tbuckley/cabot-search huggingface dataset:
Increased Cytosine DNA-Methyltransferase Activity During Colon Cancer Progression
Authors: J.-P. J. Issa, P. M. Vertino, J. Wu, S. Sazawal, P. Celano, B. D. Nelkin, S. R. Hamilton, S. B. Baylin
Journal: JNCI Journal of the National Cancer Institute (1993)

Molecular changes during progressive stages of colon cancer and other human tumors commonly involve altered regulation of DNA methylation. These changes include overall genomic hypomethylation, regional hypermethylation, and increased levels of messenger RNA (mRNA) for cytosine DNA-methyltransferase (DNA-MTase), the enzyme that catalyzes DNA methylation at CpG (cytosine-phospho-guanine) sites. This increase in DNA-MTase transcripts (mRNA), if accompanied by increased DNA-MTase activity, could play a role in the abnormal DNA methylation patterns that appear early in colon tumor progression.We sought to determine whether increased DNA-MTase mRNA levels during colon cancer progression are associated with increased cellular DNA-MTase enzymatic activity.We adapted a microassay for DNA-MTase and used it to measure activity in human colon carcinoma and in colon mucosa of normal control subjects and of patients with colon cancer or with familial adenomatous polyposis (FAP), which is a risk factor for colon cancer. Steady-state DNA-MTase gene transcripts were measured by a reverse transcriptase polymerase chain reaction assay. To compare DNA-MTase activity with mRNA levels, we determined both variables simultaneously for one colon cancer specimen, its adjacent mucosa, and the colon mucosa of a control patient and compared the values.Compared with DNA-MTase activity in mucosa from normal control subjects, activity was elevated 1.4-fold in FAP mucosa, 1.6-fold in the uninvolved mucosa of patients with cancer, and 5.4-fold in the cancer specimens. All these differences were statistically significant. Fourteen of 15 cancer samples and 47% of the uninvolved adjacent mucosa samples had values that were higher than the highest value in normal mucosa. In one patient who had both a benign adenomatous polyp and a malignant adenocarcinoma, increasing DNA-MTase activity was observed at each stage of tumor progression.These results demonstrate that an increased DNA methylation capacity accompanies the increase in DNA-MTase transcripts observed during progressive stages of colon cancer.Further studies are needed to determine whether this abnormal methylation capacity plays a role in establishing the abnormal DNA methylation patterns seen in human malignancies.
Effect of a Low–Resource-Intensive Lifestyle Modification Program Incorporating Gymnasium-Based and Home-Based Resistance Training on Type 2 Diabetes Risk in Australian Adults
Authors: Warren R. Payne, Kerry J. Walsh, Jack T. Harvey, Michelle F. Livy, Kylie J. McKenzie, Alex Donaldson, Meredith G. Atkinson, Jennifer B. Keogh, Robert S. Moss, David W. Dunstan, Wendy A. Hubbard
Journal: Diabetes Care (2008)

The purpose of this study was to assess the effectiveness of a low-resource-intensive lifestyle modification program incorporating resistance training and to compare a gymnasium-based with a home-based resistance training program on diabetes diagnosis status and risk.A quasi-experimental two-group study was undertaken with 122 participants with diabetes risk factors; 36.9% had impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) at baseline. The intervention included a 6-week group self-management education program, a gymnasium-based or home-based 12-week resistance training program, and a 34-week maintenance program. Fasting plasma glucose (FPG) and 2-h plasma glucose, blood lipids, blood pressure, body composition, physical activity, and diet were assessed at baseline and week 52.Mean 2-h plasma glucose and FPG fell by 0.34 mmol/l (95% CI -0.60 to -0.08) and 0.15 mmol/l (-0.23 to -0.07), respectively. The proportion of participants with IFG or IGT decreased from 36.9 to 23.0% (P = 0.006). Mean weight loss was 4.07 kg (-4.99 to -3.15). The only significant difference between resistance training groups was a greater reduction in systolic blood pressure for the gymnasium-based group (P = 0.008).This intervention significantly improved diabetes diagnostic status and reduced diabetes risk to a degree comparable to that of other low-resource-intensive lifestyle modification programs and more intensive interventions applied to individuals with IGT. The effects of home-based and gymnasium-based resistance training did not differ significantly.
Positive Selection on Multiple Antique Allelic Lineages of Transferrin in the Polyploid Carassius auratus
Authors: L. Yang
Journal: Molecular Biology and Evolution (2004)

