tbuckley/cabot-search huggingface dataset:
The Effect of Trandolapril and Its Fixed-Dose Combination With Verapamil on Proteinuria in Normotensive Adults With Type 2 Diabetes
Authors: Alberto Francisco Rubio-Guerra, Adalberto Arceo-Navarro, German Vargas-Ayala, Leticia Rodriguez-Lopez, Jose Juan Lozano-Nuevo, Carlos Treviño Gomez-Harper
Journal: Diabetes Care (2004)

OBJECTIVE—To compare the effect of fixed-dose trandolapril-verapamil (FDTV) with that of trandolapril on proteinuria in normotensive, type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A total of 60 normotensive, type 2 diabetic patients with 24-h proteinuria &amp;gt;300 mg were randomly assigned to two groups for open-label treatment. One group received 2 mg trandolapril/180 mg verapamil FDTV once daily; the other group received 2 mg trandolapril once daily. Study drugs were administered for 6 months in both groups. Creatinine clearance and 24-h urinary protein excretion were measured at the beginning and the end of the study. Patients were evaluated monthly for blood pressure, fasting blood glucose level, heart rate, and adverse events. Statistical analysis was performed using ANOVA. RESULTS—Both groups experienced a statistically significant (P &amp;lt; 0.005) mean decrease in mean proteinuria from baseline: FDTV ([mean ± SD] 1,200 ± 200 to 540 ± 79 mg; P &amp;lt; 0.001) and trandolapril (1,105 ± 212 to 750.9 ± 134 mg; P &amp;lt; 0.005). A significantly greater reduction from baseline in proteinuria was observed in the FDTV group compared with the trandolapril group. Patients who received trandolapril experienced a statistically significant (P &amp;lt; 0.05) decrease in mean creatinine clearance (91.1 ± 3.4 to 75.3 ± 3 ml/min; P &amp;lt; 0.05) compared with patients who received FDTV (88.3 ± 3.6 to 82.9 ± 3.5 ml/min; P &amp;gt; 0.05). Final fasting blood glucose was significantly lower in the FDTV group (139 ± 19) compared with the trandolapril group (154 ± 22; P &amp;lt; 0.001). No significant differences were observed between the two groups in mean baseline or final measurements of blood pressure, mean heart rate, or frequency of adverse events. CONCLUSIONS—Our results suggest that FDTV is more effective than trandolapril in reducing proteinuria in normotensive, type 2 diabetic patients. This effect on proteinuria is not related with blood pressure reduction.
Regular review: Tumour markers in malignancies
Authors: A. Lindblom
Journal: BMJ (2000)

In western Europe today, a third of all people develop a malignant disease at least once in their lifetime. Treatment has improved, and for many diseases, such as leukaemia and testicular cancer, the prognosis is much better today than it was 20 years ago. Screening for early diagnosis has also led to lower mortality for diseases such as breast cancer and cervical cancer; many malignancies, however, are still diagnosed after the metastatic process has already started, indicating a poor prognosis.

Tumour markers are usually proteins associated with a malignancy and might be clinically usable in patients with cancer. A tumour marker can be detected in a solid tumour, in circulating tumour cells in peripheral blood, in lymph nodes, in bone marrow, or in other body fluids (ascites, urine, and stool). A tumour marker may be used to define a particular disease entity, in which case it may be used for diagnosis, staging, or population screening. Markers may also be used to detect the presence of occult metastatic disease, to monitor response to treatment, or to detect recurrent disease (table). Recently they have even been used as targets for therapeutic intervention in clinical trials.

