tbuckley/cabot-search huggingface dataset:
Essential Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis of the Adult Vascular System
Authors: Kotaro Takeda, Ann Cowan, Guo-Hua Fong
Journal: Circulation (2007)

Background— Prolyl hydroxylase domain (PHD) proteins, including PHD1, PHD2, and PHD3, mediate oxygen-dependent degradation of hypoxia-inducible factor (HIF)-α subunits. Although angiogenic roles of hypoxia-inducible factors are well known, the roles of PHDs in the vascular system remain to be established. Methods and Results— We evaluated angiogenic phenotypes in mice carrying targeted disruptions in genes encoding different PHD isoforms. Although Phd1 −/− and Phd3 −/− mice did not display apparent angiogenic defects, broad-spectrum conditional knockout of Phd2 led to hyperactive angiogenesis and angiectasia. Blood vessels in PHD2-deficient mice were highly perfusable. Furthermore, examination of medium-sized vessels in subendocardial layer in the heart demonstrated successful recruitment of vascular smooth muscle cells. Surprisingly, increased vascular growth was independent of local efficiency of Phd2 disruption. Mice carrying significant Phd2 disruption in multiple organs, including the liver, heart, kidney, and lung, displayed excessive vascular growth not only in these organs but also in the brain, where Phd2 disruption was very inefficient. More surprisingly, increased accumulation of hypoxia-inducible factor-1α and angiectasia in the liver were not accompanied by corresponding increases in hepatic expression of Vegfa or angiopoietin-1 . However, the serum vascular endothelial growth factor-A level was significantly increased in PHD2-deficient mice. Conclusions— PHD2, but not PHD1 and PHD3, is a major negative regulator for vascular growth in adult mice. Increased angiogenesis in PHD2-deficient mice may be mediated by a novel systemic mechanism.
Recurrence of severe duodenal disease after endoscopic downstaging in familial adenomatous polyposis
Authors: D. Balmforth, K. Neale, S. Clark, R. Phillips
Journal: Gut (2011)

