tbuckley/cabot-search huggingface dataset:
Influence of body composition on exercise capacity in women after bariatric surgery
Authors: Marcela Barbalho-Moulim, Fabiana Peixoto-Souza, Flavia Sales Leite, Eli Maria Pazzianotto Forti, Luciana Sampaio Jorge, Dirceu Costa
Journal: European Respiratory Journal (2013)

Introduction: Bariatric surgery is an effective alternative for weight loss, and that seems to solve or mitigate significantly the physical limitations caused by obesity.  Objective: To evaluate the influence of body composition on exercise capacity in women after bariatric surgery.  Methods: It was evaluated 25 women (age= 43.05 ± 9.62 years) underwent bariatric surgery with minimum 6 months and maximum of 2 years postoperatively to compose the group I (GI). It was also evaluated 10 women (age= 39.10 ± 9.80 years) nonobese (BMI 18 to 24.9 kg/m2) and sedentary to compose the control group (GII). Body composition was assessed by bioelectrical impedance and exercise capacity by the six-minute walk test (6MWT). Statistical analysis was performed using parametric and nonparametric tests, depending on the distribution of variables, considering a significance level of 5%.  Results: After bariatric surgery, 17 patients of GI were still obese. So, for better analysis of the results, the GI (n= 25) was divided into 2 others groups: obese (GIA =17) and nonobese (GIB= 8). The GIA had higher body fat percentage (40.79% ± 4.79; 30.93% ± 6.72; 30.10 ± 4.30%), lower muscle mass (56.21 ± 4.55%; 66.04% ± 5.94; 65.89 ± 4.80%) and lower 6MWT distance (6MWD) (434.00 ± 69.02 m; 513.37 ± 72.96 m; 565.50 ± 112.10 m) when compared to GIB and GII, respectively. The results of body composition and 6MWD were similar between GIB and GII.  Conclusion: The results indicate that women undergoing bariatric surgery, but still remain obese have a higher percentage of body fat, less muscle mass and shorter distance in the 6MWT, compared to non-obese patients, whether operated or not.
Prednisone in Rheumatoid Arthritis: Metabolic and Clinical Effects
Authors: L. E. Ward, H. F. Polley, M. H. Power, H. L. Mason, C. H. Slocumb, P. S. Hench
Journal: Annals of the Rheumatic Diseases (1958)

C-0 Cortisone acetate Hydrocortisone CH2OH COO 1_-
C5a Receptor Targeting in Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice
Authors: Erdenechimeg Shagdarsuren, Kiril Bidzhekov, Sebastian F. Mause, Sakine Simsekyilmaz, Thomas Polakowski, Heiko Hawlisch, J. Engelbert Gessner, Alma Zernecke, Christian Weber
Journal: Circulation (2010)

Receptor binding of complement C5a leads to proinflammatory activation of many cell types, but the role of receptor-mediated action during arterial remodeling after injury has not been studied. In the present study, we examined the contribution of the C5a receptor (C5aR) to neointima formation in apolipoprotein E-deficient mice employing a C5aR antagonist (C5aRA) and a C5aR-blocking monoclonal antibody.Mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C5aRA and anti-C5aR-blocking monoclonal antibody or vehicle control. Compared with controls, neointima formation was significantly reduced in mice receiving C5aRA or anti-C5aR-blocking monoclonal antibody for 1 week but not for 3 weeks, attributable to an increased content of vascular smooth muscle cells, whereas a marked decrease in monocyte and neutrophil content was associated with reduced vascular cell adhesion molecule-1. As assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry, C5aR was expressed in lesional and cultured vascular smooth muscle cells, upregulated by injury or tumor necrosis factor-alpha, and reduced by C5aRA. Plasma levels and neointimal plasminogen activator inhibitor-1 peaked 1 week after injury and were downregulated in C5aRA-treated mice. In vitro, C5a induced plasminogen activator inhibitor-1 expression in endothelial cells and vascular smooth muscle cells in a C5aRA-dependent manner, possibly accounting for higher vascular smooth muscle cell immigration.One-week treatment with C5aRA or anti-C5aR-blocking monoclonal antibody limited neointimal hyperplasia and inflammatory cell content and was associated with reduced vascular cell adhesion molecule-1 expression. However, treatment for 3 weeks failed to reduce but rather stabilized plaques, likely by reducing vascular plasminogen activator inhibitor-1 and increasing vascular smooth muscle cell migration.
Combining Antiangiogenics to Overcome Resistance: Rationale and Clinical Experience
Authors: Victor Moreno Garcia, Bristi Basu, L. Rhoda Molife, Stan B. Kaye
Journal: Clinical Cancer Research (2012)

Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disappointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early-phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies.
Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis
Authors: Leticia Muñoz, María José Borrero, María Ubeda, Margaret Lario, David Díaz, Rubén Francés, Jorge Monserrat, Óscar Pastor, Elia Aguado-Fraile, José Such, Melchor Álvarez-Mon, Agustín Albillos
Journal: Hepatology (2012)

Cirrhosis with ascites is associated with a high rate of gut bacterial translocation (GBT) and spontaneous bacterial infections of enteric origin. We addressed the activation state and role of intestinal dendritic cells (DCs) in experimental ascitic cirrhosis and their relationship with GBT. Cirrhosis with ascites was CCl(4) induced in rats. To examine their activation state and functions, DCs (CD103(+) RT1B(+) CD3(-) CD45RA(-) ) were isolated from the intestinal lamina propria and mesenteric lymph nodes (MLNs), and the following parameters were determined by flow cytometry: surface antigen expression; spontaneous or lipopolysaccharide-stimulated tumor necrosis factor alpha (TNF-α) production; and in vitro capacity to phagocytose latex beads and to migrate toward the chemokine (C-C motif) ligand 21. GBT was defined as the growth of bacteria in MLNs culture. Bacterial DNA (Bact-DNA) in MLNs was identified by polymerase chain reaction. In rats with Bact-DNA in MLNs without GBT, intestinal and MLNs CD103(+) -DCs showed features of activation, expansion of the proinflammatory CD4(+) -DC subpopulation, augmented TNF-α production, and increased phagocytic and migratory capacities. In contrast, in rats with GBT, CD103(+) -DCs showed the absence of an activated phenotype, lowered TNF-α production, and relatively deficient phagocytosis and migration capacities. The CD103(+) -DC of rats without Bact-DNA in MLNs or GBT were similar to controls. In cirrhotic rats, bowel decontamination with antibiotics eliminated Bact-DNA in MLNs and GBT, normalized the activation state and functions of CD103(+) -DCs, and increased their TNF-α production.In experimental cirrhosis with ascites, continuous pressure of gut bacteria shapes the phenotypic and functional profile of intestinal DCs to produce effects that range from their activation and enhanced functions to their exhaustion and tolerance.
A multicentre phase II trial of primary chemotherapy with cisplatin and protracted venous infusion 5-fluorouracil followed by chemoradiation in patients with carcinoma of the oesophagus
Authors: J.S. Waters, D. Tait, D. Cunningham, A.R. Padhani, M.E. Hill, S. Falk, F. Lofts, A. Norman, J. Oates, A. Hill
Journal: Annals of Oncology (2002)

BackgroundWe undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus.Patients and methodsChemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle.ResultsThe planned treatment programme was completed by 39 of 72 patients (54%), and afurther 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths.ConclusionsThis is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.
Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies
Authors: Guido Bocci, Shan Man, Shane K. Green, Giulio Francia, John M. L. Ebos, Jeanne M. du Manoir, Adina Weinerman, Urban Emmenegger, Li Ma, Philip Thorpe, Andrew Davidoff, James Huber, Daniel J. Hicklin, Robert S. Kerbel
Journal: Cancer Research (2004)

Abstract A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non–tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.
Recent Advances in the Molecular Biology of Dopamine Receptors
Authors: J A Gingrich, M G Caron
Journal: Annual Review of Neuroscience (1993)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Immunopathology of guinea pig autoimmune enterocolitis induced by alloimmunisation with an intestinal protein.
Authors: M S Nemirovsky, J S Hugon
Journal: Gut (1986)

