tbuckley/cabot-search huggingface dataset:
Expression and Mutational Status of <b> <i>c-kit</i> </b> in Small-Cell Lung Cancer
Authors: Laura Boldrini, Silvia Ursino, Silvia Gisfredi, Pinuccia Faviana, Valentina Donati, Tiziano Camacci, Marco Lucchi, Alfredo Mussi, Fulvio Basolo, Raffaele Pingitore, Gabriella Fontanini
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The c-kit protein, also known as CD117, is a member of the type III receptor tyrosine kinase family. Kinase activity has been implicated in the pathophysiology of many tumors, including small-cell lung carcinoma (SCLC). Autocrine or paracrine activation of c-kit by its ligand has been postulated for lung cancer, but this receptor can also be activated by mutations of the c-kit gene. We examined c-kit expression and mutational status in SCLC to verify its putative expression and genetic alterations, as well as its eventual prognostic impact. Experimental Design: We studied 60 SCLC samples to determine the mutations of the coding region of the gene; the exons 9 and 11 were analyzed by PCR-single-strand conformational polymorphism and automated sequencing. Moreover, c-kit expression was evaluated in 55 samples by immunohistochemical method. Results: Expression of c-kit was demonstrated in about 40% of SCLC samples. Two mutations in exon 9 and three mutations in exon 11 were found. Kaplan-Meier analysis revealed no prognostic significance of c-kit expression for survival. Conclusions: In our series, the expression of c-kit and its mutational status failed to appear relevant or to have a significant impact on survival; this makes the therapeutic approach with an inhibitor of tyrosine kinase more difficult in SCLC until a sure demonstration of c-kit implication is obtained for this tumor.
Rosiglitazone Improves Insulin Sensitivity and Lowers Blood Pressure in Hypertensive Patients
Authors: Annaswamy Raji, Ellen W. Seely, Shannon A. Bekins, Gordon H. Williams, Donald C. Simonson
Journal: Diabetes Care (2003)

OBJECTIVE—To examine the effect of rosiglitazone on insulin resistance and blood pressure in patients with essential hypertension, classified based on abnormalities of their renin-angiotensin system. RESEARCH DESIGN AND METHODS—A total of 24 hypertensive nondiabetic patients (age 58 ± 6 years, BMI 30 ± 5 kg/m2) were studied before and after rosiglitazone treatment. After 2 weeks off antihypertensive medication, subjects received a euglycemic-hyperinsulinemic clamp (40 mU · m−2 · min−1) with 6,6-[2H2]glucose infusion, ambulatory blood pressure monitoring, and blood tests for cardiovascular risk factors. Subjects were then placed on rosiglitazone (4 mg orally b.i.d.) and their usual antihypertensive medications (but not ACE inhibitors) for 16 weeks, and baseline tests were repeated. RESULTS—There was no change in fasting plasma glucose (83 ± 2 vs. 82 ± 2 mg/dl, P = 0.60), but fasting insulin decreased (16.1 ± 1.4 vs. 12.5 ± 0.9 μU/ml, P &amp;lt; 0.01). Total glucose disposal during the clamp increased (5.0 ± 0.4 vs. 5.9 ± 0.5 mg · kg−1 · min−1, P &amp;lt; 0.001), with no change in suppression of hepatic glucose output. There were significant decreases in mean 24-h systolic (138 ± 2 vs. 134 ± 2 mmHg, P &amp;lt; 0.02) and diastolic (85 ± 2 vs. 80 ± 2 mmHg, P &amp;lt; 0.0001) blood pressure, and the decline in systolic blood pressure was correlated with the improvement in insulin sensitivity (r = 0.59, P &amp;lt; 0.005). Triglycerides (135 ± 16 vs. 89 ± 8 mg/dl, P &amp;lt; 0.01), LDL cholesterol (129 ± 6 vs. 122 ± 8 mg/dl, P = 0.18), and HDL cholesterol (51 ± 3 vs. 46 ± 3 mg/dl, P &amp;lt; 0.02) all decreased, with no change in the LDL-to-HDL ratio. Plasminogen activator inhibitor-1 and C-reactive protein also declined significantly. CONCLUSIONS—Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity, reduces systolic and diastolic blood pressure, and induces favorable changes in markers of cardiovascular risk. Insulin sensitizers may provide cardiovascular benefits when used in the treatment of patients with hypertension.
Corrigendum to “SHORT STATEMENT OF THE FIRST EUROPEAN CONSENSUS CONFERENCE ON THE TREATMENT OF CHRONIC HEPATITIS B AND C IN HIV CO-INFECTED PATIENTS”[J Hepatol 42 (2005) 615–624]
Authors: Alfredo Alberti, Nathan Clumeck, Simon Collins, Wolfram Gerlich, Jens Lundgren, Giorgio Palù, Peter Reiss, Rodolphe Thiebaut, Ola Weiland, Yazdan Yazdanpanah, Stefan Zeuzem (The ECC Jury)
Journal: Journal of Hepatology (2005)
Analysis of Acorus calamus Chloroplast Genome and Its Phylogenetic Implications
Authors: Vadim V. Goremykin, Barbara Holland, Karen I. Hirsch-Ernst, Frank H. Hellwig
Journal: Molecular Biology and Evolution (2005)

