tbuckley/cabot-search huggingface dataset:
Identifying the Safety Profile of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Anticipation of a Phase I Clinical Trial in Patients with Recurrent Ovarian Cancer
Authors: Kellie Matthews, Patricia E. Noker, Baohong Tian, Sheila D. Grimes, Ronna Fulton, Karen Schweikart, Raymond Harris, Rose Aurigemma, Minghui Wang, Mack N. Barnes, Gene P. Siegal, Akseli Hemminki, Kurt Zinn, David T. Curiel, Ronald D. Alvarez
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. Experimental Design: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. Results: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD ± GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time. Conclusions: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries
Authors: Torbjoern Broegger, Jens Christian Brings Jacobsen, Vibeke Secher Dam, Donna M. Briggs Boedtkjer, Henrik Kold-Petersen, Finn Skou Pedersen, Christian Aalkjaer, Vladimir V. Matchkov
Journal: Cardiovascular Research (2011)

We have previously characterized a cGMP-dependent Ca2+-activated Cl– current in vascular smooth muscle cells (SMCs) and have shown its dependence on bestrophin-3 expression. We hypothesize that this current is important for synchronization of SMCs in the vascular wall. In the present study, we aimed to test this hypothesis by transfecting rat mesenteric small arteries in vivo with siRNA specifically targeting bestrophin-3. The arteries were tested 3 days after transfection in vitro for isometric force development and for intracellular Ca2+ in SMCs. Bestrophin-3 expression was significantly reduced compared with arteries transfected with mutated siRNA. mRNA levels for bestrophin-1 and -2 were also significantly reduced by bestrophin-3 down-regulation. This is suggested to be secondary to specific bestrophin-3 down-regulation since siRNAs targeting different exons of the bestrophin-3 gene had identical effects on bestrophin-1 and -2 expression. The transfection affected neither the maximal contractile response nor the sensitivity to norepinephrine and arginine-vasopressin. The amplitude of agonist-induced vasomotion was significantly reduced in arteries down-regulated for bestrophins compared with controls, and asynchronous Ca2+ waves appeared in the SMCs. The average frequency of vasomotion was not different. 8Br-cGMP restored vasomotion in arteries where the endothelium was removed, but oscillation amplitude was still significantly less in bestrophin-down-regulated arteries. Thus, vasomotion properties were consistent with those previously characterized for rat mesenteric small arteries. Data from our mathematical model are consistent with the experimental results. This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.
Eating disorders in adolescent females with and without type 1 diabetes: cross sectional study
Authors: J. M Jones
Journal: BMJ (2000)

To determine the prevalence of eating disorders in adolescent females with type 1 diabetes mellitus compared with that in their non-diabetic peers.Cross sectional case-control led study.Diabetes clinics and schools in three Canadian cities.356 females aged 12-19 with type 1 diabetes and 1098 age matched non-diabetic controls.Eating disorders meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria.Eating disorders that met DSM-IV criteria were more prevalent in diabetic subjects (36, 10%) than in non-diabetic controls (49, 4%) (odds ratio 2.4, 95% confidence interval 1.5 to 3.7; P<0.001). Subthreshold eating disorders were also more common in those with diabetes (49, 14%) than in controls (84, 8%) (odds ratio 1.9, 95% confidence interval 1.3 to 2.8; P<0.001). Mean haemoglobin A(1c) concentration was higher in diabetic subjects with an eating disorder (9.4% (1.8)) than in those without (8.6% (1.6)), P=0.04).DSM-IV and subthreshold eating disorders are almost twice as common in adolescent females with type 1 diabetes as in their non-diabetic peers. In diabetic subjects, eating disorders are associated with insulin omission for weight loss and impaired metabolic control.
1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients
Authors: M. Griese, P. Latzin, M. Kappler, K. Weckerle, T. Heinzlmaier, T. Bernhardt, D. Hartl
Journal: European Respiratory Journal (2006)