#### Summary points

Tumour markers are commonly proteins associated with malignancy, offering a putative clinical use in cancer

A tumour marker can be detected in a solid tumour, in circulating tumour cells in peripheral blood, in lymph nodes, in bone marrow, or in other body fluids (urine or stool)

A tumour marker can be used for population screening and for detection, diagnosis, staging, prognosis, or follow up of malignant diseases

A specific tumour marker is a fusion protein associated with a malignant process in which an oncogene is translocated and fused to an active promoter of another gene

Unspecific markers include the oncofetal proteins (such as the carcinoembryonic antigen or …
The lower medical corridor.
Authors: J S Stewart
Journal: Gut (1989)

<h3>Abstract</h3> A large number of GPCRs are potentially valuable drug targets but remain understudied. Many of these lack well-validated activating ligands and are considered “orphan” receptors, and G protein coupling profiles have not been defined for many orphan GPCRs. Here we asked if constitutive receptor activity can be used to determine G protein coupling profiles of orphan GPCRs. We monitored nucleotide-sensitive interactions between 48 understudied orphan GPCRs and five G proteins (240 combinations) using bioluminescence resonance energy transfer (BRET). No receptor ligands were used, but GDP was used as a common G protein ligand to disrupt receptor-G protein complexes. Constitutive BRET between the same receptors and β-arrestins was also measured. We found sufficient GDP-sensitive BRET to generate G protein coupling profiles for 22 of the 48 receptors we studied. Altogether we identified 48 coupled receptor-G protein pairs, many of which have not been described previously. We conclude that receptor-G protein complexes that form spontaneously in the absence of guanine nucleotides can be used to profile G protein coupling of constitutively active GPCRs. This approach may prove useful for studying G protein coupling of other GPCRs for which activating ligands are not available.
Evidence for a Role of Mast Cells in the Evolution to Congestive Heart Failure
Authors: Masatake Hara, Koh Ono, Myung-Woo Hwang, Atsushi Iwasaki, Masaharu Okada, Kazuki Nakatani, Shigetake Sasayama, Akira Matsumori
Journal: The Journal of Experimental Medicine (2002)

Mast cells are believed to be involved in the pathophysiology of heart failure, but their precise role in the process is unknown. This study examined the role of mast cells in the progression of heart failure, using mast cell-deficient (WBB6F1-W/Wv) mice and their congenic controls (wild-type [WT] mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored over 15 wk. At 4 wk after aortic constriction, cardiac hypertrophy with preserved left ventricular performance (compensated hypertrophy) was observed in both W/Wv and WT mice. Thereafter, left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 wk (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/Wv mice; left ventricular performance was preserved throughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/Wv mice. Treatment with tranilast, a mast cell–stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.
Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter
Authors: Adèle Hannigan, Paul Smith, Gabriela Kalna, Cristiana Lo Nigro, Clare Orange, Darren I. O’Brien, Reshma Shah, Nelofer Syed, Lindsay C. Spender, Blanca Herrera, Johanna K. Thurlow, Laura Lattanzio, Martino Monteverde, Meghan E. Maurer, Francesca M. Buffa, Jelena Mann, David C.K. Chu, Catharine M.L. West, Max Patridge, Karin A. Oien, Jonathan A. Cooper, Margaret C. Frame, Adrian L. Harris, Louise Hiller, Linda J. Nicholson, Milena Gasco, Tim Crook, Gareth J. Inman
Journal: Journal of Clinical Investigation (2010)

The cytokine TGF-β acts as a tumor suppressor in normal epithelial cells and during the early stages of tumorigenesis. During malignant progression, cancer cells can switch their response to TGF-β and use this cytokine as a potent oncogenic factor; however, the mechanistic basis for this is poorly understood. Here we demonstrate that downregulation of disabled homolog 2 (DAB2) gene expression via promoter methylation frequently occurs in human squamous cell carcinomas (SCCs) and acts as an independent predictor of metastasis and poor prognosis. Retrospective microarray analysis in an independent data set indicated that low levels of DAB2 and high levels of TGFB2 expression correlate with poor prognosis. Immunohistochemistry, reexpression, genetic knockout, and RNAi silencing studies demonstrated that downregulation of DAB2 expression modulated the TGF-β/Smad pathway. Simultaneously, DAB2 downregulation abrogated TGF-β tumor suppressor function, while enabling TGF-β tumor-promoting activities. Downregulation of DAB2 blocked TGF-β–mediated inhibition of cell proliferation and migration and enabled TGF-β to promote cell motility, anchorage-independent growth, and tumor growth in vivo. Our data indicate that DAB2 acts as a tumor suppressor by dictating tumor cell TGF-β responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti–TGF-β therapies.
Patterns of Care in Early-Stage Breast Cancer Survivors in the First Year After Cessation of Active Treatment
Authors: Jeanne S. Mandelblatt, William F. Lawrence, Jennifer Cullen, Annette L. Stanton, Janice L. Krupnick, Lorna Kwan, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2005)