Determining the phylogenetic relationships among the major lines of angiosperms is a long-standing problem, yet the uncertainty as to the phylogenetic affinity of these lines persists. While a number of studies have suggested that the ANITA (Amborella-Nymphaeales-Illiciales-Trimeniales-Aristolochiales) grade is basal within angiosperms, studies of complete chloroplast genome sequences also suggested an alternative tree, wherein the line leading to the grasses branches first among the angiosperms. To improve taxon sampling in the existing chloroplast genome data, we sequenced the chloroplast genome of the monocot Acorus calamus. We generated a concatenated alignment (89,436 positions for 15 taxa), encompassing almost all sequences usable for phylogeny reconstruction within spermatophytes. The data still contain support for both the ANITA-basal and grasses-basal hypotheses. Using simulations we can show that were the ANITA-basal hypothesis true, parsimony (and distance-based methods with many models) would be expected to fail to recover it. The self-evident explanation for this failure appears to be a long-branch attraction (LBA) between the clade of grasses and the out-group. However, this LBA cannot explain the discrepancies observed between tree topology recovered using the maximum likelihood (ML) method and the topologies recovered using the parsimony and distance-based methods when grasses are deleted. Furthermore, the fact that neither maximum parsimony nor distance methods consistently recover the ML tree, when according to the simulations they would be expected to, when the out-group (Pinus) is deleted, suggests that either the generating tree is not correct or the best symmetric model is misspecified (or both). We demonstrate that the tree recovered under ML is extremely sensitive to model specification and that the best symmetric model is misspecified. Hence, we remain agnostic regarding phylogenetic relationships among basal angiosperm lineages.
Standardization of ambulatory peak flow monitoring: the importance of recent beta2-agonist inhalation
Authors: HK Reddel, SI Ware, CM Salome, GB Marks, CR Jenkins, AJ Woolcock
Journal: European Respiratory Journal (1998)

Standardization of conditions for peak expiratory flow (PEF) monitoring is much more difficult in practice than for laboratory spirometry. Patients are usually asked to record PEF before medication. The aim of this study was to determine the effect of prior bronchodilator use on PEF outcome measures in a clinical trial. Electronic PEF records from 43 subjects with poorly controlled asthma were examined to determine the frequency with which beta2-agonist was inhaled &lt;4 h before PEF measurement, as such PEF are potentially "postbronchodilator". The effect of inclusion of such PEF values on improvement in PEF outcome measures after 8 weeks of inhaled budesonide was calculated. Subjects were asked to record PEF before medication. During run-in, the median frequency of postbronchodilator PEF was 29%, falling to 0% after 8 weeks of budesonide. Inclusion of postbronchodilator PEF led to an overestimation of average morning, evening and daily PEF during run-in (p&lt;0.001). Improvement in these indices with treatment was, therefore, underestimated. Minimum morning PEF expressed as per cent personal best was unaffected. Subjects may not be able to withhold beta2-agonist for 4 h before every peak flow reading. This may change as the level of asthma control changes, leading to a systematic bias in clinical trial end-points or inaccuracy in individual treatment decisions. Simple changes to peak expiratory flow instructions and analysis are proposed.
Effects of allergen on airway narrowing dynamics as assessed by lung-slice technique
Authors: A. D. Chew, J. A. Hirota, R. Ellis, J. Wattie, M. D. Inman, L. J. Janssen
Journal: European Respiratory Journal (2007)