<h3>Introduction</h3> Duodenal polyposis is found in the majority of patients with familial adenomatous polyposis. Endoscopic surveillance programmes grade the severity of duodenal disease according to the Spigelman classification (stages 0–IV) to identify patients at risk of developing adenocarcinoma. Duodenoscopy can also be used therapeutically to remove polyps and thus reduce a patient9s Spigelman stage. This study aims to evaluate the progression of duodenal polyposis in patients with a previous diagnosis of Spigelman stage IV disease who have been downstaged by endoscopic or pharmacological means. <h3>Methods</h3> This retrospective cohort study used a database search of a large prospective polyposis registry to identify patients who had been downstaged from stage IV disease and had further opportunity for disease progression. These patients were divided into three groups according to their new Spigelman stage. A measure of a patient9s disease progression was obtained by the increase in stage over the recommended follow-up time period for their new, reduced, Spigelman stage. <h3>Results</h3> A total of 41 patients were indentified. Group 1 (n = 16) were downstaged to stage III disease, with 50% progressing back to stage IV over the recommended 1-year follow-up period. Group 2 (n = 19) were downstaged to stage II disease, with 84% undergoing progression over the recommended 3-year follow-up period. Group 3 (n = 6) were downstaged to stage I disease, with 100% undergoing progression over the recommended 5-year follow-up period. No patients were downstaged to stage 0. <h3>Conclusion</h3> Patients downstaged from Spigelman stage IV demonstrate an increased rate of disease progression back to severe disease in comparison to reported rates of primary disease progression. An amendment to the current endoscopic surveillance protocol is recommended to ensure that once a patient has been classified as having stage IV disease they are treated as a high-risk patient in perpetuity.
SNX2112, a Synthetic Heat Shock Protein 90 Inhibitor, Has Potent Antitumor Activity against HER Kinase–Dependent Cancers
Authors: Sarat Chandarlapaty, Ayana Sawai, Qing Ye, Anisa Scott, Melanie Silinski, Ken Huang, Pat Fadden, Jeff Partdrige, Steven Hall, Paul Steed, Larry Norton, Neal Rosen, David B. Solit
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The heat shock protein 90 (Hsp90) chaperone plays an important role in transformation by regulating the conformational maturation and stability of oncogenic kinases and transcription factors. Ansamycins, such as 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), inhibit Hsp90 function; induce the degradation of Hsp90 client proteins such as HER2, and have shown activity in early clinical trials. However, the utility of these drugs has been limited by their hepatotoxicity, poor solubility, and poorly tolerated formulations. Experimental Design: We determined the pharmacodynamic and antitumor properties of a novel, synthetic Hsp90 inhibitor, SNX-2112, in cell culture and xenograft models of HER kinase–dependent cancers. Results: We show in a panel of tumor cell lines that SNX-2112 and its prodrug SNX-5542 are Hsp90 inhibitors with properties and potency similar to that of 17-AAG, including: degradation of HER2, mutant epidermal growth factor receptor, and other client proteins, inhibition of extracellular signal-regulated kinase and Akt activation, and induction of a Rb-dependent G1 arrest with subsequent apoptosis. SNX-5542 can be administered to mice orally on a daily schedule. Following oral administration, SNX-5542 is rapidly converted to SNX-2112, which accumulates in tumors relative to normal tissues. A single dose of SNX-5542 causes HER2 degradation and inhibits its downstream signaling for up to 24 h, and daily dosing results in regression of HER2-dependent xenografts. SNX-5542 also shows greater activity than 17-AAG in a non–small cell lung cancer xenograft model expressing mutant EGFR. Conclusions: These results suggest that Hsp90 inhibition with SNX-2112 (delivered as a prodrug) may represent a promising therapeutic strategy for tumors whose growth and survival is dependent on Hsp90 clients.
Childhood Physical, Environmental, and Genetic Predictors of Adult Hypertension
Authors: Jonna Juhola, Mervi Oikonen, Costan G. Magnussen, Vera Mikkilä, Niina Siitonen, Eero Jokinen, Tomi Laitinen, Peter Würtz, Samuel S. Gidding, Leena Taittonen, Ilkka Seppälä, Antti Jula, Mika Kähönen, Nina Hutri-Kähönen, Terho Lehtimäki, Jorma S.A. Viikari, Markus Juonala, Olli T. Raitakari
Journal: Circulation (2012)

Hypertension is a major modifiable cardiovascular risk factor. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension and furthermore whether newly identified genetic variants for blood pressure increase the prediction of adult hypertension.The study cohort included 2625 individuals from the Cardiovascular Risk in Young Finns Study who were followed up for 21 to 27 years since baseline (1980; age, 3-18 years). In addition to dietary factors and biomarkers related to blood pressure, we examined whether a genetic risk score based on 29 newly identified single-nucleotide polymorphisms enhances the prediction of adult hypertension. Hypertension in adulthood was defined as systolic blood pressure ≥ 130 mm Hg and/or diastolic blood pressure ≥ 85 mm Hg or medication for the condition. Independent childhood risk factors for adult hypertension included the individual's own blood pressure (P<0.0001), parental hypertension (P<0.0001), childhood overweight/obesity (P=0.005), low parental occupational status (P=0.003), and high genetic risk score (P<0.0001). Risk assessment based on childhood overweight/obesity status, parental hypertension, and parental occupational status was superior in predicting hypertension compared with the approach using only data on childhood blood pressure levels (C statistics, 0.718 versus 0.733; P=0.0007). Inclusion of both parental hypertension history and data on novel genetic variants for hypertension further improved the C statistics (0.742; P=0.015).Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension.
The British hypothesis revisited
Authors: N.R. Anthonisen
Journal: European Respiratory Journal (2004)

Forty years ago, British investigators developed the hypothesis that recurrent bronchial infections were the reason that some smokers developed progressive airways obstruction and other did not 1. The classical studies of Fletcher et al. 2 were designed to test this proposition. They carried out a prospective study of working males, noting the frequency of respiratory infections, sputum quantity and quality, and rate of loss of lung function in the form of forced expiratory volume in one second (FEV1). They found that chronic cough and sputum production, and recurrent respiratory infections did not relate to lung function decline. They concluded that the chronic bronchitis syndrome (cough, sputum and episodes of acute bronchitis) was an epiphenomenon in so far as the development of chronic obstructive pulmonary disease (COPD) was concerned; both chronic bronchitis and COPD were caused by smoking, but the two were not related. This made sense, since chronic bronchitis symptoms largely reflected pathology in major conducting airways, and airways obstruction was related to lesions in small airways and the lung parenchyma.