An enterocolitis has been induced in guinea pigs by alloimmunisation with a mucosal protein. A single dose of immunogen fails to provoke a synthesis of precipitant antibodies, but a high percentage of animals, injected with two or more doses, develop these antibodies. A specific cell mediated immune response was already detectable 30 days after a single dose of immunogen. At later periods and after multiple doses of immunogen positive results were still found, although in a lesser percentage of the animals. The pathology was characterised by the appearance of multiple mucosal ulcerations, congestion, oedema and localised haemorrhage. The target organs were mainly ileum and descending colon. At later periods a combination of mononuclear cell infiltration, fibrocytic proliferation and granuloma formation appeared together with the other lesions. When an intraluminal challenge was made 48 hours before death, a heavy mononuclear cell infiltration was present in the contact area. The lesions appeared to extend to areas which usually remained unaffected. The characteristic immunopathology of this autoimmune enterocolitis in guinea pigs possesses some of the features of human inflammatory bowel diseases and makes it a useful model for further studies.
Inspiratory muscle performance relative to the anaerobic threshold in patients with COPD
Authors: T Wanke, D Formanek, H Lahrmann, M Merkle, H Rauscher, H Zwick
Journal: European Respiratory Journal (1993)

Rehabilitation programmes in chronic obstructive pulmonary disease (COPD) require exercise training above the anaerobic threshold. However, not all COPD patients develop metabolic acidosis during exercise. The hypothesis of this study was that non-exercise variables, characterizing the mechanical load on the inspiratory muscles during breathing at rest, can be used to reliably predict which patients with COPD are not able to develop metabolic acidosis during exercise. Thirty participants with COPD performed a symptom-limited cycle ergometer test. The oesophageal pressure/time index (PTIoes: the product of pressure magnitude and duration), the mean rate of pressure development during inspiration (Poes/TI), and the mean airway resistance (Raw)/maximal oesophageal pressure (Poesmax) ratio served as indices for the mechanical load on the inspiratory muscles. The oxygen uptake (VO2) at which plasma standard bicarbonate was seen to decrease from its baseline value was taken as the anaerboic threshold (AT). Mean Raw was significantly higher in those patients in whom the AT could not be detected. No other lung function parameters measured at rest allowed the accurate selection of those patients who did or did not develop exercise metabolic acidosis. On the other hand, Raw/Poesmax, PTIoes and Poes/TI were significantly different in the two patient groups. Additionally, whereas in the patient group with identifiable AT exercise hyperpnoea produced a non-linear increase of Poes/TI with respect to PTIoes above the AT, in the patient group without identifiable AT there was a linear relationship between Poes/TI and PTIoes throughout exercise. We conclude that the determination of inspiratory muscle load indices at rest may be useful in pulmonary rehabilitation programmes, for identifying those patients with COPD who do not develop exercise induced metabolic acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Multidrug Resistance Protein 1 Protects the Oropharyngeal Mucosal Layer and the Testicular Tubules against Drug-induced Damage
Authors: Jan Wijnholds, George L. Scheffer, Martin van der  Valk, Paul van der  Valk, Jos H. Beijnen, Rik J. Scheper, Piet Borst
Journal: The Journal of Experimental Medicine (1998)

The multidrug resistance protein 1 (MRP1) gene encodes a transporter protein that helps to protect cells against xenobiotics. Elevated levels of MRP1 in tumor cells can result in active extrusion of a wide range of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR). To explore the protective function of the mouse mrp1 protein during drug treatment, we investigated the toxicity caused by the anticancer drug etoposide-phosphate (ETOPOPHOS) in mice lacking the mrp1 gene (mrp1−/− mice). We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis. The high concentrations of mrp1 that we find in the basal layers of the oropharyngeal mucosa and in the basal membrane of the Sertoli cells in the testis apparently protect wild-type mice against this tissue damage. We also find drug-induced polyuria in mrp1−/− mice, which correlates with the presence of mrp1 protein in the urinary collecting tubules, the major site of kidney water reabsorption. Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.
Pharmacodynamic Imaging Guides Dosing of a Selective Estrogen Receptor Degrader
Authors: Pedram Heidari, Francis Deng, Shadi A. Esfahani, Alicia K. Leece, Timothy M. Shoup, Neil Vasdev, Umar Mahmood
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer. Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the use of 16α-18F-fluoroestradiol (18F-FES) PET for fulvestrant dose optimization in a preclinical ER+ breast cancer model. Experimental Design: In vitro, 18F-FES retention was compared with ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER+) after treatment with different fulvestrant doses. MCF7 xenografts were grown in ovariectomized nude mice and assigned to vehicle, low- (0.05 mg), medium- (0.5 mg), or high-dose (5 mg) fulvestrant treatment groups (5–7 per group). Two and 3 days after fulvestrant treatment, PET/CT was performed using 18F-FES and 18F-FDG, respectively. ER expression was assessed by immunohistochemistry, ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki67 immunohistochemistry. Results: In vitro, we observed a parallel graded reduction in 18F-FES uptake and ER expression with increased fulvestrant doses, despite enhancement of ER mRNA transcription. In xenografts, ER expression significantly decreased with increased fulvestrant dose, despite similar mRNA expression and Ki67 staining among the treatment groups. We observed a significant dose-dependent reduction of 18F-FES PET mean standardized uptake value (SUVmean) with fulvestrant treatment but no significant difference among the treatment groups in 18F-FDG PET SUVmean. Conclusions: We demonstrated that 18F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant resulting in ER degradation and/or blockade; these precede changes in tumor metabolism and proliferation. Quantitative 18F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in patients with breast cancer. Clin Cancer Res; 21(6); 1340–7. ©2015 AACR.
A Glanzmann’s mutation in β3 integrin specifically impairs osteoclast function
Authors: Xu Feng, Deborah V. Novack, Roberta Faccio, Daniel S. Ory, Kunihiko Aya, Martin I. Boyer, Kevin P. McHugh, F. Patrick Ross, Steven L. Teitelbaum
Journal: Journal of Clinical Investigation (2001)

Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the αvβ3 integrin. The structural components of the integrin that mediate osteoclast function are, however, not in hand. To address this issue, we generated mice lacking the β3 integrin gene, which have dysfunctional osteoclasts. Here, we show the full rescue of β3–/– osteoclast function following expression of a full-length β3 integrin. In contrast, truncated β3, lacking a cytoplasmic domain (hβ3Δc), is completely ineffective in restoring function to β3–/– osteoclasts. To identify the components of the β3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate β integrin signaling. Of the six, only the S752P substitution, which also characterizes a form of the human bleeding disorder Glanzmann's thrombasthenia, fails to rescue β3–/– osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation Y747F/Y759F, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the β3 integrin regulates platelets and osteoclasts.
Enhanced neutrophil migration in vivo HLA B27 positive subjects.
Authors: P Koivuranta-Vaara, H Repo, M Leirisalo, U Kiistala, T Osterman, H Vapaatalo
Journal: Annals of the Rheumatic Diseases (1984)

Chemotaxis of polymorphonuclear leucocytes in vivo was studied in patients with previous yersinia arthritis and in healthy subjects with or without HLA B27 by means of a skin chamber technique. Irrespective of previous arthritis the number of neutrophils in the chamber media was significantly higher in HLA B27 positive subjects than in those without HLA B27. The amounts of prostaglandins E2, F2 alpha, and 6-keto-F1 alpha in the chamber media correlated positively with the corresponding cell counts. The present results give credence to the view that the hyperreactive neutrophils and the vasodilatory prostaglandins produced by them can together trigger a vicious circle which results in increased inflammatory symptoms in patients with yersinia arthritis who have HLA B27 as compared with those who lack this antigen.
Redox Signaling of the Arteriolar Myogenic Response
Authors: P. T. Nowicki, S. Flavahan, H. Hassanain, S. Mitra, S. Holland, P. J. Goldschmidt-Clermont, N. A. Flavahan
Journal: Circulation Research (2001)

Arteriolar vascular smooth muscle cells (VSMCs) are mechanosensitive, constricting to elevations in transmural pressure (P TM ). The goal of the present study was to determine using mouse isolated tail arterioles and arteries whether oxidant signaling regulates this myogenic response. In response to P TM elevation, VSMCs of arterioles but not arteries generated constriction and increased reactive oxygen species (ROS) activity (using the H 2 O 2 -sensitive probe dichlorodihydrofluorescein). Arterioles had increased expression of NADPH oxidase components compared with arteries. Inhibition of NADPH oxidase, using mice with targeted impairment of enzyme components (p47 phox or rac1) or diphenyleneiodonium, prevented the pressure-induced generation of ROS. When ROS activity was inhibited, either by inhibiting NADPH oxidase or with N -acetylcysteine, the myogenic constriction was abolished. The myogenic constriction was also inhibited by catalase, which inactivates H 2 O 2 , but was unaffected by a cell-permeant mimic of superoxide dismutase (MnTMPyP). α 1 -Adrenergic constriction was not associated with altered ROS activity and was not affected by inhibition of NADPH oxidase or ROS. Exogenous H 2 O 2 constricted VSMCs of arterioles but not arteries. Thus, NADPH oxidase and ROS, in particular H 2 O 2 , contribute to the myogenic response of arteriolar VSMCs.