tbuckley/cabot-search huggingface dataset:
The Prevalence and Predictors of an Abnormal Ankle-Brachial Index in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
Authors: Premranjan P. Singh, J. Dawn Abbott, Manuel S. Lombardero, Kim Sutton-Tyrrell, Gail Woodhead, Lakshmi Venkitachalam, Nicholas P. Tsapatsaris, Thomas C. Piemonte, Rodrigo M. Lago, Martin K. Rutter, Richard W. Nesto
Journal: Diabetes Care (2011)

OBJECTIVE To examine ankle-brachial index (ABI) abnormalities in patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS An ABI was obtained in 2,240 patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. ABIs were classified as: normal, 0.91–1.3; low, ≤0.9; high, &amp;gt;1.3; or noncompressible artery (NC). Baseline characteristics were examined according to ABI and by multivariate analysis. RESULTS ABI was normal in 66%, low in 19%, and high in 8% of patients, and 6% of patients had NC. Of the low ABI patients, 68% were asymptomatic. Using normal ABI as referent, low ABI was independently associated with smoking, female sex, black race, hypertension, age, C-reactive protein, diabetes duration, and lower BMI. High ABI was associated with male sex, nonblack race, and higher BMI; and NC artery was associated with diabetes duration, higher BMI, and hypertension. CONCLUSIONS ABI abnormalities are common and often asymptomatic in patients with type 2 diabetes and CAD.
The Contribution of Blood Momentum to Left Ventricular Ejection in the Dog
Authors: MARK I. M. NOBLE
Journal: Circulation Research (1968)

In five conscious dogs and two anesthetized dogs, the pressure gradient between the left ventricle and the ascending aorta was measured with high fidelity micromanometers. Left ventricular pressure exceeded aortic pressure in the first 30 to 50% of the ejection period. Aortic pressure exceeded left ventricular pressure during the remainder of the ejection period. The magnitude of these differences varied from 5 to 20 mm Hg. This finding in late systole implies that at this time blood is flowing out of the ventricle under its own momentum and that the aorta is a pressure source for the ventricle. The ascending aorta was suddenly occluded in five dogs to verify this hypothesis. When occlusion occurred in the last third of the ejection period, there was an abrupt fall of left ventricular pressure, apparently confirming the momentum hypothesis.
Assessment of Vaccine-Induced CD4 T Cell Responses to the 119-143 Immunodominant Region of the Tumor-Specific Antigen NY-ESO-1 Using DRB1*0101 Tetramers
Authors: Maha Ayyoub, Pascale Pignon, Danijel Dojcinovic, Isabelle Raimbaud, Lloyd J. Old, Immanuel Luescher, Danila Valmori
Journal: Clinical Cancer Research (2010)

Abstract Purpose: NY-ESO-1 (ESO), a tumor-specific antigen of the cancer/testis group, is presently viewed as an important model antigen for the development of generic anticancer vaccines. The ESO119-143 region is immunodominant following immunization with a recombinant ESO vaccine. In this study, we generated DRB1*0101/ESO119-143 tetramers and used them to assess CD4 T-cell responses in vaccinated patients expressing DRB1*0101 (DR1). Experimental Design: We generated tetramers of DRB1*0101 incorporating peptide ESO119-143 using a previously described strategy. We assessed ESO119-143-specific CD4 T cells in peptide-stimulated postvaccine cultures using the tetramers. We isolated DR1/ESO119-143 tetramer+ cells by cell sorting and characterized them functionally. We assessed vaccine-induced CD4+ DR1/ESO119-143 tetramer+ T cells ex vivo and characterized them phenotypically. Results: Staining of cultures from vaccinated patients with DR1/ESO119-143 tetramers identified vaccine-induced CD4 T cells. Tetramer+ cells isolated by cell sorting were of TH1 type and efficiently recognized full-length ESO. We identified ESO123-137 as the minimal optimal epitope recognized by DR1-restricted ESO-specific CD4 T cells. By assessing DR1/ESO119-143 tetramer+ cells using T cell receptor (TCR) β chain variable region (Vβ)-specific antibodies, we identified several frequently used Vβ. Finally, direct ex vivo staining of patients' CD4 T cells with tetramers allowed the direct quantification and phenotyping of vaccine-induced ESO-specific CD4 T cells. Conclusions: The development of DR1/ESO119-143 tetramers, allowing the direct visualization, isolation, and characterization of ESO-specific CD4 T cells, will be instrumental for the evaluation of spontaneous and vaccine-induced immune responses to this important tumor antigen in DR1-expressing patients. Clin Cancer Res; 16(18); 4607–15. ©2010 AACR.
Body fatness and bevacizumab-based therapy in metastatic colorectal cancer
Authors: A. G. Renehan
Journal: Gut (2010)