Asthma is characterised by an excessive airway narrowing in response to a variety of stimuli, called airway hyperresponsiveness (AHR). Previous comparisons between mouse strains have shown that increased velocity of airway narrowing correlates with baseline airway responsiveness. These data prompted the investigation into models of induced AHR to see whether airway narrowing dynamics correlated with in vivo responsiveness. In an attempt to reproduce some of the features of asthma, BALB/c mice were sensitised and subjected to either brief or chronic periods of allergen exposure. Brief exposure involved two challenges with intranasal chicken egg ovalbumin (OVA in ). Chronic exposure involved six 2-day periods of OVA in challenges, each separated by 12 days. Control mice received intranasal saline challenges. Outcomes included videomicrometry of lung slices (magnitude and velocity of airway narrowing), in vivo respiratory physiology measurements and histological staining with morphometric analysis. Neither brief nor chronic allergen exposure resulted in greater airway narrowing and increased velocity compared with saline controls. Structural changes in the airway, such as goblet cell hyperplasia, subepithelial fibrosis and increased contractile tissue, were detected in mice chronically challenged with allergen. In conclusion, increased responsiveness to methacholine following allergen challenge may not be due to an intrinsic change to the smooth muscle per se , but rather to other changes in the lung, which ultimately manifest as an increase in respiratory resistance.
STUDIES ON THE PATHOGENESIS OF FEVER WITH INFLUENZAL VIRUSES
Authors: Elisha Atkins, Wei Cheng Huang
Journal: The Journal of Experimental Medicine (1958)

Tolerance to the pyrogenic action of intravenously injected virus has been studied in rabbits given either PR8 strain of influenza A virus or Newcastle disease virus (NDV). The following findings suggest that the capacity of the animal to release an endogenous pyrogen is a critical factor. (a) Viruses produce fever by the release of endogenous pyrogen. (b) Tolerance to the pyrogenic effect of reinjected virus is associated with a decrease or absence of endogenous pyrogen production. (c) Tolerance to virus fever may be induced by the prior injection of endogenous pyrogen. (d) Cross-tolerance has been demonstrated between virus and bacterial endotoxin (typhoid vaccine), both of which cause the release of endogenous pyrogen. A difference has been noted in the mechanism of tolerance to successive injections of virus and of bacterial endotoxin. Repeated injections of endotoxins bring about an accelerated clearance of these substances from the blood stream with the result that there is a diminished stimulus to endogenous pyrogen production. Tolerance to virus, on the other hand, is unaccompanied by changes in the rate at which virus disappears from the circulation. It is postulated that circulating endogenous pyrogen, induced by the injection of a number of pyrogenic agents including viruses, temporarily suppresses the further release of endogenous pyrogen and thereby contributes to virus tolerance.
A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07)
Authors: Markus Hutterer, Martha Nowosielski, Johannes Haybaeck, Sabine Embacher, Florian Stockhammer, Thaddäus Gotwald, Bernhard Holzner, David Capper, Matthias Preusser, Christine Marosi, Stefan Oberndorfer, Martin Moik, Johanna Buchroithner, Marcel Seiz, Jochen Tuettenberg, Ulrich Herrlinger, Antje Wick, Peter Vajkoczy, Günther Stockhammer
Journal: Neuro-Oncology (2013)

Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4–41.4 mo) and a median OS of 46.9 months (range, 21.2–49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.
<i>TWIST2</i> Demonstrates Differential Methylation in Immunoglobulin Variable Heavy Chain Mutated and Unmutated Chronic Lymphocytic Leukemia
Authors: Aparna Raval, David M. Lucas, Jennifer J. Matkovic, Kristi L. Bennett, Sandya Liyanarachchi, Donn C. Young, Laura Rassenti, Thomas J. Kipps, Michael R. Grever, John C. Byrd, Christoph Plass
Journal: Journal of Clinical Oncology (2005)

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease for which natural history can be predicted based on the presence or absence of immunoglobulin (Ig) variable heavy chain (V(H)) gene mutations. Herein we report selective epigenetic silencing of the transcription factor TWIST2 (DERMO1) in Ig V(H) mutated CLL and describe a semiquantitative assay to study promoter methylation of this gene in primary tumor cells.TWIST2 promoter methylation was identified by restriction landmark genome scanning. Southern blot (SB), bisulfite sequencing, and combined bisulfite restriction analysis (COBRA), and quantitative SB-COBRA was performed to study methylation of the TWIST2 promoter. Reverse transcription polymerase chain reaction assays were used to study TWIST2 expression in CLL cells.Following identification and confirmation of TWIST2 methylation in CLL patients, we demonstrated that expression of this transcription factor is related to the degree of promoter methylation. Expression of TWIST2 in a CLL cell line in which the promoter is methylated was increased following decitabine treatment. We next studied 53 patients by COBRA and demonstrated that 72% of patient samples with mutated Ig V(H) show TWIST2 methylation, while only 16% of patient samples with unmutated Ig V(H) were methylated (P < .001). In a subset of patients, methylation of TWIST2 correlated with mRNA expression.TWIST2 is differentially methylated in CLL cells relative to Ig V(H) mutational status and can be quantitatively monitored by SB-COBRA. Based on the known role of TWIST2 in silencing p53 function in other malignancies, future studies should focus on the role of TWIST2 in CLL and related lymphoproliferative diseases.
CX3CL1-CX3CR1 Interaction Prevents Carbon Tetrachloride-Induced Liver Inflammation and Fibrosis in Mice
Authors: Tomonori Aoyama, Sayaka Inokuchi, David A. Brenner, Ekihiro Seki
Journal: Hepatology (2010)

Chronic liver disease is associated with hepatocyte injury, inflammation, and fibrosis. Chemokines and chemokine receptors are key factors for the migration of inflammatory cells such as macrophages and noninflammatory cells such as hepatic stellate cells (HSCs). The expression of CX3CR1 and its ligand, CX3CL1, is up-regulated in chronic liver diseases such as chronic hepatitis C. However, the precise role of CX3CR1 in the liver is still unclear. Here we investigated the role of the CX3CL1-CX3CR1 interaction in a carbon tetrachloride (CCl4)–induced liver inflammation and fibrosis model. CX3CR1 was dominantly expressed in Kupffer cells in the liver. In contrast, the main source of CX3CL1 was HSCs. Mice deficient in CX3CR1 showed significant increases in inflammatory cell recruitment and cytokine production [including tumor necrosis factor α (TNF-α); monocyte chemoattractant protein 1; macrophage inflammatory protein 1β; and regulated upon activation, normal T cell expressed, and secreted (RANTES)] after CCl4 treatment versus wild-type (WT) mice. This suggested that CX3CR1 signaling prevented liver inflammation. Kupffer cells in CX3CR1-deficient mice after CCl4 treatment showed increased expression of TNF-α and transforming growth factor β and reduced expression of the anti-inflammatory markers interleukin-10 (IL-10) and arginase-1. Coculture experiments showed that HSCs experienced significantly greater activation by Kupffer cells from CCl4-treated CX3CR1-deficient mice versus WT mice. Indeed, augmented fibrosis was observed in CX3CR1-deficient mice versus WT mice after CCl4 treatment. Finally, CX3CL1 treatment induced the expression of IL-10 and arginase-1 in WT cultured Kupffer cells through CX3CR1, which in turn suppressed HSC activation. Conclusion: The CX3CL1-CX3CR1 interaction inhibits inflammatory properties in Kupffer cells/macrophages and results in decreased liver inflammation and fibrosis. (Hepatology 2010)
Prediction at First Year of Incident New-Onset Diabetes After Kidney Transplantation by Risk Prediction Models
Authors: Emilio Rodrigo, Lidia Santos, Celestino Piñera, Juan Carlos Ruiz San Millán, Maria Estrella Quintela, Carmen Toyos, Natalia Allende, Carlos Gómez-Alamillo, Manuel Arias
Journal: Diabetes Care (2012)

