tbuckley/cabot-search huggingface dataset:
Reduced Endothelial Nitric Oxide Synthase Expression and Production in Human Atherosclerosis
Authors: Barry S. Oemar, Marcel R. Tschudi, Nelson Godoy, Victor Brovkovich, Tadeusz Malinski, Thomas F. Lüscher
Journal: Circulation (1998)

Background —NO regulates vascular tone and structure, platelets, and monocytes. NO is synthesized by endothelial NO synthase (eNOS). Endothelial dysfunction occurs in atherosclerosis. Methods and Results —With a porphyrinic microsensor, NO release was measured in atherosclerotic human carotid arteries and normal mammary arteries obtained during surgery. eNOS protein expression was analyzed by immunohistochemistry. In normal arteries, the initial rate of NO release after stimulation with calcium ionophore A23187 (10 μmol/L) was 0.42±0.05 (μmol/L)/s (n=10). In contrast, the initial rate of NO release was markedly reduced in atherosclerotic segments, to 0.08±0.04 (μmol/L)/s (n=10, P &lt;0.0001). NO peak concentration in normal arteries was 0.9±0.09 μmol/L (n=10) and in atherosclerotic segments, 0.1±0.03 μmol/L (n=10, P &lt;0.0001). Reduced NO release in atherosclerotic segments was accompanied by marked reduction of immunoreactive eNOS in luminal endothelial cells, although specific endothelial cell markers (CD31) were present (n=13). Endothelial cells of vasa vasorum of atherosclerotic segments, however, remained positive for eNOS, as was the endothelium of normal arteries. Conclusions —In clinically relevant human atherosclerosis, eNOS protein expression and NO release are markedly reduced. This may be involved in the progression of atherosclerosis.
Development, Progression, and Regression of Microalbuminuria in Japanese Patients With Type 2 Diabetes Under Tight Glycemic and Blood Pressure Control
Authors: Takashi Yamada, Mitsuhisa Komatsu, Ichiro Komiya, Yasuhiro Miyahara, Yukino Shima, Mitsuko Matsuzaki, Yuka Ishikawa, Reiko Mita, Mika Fujiwara, Nobuko Furusato, Kazue Nishi, Toru Aizawa
Journal: Diabetes Care (2005)

OBJECTIVE— The goal of this study was to know the fate of albuminuria in Japanese patients with type 2 diabetes under tight blood pressure and glycemic control. RESEARCH DESIGN AND METHODS— Patients having normoalbuminuria (urinary albumin excretion &amp;lt;30 mg/g creatinine, n = 179) or microalbuminuria (albumin excretion 30–299 mg/g creatinine, n = 94) at baseline have been followed up for 8 years: ratio of men to women was 160/113, the mean age was 58 years, pretreatment HbA1c (A1C) was 8.8%, and blood pressure was 136/76 mmHg. A1C &amp;lt;6.5% and blood pressure &amp;lt;130/80 mmHg were targeted, and the A1C of 6.5 ± 0.7% (mean ± SD) and blood pressure of 127 ± 11/72 ± 6 mmHg have been maintained during the 8 years. Development of microalbuminuria or macroalbuminuria (albumin excretion ≥300 mg/g creatinine) in initially normoalbuminuric patients and progression to macroalbuminuria or regression to normoalbuminuria in initially microalbuminuric patients were assessed at year 8. RESULTS— Development occurred in 27 (15%) of the normoalbuminuric patients and progression and regression in 16 (17%) and 20 (21%), respectively, of the microalbuminuric patients. Significant independent relationships existed between development and higher achieved mean systolic blood pressure (SBP) and regression and lower achieved mean SBP. In the patients with achieved mean SBP &amp;lt;120 mmHg, development was 3%, progression was 11%, and regression was 44% during 8 years. Prediction for nephropathy by blood pressure and glycemia alone was limited. Nevertheless, albumin excretion at year 8 was positively correlated with achieved mean SBP and baseline albuminuria. CONCLUSIONS— Development and progression were low and regression was high with SBP of 120 mmHg, provided A1C was maintained at 6.5%.
The interactome of the amyloid β precursor protein family members is shaped by phosphorylation of their intracellular domains
Authors: Robert Tamayev, Dawang Zhou, Luciano D'Adamio
Journal: Molecular Neurodegeneration (2009)