This view of the pathogenesis of COPD was essentially unchallenged for many years, in a large part because it was hard to do a better study that that of …
High rate lond term response after one year interferon (IFN) plus ribavirine treatment for hepatitis C relapsers. Results of a controlled randomized study in 191 patients
Authors: E.J. Boucher, S. Jacquelinet, V. Canva, B. Turlin, R. Colimon, C. Jacquelinet, D. Guyader, Y. Deugnier, P. Brissot
Journal: Journal of Hepatology (2001)
Diabetes and Risk of Fracture
Authors: Rebecca Q. Ivers, Robert G. Cumming, Paul Mitchell, Anthony J. Peduto
Journal: Diabetes Care (2001)

OBJECTIVE—To examine associations between measures of diabetes and risk of fracture in a population-based sample of older Australians. RESEARCH DESIGN AND METHODS—This was a prospective study of 3,654 subjects aged 49 years and older who were residents in the Blue Mountains, west of Sydney, Australia. At baseline, subjects were asked questions about history and treatment of diabetes, and fasting blood samples were taken. Photographs were taken of the retina and lens to grade retinopathy and cataract. Details of fractures (excluding rib and vertebral fractures) were collected by a combination of self-report and medical record searches; all fractures were radiologically confirmed. RESULTS—After 2 years of follow-up, we found that several diabetes-related factors were significantly associated (in multivariate models) with increased risk of all fractures combined, including presence of diabetic retinopathy (adjusted RR 5.4, 95% CI 2.7–10.8), diabetes duration ≥10 years (3.3, 1.3–8.2), cortical cataract involving ≥25% of the lens area (2.5, 1.3–4.7), and insulin treatment (5.9, 2.6–13.5). The proximal humerus was the only individual fracture site associated with diabetes. Diabetic retinopathy (10.3, 2.2–48.0), diabetes duration (for ≥10 years duration; 11.4, 2.4–54.2), and insulin treatment (18.8, 4.0–88.7) were all associated with proximal humerus fracture. CONCLUSIONS—These data suggest a significantly increased risk of fracture associated with diabetic retinopathy, advanced cortical cataract, longer diabetes duration, and insulin treatment. However, there are some shortcomings in this study that may limit these findings.
IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells
Authors: Daniel T. Fisher, Qing Chen, Joseph J. Skitzki, Jason B. Muhitch, Lei Zhou, Michelle M. Appenheimer, Trupti D. Vardam, Emily L. Weis, Jessica Passanese, Wan-Chao Wang, Sandra O. Gollnick, Mark W. Dewhirst, Stefan Rose-John, Elizabeth A. Repasky, Heinz Baumann, Sharon S. Evans
Journal: Journal of Clinical Investigation (2011)

Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor–α and thermally induced gp130 to promote E/P-selectin– and ICAM-1–dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor–α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6–dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6–rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell–mediated antitumor immunity and immunotherapy.
Sympathetic Activation in Chronic Renal Failure
Authors: Markus P. Schlaich, Flora Socratous, Sarah Hennebry, Nina Eikelis, Elisabeth A. Lambert, Nora Straznicky, Murray D. Esler, Gavin W. Lambert
Journal: Journal of the American Society of Nephrology (2008)

The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.
Desmoplakin and Talin2 Are Novel mRNA Targets of Fragile X–Related Protein-1 in Cardiac Muscle
Authors: Samantha A. Whitman, Cathleen Cover, Lily Yu, David L. Nelson, Daniela C. Zarnescu, Carol C. Gregorio
Journal: Circulation Research (2011)