Evidence accumulated over the past decade has clearly established excess body fatness as a risk factor for colorectal cancer. Specifically, using body mass index (BMI) as an approximation of body fatness, risk increases with increasing BMI in a sex- (men>women) and site- (colon>rectum) specific manner.1 A number of plausible biological mechanisms may underpin these associations,2 including increased insulin resistance, increased availability of insulin-like growth factor (IGF)-I (mitogenic, pro-apoptotic, pro-angiogenic, increases cell motility), and altered adipokine metabolism; for example, increased leptin (mitogenic, anti-apoptotic, pro-angiogenic) and/or decreased adiponectin (anti-angiogenic, anti-inflammatory). Population-based cohort data report that increased BMI is also associated with an increased risk of colon cancer-related mortality suggesting that excess body weight impacts unfavourably on outcome in patients with established disease.3 However, the above study design is limited by lack of details on staging and treatment (key determinants of outcome), and hence, it remains unclear whether the increased mortality observed among obese individuals represents increased incidence, delayed diagnosis, differential primary treatment, differential selection for adjuvant therapies, increased risk from treatment-related complications and/or a differential response to treatment, compared with leaner counterparts. Addressing one possible mechanism of adverse treatment outcome, secondary analyses from at least two randomised trials of adjuvant 5-fluorouracil (5-FU)-based chemotherapies in patients with colon cancer demonstrate increased …
Transient mismatch repair gene transfection for functional analysis of genetic hMLH1 and hMSH2 variants
Authors: A Brieger
Journal: Gut (2002)

Germline mutations in the mismatch repair (MMR) genes hMLH1 and hMSH2 can cause hereditary non-polyposis colorectal cancer (HNPCC). However, the functional in vitro analysis of hMLH1 and hMSH2 mutations remains difficult.To establish an in vitro method for the functional characterisation of hMLH1 and hMSH2 mutations.hMLH1 and hMSH2 wild type (wt) genes and several mutated subclones were transiently transfected in mismatch repair deficient cell lines (HCT-116 and LOVO). Apoptosis, proliferation, and regulation of mRNA expression and protein expression of interacting proteins were analysed by Hoechst staining, AlamarBlue staining, real time polymerase chain reaction, and western blotting, respectively.The protein expression of hMLH1 and hMSH2 mutants was significantly decreased after transfection compared with wild type transfections. The hMLH1 and hMSH2 interacting proteins hPMS2 and hMSH6 became detectable only after transfection of the respective wild type genes. In parallel, hMSH6 mRNA levels were increased in hMSH2 wt transfected cells. However, hPMS2 mRNA levels were independent of the mutation status of its interacting partner hMLH1, indicating a post-transcriptional regulating pathway. In the hMLH1 deficient HCT-116 cell line apoptosis was not affected by transfection of any mismatch repair gene, whereas complementation of hMSH2 deficiency in LOVO cells increased apoptosis. Conversely, proliferative activity of HCT-116 was decreased by complementation with hMLH1wt and unaffected in hMSH2 deficient LOVO cells.These data show that the cellular role of the MMR genes and its mutations are assessable in a simple transient transfection system and show the influence of MMR gene regulation on major cell growth regulating mechanisms. This method is applicable for the functional definition of mutations in hMLH1 and hMSH2 genes observed in patients with suspected HNPCC.
An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation
Authors: Frances A. High, Maozhen Zhang, Aaron Proweller, LiLi Tu, Michael S. Parmacek, Warren S. Pear, Jonathan A. Epstein
Journal: Journal of Clinical Investigation (2007)