Brain tissue from patients with Alzheimer's disease has shown an increase of phosphorylation of Tyr-682, located on the conserved Y682ENPTY motif, and Thr-668 residues, both in the intracellular domain (AID) of amyloid beta precursor protein (APP), although the role of these two residues is not yet known.Here, we report that the phosphorylation status of Tyr-682, and in some cases Thr-668, shapes the APP interactome. It creates a docking site for SH2-domain containing proteins, such as ShcA, ShcB, ShcC, Grb7, Grb2, as well as adapter proteins, such as Crk and Nck, that regulate important biological processes, cytosolic tyrosine kinases, such as Abl, Lyn and Src, which regulate signal transduction pathways, and enzymes that control phosphatidylinositols levels and signaling, such as PLC-gamma. At the same time, it either reduces (like for JIP1, NUMB, NUMBL and ARH) or abolishes (like for Fe65, Fe65L1 and Fe65L2) binding of other APP interactors. Phosphorylation of Thr-668, unlike Tyr-682, does not seem to affect APP's ability to interact with the various proteins, with Pin1 and X11 being the exclusions. We also found that there are some differences between the interactions to AID and to ALID1 and ALID2, its two homologues.Our data indicates that APP can regulate diverse cellular processes and that, vice versa, a network of signaling events can impact APP processing. Our results also suggest that phosphorylation of the APP Intracellular Domain will dramatically shape the APP interactome and, consequently, will regulate APP processing, APP transport and APP/AID-mediated functions.
Ambulatory 24 hour intraesophageal pH-monitoring in the diagnosis of gastroesophageal reflux disease.
Authors: F Johnsson, B Joelsson, P E Isberg
Journal: Gut (1987)

The results of ambulatory 24 hour oesophageal pH monitoring in 20 patients with established gastro-oesophageal reflux disease were compared with those of 20 healthy individuals with normal endoscopy. Cut off limits of pH 3, 4, and 5 were superior to pH 2 with respect to the discrimination of patients from normal subjects, and for the detection of pathological reflux. Using pH 4 as a cut off limit, the ambulant and recumbent periods of pH monitoring were more discriminatory than the postprandial period. Furthermore, it was possible to get complete separation between patients and normal subjects using several combinations of two reflux variables. Another group of 30 patients and 30 controls were investigated. Using percentage time at pH less than 4 as a single determinant of gastro-oesophageal reflux, the sensitivity and specificity were 87% and 97%, respectively, with 3.4% as upper limit for normality. Twenty four hour oesophageal pH monitoring in an ambulatory outpatient environment afforded clinically useful diagnostic accuracy in separating patients with gastro-oesophageal reflux disease from asymptomatic controls.
Quantitative Assessment of Left Ventricular Size and Function
Authors: Lissa Sugeng, Victor Mor-Avi, Lynn Weinert, Johannes Niel, Christian Ebner, Regina Steringer-Mascherbauer, Frank Schmidt, Christian Galuschky, Georg Schummers, Roberto M. Lang, Hans-Joachim Nesser
Journal: Circulation (2006)

Background— Cardiac CT (CCT) and real-time 3D echocardiography (RT3DE) are being used increasingly in clinical cardiology. CCT offers superb spatial and contrast resolution, resulting in excellent endocardial definition. RT3DE has the advantages of low cost, portability, and live 3D imaging without offline reconstruction. We sought to compare both CCT and RT3DE measurements of left ventricular size and function with the standard reference technique, cardiac MR (CMR). Methods and Results— In 31 patients, RT3DE data sets (Philips 7500) and long-axis CMR (Siemens, 1.5 T) and CCT (Toshiba, 16-slice MDCT) images were obtained on the same day without β-blockers. All images were analyzed to obtain end-systolic and end-diastolic volumes and ejection fractions using the same rotational analysis to eliminate possible analysis-related differences. Intertechnique agreement was tested through linear regression and Bland-Altman analyses. Repeated measurements were performed to determine intraobserver and interobserver variability. Both CCT and RT3DE measurements resulted in high correlation ( r 2 &gt;0.85) compared with CMR. However, CCT significantly overestimated end-diastolic and end-systolic volumes (26 and 19 mL; P &lt;0.05), resulting in a small but significant bias in ejection fraction (−2.8%). RT3DE underestimated end-diastolic and end-systolic volumes only slightly (5 and 6 mL), with no significant bias in EF (0.3%; P =0.68). The limits of agreement with CMR were comparable for the 2 techniques. The variability in the CCT measurements was roughly half of that in either RT3DE or CMR values. Conclusions— CCT provides highly reproducible measurements of left ventricular volumes, which are significantly larger than CMR values. RT3DE measurements compared more favorably with the CMR reference, albeit with higher variability.
The Human Cytomegalovirus–Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2
Authors: David Maussang, Ellen Langemeijer, Carlos P. Fitzsimons, Marijke Stigter-van Walsum, Remco Dijkman, Martin K. Borg, Erik Slinger, Andreas Schreiber, Detlef Michel, Cornelis P. Tensen, Guus A.M.S. van Dongen, Rob Leurs, Martine J. Smit
Journal: Cancer Research (2009)

