tbuckley/cabot-search huggingface dataset:
Regulation of Vascular Endothelial Growth Factor Receptors by Rb and E2F1: Role of Acetylation
Authors: Smitha Pillai, Michelle Kovacs, Srikumar Chellappan
Journal: Cancer Research (2010)

E2F transcription factors regulate a variety of cellular processes, but their role in angiogenesis is not clear. We find that many genes involved in angiogenesis such as FLT-1, KDR, and angiopoietin 2 have potential E2F1 binding sites in their promoter. Chromatin immunoprecipitation (ChIP) assays showed that E2F1 can associate with these promoters and the recruitment of E2F1 was enhanced upon vascular endothelial growth factor (VEGF) stimulation with concomitant dissociation of Rb, leading to the transcriptional activation of these promoters. Transient transfection experiments showed that these promoters were induced by E2F1 and repressed by Rb, whereas depletion of E2F1 decreased their expression. The increased binding of E2F1 to these promoters upon VEGF stimulation correlated with the acetylation of histones and E2F1; this required VEGF receptor function, as seen in ChIP-re-ChIP experiments. This suggests the existence of a positive feedback loop regulating E2F1 acetylation and VEGF receptor expression. Acetylation associated with VEGF signaling seems to be predominantly mediated by P300/CBP-associated factor, and the depletion of histone acetyl transferases disrupted the formation of angiogenic tubules. These results suggest a novel role for E2F1 and acetylation in the angiogenic process.
The use of dietary manipulation by parents of children with atopic dermatitis
Authors: G.A. Johnston, R.M. Bilbao, R.A.C. Graham-Brown
Journal: British Journal of Dermatology (2004)

In 1989 we demonstrated that 71% of children referred to our paediatric dermatology clinic with atopic dermatitis (AD) had been subject to dietary manipulation by their parents in order to manage their disease. We have re-examined our clinic population to determine whether the documented rise in the use of complementary therapy in children with skin disease has been accompanied by a rise in dietary manipulation.To qualify and quantify the usage of dietary manipulation in children with AD in secondary care.A face-to-face structured questionnaire study of 100 children with AD.The mean age of the children interviewed was 7.3 years (median 5.9, range 0.6-17.1) and ethnic origin was 59% white, 35% Indo-Asian, 3% Afro-Caribbean and 3% mixed race. Seventy-five per cent of patients (75 of 100) had tried some form of dietary exclusion; the most common foods omitted were dairy products in 48% (36 of 75), eggs in 27% (20 of 75) and cow's milk in 25% (19 of 75). Forty-one per cent of patients (41 of 100) had tried some form of dietary supplementation. The most common dietary supplement was evening primrose oil in 59% (24 of 41), of whom 13% (three of 24) felt this had helped their skin. Only 51% (38 of 75) had consulted a doctor or dietician before commencing any dietary change, but 39% (29 of 75) felt that their skin had improved as a result of this dietary manipulation.In comparison with our previous study, the proportion of patients excluding foods from their diet had increased from 71% to 75%. The proportion of these dietary changes that are unsupervised has remained the same, as have the food types avoided. The proportion of patients who report that unsupervised dietary manipulation is beneficial has increased from 10% to 39%.
Pharmacogenetics in type 2 diabetes: potential implications for clinical practice
Authors: Chunmei Huang, Jose C Florez
Journal: Genome Medicine (2011)

Pharmacogenetic research aims to study how genetic variation may influence drug efficacy and/or toxicity; pharmacogenomics expands this quest to the entire genome. Pharmacogenetic findings may help to uncover new drug targets, illuminate pathophysiology, clarify disease heterogeneity, aid in the fine-mapping of genetic associations, and contribute to personalized treatment. In diabetes, there is precedent for the successful application of pharmacogenetic concepts to monogenic forms of the disease, such as maturity onset diabetes of the young or neonatal diabetes. Whether similar insights will be produced for the common form of type 2 diabetes remains to be seen. With recent advances in genetic approaches, the successive application of candidate gene studies, large-scale genotyping studies and genome-wide association studies has begun to generate suggestive results that may lead to changes in clinical practice. However, many potential barriers to the translation of pharmacogenetic discoveries to the clinical management of diabetes still remain. Here, we offer a contemporary overview of the field in its current state, identify potential obstacles, and highlight future directions.
Is quadriceps muscle endurance reduced in COPD? A systematic review and meta-analysis
Authors: Rachael Evans, Eric Kaplovitch, Marla Beauchamp, Clare Gillies, Roger Goldstein, Dina Brooks, Sunita Mathur
Journal: European Respiratory Journal (2012)