The cardiac outflow tract develops as a result of a complex interplay among several cell types, including cardiac neural crest cells, endothelial cells, and cardiomyocytes. In both humans and mice, mutations in components of the Notch signaling pathway result in congenital heart disease characterized by cardiac outflow tract defects. However, the specific cell types in which Notch functions during cardiovascular development remain to be defined. In addition, in vitro studies have provided conflicting data regarding the ability of Notch to promote or inhibit smooth muscle differentiation, while the physiological role for Notch in smooth muscle formation during development remains unclear. In this study, we generated mice in which Notch signaling was specifically inactivated in derivatives of the neural crest. These mice exhibited cardiovascular anomalies, including aortic arch patterning defects, pulmonary artery stenosis, and ventricular septal defects. We show that Notch plays a critical, cell-autonomous role in the differentiation of cardiac neural crest precursors into smooth muscle cells both in vitro and in vivo, and we identify specific Notch targets in neural crest that are implicated in this process. These results provide a molecular and cellular framework for understanding the role of Notch signaling in the etiology of congenital heart disease.
Increased serum and synovial fluid antibodies to immunoselected peptides in patients with rheumatoid arthritis.
Authors: A Dybwad, O Forre, M Sioud
Journal: Annals of the Rheumatic Diseases (1996)

OBJECTIVES: To investigate the role of potential immunoselected phages displaying random peptides in addition to possible antigen leads in rheumatoid arthritis (RA) by assaying the levels of synovial fluid (SF) and serum antibodies to synthetic peptides. METHODS: Serum and SF antibodies from patients and controls were measured using an enzyme linked immunosorbent assay (ELISA). RESULTS: Sera and SF from RA patients reacted significantly more strongly to a 12 amino acid peptide, EFHELGDIAIAA, that shares a significant homology with collagen type IX, than did SF and sera from control groups (p &lt; 0.0209 and p &lt; 0.0115, respectively). In addition, the humoral responses to a 15 amino acid peptide, GGYGDGGAHGGGYGG, derived from the glycine-rich cell wall protein (GRP) 1.8, and to a 16 amino acid synthetic peptide, LGSISESRRALQDSQR, derived from the Proteus haemolysin protein were significantly stronger in RA patients compared with healthy individuals (p &lt; 0.0001 and p &lt; 0.0011, respectively). CONCLUSION: Our data indicate that peptide phage libraries can be used as tools for the identification of the (auto)antigen leads that may be responsible for the initiation, perpetuation, or both, of the immune response in patients with RA.
STUDIES OF THE REGULATORY EFFECTS OF THE SEX HORMONES ON ANTIBODY FORMATION AND STEM CELL DIFFERENTIATION
Authors: David Eidinger, Thomas J. Garrett
Journal: The Journal of Experimental Medicine (1972)