The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes the constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-kappaB, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2. Finally, the involvement of COX-2 in US28-mediated tumor formation was evaluated using the COX-2 selective inhibitor Celecoxib. Targeting COX-2 in vivo with Celecoxib led to a marked delay in the onset of tumor formation in nude mice injected with US28-transfected NIH-3T3 cells and a reduction of subsequent growth by repressing the US28-induced angiogenic activity. Hence, the development of HCMV-related proliferative diseases may partially be ascribed to the ability of US28 to activate COX-2.
Choices Following Antigen Entry: Antibody Formation or Immunologic Tolerance?
Authors: G. J. V. Nossal
Journal: Annual Review of Immunology (1995)

The research briefly summarized here covers 38 years of work in cellular immunology, briefly devoted to understanding how antigen subserves the antithetical functions of stimulating antibody formation and inducing tolerance. The three interlocking themes running through the work are the development of methods to beat the problem of heterogeneity among lymphocytes by studying single cells and single clones; critical pursuit of antigen-trapping patterns within lymphoid tissues and analysis of consequent cellular events; and construction of models of tolerance that permit the detection of events subtler than direct purging of the B cell repertoire. One of the best features of this adventure has been its international character, the interaction with colleagues in many countries, and the influence that this work, despite its entirely fundamental character, has exerted in the practical world of preventive and clinical medicine.
Accumulation of Ultrasmall Superparamagnetic Particles of Iron Oxide in Human Atherosclerotic Plaques
Authors: Rikin Trivedi, Jean U-King-Im, Jonathan Gillard
Journal: Circulation (2003)

We read with interest the recent article by Kooi et al, 1 reporting their experience with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging of carotid atheroma.This exploratory study holds promise for contrast-enhanced MR imaging of inflammatory lesions.We do express some reservations, however, regarding the authors' methodology, conclusions, and the quality of the MR images on which they base their findings.It is unclear exactly how many of the patients given USPIO had a positive effect (ie, area of new/increased signal-intensity reduction) and in how many MR images this was evident.The authors, having made an effort to correlate USPIO accumulation with ruptured/rupture-prone histological sections, failed to say whether this translated to a signal loss on corresponding MR images, which is an important consideration before advocating the use of this methodology to identify inflamed carotid plaques.The authors suggested that in one patient, no USPIOs had accumulated because of a short infusion-surgery interval of 3 days; yet they conclude that USPIO-induced signal intensity reduction was optimal at 24 hours.Additionally, it is difficult to determine why one patient was excluded, because the infusionsurgery interval was too long as USPIOs were still present in the plaque nonetheless.The authors' demonstration of USPIOs in the plaque, and their colocalization with macrophages, is commendable.We are concerned, however, that the authors have not shown the histological section corresponding to the axial MR images in which they claim to visualize the reduction in signal intensity (the images do not appear to be corresponding).Admittedly, the authors note that they were unable to adequately co-register histological sections with MR images, and they may have elected to provide a representative image.In light of the inadequacy of image correspondence, one must interpret the outcome of the relative signal intensity analysis with caution.The use of vessel wall quadrants as the user-defined area from which relative signal intensity measurements were taken is inherently susceptible to measurement error, and this is made worse by poor quality images.Perhaps greater weight could be added to their conclusions if the authors attempted to measure the agreement in user-defined areas between pre-and postinfusion images.Overall, we are encouraged that the authors found no difficulty in the usage of this USPIO agent and agree that the way has been paved for larger studies evaluating the utility of USPIOenhanced plaque imaging.
Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers
Authors: Elisabet Ognedal Berge, Stian Knappskog, Stephanie Geisler, Vidar Staalesen, Marec Pacal, Anne-Lise Børresen-Dale, Pål Puntervoll, Johan Richard Lillehaug, Per Eystein Lønning
Journal: Molecular Cancer (2010)

