tbuckley/cabot-search huggingface dataset:
NF-κB/STAT3/PI3K signaling crosstalk in iMycEμ B lymphoma
Authors: Seong-Su Han, Hwakyung Yun, Dong-Ju Son, Van S. Tompkins, Liangping Peng, Seung-Tae Chung, Joong-Su Kim, Eun-Sung Park, Siegfried Janz
Journal: Molecular Cancer (2010)

Abstract Background Myc is a well known driver of lymphomagenesis, and Myc-activating chromosomal translocation is the recognized hallmark of Burkitt lymphoma, an aggressive form of non-Hodgkin's lymphoma. We developed a model that mimics this translocation event by inserting a mouse Myc cDNA gene into the immunoglobulin heavy chain locus, just upstream of the intronic Eμ enhancer. These mice, designated iMyc Eμ , readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMyc Eμ mice, and an LBL-derived cell line, iMyc Eμ -1. Results Nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMyc Eμ mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMyc Eμ -1 cells suppressed growth and caused apoptosis, and the abrogation of NF-κB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-κB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMyc Eμ -1 cells NF-κB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-κB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMyc Eμ -1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMyc Eμ -1 cell proliferation and caused apoptosis, via downregulation of NF-κB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-κB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMyc Eμ -1 cell proliferation, suggesting that these signaling pathways converge. Conclusions Our findings support the notion that constitutive activation of NF-κB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-κB, STAT3 and PI3K in the development of iMyc Eμ B-cell lymphomas.
Scattered Lung Cysts as the Main Radiographic Finding of Constrictive Bronchiolitis
Authors: Letícia Kawano-Dourado, Bruno G. Baldi, Olívia M. Dias, Fabiola D. C. Bernardi, Carlos R. R. Carvalho, Marisa Dolhnikoff, Ronaldo A. Kairalla
Journal: American Journal of Respiratory and Critical Care Medicine (2012)
Peripheral Blood Mitochondrial DNA Content Is Related to Insulin Sensitivity in Offspring of Type 2 Diabetic Patients
Authors: Jihyun Song, Jee Young Oh, Yeon-Ah Sung, Youngmi Kim Pak, Kyong Soo Park, Hong Kyu Lee
Journal: Diabetes Care (2001)

OBJECTIVE—To investigate whether the peripheral blood mtDNA (pb-mtDNA) content is decreased and linked to insulin resistance in the offspring of type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A total of 82 offspring of type 2 diabetic patients and 52 age-, sex-, and BMI-matched normal subjects from the Mokdong, Korea, population were selected for this study by stratified, randomized sampling. Of the offspring of diabetic patients, 52 had normal glucose tolerance (NGT), 21 had impaired glucose tolerance (IGT), and 9 had newly diagnosed type 2 diabetes. The pb-mtDNA content was measured by real-time polymerase chain reaction with a mitochondria-specific fluorescent probe, normalized by a nuclear DNA, 28S rRNA gene. The associations between pb-mtDNA content and several parameters of insulin resistance were studied. RESULTS—The pb-mtDNA contents tended to be lower in the 82 offspring of type 2 diabetic patients (1,084.7 ± 62.6 vs. 1,304.0 ± 99.2 in the offspring and control subjects, respectively, P = 0.051) and was significantly lower in the combined NGT and IGT offspring group (NGT+IGT, 1,068.0 ± 67.8, P &amp;lt; 0.05) than in the control subjects. In NGT+IGT offspring, the pb-mtDNA content was significantly correlated with logarithmically transformed insulin sensitivity (r = 0.253, P &amp;lt; 0.05) and was the main predictor of insulin sensitivity. CONCLUSIONS—Quantitative mtDNA status might be a hereditary factor associated with type 2 diabetes and could serve as an indicator for insulin sensitivity.
Programmed Cell Death Protein 4 Down-regulates Y-Box Binding Protein-1 Expression via a Direct Interaction with Twist1 to Suppress Cancer Cell Growth
Authors: Masaki Shiota, Hiroto Izumi, Akihide Tanimoto, Mayu Takahashi, Naoya Miyamoto, Eiji Kashiwagi, Akihiko Kidani, Gen Hirano, Daisuke Masubuchi, Yasushi Fukunaka, Yoshihiro Yasuniwa, Seiji Naito, Shigeru Nishizawa, Yasuyuki Sasaguri, Kimitoshi Kohno
Journal: Cancer Research (2009)