Transferrin polymorphism has been studied in the polyploid Carassius auratus by cloning and sequence analysis of cDNAs from its three subspecies C. auratus gibelio, C. auratus auratus, and C. auratus cuvieri. DNA polymorphism of extremely high extent was shown for the transferrin gene by the 248 segregation sites among coding region sequences of its alleles. The deduced amino acid sequences of the transferrin alleles showed variable theoretical physicochemical parameters, which might constitute molecular basis for their electrophoretic heterogeneity. Positive selection was inferred by the replacement/synonymous ratios larger than 1 in partial allelic lineages which was subsequently confirmed by likelihood simulation under neutral or selection models. Furthermore, the correspondent sites to these selected codons were collectively located at two planes in the crystallographic structure of rabbit transferrin, which suggested that the rapid evolution of C. auratus transferrin might correlate to its adaptation to variable environmental elements such as oxygen pressure. The minimal 26 recombination events were detected among coding sequences of C. auratus transferrin, with partial mosaic sequences and breakpoints identified by identity scanning and information site analyses. Phylogenetic analyses revealed multiple antique allelic lineages of transferrin, which was estimated to diverge fifteen to twenty MYA. All these features strongly suggested the role of balancing selection in long persistence of high transferrin polymorphism in C. auratus. Furthermore, owing to its particular evolutionary backgrounds, the silver crucian carp might possess a distinctive balancing selection mechanism.
Isolation, characterization, and localization of heparin-binding growth factors in the heart.
Authors: W Casscells, E Speir, J Sasse, M Klagsbrun, P Allen, M Lee, B Calvo, M Chiba, L Haggroth, J Folkman
Journal: Journal of Clinical Investigation (1990)

Acidic and basic fibroblast growth factors (aFGF and bFGF) are angiogenic polypeptide mitogens for cells of mesodermal and neuroectodermal origin. In this report we describe the purification from several normal human hearts (including a very fresh, nonischemic sample) of heparin-binding, acid-, heat- and trypsin-sensitive 14-18-kD peptides that crossreact with antisera against aFGF and bFGF. Further evidence includes (a) prevention of mitogenicity by protamine and by anti-bFGF, (b) displacement of 125I-bFGF from cell membranes, and (c) stimulation of capillary endothelial cell migration. Specific immunohistochemistry localized bFGF to endothelial cells and, surprisingly, to cardiac myocytes, with almost no immunoreactivity in smooth muscle cells. These peptides may function in cardiac embryogenesis, hypertrophy, atherogenesis, angiogenesis, and wound healing, and may also have endocrine, neurotropic, or vasomotor functions.
Fundoplication eliminates chronic cough due to non-acid reflux identified by impedance pH monitoring
Authors: I Mainie
Journal: Thorax (2005)

The symptoms of extra-oesophageal gastro-oesophageal reflux disease (GORD) (such as chronic cough and hoarseness) are traditionally more difficult to treat than typical GORD symptoms (heartburn and regurgitation). Patients with extra-oesophageal manifestations may require longer and higher doses of acid suppressive therapy. In patients not responding to acid suppressive therapy the physician faces a dilemma as to whether the symptoms are due to ongoing acid reflux, non-acid reflux, or not associated with reflux. We report the case of a 45 year old woman with a history of a chronic cough referred for fundoplication after documenting her symptoms were associated with non-acid reflux using multichannel intraluminal impedance and pH (MII-pH).
Safety and performance of the drug-eluting absorbable metal scaffold (DREAMS) in patients with de-novo coronary lesions: 12 month results of the prospective, multicentre, first-in-man BIOSOLVE-I trial
Authors: Michael Haude, Raimund Erbel, Paul Erne, Stefan Verheye, Hubertus Degen, Dirk Böse, Paul Vermeersch, Inge Wijnbergen, Neil Weissman, Francesco Prati, Ron Waksman, Jacques Koolen
Journal: The Lancet (2013)
Prevention of Intraoperative Awareness in a High-Risk Surgical Population
Authors: Michael S. Avidan, Eric Jacobsohn, David Glick, Beth A. Burnside, Lini Zhang, Alex Villafranca, Leah Karl, Saima Kamal, Brian Torres, Michael O'Connor, Alex S. Evers, Stephen Gradwohl, Nan Lin, Ben J. Palanca, George A. Mashour
Journal: New England Journal of Medicine (2011)