Purpose Patterns of health care use have not been well described for breast cancer survivors. The purpose of this study was to describe the health service use in a survivor cohort. Patients and Methods Women with stage I or II breast cancer were recruited (n = 558) after primary treatment for a multicenter, randomized trial of psychoeducational interventions for facilitating transition to survivorship; 418 women completed the study. Participants completed calendar diaries detailing health care use for 1 year after treatment. Services were coded using Current Procedural Terminology–Fourth Edition codes; costs were estimated using year 2000 Medicare reimbursements. Results Health care use diary data were available for 391 women (70% of the sample). On average, these survivors reported 30 episodes of health service use in the year after treatment. Total annual costs of care averaged more than $1,800 per survivor; medical office visits were the major component of costs. Type of cancer treatment, depression, and physical function and comorbid illness were independent predictors of the costs of services. There were geographic variations in initial local treatment patterns and in post-treatment costs. Notably, all women should have received surveillance mammography in the time period, but only 61.9% did so; the odds of mammogram receipt were higher for women who had a lumpectomy (v mastectomy) and women who were white (v nonwhite). Conclusion Use of health services is frequent and intensive in the first year after treatment for breast cancer. Despite frequent contact with the health care system, there is room for improvement in providing guideline-suggested surveillance mammography for survivors.
Joint effect of obesity and TNFA variability on asthma: two international cohort studies
Authors: F. Castro-Giner, M. Kogevinas, M. Imboden, R. de Cid, D. Jarvis, M. Mächler, W. Berger, P. Burney, K. A. Franklin, J. R. Gonzalez, J. Heinrich, C. Janson, E. Omenaas, I. Pin, T. Rochat, J. Sunyer, M. Wjst, J-M. Antó, X. Estivill, N. M. Probst-Hensch
Journal: European Respiratory Journal (2009)

Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-α ( TNFA ) gene. The current authors examined the joint effect of obesity and TNFA variability on asthma in adults by combining two population-based studies. The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped for TNFA -308 and lymphotoxin-α ( LTA ) +252 gene variants. Obesity and TNFA were associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (CI) 1.7–3.2; OR for TNFA -308 polymorphism 1.3, 95% CI 1.1–1.6). The association of obesity with asthma was stronger for subjects carrying the G/A and A/A TNFA -308 genotypes compared with the more common G/G genotype, particularly among nonatopics (OR for G/A and A/A genotypes 6.1, 95% CI 2.5–14.4; OR for G/G genotype 1.7, 95% CI 0.8–3.3). The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.
CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow
Authors: Thomas C. Beck, Ana Cordeiro Gomes, Jason G. Cyster, João P. Pereira
Journal: The Journal of Experimental Medicine (2014)