The proper function of cardiac muscle requires the precise assembly and interactions of numerous cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and force transmission. Evidence suggests that posttranscriptional regulation is critical for muscle function, but the mechanisms involved remain understudied.To investigate the molecular mechanisms and targets of the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1), an RNA binding protein whose loss leads to perinatal lethality in mice and cardiomyopathy in zebrafish.Using RNA immunoprecipitation approaches we found that desmoplakin and talin2 mRNAs associate with FXR1 in a complex. In vitro assays indicate that FXR1 binds these mRNA targets directly and represses their translation. Fxr1 KO hearts exhibit an up-regulation of desmoplakin and talin2 proteins, which is accompanied by severe disruption of desmosome as well as costamere architecture and composition in the heart, as determined by electron microscopy and deconvolution immunofluorescence analysis.Our findings reveal the first direct mRNA targets of FXR1 in striated muscle and support translational repression as a novel mechanism for regulating heart muscle development and function, in particular the assembly of specialized cytoskeletal structures.
Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy
Authors: Kalev Freeman, Imanuel Lerman, Evangelia G. Kranias, Teresa Bohlmeyer, Michael R. Bristow, Robert J. Lefkowitz, Guido Iaccarino, Walter J. Koch, Leslie A. Leinwand
Journal: Journal of Clinical Investigation (2001)

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including β-adrenergic receptor (βAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in βAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the β2AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the βAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of βAR signaling or excitation-contraction coupling can provide therapeutic benefit.
SIRS Is Valid in Discriminating Between Severe and Moderate Diabetic Foot Infections
Authors: Dane K. Wukich, Kimberlee B. Hobizal, Katherine Marie Raspovic, Bedda L. Rosario
Journal: Diabetes Care (2013)

This retrospective, single-center study was designed to distinguish severe diabetic foot infection (DFI) from moderate DFI based on the presence or absence of systemic inflammatory response syndrome (SIRS).The database of a single academic foot and ankle program was reviewed and 119 patients were identified. Severe DFI was defined as local infection associated with manifestation of two or more objective findings of systemic toxicity using SIRS criteria.Patients with severe DFI experienced a 2.55-fold higher risk of any amputation (95% CI 1.21-5.36) and a 7.12-fold higher risk of major amputation (1.83-41.05) than patients with moderate DFI. The risk of minor amputations was not significantly different between the two groups (odds ratio 1.02 [95% CI 0.51-2.28]). The odds of having a severe DFI was 7.82 times higher in patients who presented with gangrene (2.03-44.81) and five times higher in patients who reported symptoms of anorexia, chills, nausea, or vomiting (2.22-11.25). The mean hospital length of stay for patients with severe DFI was ∼4 days longer than for patients with moderate DFI, and this difference was statistically significant.SIRS is valid in distinguishing severe from moderate DFI in hospitalized patients. Patients with severe DFI, as by manifesting two or more signs of systemic inflammation or toxicity, had higher rates of major amputation and longer hospital stays and required more surgery and more subsequent admissions than patients who did not manifest SIRS.
Analysis of Events Associated With Cell Cycle Arrest at G2 Phase and Cell Death Induced by Cisplatin
Authors: C. M. Sorenson, M. A. Barry, A. Eastman
Journal: JNCI Journal of the National Cancer Institute (1990)

DNA is the accepted target for cisplatin, but recent evidence has shed doubt on DNA synthesis as the critical process. L1210/0 cells incubated for 2 hours with cisplatin progress to the G 2 phase of the cell cycle and are arrested there for several days. They then either progress in the cell cycle or die. In cells that eventually die, total transcription, polyadenylated [poly(A) + ] RNA synthesis, and protein synthesis were markedly inhibited only after 48 hours. Nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP) levels decreased after 3 days. Cell membrane integrity was lost after 4 days. These results demonstrate that cells can be lethally damaged, yet continue to undergo apparently normal metabolic activities for several days. In a previous study, DNA double-strand breaks were detected after 1 day. We now show that by 2 days, breaks are visible as fragmentation in the nucleosome spacer regions of chromatin. This type of damage is consistent with cell death occurring by the process of apoptosis. Cell shrinkage and morphology were also consistent with this type of cell death. The slow cell death reported here appears to occur at the G 2 /M transition and may involve events that normally occur at this stage of the cell cycle. These results demonstrate the importance of DNA degradation as an early and possibly essential step in cell death. [J Natl Cancer Inst 82: 749–755, 1990]