tbuckley/cabot-search huggingface dataset:
Wound Healing Is Accelerated by Agonists of Adenosine A2 (Gαs-linked) Receptors
Authors: M. Carmen Montesinos, Pratap Gadangi, Michael Longaker, Joanne Sung, Jamie Levine, Diana Nilsen, Joan Reibman, Min Li, Chuan-Kui Jiang, Rochelle Hirschhorn, Phoebe A. Recht, Edward Ostad, Richard I. Levin, Bruce N. Cronstein
Journal: The Journal of Experimental Medicine (1997)

The complete healing of wounds is the final step in a highly regulated response to injury. Although many of the molecular mediators and cellular events of healing are known, their manipulation for the enhancement and acceleration of wound closure has not proven practical as yet. We and others have established that adenosine is a potent regulator of the inflammatory response, which is a component of wound healing. We now report that ligation of the Gαs-linked adenosine receptors on the cells of an artificial wound dramatically alters the kinetics of wound closure. Excisional wound closure in normal, healthy mice was significantly accelerated by topical application of the specific A2A receptor agonist CGS-21680 (50% closure by day 2 in A2 receptor antagonists. In rats rendered diabetic (streptozotocin-induced diabetes mellitus) wound healing was impaired as compared to nondiabetic rats; CGS-21680 significantly increased the rate of wound healing in both nondiabetic and diabetic rats. Indeed, the rate of wound healing in the CGS-21680–treated diabetic rats was greater than or equal to that observed in untreated normal rats. These results appear to constitute the first evidence that a small molecule, such as an adenosine receptor agonist, accelerates wound healing in both normal animals and in animals with impaired wound healing.
HORMONAL CONTROL OF LYSOSOMAL ENZYME RELEASE FROM HUMAN NEUTROPHILS
Authors: L. J. Ignarro, T. F. Lint, W. J. George
Journal: The Journal of Experimental Medicine (1974)

The purpose of this investigation was to examine the effects of autonomic neurohormones, cyclic nucleotides, and related agents on the immunologic discharge of lysosomal enzymes from, and phagocytosis by, purified human neutrophils. In order to discern the possible intracellular mechanisms by which certain neurohormones influence neutrophil function, the concentrations of cyclic AMP and cyclic GMP in neutrophils were assessed during cell contact with phagocytizable particles and autonomic agents. The model system employed for study was the interaction of purified human neutrophils with rheumatoid arthritic (RA) serum-treated zymosan particles at 37°C in a neutral, balanced salt solution containing glucose. Neutrophils ingested the particles and discharged ß-glucuronidase but not lactate dehydrogenase activity during 30 min of incubation. Treatment of zymosan particles with RA serum was more effective than treatment with normal serum with regard to the extent of both particle uptake and lysosomal enzyme release. During contact of neutrophils with RA serum-treated zymosan particles epinephrine, isoproterenol, and cyclic AMP inhibited both particle ingestion and ß-glucuronidase discharge. These actions of epinephrine were associated with a concomitant elevation of cyclic AMP levels. In contrast to the actions of catecholamines and cyclic AMP, acetylcholine and cyclic GMP accelerated lysosomal enzyme release without affecting particle uptake. The actions of acetylcholine were associated with a concomitant elevation of cyclic GMP levels. Increases in neutrophil levels of cyclic GMP but not of cyclic AMP were associated also with the discharge of ß-glucuronidase provoked by particles in the absence of added cholinergic agents. The data suggest that the immunologic release of lysosomal enzymes from human neutrophils can be regulated by autonomic neurohormones, perhaps via the selective formation of appropriate nucleotides.
Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function
Authors: Gabriel Bidaux, Matthieu Flourakis, Stéphanie Thebault, Alexander Zholos, Benjamin Beck, Dimitra Gkika, Morad Roudbaraki, Jean-Louis Bonnal, Brigitte Mauroy, Yaroslav Shuba, Roman Skryma, Natalia Prevarskaya
Journal: Journal of Clinical Investigation (2007)