The airways of cystic fibrosis (CF) patients are characterised by neutrophils that release high amounts of elastase overwhelming the local antiprotease shield. Inhalation of α 1 -antitrypsin (AAT) may restore the protease–antiprotease balance and attenuate airway inflammation in CF airways. The aims of the present study were: 1) to assess the best deposition region for inhaled AAT by two different inhalation strategies; and 2) to examine the effect of 4 weeks of AAT inhalation on lung function, protease–antiprotease balance and airway inflammation in CF patients. In a prospective, randomised study, 52 CF patients received a daily deposition by inhalation of 25 mg AAT for 4 weeks targeting their peripheral or bronchial compartment. The levels of elastase activity, AAT, pro-inflammatory cytokines, neutrophils, immunoglobulin G fragments and the numbers of Pseudomonas aeruginosa were assessed in induced sputum before and after the inhalation period. Inhalation of AAT increased AAT levels and decreased the levels of elastase activity, neutrophils, pro-inflammatory cytokines and the numbers of P. aeruginosa . However, it had no effect on lung function. No difference was found between the peripheral and bronchial inhalation mode. In conclusion, although no effect on lung function was observed, the clear reduction of airway inflammation after α 1 -antitrypsin treatment may precede pulmonary structural changes. The α 1 -antitrypsin deposition region may play a minor role for α 1 -antitrypsin inhalation in cystic fibrosis patients.
Gadd45 proteins: Relevance to aging, longevity and age-related pathologies
Authors: Alexey A. Moskalev, Zeljka Smit-McBride, Mikhail V. Shaposhnikov, Ekaterina N. Plyusnina, Alex Zhavoronkov, Arie Budovsky, Robi Tacutu, Vadim E. Fraifeld
Journal: Ageing Research Reviews (2011)
Positive Selection Versus Demography: Evolutionary Inferences Based on an Unusual Haplotype Structure in Drosophila simulans
Authors: Humberto Quesada, Sebastián E. Ramos-Onsins, Julio Rozas, Montserrat Aguadé
Journal: Molecular Biology and Evolution (2006)

Coalescent simulations were used to investigate the possible role of population subdivision and history in shaping nucleotide variation in a recombining 88-kb genomic fragment of Drosophila simulans displaying an unusual large-scale haplotype structure. The multilocus analysis, based on summary statistics using specific demographic null models under recombination, indicates that the observed levels of linkage disequilibrium differed significantly from the values expected under different bottleneck and population admixture scenarios. These results indicate that demography alone may not account for the observed pattern of variation and support the previous claim that the data are better described by a model in which an adaptive mutation has not yet gone to fixation.
Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer
Authors: Juan P. Cerliani, Tomás Guillardoy, Sebastián Giulianelli, José P. Vaque, J. Silvio Gutkind, Silvia I. Vanzulli, Rubén Martins, Eduardo Zeitlin, Caroline A. Lamb, Claudia Lanari
Journal: Cancer Research (2011)

Abstract Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment. Cancer Res; 71(10); 3720–31. ©2011 AACR.
A Genetic Expression Profile Associated with Oral Cancer Identifies a Group of Patients at High Risk of Poor Survival
Authors: Eduardo Méndez, John R. Houck, David R. Doody, Wenhong Fan, Pawadee Lohavanichbutr, Tessa C. Rue, Bevan Yueh, Neal D. Futran, Melissa P. Upton, D. Gregory Farwell, Patrick J. Heagerty, Lue Ping Zhao, Stephen M. Schwartz, Chu Chen
Journal: Clinical Cancer Research (2009)

To determine if gene expression signature of invasive oral squamous cell carcinoma (OSCC) can subclassify OSCC based on survival.We analyzed the expression of 131 genes in 119 OSCC, 35 normal, and 17 dysplastic mucosa to identify cluster-defined subgroups. Multivariate Cox regression was used to estimate the association between gene expression and survival. By stepwise Cox regression, the top predictive models of OSCC-specific survival were determined and compared by receiver operating characteristic analysis.The 3-year overall mean+/-SE survival for a cluster of 45 OSCC patients was 38.7+/-0.09% compared with 69.1+/-0.08% for the remaining patients. Multivariate analysis adjusted for age, sex, and stage showed that the 45 OSCC patient cluster had worse overall and OSCC-specific survival (hazard ratio, 3.31; 95% confidence interval, 1.66-6.58 and hazard ratio, 5.43; 95% confidence interval, 2.32-12.73, respectively). Stepwise Cox regression on the 131 probe sets revealed that a model with a term for LAMC2 (laminin gamma2) gene expression best identified patients with worst OSCC-specific survival. We fit a Cox model with a term for a principal component analysis-derived risk score marker and two other models that combined stage with either LAMC2 or PCA. The area under the curve for models combining stage with either LAMC2 or PCA was 0.80 or 0.82, respectively, compared with 0.70 for stage alone (P=0.013 and 0.008, respectively).Gene expression and stage combined predict survival of OSCC patients better than stage alone.
Tolerance to the Organic Nitrates
Authors: John D. Parker, Tommaso Gori
Journal: Circulation (2001)