Leukocyte residence in lymphoid organs is controlled by a balance between retention and egress-promoting chemoattractants sensed by pertussis toxin (PTX)–sensitive Gαi protein–coupled receptors (GPCRs). Here, we use two-photon intravital microscopy to show that immature B cell retention within bone marrow (BM) was strictly dependent on amoeboid motility mediated by CXCR4 and CXCL12 and by α4β1 integrin–mediated adhesion to VCAM-1. However, B lineage cell egress from BM is independent of PTX-sensitive GPCR signaling. B lineage cells expressing PTX rapidly exited BM even though their motility within BM parenchyma was significantly reduced. Our experiments reveal that when immature B cells are near BM sinusoids their motility is reduced, their morphology is predominantly rounded, and cells reverse transmigrate across sinusoidal endothelium in a largely nonamoeboid manner. Immature B cell egress from BM was dependent on a twofold CXCR4 down-regulation that was antagonized by antigen-induced BCR signaling. This passive mode of cell egress from BM also contributes significantly to the export of other hematopoietic cells, including granulocytes, monocytes, and NK cells, and is reminiscent of erythrocyte egress.
Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ
Authors: Christel Rousseaux, Bruno Lefebvre, Laurent Dubuquoy, Philippe Lefebvre, Olivier Romano, Johan Auwerx, Daniel Metzger, Walter Wahli, Béatrice Desvergne, Gian Carlo Naccari, Philippe Chavatte, Amaury Farce, Philippe Bulois, Antoine Cortot, Jean Frédéric Colombel, Pierre Desreumaux
Journal: The Journal of Experimental Medicine (2005)

5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator–activated receptor-γ (PPAR-γ) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-γ+/− mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-γ expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element–driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.
Abstract S6-1: Menopausal Hormone Therapy Influence on Cancer Incidence and Related Cancer Mortality in the Women's Health Initiative Randomized Trials
Authors: RT Chlebowski
Journal: Cancer Research (2010)

Abstract The Women's Health Initiative (WHI) has conducted two phase III randomized placebo controlled trials evaluating menopausal hormone therapy. Conjugated equine estrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily (E+P) was evaluated in 16,608 postmenopausal women with no prior hysterectomy and conjugated equine estrogen alone 0.625 mg daily (E alone) was evaluated in 10,738 postmenopausal women with prior hysterectomy. Previous analyses suggested differences in E+P vs E alone influence on incidence and related mortality of several cancers. More recent analyses after additional follow-up clarify these issues and suggest a unifying hypothesis regarding hormone therapy influence on cancer. In cross study comparisons using multivariate Cox regression models statistically significant differences between the two WHI trials regarding E+P vs E alone influence on breast cancer incidence (P=0.01), colorectal cancer incidence (P=0.004) and deaths from non-small cell lung cancer (P=0.03) are seen. In addition, E+P, but not E alone, had a greater adverse influence on mortality attributed to breast cancer, colorectal cancer, and NSCLC then on the incidence of these cancers. Results are summarized below. Menopausal Hormone Therapy Influence on Incidence and Related Mortality of Selected Cancer Chlebowski JAMA 2003;289:3243, Chlebowski NEJM 2004;350:991, Stefanick JAMA 2006;242:1048, Ritenbaugh Cancer Epi Bio Prev 2008;17:2609, Prentice Cancer Epi Bio Prev 2009;18:1531, Chlebowski NEJM 2009;360:573, Chlebowski Gynecologic Oncology 2010;117:394; abst, Chlebowski Proc ASCO 2010;abst 1705 As estrogen plus progestin simulates angiogenesis, these findings suggest an hypothesis that, in addition to its influence on cancer incidence, combined E+P use, thru angiogenesis stimulation or other mechanisms, broadly enhances growth of already established cancers, differentially impacting cancer-related survival across several cancer categories. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-1.
Mold and Endotoxin Levels in the Aftermath of Hurricane Katrina: A Pilot Project of Homes in New Orleans Undergoing Renovation
Authors: Ginger L. Chew, Jonathan Wilson, Felicia A. Rabito, Faye Grimsley, Shahed Iqbal, Tiina Reponen, Michael L. Muilenberg, Peter S. Thorne, Dorr G. Dearborn, Rebecca L. Morley
Journal: Environmental Health Perspectives (2006)