Abstract Programmed cell death protein 4 (PDCD4) has recently been shown to be involved in both transcription and translation, and to regulate cell growth. However, the mechanisms underlying PDCD4 function are not well understood. In this study, we show that PDCD4 interacts directly with the transcription factor Twist1 and leads to reduced cell growth through the down-regulation of the Twist1 target gene Y-box binding protein-1 (YB-1). PDCD4 interacts with the DNA binding domain of Twist1, inhibiting its DNA binding ability and YB-1 expression. Immunohistochemical analysis showed that an inverse correlation between nuclear PDCD4 and YB-1 expression levels was observed in 37 clinical prostate cancer specimens. Growth suppression by PDCD4 expression was completely recovered by either Twist1 or YB-1 expression. Moreover, PDCD4-overexpressing cells are sensitive to cisplatin and paclitaxel but not to etoposide or 5-fluorouracil. In summary, PDCD4 negatively regulates YB-1 expression via its interaction with Twist1 and is involved in cancer cell growth and chemoresistance. [Cancer Res 2009;69(7):3148–56]
Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicentre study.
Authors: A W van Rijthoven, B A Dijkmans, H S Goei The, J Hermans, Z L Montnor-Beckers, P C Jacobs, A Cats
Journal: Annals of the Rheumatic Diseases (1986)

The efficacy and safety of cyclosporin for patients with rheumatoid arthritis (RA) were assessed in a six month double blind, placebo controlled, multicentre study. The initial dosage of the drug was 10 mg/kg daily for two months. There were many discontinuations in both the cyclosporin group (eight out of 17) and the placebo group (six out of 19). Of the patients who completed the six months of therapy, those who had received cyclosporin showed a significant improvement in the number of swollen joints, the Ritchie articular index, and pain at active movement and at rest, compared not only with their condition at the start of the study, but also with the end results of the placebo group. Major adverse reactions to the drug were gastrointestinal disturbances and nephrotoxicity, which were probably due to the relatively high dosages of cyclosporin given in combination with non-steroidal anti-inflammatory drugs.
Effect of Bretylium Tosylate (Darenthin) on Pulmonary Circulation
Authors: D. F. J. HALMAGYI, H. J. H. COLEBATCH
Journal: Circulation Research (1961)

In a dose sufficient to produce a mild systemic hypotension, bretylinm increases pulmonary arterial pressure and venous admixture in the experimental animal. The clinical significance of these side effects appears to deserve some consideration.
Effects of 15% oxygen on breathing patterns and oxygenation in infants
Authors: A. D Milner
Journal: BMJ (1998)

Papers p 887 

An article in this week's issue raises the spectre that exposing a young infant to the relative hypoxia of an airline flight may increase the risk of sudden infant death (p 887).1 The authors base this claim on their findings that exposing 3 month old infants to 15% oxygen for about six hours led to an increase in the time spent in periodic respiration and the number of episodes of mild desaturation. In addition, four of the 34 infants had more prolonged hypoxia, with transcutaneous arterial saturation values below 80% for more than one minute, for which they were given oxygen therapy. They could not predict which infants were likely to develop the more prolonged pattern of desaturation from their baseline cardiorespiratory monitoring. They conclude that further research is urgently needed into the effects of airline flights …
Evidence That Rho-Kinase Activity Contributes to Cerebral Vascular Tone In Vivo and Is Enhanced During Chronic Hypertension
Authors: Sophocles Chrissobolis, Christopher G. Sobey
Journal: Circulation Research (2001)

The small G protein Rho and its target Rho-kinase may participate in the mechanisms underlying vascular contractile tone via inhibition of myosin light chain phosphatase. The present study has tested the hypothesis that Rho-kinase activity normally contributes to cerebral vascular tone in vivo, and that this effect is augmented during chronic hypertension. Comparative studies also examined the role of protein kinase C (PKC) in regulation of cerebral artery tone. Two Rho-kinase inhibitors, Y-27632 (0.1 to 100 micromol/L) and HA1077 (1 to 10 micromol/L), caused marked concentration-dependent increases in basilar artery diameter of anesthetized normotensive rats (Sprague-Dawley and Wistar-Kyoto [WKY] strains), as measured using a cranial window approach. By comparison, the selective PKC inhibitors calphostin C (0.01 to 0.5 micromol/L) and Ro 31-8220 (5 micromol/L) had little or no effect on basilar artery diameter. Vasodilator responses to Y-27632 were unaffected by PKC inhibition or activation. In two models of chronic hypertension (spontaneously hypertensive rats and WKY rats treated with N-nitro-L-arginine methyl ester for 4 weeks), Y-27632 elicited cerebral vasodilator responses that were significantly greater than in control WKY rats (P<0.05), indicating that the chronically hypertensive state and not genetic factors contributed to the increased responses to Rho-kinase inhibition. PKC inhibition had no significant effect on basilar artery diameter in chronically hypertensive rats. These data suggest that Rho-kinase, but not PKC, activity contributes substantially to cerebral artery tone in vivo, and this effect is augmented in the cerebral circulation during chronic hypertension.
A 26-Week, Randomized, Parallel, Treat-to-Target Trial Comparing Insulin Detemir With NPH Insulin as Add-On Therapy to Oral Glucose-Lowering Drugs in Insulin-Naïve People With Type 2 Diabetes
Authors: Kjeld Hermansen, Melanie Davies, Taudeusz Derezinski, Gabrielle Martinez Ravn, Per Clauson, Philip Home
Journal: Diabetes Care (2006)