itroglycerin (NTG) and other organic nitrates continue to be important drugs that are often used in cardiovascular medicine.All organic nitrates undergo denitrification, releasing nitric oxide (NO) through a biotransformation process that remains poorly understood to date.NO activates the enzyme soluble guanylyl cyclase in smooth muscle cells, causing increased levels of the second messenger cGMP.Finally, cGMP activates a cGMPdependent protein kinase.This enzyme mediates vasorelaxation through inhibitory phosphorylation of different proteins involved in the regulation of intracellular Ca 2ϩ levels. See p 2338All of the organic nitrates have potent short-term vascular, hemodynamic, and clinical effects.A critical limitation in their clinical application is the development of tolerance, whereby their initial effects are rapidly lost during sustained administration.Although there seems to be little doubt that NO, or some NO adjunct, mediates the pharmacodynamic effect of nitrates, the mechanism(s) underlying the development of tolerance remain an important and vexing problem for cardiovascular pharmacology.
Timing of right ventricular electrograms: New criterion for localizing the site of origin of left ventricular tachycardia
Authors: Vickas V. Patel, Edward P. Gerstenfeld, Robert W. Rho, Sanjay Dixit, Dusan Z. Kocovic, Henry H. Hsia, David J. Callans, Francis E. Marchlinski
Journal: Journal of the American College of Cardiology (2003)
Smad7 Expression in T cells Prevents Colitis-Associated Cancer
Authors: Angelamaria Rizzo, Maximilian J. Waldner, Carmine Stolfi, Massimiliano Sarra, Daniele Fina, Christoph Becker, Markus F. Neurath, Thomas T. Macdonald, Francesco Pallone, Giovanni Monteleone, Massimo C. Fantini
Journal: Cancer Research (2011)

Abstract Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer due to chronic inflammation. In IBD, chronic inflammation relies upon a TGFβ signaling blockade, but its precise mechanistic relationship to colitis-associated colorectal cancer (CAC) remains unclear. In this study, we investigated the role of the TGFβ signaling inhibitor Smad7 in CAC pathogenesis. In human colonic specimens, Smad7 was downregulated in CD4+ T cells located in the lamina propria of patients with complicated IBD compared with uncomplicated IBD. Therefore, we assessed CAC susceptibility in a transgenic mouse model where Smad7 was overexpressed specifically in T cells. In this model, Smad7 overexpression increased colitis severity, but the mice nevertheless developed fewer tumors than nontransgenic mice. Protection was associated with increased expression of IFNγ and increased accumulation of cytotoxic CD8+ and natural killer T cells in the tumors and peritumoral areas. Moreover, genetic deficiency in IFNγ abolished the Smad7-dependent protection against CAC. Taken together, our findings defined a novel and unexpected role for Smad7 in promoting a heightened inflammatory response that protects against CAC. Cancer Res; 71(24); 7423–32. ©2011 AACR.
The directions of mild asthma evolution
Authors: Olga Vakhno, Vitaly Kupaev, Dmitry Nagatkin, Alexander Zhestkov
Journal: European Respiratory Journal (2012)

Mild asthma is the heterogenic cohort with low level of adherence and asthma control, so investigators curiously study it.

The aim was to study the results of evolution of the disease in mild asthma cohort for the period of 3 years.

We studied the history of 141 patients with a 3 year history of mild persistent asthma. Three groups were formed: 1st group – had actual controlled asthma (n=43), 2nd – had partly controlled asthma (n=74),3d- uncontrolled asthma (n=24). E-data base collected the data of all the patients and includes information concerning educational level, passing educational asthma programs, lung function, Ig E level, treatment regimens, asthma control, measured by ACQ and ACT, cooperation index, life quality level and etc.

We observed in the 1st group – higher level of lung function and life quality level. Patients of this group more often took part in asthma educational programs, had higher cooperation index (p<0.05). Besides this, 28% this group didn't get any therapy for 3 last months and 6.9% passed successfully allergen-specific immunotherapy. We have revealed difference in educational status and life quality level in other two groups. Patients of the 3d group had significantly higher ICSs current dose (269.6±13.9 mkg per day vs 108.9±119.5 mkg per day in the 2nd group), Ig E level, low cooperation index, more rarely have made planned visits to their physician (p<0.05). Obvious difference in asthma control assessed by ACT test between 2nd and 3d groups was not found.