The primary and secondary immune responses to thymus-dependent and -independent antigens were evaluated in normal male and female mice and in castrated male mice. Both IgM antibody production in the primary response and IgG antibody production in the secondary response were enhanced in females vs. males of equivalent age. Castration of the male converted this animal to a female in terms of responsiveness to the thymus-dependent group of antigens, while inducing equivalent or even greater enhanced responsiveness over the female to the thymus-independent antigen, polyvinylpyrrolidone. Further characteristics of the changes in lymphoid organs were determined in the castrated animal vs. normal males and females. It was shown that the spleen and thymus became markedly hyperplastic, the organ weights exceeding the female, which in turn were greater than in the male. The enhanced weight of the thymus was shown to be due to increased numbers of cortisone-sensitive cells, the absolute number of cortisone-resistant cells remaining equivalent to normal males and females. Thus, the increased thymic weight of the female also resided in the cortisone-sensitive population. Peripheral lymphocyte counts in castrated animals exceeded both normal males and females. Further experiments in gonadectomized males provided evidence that increased thymic cell activity per se played a role in enhanced response to thymus-dependent antigens, but that a thymic-derived hormone mediated the enhanced effect to the thymus-independent antigen in the castrated animal. The capacity for loss of androgenic hormone-producing tissue to generate enhanced differentiation of stem cells was denoted by experiments in which numbers of spleen colonies and uptake of (59)Fe, employed as an index of hematopoiesis 1 wk after reconstitution of lethally irradiated castrated and normal recipients, were enhanced in gonadectomized male animals. Thus, in summary, changes in sex hormone levels exerted a marked influence on immune responsiveness and stem cell differentiation, by increasing numbers of functioning cells, by promoting cellular differentiation, as well as by promoting cellular function via hormonal effects.
Arteriogenesis Is Modulated By Bradykinin Receptor Signaling
Authors: Philipp Hillmeister, Nora Gatzke, André Dülsner, Michael Bader, Ines Schadock, Imo Hoefer, Isabell Hamann, Carmen Infante-Duarte, Georg Jung, Kerstin Troidl, Daniel Urban, Philipp Stawowy, Marco Frentsch, Meijing Li, Stephanie Nagorka, Haitao Wang, Yu Shi, Ferdinand le Noble, Ivo Buschmann
Journal: Circulation Research (2011)

Positive outward remodeling of pre-existing collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent cardiovascular ischemia. Collateral arterial growth is accompanied by expression of kinin precursor. However, the role of kinin signaling via the kinin receptors (B1R and B2R) in arteriogenesis is unclear.The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis.Bradykinin receptors positively affected arteriogenesis, with the contribution of B1R being more pronounced than B2R. In mice, arteriogenesis upon femoral artery occlusion was significantly reduced in B1R mutant mice as evidenced by reduced microspheres and laser Doppler flow perfusion measurements. Transplantation of wild-type bone marrow cells into irradiated B1R mutant mice restored arteriogenesis, whereas bone marrow chimeric mice generated by reconstituting wild-type mice with B1R mutant bone marrow showed reduced arteriogenesis after femoral artery occlusion. In the rat brain 3-vessel occlusion arteriogenesis model, pharmacological blockade of B1R inhibited arteriogenesis and stimulation of B1R enhanced arteriogenesis. In the rat, femoral artery ligation combined with arterial venous shunt model resulted in flow-driven arteriogenesis, and treatment with B1R antagonist R715 decreased vascular remodeling and leukocyte invasion (monocytes) into the perivascular tissue. In monocyte migration assays, in vitro B1R agonists enhanced migration of monocytes.Kinin receptors act as positive modulators of arteriogenesis in mice and rats. B1R can be blocked or therapeutically stimulated by B1R antagonists or agonists, respectively, involving a contribution of peripheral immune cells (monocytes) linking hemodynamic conditions with inflammatory pathways.
Impact of patatin-like phospholipase-3 (rs738409 C&gt;G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C
Authors: Eric Trépo, Pierre Pradat, Andrej Potthoff, Yukihide Momozawa, Eric Quertinmont, Thierry Gustot, Arnaud Lemmers, Pascale Berthillon, Leila Amininejad, Michéle Chevallier, Jerome Schlué, Hans Kreipe, Jacques Devière, Michael Manns, Christian Trépo, John Sninsky, Heiner Wedemeyer, Denis Franchimont, Christophe Moreno
Journal: Hepatology (2011)

Abstract: Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C&gt;G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n = 229]; Hannover, Germany [n = 171]; Lyon, France [n = 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C&gt;G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C&gt;T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08–6.03, P = 0.034), fibrosis (OR 3.13, 95% CI 1.50–6.51, P = 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22–5.67, P = 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46–2.49, P = 0.875) and did not influence clinical or biological variables. Conclusion: The PNPLA3 (rs738409 C&gt;G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage. (HEPATOLOGY 2011;)
Role of Specific Glycopeptides of Human Serum Lipoproteins in the Activation of Lipoprotein Lipase
Authors: RICHARD J. HAVEL, VIRGIE G. SHORE, BERNARD SHORE, DENNIS M. BIER
Journal: Circulation Research (1970)