Background   Although quadriceps Type 1 muscle fibre proportion is reduced in patients with COPD, there is conflicting evidence as to whether quadriceps muscle endurance is impaired. We therefore performed a systematic review and meta-analysis of studies comparing quadriceps endurance in COPD to healthy controls.   Methods   Studies comparing quadriceps endurance between patients with COPD and healthy controls were identified using six databases (1946-2011) and grey literature. Full text articles were obtained after two researchers independently reviewed the abstracts. Weight standardised mean difference (WSMD) with 95% confidence intervals were calculated by a random effects model for measures of quadriceps endurance.   Results   Data were extracted from 17 studies involving 565 patients with COPD and 353 healthy controls. The outcome measurements involved a mixture of techniques. Quadriceps endurance was greater in the controls compared with COPD (WSMD -1.46 [-0.84 to -2.09]) p   Conclusions   Quadriceps endurance is reduced in patients with COPD compared to healthy controls. The results were independent of the type of muscle endurance test used.
Effect of curing Helicobacter pylori infection on intragastric pH during treatment with omeprazole.
Authors: E F Verdu, D Armstrong, J P Idstrom, J Labenz, M Stolte, G Dorta, G Borsch, A L Blum
Journal: Gut (1995)

It has been shown that omeprazole treatment produces higher intragastric pH values in Helicobacter pylori positive subjects than in H pylori negative subjects. This study aimed to investigate the effect of curing H pylori on the intragastric pH in both the presence and absence of omeprazole therapy. Twenty four hour intragastric pH recordings were performed before and after a one week course of omeprazole (20 mg once daily) in 18 H pylori positive subjects and were repeated after the infection had been cured. In the absence of omeprazole, the total 24 hour pH values before cure did not differ from those afterwards. During omeprazole treatment the 24 hour pH values were much higher before (median (95% CI) 5.4: 4.3, 6.0), than after cure of infection (3.6: 2.1, 4.4; p &lt; 0.001). The omeprazole induced fall in H+ activity before cure of H pylori did not, however, differ from that afterwards. It is concluded that the apparently greater antisecretory effect of omeprazole during H pylori infection may be a result of the production of acid neutralising compounds by the H pylori. Although a direct interaction between H pylori and omeprazole cannot be excluded, it seems unlikely.
Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications
Authors: J Waltenberger
Journal: Cardiovascular Research (2001)

The formation of coronary collateral vessels is a compensatory mechanism secondary to repetitive or chronic myocardial ischemia. During the past three decades the functional and prognostic benefit of such collateral vessels has been established. There are large interindividual differences in the number and extent of collateral vessels that may be explained by differences in the anatomic situation or by differences in the individual capacity to develop functional collateral vessels. Diabetes mellitus has recently been identified as one of the first negative predictors of collateral vessel formation. Novel molecular approaches have helped to improve our understanding of the process of collateral vessel formation in recent years. Besides the process of true angiogenesis, i.e. the formation of new capillaries out of preexisting ones, the formation of a collateral circulation is largely based on the growth of preexisting arterioles (collateral vessels or anastomoses) named arteriogenesis. One important feature of arteriogenesis is the infiltration of monocytes into the growing collateral vessel. Our group shows that the ability of monocytes to migrate towards a gradient of VEGF-A is severely impaired in diabetic individuals, and this impaired response seems to be secondary to a signal transduction defect within the monocyte. In this review the pathophysiology of diabetes-related monocyte dysfunction and the potential role of VEGF-A in collateral vessel formation are discussed.
Frameshift mutations in the type VII collagen gene (COL7A1) in five Mexican cousins with recessive dystrophic epidermolysis bullosa
Authors: None Salas‐Alanis, None Mellerio, None Amaya‐Guerra, None Ashton, None Eady, None Mcgrath
Journal: British Journal of Dermatology (1998)

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). In this study, we assessed the molecular basis of recessive DEB in five affected individuals from two Mexican families. Both fathers of the affected children were first cousins. Genomic DNA was extracted from peripheral blood samples and assessed for COL7A1 mutations by polymerase chain reaction (PCR) amplification, heteroduplex analysis and direct automated sequencing of PCR products displaying heteroduplex bandshifts. In one family, we identified a homozygous 1 bp insertion of a G nucleotide in exon 19 of COL7A1, designated 2470insG, in three affected sisters. This mutation causes a frameshift and a premature termination codon on both alleles 178 bp downstream from the insertion; both parents were shown to be heterozygous carriers of this mutation. In the second family, the father of the other two affected children was also found to be a heterozygous carrier of this frameshift mutation. In addition, his unrelated partner was shown to be a heterozygous carrier of a different COL7A1 frameshift mutation, an insertion of a T nucleotide in exon 32, designated 3948insT. This mutation also results in a premature termination codon, 126 bp downstream from the insertion. Both affected children were compound heterozygotes for the 2470insG/3948insT mutations in COL7A1. Overall, these molecular findings offer a genetic explanation for the skin fragility in these related Mexican patients with recessive DEB. Immediate benefits from elucidation of the mutations include assessment of carrier status in other members of the family and the feasibility of DNA‐based prenatal testing in subsequent pregnancies.
Phase III Trial of Chemotherapy Plus Radiotherapy Compared With Radiotherapy Alone for Pure and Mixed Anaplastic Oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402
Authors: Gregory Cairncross, Brian Berkey, Edward Shaw, Robert Jenkins, Bernd Scheithauer, David Brachman, Jan Buckner, Karen Fink, Luis Souhami, Normand Laperierre, Minesh Mehta, Walter Curran
Journal: Journal of Clinical Oncology (2006)

Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery and radiotherapy (RT) at diagnosis, but they also respond to procarbazine, lomustine, and vincristine (PCV), raising the possibility that early chemotherapy will improve survival. Furthermore, better outcomes in AO have been associated with 1p and 19q allelic loss.Patients with AO and AOA were randomly assigned to PCV chemotherapy followed by RT versus postoperative RT alone. The primary end point was overall survival. The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization.Two hundred eighty-nine eligible patients were randomly assigned to either PCV plus RT (n = 147) or RT alone (n = 142). At progression, 80% of patients randomly assigned to RT had chemotherapy. With 3-year follow-up on most patients, the median survival times were similar (4.9 years after PCV plus RT v 4.7 years after RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26). Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of patients experienced grade 3 or 4 toxicity, and one patient died. Patients with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and 19q had longer median survival times (> 7 v 2.8 years, respectively; P < or = .001); longer progression-free survival was most apparent in this subset.For patients with AO and AOA, PCV plus RT does not prolong survival. Longer progression-free survival after PCV plus RT is associated with significant toxicity. Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both.
Sex matters in pulmonary arterial hypertension
Authors: Robert Naeije, Michele D’Alto
Journal: European Respiratory Journal (2014)

To the Editor: 

It has been known for a while that female sex is a risk factor for pulmonary arterial hypertension (PAH), but that women with the condition survive better than men [1–3]. Further light has been shed on this paradox by the excellent meta-analysis recently reported by Ventetuolo et al. [4] in the European Respiratory Journal . The authors showed that female patients with idiopathic or connective tissue-associated PAH have higher cardiac output and lower pulmonary vascular resistance. …
Prevalence and Course of Diabetes Modified by Fasting Blood Glucose Levels: Implications for Diagnostic Criteria
Authors: John B O'Sullivan
Journal: Diabetes Care (1979)

Data from the epidemiologic survey in Sudbury, Massachusetts, demonstrate that the prevalence of new cases of diabetes, based on the USPHS criteria for the standard 3-h oral glucose tolerance test as originally published, was 0.7%. If a fasting blood sugar ≥ to 110 mg/dl had been required for those USPH diagnoses, the prevalence would have fallen to 0.28%. Further, if a peak serum insulin level of ≤ 60 μU/ml had been required, the original prevalence rate would have dropped to 0.02%. Data from a prospeh criteria for diabetes indicate by life table analyses that 41% show further deterioration of carbohydrate control over the first 13 yr of the study when the fasting blood sugar was &amp;lt; 110 mg/dl in the initial diagnostic test and 82% when the fasting blood sugar was ≥ to 110 mg/dl. The relationship of fasting blood glucose to later decompensation proved to be a continuous one without evidence of a threshold effect. The implications of both of these studies for diagnostic criteria, particularly recent proposals, is discussed.
Heparin-II Domain of Fibronectin Is a Vascular Endothelial Growth Factor-Binding Domain
Authors: Errol S. Wijelath, Salman Rahman, Mayumi Namekata, Jacqueline Murray, Tomoaki Nishimura, Zohreh Mostafavi-Pour, Yatin Patel, Yasuo Suda, Martin J. Humphries, Michael Sobel
Journal: Circulation Research (2006)