OBJECTIVE—To assess efficacy and tolerability of insulin detemir or NPH insulin added to oral therapy for type 2 diabetes in a treat-to-target titration protocol. RESEARCH DESIGN AND METHODS—Individuals (n = 476) with HbA1c (A1C) 7.5–10.0% were randomized to addition of twice-daily insulin detemir or NPH insulin in a parallel-group, multicenter trial. Over 24 weeks, insulin doses were titrated toward prebreakfast and predinner plasma glucose targets of ≤6.0 mmol/l (≤108 mg/dl). Outcomes assessed included A1C, percentage achieving A1C ≤7.0%, risk of hypoglycemia, and body weight. RESULTS—At 24 weeks, A1C had decreased by 1.8 and 1.9% (from 8.6 to 6.8 and from 8.5 to 6.6%) for detemir and NPH, respectively (NS). In both groups, 70% of participants achieved an A1C ≤7.0%, but the proportion achieving this without hypoglycemia was higher with insulin detemir than with NPH insulin (26 vs. 16%, P = 0.008). Compared with NPH insulin, the risk for all hypoglycemia with insulin detemir was reduced by 47% (P &amp;lt; 0.001) and nocturnal hypoglycemia by 55% (P &amp;lt; 0.001). Mean weight gain was 1.2 kg with insulin detemir and 2.8 kg with NPH insulin (P &amp;lt; 0.001), and the difference in baseline-adjusted final weight was −1.58 (P &amp;lt; 0.001). CONCLUSIONS—Addition of basal insulin to oral drug therapy in people with suboptimal control of type 2 diabetes achieves guideline-recommended A1C values in most people with aggressive titration. Insulin detemir compared with NPH insulin achieves this with reduced hypoglycemia and less weight gain.
The Human Insulin Analog Aspart Can Induce Insulin Allergy
Authors: Xu JiXiong, Liu Jianying, Chang Yulan, Chen Huixian
Journal: Diabetes Care (2004)

The human insulin analog aspart is produced by recombinant technology that replaces the proline at position 28 on the β-chain of insulin with negatively charged aspartic acid. Insulin aspart exists as hexamers that rapidly dissociate into monomers and dimers after the subcutaneous injection (1); it appears that it has a reduced antigenicity. It has been confirmed to be less immunogenic for development of antibodies than human insulin (2). Several case reports indicated that the human insulin analog aspart does not cause insulin allergy and is a safe alternative in insulin allergy (3,4). But a case report showed that the patient developed cutaneous allergic reactions not only to human …
Pressure-volume analysis of the lung with an exponential and linear-exponential model in asthma and COPD. Dutch CNSLD Study Group
Authors: JM Bogaard, SE Overbeek, AF Verbraak, C Vons, HT Folgering, TW van der Mark, CM Roos, PJ Sterk
Journal: European Respiratory Journal (1995)

The prevalence of abnormalities in lung elasticity in patients with asthma or chronic obstructive pulmonary disease (COPD) is still unclear. This might be due to uncertainties concerning the method of analysis of quasistatic deflation lung pressure-volume curves. Pressure-volume curves were obtained in 99 patients with moderately severe asthma or COPD. These patients were a subgroup from a Dutch multicentre trial; the entire group was selected on the basis of a moderately lowered % predicted forced expiratory volume in one second (FEV1), and a provocative concentration of histamine producing a 20% decrease in FEV1 (PC20) &lt; 8 mg.mL-1 obtained with the 2 min tidal breathing technique. The curves were fitted with an exponential (E) model and an exponential model which took the linear appearance in the mid vital capacity range into account (linear-exponential (LE)). The linear-exponential model showed a markedly better fit ability, yielding additional parameters, such as the compliance at functional residual capacity (FRC) level as slope of the linear part (b), and the volume at which the linear part changed into the exponential part of the curve (transition volume (Vtr)). Vtr (mean value Vtr/total lung capacity (TLC) = 0.79 (SD 0.07)) showed a close positive linear correlation with obstruction and hyperinflation variables, which might be due to airway closure, already starting at elevated lung volumes. The exponential shape factor K was closely correlated with b and mean values (K = 1.32 (SD 0.05) kPa-1; b = 2.96 (SD 1.16) L,kPa-1) and the relationship with age was comparable with data reported in healthy individuals. The shape factor of the linear-exponential fit showed no correlation with any elasticity related variable. Neither the elastic recoil at 90% TLC, as obtained from the linear-exponential fit, nor its relationship with age were significantly different from healthy individuals. We conclude that, for a more accurate description of the lung pressure-volume curve, a linear-exponential fit is preferable to an exponential model. However, the physiological relevance of the shape parameter (KLE) is still unclear. These results indicate that patients with moderately severe asthma or COPD had, on average, no appreciable loss of elastic lung recoil as compared with healthy individuals.
CARRIER-MEDIATED MEMBRANE TRANSPORT OF FOLATES IN MAMMALIAN CELLS
Authors: F. M. Sirotnak, Berend Tolner
Journal: Annual Review of Nutrition (1999)