Our aim was to analyze the performance of two scores developed for predicting diabetes in nontransplant populations for identifying kidney transplant recipients with a higher new-onset diabetes mellitus after transplantation (NODAT) risk beyond the first year after transplantation.We analyzed 191 kidney transplants, which had at least 1-year follow-up posttransplant. First-year posttransplant variables were collected to estimate the San Antonio Diabetes Prediction Model (SADPM) and Framingham Offspring Study-Diabetes Mellitus (FOS-DM) algorithm.Areas under the receiver operating characteristic curve of FOS-DM and SADPM scores to predict NODAT were 0.756 and 0.807 (P < 0.001), respectively. FOS-DM and SADPM scores over 75 percentile (hazard ratio 5.074 and 8.179, respectively, P < 0.001) were associated with NODAT.Both scores can be used to identify kidney recipients at higher risk for NODAT beyond the first year. SADPM score detects some 25% of kidney transplant patients with an eightfold risk for NODAT.
Serum Cholesterol and Cancer Risk: An Epidemiologic Perspective
Authors: S B Kritchevsky, D Kritchevsky
Journal: Annual Review of Nutrition (1992)

This review has examined the evidence surrounding two questions: (a) Is having low serum cholesterol associated with increased risk of cancer? (b) Does reducing serum cholesterol increase the occurrence of cancer? Some elevated risk of cancer for males with low serum cholesterol levels has been noted: the median of the studies examined is consistent with a 30% increased risk. The answer for females is less clear. The median of the studies examined suggests no more than a 5-10% increased risk associated with having low serum cholesterol. However, the risk seems to depend strongly on whether females have a central or peripheral body fat pattern (54). The cancers most consistently associated with low serum cholesterol levels are those of the colon and lung in males, the cervix and breast (but only for females under 50 years of age) in females, and leukemia in both sexes. In contrast, high cholesterol levels have been linked with an increase in brain cancer. While immunologic, genetic, and dietary explanations have been offered to explain the association, it is difficult to support the idea that low serum cholesterol causes cancer in any direct manner. First, the findings themselves tend to be generally weak and somewhat inconsistent. Second, the strong influence of fat distribution in women suggests that a metabolic/hormonal basis underlies the association. One would not expect the results to differ by body fat pattern if the relationship were a causal one. Finally, if there were a direct causal role, one would expect populations with low serum cholesterol levels to have higher cancer rates. In China, counties with the lowest average plasma cholesterol levels have the lowest cancer rates (78). While this observation is open to a number of interpretations, it does not support the idea that low serum cholesterol is a tumor initiator. In aggregate, the trials of lipid-lowering interventions reviewed here show an increase in cancer occurrence (primarily mortality) of approximately 24% in the cholesterol-lowered groups. However, the post-trial experience has shown a comparative deficit of cancer occurrence in the experimental groups. Recent evidence indicates that products in the cholesterol biosynthetic pathway affect DNA replication and cell proliferation. These findings suggests a mechanism by which cholesterol lowering might accelerate the development of tumors already initiated. The data that have been reviewed in no way suggest that treatment of hypercholesterolemia should not be pursued. They do suggest the presence of a relatively small subpopulation in whom reduction of plasma cholesterol may lead to increased occurrence of cancer.(ABSTRACT TRUNCATED AT 400 WORDS)