In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer (PCa). However, the mechanisms of prostate-specific regulation and functional evolution of TRPM8 during PCa progression remain unclear. Here we show, for the first time to our knowledge, that only secretory mature differentiated human prostate primary epithelial (PrPE) luminal cells expressed functional plasma membrane TRPM8 ((PM)TRPM8) channels. Moreover, PCa epithelial cells obtained from in situ PCa were characterized by a significantly stronger (PM)TRPM8-mediated current than that in normal cells. This (PM)TRPM8 activity was abolished in dedifferentiated PrPE cells that had lost their luminal secretory phenotype. However, we found that in contrast to (PM)TRPM8, endoplasmic reticulum TRPM8 ((ER)TRPM8) retained its function as an ER Ca(2+) release channel, independent of cell differentiation. We hypothesize that the constitutive activity of (ER)TRPM8 may result from the expression of a truncated TRPM8 splice variant. Our study provides insight into the role of TRPM8 in PCa progression and suggests that TRPM8 is a potentially attractive target for therapeutic intervention: specific inhibition of either (ER)TRPM8 or (PM)TRPM8 may be useful, depending on the stage and androgen sensitivity of the targeted PCa.
Multi-site and multi-depth near-infrared spectroscopy in a model of simulated (central) hypovolemia: lower body negative pressure
Authors: Sebastiaan A. Bartels, Rick Bezemer, Floris J. Wallis de Vries, Dan M. J. Milstein, Alexandre Lima, Thomas G. V. Cherpanath, Anton H. van den Meiracker, Jasper van Bommel, Michal Heger, John M. Karemaker, Can Ince
Journal: Intensive Care Medicine (2011)

To test the hypothesis that the sensitivity of near-infrared spectroscopy (NIRS) in reflecting the degree of (compensated) hypovolemia would be affected by the application site and probing depth. We simultaneously applied multi-site (thenar and forearm) and multi-depth (15–2.5 and 25–2.5 mm probe distance) NIRS in a model of simulated hypovolemia: lower body negative pressure (LBNP). The study group comprised 24 healthy male volunteers who were subjected to an LBNP protocol in which a baseline period of 30 min was followed by a step-wise manipulation of negative pressure in the following steps: 0, −20, −40, −60, −80 and −100 mmHg. Stroke volume and heart rate were measured using volume-clamp finger plethysmography. Two multi-depth NIRS devices were used to measure tissue oxygen saturation (StO2) and tissue hemoglobin index (THI) continuously in the thenar and the forearm. To monitor the shift of blood volume towards the lower extremities, calf THI was measured by single-depth NIRS. The main findings were that the application of LBNP resulted in a significant reduction in stroke volume which was accompanied by a reduction in forearm StO2 and THI. NIRS can be used to detect changes in StO2 and THI consequent upon central hypovolemia. Forearm NIRS measurements reflect hypovolemia more sensitively than thenar NIRS measurements. The sensitivity of these NIRS measurements does not depend on NIRS probing depth. The LBNP-induced shift in blood volume is reflected by a decreased THI in the forearm and an increased THI in the calf.
C-Reactive Protein Is Independently Associated With Glucose but Not With Insulin Resistance in Healthy Men
Authors: Anne G. Niehoff, Timon W. van Haeften, N. Charlotte Onland-Moret, Clara C. Elbers, Cisca Wijmenga, Yvonne T. van der Schouw
Journal: Diabetes Care (2007)

Recent studies have shown that low-grade inflammation is linked both to insulin resistance (1,2) and the metabolic syndrome (3,4) and may even predict the development of type 2 diabetes (5–8).

However, adipose tissue might play an important role in these relationships. There is still controversy about whether low-grade inflammation is an intermediate factor between obesity and insulin resistance or whether it has an independent effect on the development of type 2 diabetes through a mechanism separate from obesity.

The aim of this study was to explore whether low-grade inflammation (measured by plasma C-reactive protein (CRP) levels) was related to insulin resistance and to parameters of metabolic syndrome, independent of obesity.

We conducted a cross-sectional, single-center study on 400 men aged between 40 and 80 years. The subjects, methods of recruitment, study procedures and anthropometrical and laboratory measurements have been described elsewhere (9). Twenty-one participants had prevalent diabetes and were excluded from the study; 13 participants were excluded because their level of CRP was above 10 mg/l and 2 because blood samples had been taken in a nonfasting state. Our final study population comprised 364 participants.

Various measures of obesity were obtained: weight, BMI, waist circumference, waist-to-hip ratio, visceral and subcutaneous fat using ultrasound measurement (10), and total body fat mass using dual-energy X-ray absorptiometry.

Information on prevalent diseases, medication use, and …
Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes and Mechanisms of Action
Authors: Francesco Rubino, Philip R. Schauer, Lee M. Kaplan, David E. Cummings
Journal: Annual Review of Medicine (2010)