We describe extracellular interactions between fibronectin (Fn) and vascular endothelial growth factor (VEGF) that influence integrin-growth factor receptor crosstalk and cellular responses. In previous work, we found that VEGF bound specifically to fibronectin (Fn) but not vitronectin or collagens. Herein we report that VEGF binds to the heparin-II domain of Fn and that the cell-binding and VEGF-binding domains of Fn, when physically linked, are necessary and sufficient to promote VEGF-induced endothelial cell proliferation, migration, and Erk activation. Using recombinant Fn domains, the C-terminal heparin-II domain of Fn (type III repeats 13 to 14) was identified as a key VEGF-binding site. Mutation of the heparin-binding residues on FnIII 13–14 abolished VEGF binding, and peptides corresponding to the heparin-binding sequences in FnIII 13–14 inhibited VEGF binding to Fn. Fn fragments containing both the α 5 β 1 integrin-binding domain (III 9 to 10) and the VEGF-binding domain (III 13 to 14) significantly enhanced VEGF-induced EC migration and proliferation and induced strong phosphorylation of the VEGF receptor and Erk. Neither the cell-binding or VEGF-binding fragment of Fn alone had comparable VEGF-promoting effects. These results suggest that the mechanism of VEGF/Fn synergism is mediated extracellularly by the formation of a novel VEGF/Fn complex requiring both the cell-binding and VEGF-binding domains linked in a single molecular unit. These data also highlight a new function for the Fn C-terminal heparin-binding domain that may have important implications for angiogenesis and tumor growth.
CXCL5 Mediates UVB Irradiation–Induced Pain
Authors: John M. Dawes, Margarita Calvo, James R. Perkins, Kathryn J. Paterson, Hannes Kiesewetter, Carl Hobbs, Timothy K. Y. Kaan, Christine Orengo, David L. H. Bennett, Stephen B. McMahon
Journal: Science Translational Medicine (2011)

Many persistent pain states (pain lasting for hours, days, or longer) are poorly treated because of the limitations of existing therapies. Analgesics such as nonsteroidal anti-inflammatory drugs and opioids often provide incomplete pain relief and prolonged use results in the development of severe side effects. Identification of the key mediators of various types of pain could improve such therapies. Here, we tested the hypothesis that hitherto unrecognized cytokines and chemokines might act as mediators in inflammatory pain. We used ultraviolet B (UVB) irradiation to induce persistent, abnormal sensitivity to pain in humans and rats. The expression of more than 90 different inflammatory mediators was measured in treated skin at the peak of UVB-induced hypersensitivity with custom-made polymerase chain reaction arrays. There was a significant positive correlation in the overall expression profiles between the two species. The expression of several genes [interleukin-1β (IL-1β), IL-6, and cyclooxygenase-2 (COX-2)], previously shown to contribute to pain hypersensitivity, was significantly increased after UVB exposure, and there was dysregulation of several chemokines (CCL2, CCL3, CCL4, CCL7, CCL11, CXCL1, CXCL2, CXCL4, CXCL7, and CXCL8). Among the genes measured, CXCL5 was induced to the greatest extent by UVB treatment in human skin; when injected into the skin of rats, CXCL5 recapitulated the mechanical hypersensitivity caused by UVB irradiation. This hypersensitivity was associated with the infiltration of neutrophils and macrophages into the dermis, and neutralizing the effects of CXCL5 attenuated the abnormal pain-like behavior. Our findings demonstrate that the chemokine CXCL5 is a peripheral mediator of UVB-induced inflammatory pain, likely in humans as well as rats.
Chest Pain in Asbestos-exposed Individuals with Benign Pleural and Parenchymal Disease
Authors: SUTAPA MUKHERJEE, NICHOLAS de KLERK, LYLE J. PALMER, N. J. OLSEN, S. C. PANG, A. WILLIAM MUSK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Many asbestos-exposed individuals complain of chest pain for which there is no clear explanation. To determine whether chest pain is associated with the presence of benign pleural or parenchymal disease on chest radiograph, we studied 1,280 subjects undergoing surveillance because of prior asbestos exposure at Wittenoom, Western Australia. All subjects completed the Rose questionnaire on chest pain and this revealed 556 subjects (43%) who experienced some chest pain. A posterior-anterior chest radiograph was performed at the same clinic visit and was subsequently graded independently by two experienced readers for diffuse parenchymal disease and pleural disease. Logistic regression models adjusted for sex, age, and cumulative asbestos exposure indicated that the presence of chest pain was significantly associated with the presence of both benign pleural disease and diffuse parenchymal disease. Further analysis after stratification of chest pain into nonanginal and anginal pain showed that there was a significant association between anginal pain and the presence of pleural and parenchymal asbestos-induced radiologic abnormalities and an association of nonanginal pain with parenchymal disease. We conclude that radiographic evidence of either parenchymal or pleural disease in subjects exposed to asbestos is significantly related to the presence of chest pain, particularly anginal pain.
Hot spots in dynamic18FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas
Authors: M. Kunz, N. Thon, S. Eigenbrod, C. Hartmann, R. Egensperger, J. Herms, J. Geisler, C. la Fougere, J. Lutz, J. Linn, S. Kreth, A. von Deimling, J. C. Tonn, H. A. Kretzschmar, G. Popperl, F. W. Kreth
Journal: Neuro-Oncology (2011)

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine (18FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4–44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of 18FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.