Unintended intraoperative awareness, which occurs when general anesthesia is not achieved or maintained, affects up to 1% of patients at high risk for this complication. We tested the hypothesis that a protocol incorporating the electroencephalogram-derived bispectral index (BIS) is superior to a protocol incorporating standard monitoring of end-tidal anesthetic-agent concentration (ETAC) for the prevention of awareness.
Concerted Evolution of Duplicated Control Regions within an Ostracod Mitochondrial Genome
Authors: Katsunori Ogoh, Yoshihiro Ohmiya
Journal: Molecular Biology and Evolution (2006)

The luminescent marine ostracod Vargula hilgendorfii comprises distinct populations around the Japanese islands. Its mitochondrial DNA is unusual, with duplicated control regions (CRs; CR#1 and CR#2). We determined the sequences of ostracod CRs in 7 different populations. The sequences of CR#1 and CR#2 within any population were extremely similar, above 99.7%; moreover, their derived evolutionary tree indicates that the pairs of CRs have evolved in concert within each mitochondrial genome. These results suggest that an exact replication mechanism controls the concerted evolution of CRs.
Population need for renal replacement therapy in Thames regions: ethnic dimension
Authors: P J Roderick, I Jones, V S Raleigh, M McGeown, N Mallick
Journal: BMJ (1994)

<h3>Abstract</h3> <b>Objectives</b>: To determine the use of renal replacement therapy by ethnic origin and to ascertain the variation in provision of such therapy and to relate this to the distribution of ethnic minority populations. Design- Analysis of retrospective and cross20sectional data from 19 renal units. <b>Setting</b>: All four Thames regional health authorities. Subjects - Patients resident in the Thames regions who were accepted as new patients for renal replacement therapy during 1991 and 1992 and the patients who were already undergoing such treatment between December 1992 and April 1993. <b>Main outcome measures</b>: Rates of acceptance for and prevalence of renal replacement therapy among white, black, and Asian people. Results - The average annual acceptance rates per million in 1991-2 were 61 for white people, 175 for black people, and 178 for Asians, and the prevalences per million were 351, 918, and 957 respectively. The relative risks increased with age. A threefold increase in the acceptance rate occurred in people aged under 55 in both the black and Asian populations, suggesting that the higher rates are probably not due to factors related to access alone. Treatment rates varied considerably among districts, reflecting both the distribution of ethnic minority populations and access to services. <b>Conclusion</b>: Black and Asian people receive and20have a greater need for renal replacement therapy,20and the need will increase as these populations age.20These findings have important implications for the provision of renal services in districts with a high proportion of ethnic minorities and for the management of diabetes mellitus and hypertension, two important causes of end stage renal failure in these populations.
Calcineurin?NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs
Authors: J MOLKENTIN
Journal: Cardiovascular Research (2004)

Prolonged cardiac hypertrophy of pathologic etiology is associated with arrhythmia, sudden death, decompensation, and dilated cardiomyopathy. In an attempt to understand the mechanisms that underlie the hypertrophic response, extensive investigation has centered on a characterization of the molecular pathways that initiate or maintain the pathologic growth of individual cardiac myocytes. While a large number of signal transduction cascades have been identified as critical regulators of cardiac hypertrophy, here the scientific evidence implicating the protein phosphatase calcineurin (PP2B) and the mitogen-activated protein kinases (MAPK) as co-regulators of reactive hypertrophy will be discussed. Gain- and loss-of-function studies in genetically altered mice and in cultured cardiomyocytes have demonstrated the necessity and sufficiency of calcineurin to regulate pathologic cardiac hypertrophy. However, using similar approaches, the hypertrophic regulatory role attributed to various branches of the MAPK signaling pathway has been less conclusive, although a loose consensus suggests that the c-Jun N-terminal kinases (JNK) and p38 kinases function as mediators of dilated cardiomyopathy, while extracellular signal-regulated kinases (ERKs) function as regulators of hypertrophy. More recently, the actions of calcineurin and MAPK signaling pathways have been shown to be co-dependent such that unitary activation of calcineurin in myocytes leads to up-regulation in ERK and JNK signaling, but down-regulation in p38 signaling. Conversely, unitary activation of JNK or p38 in cardiac myocytes leads to down-regulation of calcineurin effectiveness by directly antagonizing nuclear factor of activated T cells (NFAT) nuclear occupancy. Thus, an emerging paradigm suggests that calcineurin-NFAT and MAPK signaling pathways are inter-dependent and together orchestrate the cardiac hypertrophic response.
Spinal Glioma: Platelet-Derived Growth Factor B–Mediated Oncogenesis in the Spinal Cord
Authors: Yasuyuki Hitoshi, Brent T. Harris, Huan Liu, Brian Popko, Mark A. Israel
Journal: Cancer Research (2008)