BackgroundAfter Hurricane Katrina, many New Orleans homes remained flooded for weeks, promoting heavy microbial growth.ObjectivesA small demonstration project was conducted November 2005–January 2006 aiming to recommend safe remediation techniques and safe levels of worker protection, and to characterize airborne mold and endotoxin throughout cleanup.MethodsThree houses with floodwater lines between 0.3 and 2 m underwent intervention, including disposal of damaged furnishings and drywall, cleaning surfaces, drying remaining structure, and treatment with a biostatic agent. We measured indoor and outdoor bioaerosols before, during, and after intervention. Samples were analyzed for fungi [culture, spore analysis, polymerase chain reaction (PCR)] and endotoxin. In one house, real-time particle counts were also assessed, and respirator-efficiency testing was performed to establish workplace protection factors (WPF).ResultsAt baseline, culturable mold ranged from 22,000 to 515,000 colony-forming units/m3, spore counts ranged from 82,000 to 630,000 spores/m3, and endotoxin ranged from 17 to 139 endotoxin units/m3. Culture, spore analysis, and PCR indicated that Penicillium, Aspergillus, and Paecilomyces predominated. After intervention, levels of mold and endotoxin were generally lower (sometimes, orders of magnitude). The average WPF against fungal spores for elastomeric respirators was higher than for the N-95 respirators.ConclusionsDuring baseline and intervention, mold and endotoxin levels were similar to those found in agricultural environments. We strongly recommend that those entering, cleaning, and repairing flood-damaged homes wear respirators at least as protective as elastomeric respirators. Recommendations based on this demonstration will benefit those involved in the current cleanup activities and will inform efforts to respond to future disasters.
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial
Authors: Michael Gnant, Brigitte Mlineritsch, Herbert Stoeger, Gero Luschin-Ebengreuth, Dietmar Heck, Christian Menzel, Raimund Jakesz, Michael Seifert, Michael Hubalek, Gunda Pristauz, Thomas Bauernhofer, Holger Eidtmann, Wolfgang Eiermann, Guenther Steger, Werner Kwasny, Peter Dubsky, Gerhard Hochreiner, Ernst-Pius Forsthuber, Christian Fesl, Richard Greil
Journal: The Lancet Oncology (2011)
Elastin and collagen degradation products in urine of smokers with and without chronic obstructive pulmonary disease.
Authors: P J Stone, D J Gottlieb, G T O'Connor, D E Ciccolella, R Breuer, J Bryan-Rhadfi, H A Shaw, C Franzblau, G L Snider
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

It has been hypothesized that emphysema results from damage to the elastic fiber network of the lungs as a result of elastase-antielastase imbalance. We used a new assay for urinary desmosine (DES) and isodesmosine (IDES), specific markers for the degradation of mature crosslinked elastin, and hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), specific markers for the degradation of mature crosslinked collagen, in order to examine elastin and collagen degradation in relation to current cigarette smoking and the presence of chronic obstructive pulmonary disease (COPD). The study sample consisted of 22 never-smokers (NSM group), 13 current smokers without airflow obstruction (SM group), and 21 patients with COPD (COPD group), including both current and former smokers. The relation between the creatinine-height index and FEV1 was used to correct for possible loss of muscle mass and decreased excretion of creatinine in the COPD group. Mean urinary excretion of elastin-derived crosslinks in the COPD group (DES, 11.8 +/- 5.1 [mean +/- SD]; IDES, 11.3 +/- 5.0 micrograms/g creatinine) and in the SM group (DES, 11.0 +/- 4.2; IDES, 10.2 +/- 2.5 micrograms/g creatinine) was significantly higher than in the NSM group (DES, 7.5 +/- 1.4; IDES, 6.9 +/- 1.3 micrograms/g creatinine). In multivariate analysis, current smoking and the presence of COPD were significantly and independently associated with higher urinary excretion of elastin degradation products, and there was no significant interaction between current smoking and the presence of COPD.(ABSTRACT TRUNCATED AT 250 WORDS)