Several gastrointestinal (GI) operations that were designed to promote weight loss can powerfully ameliorate type 2 diabetes mellitus (T2DM). Although T2DM is traditionally viewed as a chronic, relentless disease in which delay of end-organ complications is the major treatment goal, GI surgery offers a novel endpoint: complete disease remission. Ample data confirm the excellent safety and efficacy of conventional bariatric operations-especially Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding-to treat T2DM in severely obese patients. Use of experimental procedures as well as conventional bariatric operations is increasingly being explored in less obese diabetic patients, with generally favorable results, although further assessment of risk:benefit profiles is needed. Mounting evidence indicates that certain operations involving intestinal diversions improve glucose homeostasis through varied mechanisms beyond reduced food intake and body weight, for example by modulating gut hormones. Research to elucidate such mechanisms should facilitate the design of novel pharmacotherapeutics and dedicated antidiabetes GI manipulations. Here we review evidence regarding the use and study of GI surgery to treat T2DM, focusing on available published reports as well as results from the Diabetes Surgery Summit (DSS) in Rome and the World Congress on Interventional Therapies for T2DM in New York City.
Sympathetically maintained pain: Confusing classification, ill-defined diagnostic criteria, and puzzling pathophysiology
Authors: Srinivasa N. Raja, Ursula Wesselmann
Journal: Behavioral and Brain Sciences (1997)

Recent studies indicate a role of the sympathetic nervous system in acute and chronic pain. However, the terminology of the clinical sympathetically maintained pain (SMP) syndromes continues to be confusing and the criteria for diagnosis of SMP are being refined. ( blumberg et al. ) Despite significant progress in recent years, the mechanisms of the interaction between the sympathetic and sensory systems in SMP remain puzzling.
TNM Staging of Neoplasms of the Endocrine Pancreas: Results From a Large International Cohort Study
Authors: G. Rindi, M. Falconi, C. Klersy, L. Albarello, L. Boninsegna, M. W. Buchler, C. Capella, M. Caplin, A. Couvelard, C. Doglioni, G. Delle Fave, L. Fischer, G. Fusai, W. W. de Herder, H. Jann, P. Komminoth, R. R. de Krijger, S. La Rosa, T. V. Luong, U. Pape, A. Perren, P. Ruszniewski, A. Scarpa, A. Schmitt, E. Solcia, B. Wiedenmann
Journal: JNCI Journal of the National Cancer Institute (2012)

Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II–III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
Fibronectin is produced by blood vessels in response to injury.
Authors: R A Clark, J H Quinn, H J Winn, J M Lanigan, P Dellepella, R B Colvin
Journal: The Journal of Experimental Medicine (1982)

During the time of tissue repair that ensues subsequent to tissue injury, blood vessel wall fibronectin increases concomitantly with endothelial proliferation and angiogenesis. However, the source of this blood vessel fibronectin had not been delineated. In this report we have demonstrated that microvascular fibronectin is produced in situ by the proliferating vessels surrounding excisional wounds. This finding was established by extirpating 3 mm of skin from the center of a well-healed rat xenograph on the flanks of immunosuppressed mice, harvesting the injured skin sites at various stages during the healing process, and staining the specimens with reciprocal species-specific anti-fibronectin. The proliferating donor vessels that surrounded the wounded graft had increased fluorescence staining with FITC conjugated mouse anti-rat fibronectin and no staining with rat anti-mouse fibronectin. This finding was taken as direct evidence that the fibronectin was produced in situ by the rat vessels and not derived from circulating mouse plasma.
Prospective Cohort Study of Type 2 Diabetes and the Risk of Parkinson's Disease
Authors: Jane A. Driver, Ashley Smith, Julie E. Buring, J. Michael Gaziano, Tobias Kurth, Giancarlo Logroscino
Journal: Diabetes Care (2008)