Abstract Background The tumor suppressor pRb plays a key role regulating cell cycle arrest, and disturbances in the RB1 gene have been reported in different cancer forms. However, the literature reports contradictory findings with respect to a pro - versus anti - apoptotic role of pRb, and the consequence of alterations in RB1 to chemotherapy sensitivity remains unclear. This study is part of a project investigating alterations in pivotal genes as predictive factors to chemotherapy sensitivity in breast cancer. Results Analyzing 73 locally advanced (stage III) breast cancers, we identified two somatic and one germline single nucleotide changes, each leading to amino acid substitution in the pRb protein (Leu607Ile, Arg698Trp, and Arg621Cys, respectively). This is the first study reporting point mutations affecting RB1 in breast cancer tissue. In addition, MLPA analysis revealed two large multiexon deletions (exons 13 to 27 and exons 21 to 23) with the exons 21-23 deletion occurring in the tumor also harboring the Leu607Ile mutation. Interestingly, Leu607Ile and Arg621Cys point mutations both localize to the spacer region of the pRb protein, a region previously shown to harbor somatic and germline mutations. Multiple sequence alignment across species indicates the spacer to be evolutionary conserved. All three RB1 point mutations encoded nuclear proteins with impaired ability to induce apoptosis compared to wild-type pRb in vitro . Notably, three out of four tumors harboring RB1 mutations displayed primary resistance to treatment with either 5-FU/mitomycin or doxorubicin while only 14 out of 64 tumors without mutations were resistant (p = 0.046). Conclusions Although rare, our findings suggest RB1 mutations to be of pathological importance potentially affecting sensitivity to mitomycin/anthracycline treatment in breast cancer.
Serum Uric Acid and Coronary Heart Disease in 9,458 Incident Cases and 155,084 Controls: Prospective Study and Meta-Analysis
Authors: Jeremy G Wheeler, Kelsey D. M Juzwishin, Gudny Eiriksdottir, Vilmundur Gudnason, John Danesh
Journal: PLoS Medicine (2005)

Background It has been suggested throughout the past fifty years that serum uric acid concentrations can help predict the future risk of coronary heart disease (CHD), but the epidemiological evidence is uncertain. Methods and Findings We report a “nested” case-control comparison within a prospective study in Reykjavik, Iceland, using baseline values of serum uric acid in 2,456 incident CHD cases and in 3,962 age- and sex-matched controls, plus paired serum uric acid measurements taken at baseline and, on average, 12 y later in 379 participants. In addition, we conducted a meta-analysis of 15 other prospective studies in eight countries conducted in essentially general populations. Compared with individuals in the bottom third of baseline measurements of serum uric acid in the Reykjavik study, those in the top third had an age- and sex-adjusted odds ratio for CHD of 1.39 (95% confidence interval [CI], 1.23–1.58) which fell to 1.12 (CI, 0.97–1.30) after adjustment for smoking and other established risk factors. Overall, in a combined analysis of 9,458 cases and 155,084 controls in all 16 relevant prospective studies, the odds ratio was 1.13 (CI, 1.07–1.20), but it was only 1.02 (CI, 0.91–1.14) in the eight studies with more complete adjustment for possible confounders. Conclusions Measurement of serum uric acid levels is unlikely to enhance usefully the prediction of CHD, and this factor is unlikely to be a major determinant of the disease in general populations.
Abundance and Distribution of Transposable Elements in Two Drosophila QTL Mapping Resources
Authors: Julie M. Cridland, Stuart J. Macdonald, Anthony D. Long, Kevin R. Thornton
Journal: Molecular Biology and Evolution (2013)