Abstract Human platelet-derived growth factor B (hPDGFB) has been characterized in vitro and shown to mediate numerous cellular responses including glial proliferation and differentiation. Expression of PDGFB is thought to be important in the pathogenesis of glioma and several animal models of cerebral glioma based on PDGF expression have been described. To examine whether PDGF could contribute to the pathogenesis of spinal cord glioma, we developed transgenic mice that express hPDGFB under the control of a tetracycline-responsive element (TRE/hPDGFB). These TRE/hPDGFB mice were mated with transgenic mice expressing the tetracycline transcriptional activator (tet-off), tTA, regulated by the human glial fibrillary acidic protein (GFAP) promoter and exhibiting uniquely strong promoter activity in the spinal cord. These transgenic mice (GFAP/tTA:TRE/hPDGFB) expressed hPDGFB in GFAP-expressing glia in a manner responsive to doxycycline administration. Without doxycycline, almost all GFAP/tTA:TRE/hPDGFB mice developed spinal cord neoplasms resembling human mixed oligoastrocytoma. Tumorigenesis in these animals was suppressed by doxycycline. To further examine the importance of PDGFB in mouse primary intramedullary spinal cord tumors, we also created transgenic mice expressing hPDGFB under the control of the human GFAP promoter (GFAP/hPDGFB). These GFAP/hPDGFB mice also developed spinal oligoastrocytoma. PDGFB can mediate the development of mouse spinal tumors that are histologically and pathologically indistinguishable from primary intramedullary spinal tumors of humans and may provide opportunities for both novel insights into the pathogenesis of these tumors and the development of new therapeutics. [Cancer Res 2008;68(20):8507–15]
Exciting news: catecholamines in induction and regionalization of the heart
Authors: T. Brand
Journal: Cardiovascular Research (2010)

This editorial refers to ‘Tyrosine hydroxylase is expressed during early heart development and is required for cardiac chamber formation’ by C. Lopez-Sanchez, doi:10.1093/cvr/cvq179 

The heart develops in the anterior half of the vertebrate embryo. Soon after gastrulation has commenced, the heart starts to develop from cells that are part of the splanchnic layer of the lateral plate mesoderm ( Figure 1 ).1 The identification of molecules involved in cardiac induction in the embryo is of great interest, since these are same as those that would be required to efficiently control cardiac differentiation in stem cells. Thus, the knowledge gained in embryos appears to be directly relevant for regenerative medicine.2 



Figure 1 
Signalling molecules involved in cardiac specification. ( A ) Depicted is a schematized chick embryo at mid-gastrulation. The left ventricular portion of the heart derives from two heart fields (red) that are bilaterally organized in the anterior half of the embryo. Other parts of the heart (right ventricle, outflow tract, and atria) will form from precursors, which are positioned more medially (orange area). ( B ) Schematic depiction of a transversal section through the heart field region. The heart fields (red) are part of the splanchnic layer of the lateral plate mesoderm (light blue). Inducing factors that are involved in cardiac specification are mostly derived from the foregut endoderm (dark green), which is part of the … 



*Corresponding author. Tel: +44 1895 453 826, fax: +44 1895 828 900, Email: tbrand{at}imperial.ac.uk
Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver
Authors: R Jalan
Journal: Gut (2003)