OBJECTIVE—To evaluate the association between type 2 diabetes and newly reported Parkinson's disease. RESEARCH DESIGN AND METHODS—Our study included 21,841 participants in the Physicians’ Health Study, a cohort of U.S. male physicians. Diabetes and Parkinson's disease were self-reported via questionnaire. We used time-varying Cox regression to calculate adjusted relative risk (RR) for Parkinson's disease. RESULTS—Over 23 years, 556 individuals with Parkinson's disease were identified. Subjects with diabetes had an increased Parkinson's disease risk (multivariable-adjusted RR 1.34 [95% CI 1.01–1.77]). The association remained significant after exclusion of those with known vascular disease. The diagnosis of diabetes was clustered around the diagnosis of Parkinson's disease and was more apparent among men with short diabetes duration and those without complications from diabetes. CONCLUSIONS—Results of this large prospective study in men do not suggest that diabetes is a preceding risk factor for Parkinson's disease. Whether the positive association may be explained by ascertainment bias or a common underlying biological mechanism remains to be established.
Epigenetic Silencing of <i>Death Receptor 4</i> Mediates Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Resistance in Gliomas
Authors: Agnes Elias, Markus D. Siegelin, Albert Steinmüller, Andreas von Deimling, Ulrike Lass, Bernhard Korn, Wolf Mueller
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To identify and characterize epigenetically regulated genes able to predict sensitivity or resistance to currently tested chemotherapeutic agents in glioma therapy. Experimental Design: We used methylation-sensitive BeadArray technology to identify novel epigenetically regulated genes associated with apoptosis and with potential therapeutic targets in glioma therapy. To elucidate the functional consequences of promoter methylation in the identified target death receptor 4 (DR4), we investigated tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated and anti-DR4–mediated apoptosis in glioma cell lines (U373 and A172) with loss of DR4 and one glioma cell line (LN18) with robust DR4 expression. Results: In human astrocytic tumors, we detected DR4 promoter hypermethylation in 60% (n = 5) of diffuse astrocytomas WHO grade 2, in 75% (n = 8) of anaplastic astrocytomas WHO grade 3, and in 70% of glioblastomas WHO grade 4 (n = 33). DR4 is a cell surface protein restricted to glioma cells and is targeted by TRAIL. Glioma cell lines U373 and A172 harbored heavily methylated DR4 promoters, and 5-aza-2-deoxycytidine–mediated demethylation reconstituted DR4 expression in these cell lines. Functional knockdown of DR4 by DR4-specific small interfering RNA in TRAIL-sensitive glioma cell line LN18 significantly mitigated apoptosis induced by an agonistic anti-DR4 antibody. 5-Aza-2-deoxycytidine–mediated demethylation resulted in a functional reconstitution of DR4 on the cell surface of TRAIL-resistant glioma cell line U373 and sensitized U373 to TRAIL-mediated apoptosis. Suppression of DR4 by small interfering RNA in demethylated U373 successfully reestablished the TRAIL-resistant phenotype of U373. Conclusions: DR4 promoter methylation is frequent in human astrocytic gliomas, and epigenetic silencing of DR4 mediates resistance to TRAIL/DR4-based glioma therapies. (Clin Cancer Res 2009;15(17):5457–65)
Her-2 Overexpression Increases the Metastatic Outgrowth of Breast Cancer Cells in the Brain
Authors: Diane Palmieri, Julie L. Bronder, Jeanne M. Herring, Toshiyuki Yoneda, Robert J. Weil, Andreas M. Stark, Raffael Kurek, Eleazar Vega-Valle, Lionel Feigenbaum, Douglas Halverson, Alexander O. Vortmeyer, Seth M. Steinberg, Kenneth Aldape, Patricia S. Steeg
Journal: Cancer Research (2007)

Abstract Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2–amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2–overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (&amp;gt;50 μm2; P &amp;lt; 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system. [Cancer Res 2007;67(9):4190–8]
DNA Copy Number Gains at Loci of Growth Factors and Their Receptors in Salivary Gland Adenoid Cystic Carcinoma
Authors: Hedy Vékony, Bauke Ylstra, Saskia M. Wilting, Gerrit A. Meijer, Mark A. van de Wiel, C. René Leemans, Isaäc van der Waal, Elisabeth Bloemena
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Adenoid cystic carcinoma (ACC) is a malignant salivary gland tumor with a high mortality rate due to late, distant metastases. This study aimed at unraveling common genetic abnormalities associated with ACC. Additionally, chromosomal changes were correlated with patient characteristics and survival. Experimental Design: Microarray-based comparative genomic hybridization was done to a series of 18 paraffin-embedded primary ACCs using a genome-wide scanning BAC array. Results: A total of 238 aberrations were detected, representing more gains than losses (205 versus 33, respectively). Most frequent gains (&amp;gt;60%) were observed at 9q33.3-q34.3, 11q13.3, 11q23.3, 19p13.3-p13.11, 19q12-q13.43, 21q22.3, and 22q13.33. These loci harbor numerous growth factor [fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF)] and growth factors receptor (FGFR3 and PDGFRβ) genes. Gains at the FGF(R) regions occurred significantly more frequently in the recurred/metastasized ACCs compared with indolent ACCs. Furthermore, patients with 17 or more chromosomal aberrations had a significantly less favorable outcome than patients with fewer chromosomal aberrations (log-rank = 5.2; P = 0.02). Conclusions: Frequent DNA copy number gains at loci of growth factors and their receptors suggest their involvement in ACC initiation and progression. Additionally, the presence of FGFR3 and PDGFRβ in increased chromosomal regions suggests a possible role for autocrine stimulation in ACC tumorigenesis.
Higher mast cell load decreases the risk of Hymenoptera venom–induced anaphylaxis in patients with mastocytosis
Authors: Bjorn van Anrooij, Eveline van der Veer, Jan G.R. de Monchy, Sicco van der Heide, Johanna C. Kluin-Nelemans, Pieter C. van Voorst Vader, Jasper J. van Doormaal, Joanne N.G. Oude Elberink
Journal: Journal of Allergy and Clinical Immunology (2013)