Here we present computational machinery to efficiently and accurately identify transposable element (TE) insertions in 146 next-generation sequenced inbred strains of Drosophila melanogaster. The panel of lines we use in our study is composed of strains from a pair of genetic mapping resources: the Drosophila Genetic Reference Panel (DGRP) and the Drosophila Synthetic Population Resource (DSPR). We identified 23,087 TE insertions in these lines, of which 83.3% are found in only one line. There are marked differences in the distribution of elements over the genome, with TEs found at higher densities on the X chromosome, and in regions of low recombination. We also identified many more TEs per base pair of intronic sequence and fewer TEs per base pair of exonic sequence than expected if TEs are located at random locations in the euchromatic genome. There was substantial variation in TE load across genes. For example, the paralogs derailed and derailed-2 show a significant difference in the number of TE insertions, potentially reflecting differences in the selection acting on these loci. When considering TE families, we find a very weak effect of gene family size on TE insertions per gene, indicating that as gene family size increases the number of TE insertions in a given gene within that family also increases. TEs are known to be associated with certain phenotypes, and our data will allow investigators using the DGRP and DSPR to assess the functional role of TE insertions in complex trait variation more generally. Notably, because most TEs are very rare and often private to a single line, causative TEs resulting in phenotypic differences among individuals may typically fail to replicate across mapping panels since individual elements are unlikely to segregate in both panels. Our data suggest that “burden tests” that test for the effect of TEs as a class may be more fruitful.
Cancers of the Colon and Rectum: Identical or Fraternal Twins?
Authors: Theodore S. Hong, Jeffrey W. Clark, Kevin M. Haigis
Journal: Cancer Discovery (2012)

Colorectal cancer represents a major cause of cancer morbidity and mortality, with approximately 1.2 million cases and 600,000 deaths worldwide each year. Because of the anatomic continuity of the colon into the rectum, cancers affecting these organs have historically been considered equivalent. In this Prospective, we discuss the clinical and experimental data suggesting that colon cancer and rectal cancer are highly related, but distinct, diseases. Reconsidering the relationship between these cancers has implications for the development of new therapeutic paradigms.
Atrial Natriuretic Peptide Inhibits Transforming Growth Factor β–Induced Smad Signaling and Myofibroblast Transformation in Mouse Cardiac Fibroblasts
Authors: Peng Li, Dajun Wang, Jason Lucas, Suzanne Oparil, Dongqi Xing, Xu Cao, Lea Novak, Matthew B. Renfrow, Yiu-Fai Chen
Journal: Circulation Research (2007)

This study tested the hypothesis that activation of atrial natriuretic peptide (ANP)/cGMP/protein kinase G signaling inhibits transforming growth factor (TGF)-beta1-induced extracellular matrix expression in cardiac fibroblasts and defined the specific site(s) at which this molecular merging of signaling pathways occurs. Left ventricular hypertrophy and fibrosis, collagen deposition, and myofibroblast transformation of cardiac fibroblasts in response to pressure overload by transverse aortic constriction were exaggerated in ANP-null mice compared with wild-type controls. ANP and cGMP inhibited TGF-beta1-induced myofibroblast transformation, proliferation, collagen synthesis, and plasminogen activator inhibitor-1 expression in cardiac fibroblasts isolated from wild-type mice. Following pretreatment with cGMP, TGF-beta1 induced phosphorylation of Smad3, but the resultant pSmad3 could not be translocated to the nucleus. pSmad3 that had been phosphorylated with recombinant protein kinase G-1alpha was analyzed by use of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and ion trap tandem mass spectrometry. The analysis revealed phosphorylation of Ser309 and Thr388 residues, sites distinct from the C-terminal Ser423/425 residues that are phosphorylated by TGF-beta receptor kinase and are critical for the nuclear translocation and down-stream signaling of pSmad3. These results suggest that phosphorylation of Smad3 by protein kinase G is a potential molecular mechanism by which activation of ANP/cGMP/protein kinase G signaling disrupts TGF-beta1-induced nuclear translocation of pSmad3 and downstream events, including myofibroblast transformation, proliferation, and expression of extracellular matrix molecules in cardiac fibroblasts. We postulate that this process contributes to the antifibrogenic effects of the natriuretic peptide in heart.