Conclusion: The results of evolution of the disease finally demonstrate several interventions that could influence predictably on it: taking part in asthma educational programs, pass allergen-specific immunotherapy, making planned visits to the physician.
Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review
Authors: Roger Chou, Daniel Hartung, Basmah Rahman, Ngoc Wasson, Erika Barth Cottrell, Rongwei Fu
Journal: Annals of Internal Medicine (2013)

Background: Multiple treatments are available for chronic hepatitis C virus (HCV) infection. Purpose: To compare benefits and harms of antiviral regimens for chronic HCV infection in treatment-naive adults. Data Sources: English-language literature from MEDLINE (1947 to August 2012), the Cochrane Library Database, Embase, Scopus, PsychINFO, and clinical trial registries. Study Selection: Randomized trials of antiviral treatments and cohort studies examining associations between sustained virologic response (SVR) after therapy and clinical outcomes. Data Extraction: Several investigators abstracted study details and quality by using predefined criteria. Data Synthesis: No trial evaluated effectiveness of treatment on long-term clinical outcomes. Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower likelihood of SVR than was pegylated interferon alfa-2a plus ribavirin (absolute difference, 8 percentage points [95% CI, 3 to 14 percentage points]) on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood of SVR than was therapy for 24 weeks, and lower doses of pegylated interferon alfa-2b were less effective than standard doses (2 to 4 fair-quality trials). For genotype 1 infection, fair-quality trials found that triple therapy with pegylated interferon, ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likelihood of SVR than was dual therapy (absolute difference, 22 to 31 percentage points). Compared with dual therapy, boceprevir triple therapy increased risk for hematologic adverse events and telaprevir triple therapy increased risk for anemia and rash. A large well-designed cohort study and 18 smaller cohort studies found that an SVR after antiviral therapy was associated with lower risk for all-cause mortality than was no SVR. Limitations: Trials involved highly selected populations. Observational studies did not always adequately control for confounders. Conclusion: SVR rates for genotype 1 infection are higher with triple therapy that includes a protease inhibitor than with standard dual therapy. An SVR after antiviral therapy appears associated with improved clinical outcomes. Primary Funding Source: Agency for Healthcare Research and Quality.
Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors
Authors: Z Liu
Journal: Thorax (2003)

The extracellular matrix metalloproteases (MMPs) produced by tumour and stromal cells are believed to play a key role in tumour cell invasion and metastasis. Malignant mesothelioma is a highly aggressive tumour. Previous studies have shown that malignant mesothelioma cells express MMP-1, -2, -3, -7 and -9. However, the regulation of MMP expression in malignant mesothelioma cells has not been thoroughly investigated.The effects of a number of growth factors on the secretion of MMP-2, -3 and -9 in malignant mesothelioma cells were studied by substrate zymography. The expression of relevant growth factor receptors in malignant mesothelioma cells was also examined using RT-PCR.The exposure of malignant mesothelioma cells to different growth factors including epidermal growth factor (EGF), transforming growth factor-alpha, amphiregulin, heparin binding EGF, beta-cellulin (BTC), stem cell factor, insulin-like growth factors I and II, acidic and basic fibroblast growth factors, and hepatocyte growth factor increased secretion of MMP-9 and/or MMP-3. EGF receptor ligands BTC and EGF had the most potent effect on MMP-9 and MMP-3 production, respectively. Production of MMP-2 was not affected by any growth factors used in this study. We have also demonstrated mRNA expression of different growth factor receptors in malignant mesothelioma cells, and found that the tyrosine kinase inhibitor genistein inhibited the increased production of MMPs resulting from stimulation with different growth factors.This study shows, for the first time, the broad extent of regulation of MMPs by various growth factors in malignant mesothelioma cells.
IMMUNOLOGIC PRODUCTION OF ANTIANGIOTENSIN
Authors: Sharad D. Deodhar
Journal: The Journal of Experimental Medicine (1960)

The parenteral administration of benzoylangiotensin II-azo-BGG to rabbits produced an antiserum with antiangiotensin activity. Antiangiotensin inhibited the biological action of p-aminobenzoylangiotensin II, valine(5)-angiotensin II (free acid form), isoleucine(5)-angiotensin II and valine(5)-angiotensin II (amide form), but it was totally inert towards angiotensin 1. Antiangiotensin activity was distinguished from that of serum angiotensinase by the following observations: (a) an angiotensinase-free gamma-globulin fraction contained antiangiotensin, (b) angiotensinase inactivated angiotensin II (both the amide and free acid forms) and angiotensin I in contrast to the remarkable specificity for angiotensin II exhibited by antiangiotensin. Serological demonstration of antiangiotensin included: (a) a comparison of its precipitin reaction with the angiotensin BGG complex with the reaction with BGG alone, (b) the partial inhibition of the precipitin reaction with the angiotensin BGG complex by angiotensin II, (c) a precipitin reaction with a different angiotensin II protein complex (cat serum). Angiotensin II administered parenterally as the free polypeptide was not antigenic.