In patients with cirrhosis, hepatic encephalopathy is often precipitated by dehydration. This study tests the hypothesis that volume expansion in cirrhotic patients increases renal ammonia excretion.Sixteen well compensated cirrhotic patients (mean Pugh score 6.7 (SEM 0.4)) were studied after an overnight fast. One litre of 0.9% saline was administered to patients intravenously over one hour. Plasma and urinary ammonia and sodium, renal plasma flow (RPF), glomerular filtration rate (GFR), plasma renin activity (PRA), and angiotensin II (ANG II) were measured before, during, and two hours after saline infusion.Saline infusion resulted in a significant reduction in plasma ammonia (93 (SEM 7) to 56 (4) micromol/l; p<0.05) and RPF and GFR increased (p<0.05). Urinary ammonia excretion increased (p<0.05) significantly. There was a significant reduction in ANG II and PRA (p<0.05 for each) and the change in ammonia excretion correlated directly with the change in urinary sodium excretion (p<0.007), ANG II (p<0.002), and PRA (p<0.01). The mean increase in urinary ammonia excretion during the observation period was 1.08 mmol. Assuming a volume of distribution of 45 litres, the corresponding change in whole body ammonia during the same period was 1.67 mmol.The results of this study suggest that volume expansion reduces plasma ammonia concentration by increasing ammonia excretion and reducing ammoniagenesis.
Body Mass Index Increases Risk of Colorectal Adenomas in Men With Lynch Syndrome: The GEOLynch Cohort Study
Authors: Akke Botma, Fokko M. Nagengast, Marieke G.M. Braem, Jan C.M. Hendriks, Jan H. Kleibeuker, Hans F.A. Vasen, Ellen Kampman
Journal: Journal of Clinical Oncology (2010)

High body mass index (BMI) is an established risk factor for sporadic colorectal cancer. Still, the influence of BMI on hereditary colorectal cancer (eg, Lynch syndrome [LS]), is unknown. The objective of this study was to assess whether BMI is associated with colorectal adenoma occurrence in persons with LS.A prospective cohort study of 486 patients with LS was conducted. Cox regression models with robust sandwich estimates controlling for age, sex, extent of colon surgery, smoking, and alcohol intake were used to evaluate associations between BMI, height, weight, weight change, and risk of colorectal adenomas. Analyses were performed separately for those without (incident cohort; n = 243) and those with (prevalent cohort; n = 243) a history of colorectal cancer neoplasms at baseline.A statistically significant association between current overweight (≥ 25 kg/m(2)) and developing colorectal adenomas was seen among men in the incident cohort (overweight v normal weight hazard ratio [HR], 8.72; 95% CI, 2.06 to 36.96). This association was not observed among women (overweight v normal weight HR, 0.75; 95% CI, 0.19 to 3.07), nor was it observed in the prevalent cohort. In the incident cohort, height was statistically significantly associated with a decreased risk of adenomatous polyps among men (per 5 cm HR, 0.43; 95% CI, 0.23 to 0.83), but the association between weight and adenomatous polyps among men was of marginal significance (per 5 kg HR, 1.17; 95% CI, 1.00 to 1.37). No statistically significant associations were observed among women in either the incident cohort or the prevalent cohort.Excess body weight increased the risk of incident colorectal adenomas in people with LS. This increased risk was seen only in men.
MicroRNAs and respiratory diseases
Authors: Hitasha Rupani, Tilman Sanchez-Elsner, Peter Howarth
Journal: European Respiratory Journal (2012)

MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that modulate physiological and pathological processes by post-transcriptional inhibition of gene expression. They were first recognised as regulators of development in worms and fruitflies. In recent years extensive research has explored their pivotal role in the pathogenesis of human diseases. Over 1,000 human miRNAs have been discovered to date; however, the biological function and protein targets for the majority remain to be uncovered. Within the respiratory system, miRNAs are important in normal pulmonary development and maintaining lung homeostasis. Recent studies have also begun to reveal that altered miRNA expression profiles may be associated with pathological processes within the lung and lead to the development of various pulmonary diseases, ranging from inflammatory diseases to lung cancers. Advancing our understanding of the role of miRNAs in the respiratory system will help provide new perspectives on disease mechanisms and reveal intriguing therapeutic targets and diagnostic markers for respiratory disorders.
Transferrin receptors on the human placental microvillous membrane.
Authors: T T Loh, D A Higuchi, F M van Bockxmeer, C H Smith, E B Brown
Journal: Journal of Clinical Investigation (1980)

A preparation of microvillous membrane vesicles from human placental syncytiotrophoblast binds transferrin to specific transferrin receptors. Transferrin binding to placental receptors is rapid, saturable, reversible, and specific. Approximately 2.5 X 10(13) receptors are present per milligram of membrane protein; the apparent association constant of transferrin for the placental receptor is 2.2 X 10(7) X M-1. No evidence for removal of iron from transferrin bound to intact membrane receptors was observed in these studies. Nonionic detergent solubilization and partial purification of the microvillous membrane transferrin receptor were carried out with preservation of the functional properties of the receptor.