Lipoprotein lipase forms an enzyme-substrate complex with fat emulsions in the presence of serum lipoproteins. Lipoproteins of very low density and high density have this property, but the former are much more active per unit weight of protein. In this investigation, the activity, expressed as quantity giving half-maximal rate of production of free fatty acids, of specific glycopeptides isolated from very low density and high density lipoproteins was tested in an incubation mixture containing lipoprotein lipase from cows' milk and 1.8 mg triglyceride per ml. The two major polypeptides of high density lipoproteins were virtually inactive in amounts up to 100 µg per ml. Activity of the unfractionated apoproteins of very low density lipoprotein was similar to that of the native lipoprotein (about 4 µg/ml). Two of its polypeptides were active: one with carboxyl-terminal glutamic acid at 0.45 to 0.60µg/ml and one with carboxyl-terminal alanine at 1.8.2.8 µg/ml. Some preparations of the latter peptide were less active and inhibited at high levels. Three other glycopeptides from very low density lipoprotein were inactive. Low density lipoprotein from subjects with primary biliary cirrhosis and a lipoprotein of density 1.04 to 1.06 from a subject with specific elevation of this fraction, both containing the active glycopeptides, had considerable activity (5 to 11 µg/ml). These studies indicate that specific glycopeptides are required for the action of lipoprotein lipase on emulsified triglycerides and suggest that they are important components of the mechanism for extra-hepatic utilization of plasma triglycerides.
Commentary: the British Thoracic Society guideline on pulmonary rehabilitation in adults
Authors: Charlotte E Bolton, Sally J Singh, Paul P Walker
Journal: Thorax (2013)

The first British Thoracic Society guideline on pulmonary rehabilitation in adults is published in the accompanying Thorax supplement. Focusing on delivery of a quality pulmonary rehabilitation service, the evidenced-based guideline encompasses recommendations on the composition of the service, referral of patients and who benefits, the expected patient-related outcome measures and markers, pulmonary rehabilitation following exacerbations, the post-rehabilitation period and areas requiring further research. In this commentary, we introduce the guideline and discuss pulmonary rehabilitation in the wider context of chronic disease management of respiratory patients.
H7N9: Preparing for the Unexpected in Influenza
Authors: Daniel B. Jernigan, Nancy J. Cox
Journal: Annual Review of Medicine (2014)

In the years prior to 2013, avian influenza A H7 viruses were a cause of significant poultry mortality; however, human illness was generally mild. In March 2013, a novel influenza A(H7N9) virus emerged in China as an unexpected cause of severe human illness with 36% mortality. Chinese and other public health officials responded quickly, characterizing the virus and identifying more than 400 cases through use of new technologies and surveillance tools made possible by past preparedness and response efforts. Genetic sequencing, glycan-array receptor-binding assays, and ferret studies reveal the H7N9 virus to have increased binding to mammalian respiratory cells and to have mutations associated with higher virus replication rates and illness severity. New risk-assessment tools indicate H7N9 has the potential for further mammalian adaptation with possible human-to-human transmission. Vigilant virologic and epidemiologic surveillance is needed to monitor H7N9 and detect other unexpected novel influenza viruses that may emerge.
NPM-ALK–dependent expression of the transcription factor CCAAT/enhancer binding protein β in ALK-positive anaplastic large cell lymphoma
Authors: Leticia Quintanilla-Martinez, Stefania Pittaluga, Cornelius Miething, Margit Klier, Martina Rudelius, Theresa Davies-Hill, Natasa Anastasov, Antonio Martinez, Angelica Vivero, Justus Duyster, Elaine S. Jaffe, Falko Fend, Mark Raffeld
Journal: Blood (2006)