the synthesis of cytokines by Vα14i NKT cells and by conventional CD4+ T cells in the lung, demonstrating a profound immune response synergy for both Th2 cytokines and IL-17A. These data demonstrate that iNKT cell antigens are far more widely dispersed in the environment than previously anticipated. Furthermore, as the antigenic activity in different houses varied greatly, they further suggest that iNKT cell responses to ambient antigens, particular to certain environments, might promote sensitization to conventional respiratory allergens.
Anti-inflammatory effects of high-dose inhaled fluticasone versus oral prednisone in asthma exacerbations
Authors: J. Belda, G. Margarit, C. Martínez, J. Bellido-Casado, P. Casan, M. Torrejón, M. Brufal, F. Rodríguez-Jerez, J. Sanchis
Journal: European Respiratory Journal (2007)

The objective of the present study was to investigate the kinetics of high doses of inhaled steroid fluticasone in comparison with oral steroid prednisone on plasma protein leakage and bronchial eosinophilia in adults with moderate asthma exacerbations. The study design was a randomised, double-blind, placebo-controlled prospective trial. In total, 45 patients treated at the emergency department for moderate asthma exacerbations were recruited and 39 were assigned to receive fluticasone and placebo of prednisone (19 patients), or prednisone and placebo of fluticasone (20 patients). Medication was administered to all patients via a metered-dose inhaler and spacer (16 puffs; 4,000 μg·day −1 or placebo) plus one pill (prednisone 30 mg·day −1 or placebo). Spirometry and induced sputum for differential cell counts, albumin and α 2 -macroglobulin levels and blood eosinophils, interleukin-5 and granulocyte-macrophage colony-stimulating factor levels were obtained before treatment and at 2, 6 and 24 h after treatment. Symptoms clearly improved after 24 h in both groups. No differences were seen between groups in peak expiratory flow or forced expiratory flow in one second, which improved progressively but then decayed slightly after 24 h. Eosinophil counts in sputum also improved over time in both groups. The effect was faster with fluticasone than with prednisone, but was partially lost at 24 h. However, plasma proteins in sputum and eosinophil count in blood both decreased until 24 h, with no significant differences between groups. There was no correlation between eosinophil counts and plasmatic protein levels. In conclusion, both treatments improved symptoms, airway obstruction and inflammation, and plasma protein leakage at 24 h. Prednisone reduced blood eosinophil counts, while fluticasone reduced airway eosinophil counts, suggesting that the anti-inflammatory performance of fluticasone is exerted locally.
Effect of the glyceryl monooleate-based lyotropic phases on skin permeation using in vitro diffusion and skin imaging
Authors: Dae Gon Lim, Won-Wook Jeong, Nam Ah Kim, Jun Yeul Lim, Seol-Hoon Lee, Woo Sun Shim, Nae-Gyu Kang, Seong Hoon Jeong
Journal: Asian Journal of Pharmaceutical Sciences (2014)

Glyceryl monooleate (GMO) is a polar lipid that can exist in various liquid crystalline phases in the presence of different amounts of water. It is regarded as a permeation enhancer due to its amphiphilic property. Various phases of GMO/solvent system containing sodium fluorescein were prepared to compare permeability using confocal laser scanning microscopy (CLSM). GMO was melted in a vial in a water bath heated to 45 °C. Propylene glycol and hexanediol were homogeneously dissolved in the melted GMO. Sodium fluorescein in aqueous solution was diluted to various ratios and thoroughly mixed by an ultrasonic homogenizer. Each GMO/Solvent system with fluorescein was applied onto the epidermal side of excised pig skin and incubated overnight. CLSM was performed to observe how the GMO/solvent system in its different phases affect skin permeability. Cubic and lamellar phase formulations enhanced the fluorescein permeation through the stratum corneum. A solution system had the weakest permeability compared to the other two phases. Due to the amphiphilic nature of GMO, cubic and lamellar phases might reduce the barrier function of stratum corneum which was observed by CLSM as fluorescein accumulated in the dermis. Based on the results, the glyceryl monooleate lyotropic mixtures could be applied to enhance skin permeation in various topical and transdermal formulations.