▪ Abstract Mediated internalization of folates is required for cellular macromolecular biosynthesis. Multiple carrier-mediated mechanisms have been identified that can fulfill this role in a variety of mammalian cell types, including neoplastic cells, with and without proliferative potential. The absorption of dietary folates also relies on the function of a carrier-mediated system in mature luminal epithelium of small intestine. The various carrier-mediated systems can be distinguished by their preferences for various folate compounds as permeants as well as by differences in temperature and pH dependence. The widely studied one-carbon, reduced-folate transport system is mediated by a transporter encoded by the newly discovered RFC-1 (reduced-folate carrier) gene. The characteristics of this gene in rodent and human cells are similar, consistent with the close similarity between these species of folate transport mediated by this transporter. However, differences occur in the form of tissue-specific expression, alternate splicing, and 5′ end mRNA heterogeneity, as well as in promoter utilization regulating transcription. RFC-1 gene expression also appears to regulate luminal epithelial cell folate absorption in small intestine. However, the properties of RFC-1–mediated folate transport in these cells is anomalous when compared with that seen in nonabsorptive cell types. Detailed mechanisms as to the regulation of RFC-1 transcription are now emerging along with other information on structure and function of the transporter and its alteration following mutation.
Multiplex Coherent Anti-Stokes Raman Spectroscopy Images Intact Atheromatous Lesions and Concomitantly Identifies Distinct Chemical Profiles of Atherosclerotic Lipids
Authors: Se-Hwa Kim, Eun-Soo Lee, Jae Yong Lee, Eun Seong Lee, Bok-Soo Lee, Jeong Euy Park, Dae Won Moon
Journal: Circulation Research (2010)

Lipids are a key component of atherogenesis. However, their physiological role on the progression of atherosclerosis including plaque vulnerability has not been clearly understood, because of the lack of appropriate tools for chemical assessment.We aimed to develop a label-free chemical imaging platform based on multiplex coherent anti-Stokes Raman scattering (CARS) for the correlative study of the morphology and chemical profile of atherosclerotic lipids.Whole aortas from atherosclerotic apolipoprotein E knock-out mice were en face examined by multiplex CARS imaging and 4 distinctive morphologies of the lipids (intra/extracellular lipid droplets and needle-/plate-shaped lipid crystals) were classified. The chemical profiles of atherosclerotic lipids depending on morphologies were firstly identified from intact atheromatous tissue by multiplex CARS. We demonstrated that needle-/plate-shaped lipid crystals in advanced plaques had undergone a phase shift to the solid state with increased protein contents, implying that lipid modification had occurred beforehand. The validity of lipid-selective multiplex CARS imaging was supported by comparative results from oil red O staining and whole-mount immunohistochemistry. By spatial CARS analysis of atherosclerosis progression, we found greater accumulation of lipid crystals in both the lesser curvature of the aortic arch and the innominate artery. Furthermore, multiplex CARS measurement successfully demonstrated the effect of a drug, statin, on atherosclerotic lipids by showing the change of their chemical profiles.Multiplex CARS imaging directly provides intact morphologies of atherosclerotic lipids with correlative chemical information, thereby suggesting its potential applications in the investigation of lipid-associated disorders and the preclinical drug screening.
Postprandial changes in portal haemodynamics in patients with cirrhosis.
Authors: S O'Brien, M Keogan, S Patchett, P A McCormick, N Afdhal, J E Hegarty
Journal: Gut (1992)

Previous studies have shown that portal venous pressure increases in patients with cirrhosis after a protein meal. Since this increase may be mediated by an increase in hepatic blood flow or postsinusoidal hepatic vascular resistance, the present study was designed to examine the precise relation between the postprandial changes in these three variables in patients with cirrhosis and portal hypertension. Estimated hepatic blood flow (EHBF; indocyanine green clearance), portosystemic gradient (PSG; wedged free hepatic venous pressure), and postsinusoidal hepatic vascular resistance (PSR = PSG/EHBF) were measured simultaneously before and at 10 minute intervals after a high protein meal, containing 80 g protein, 40 g carbohydrate and 12 g fat (600 kcal) in nine patients (seven alcoholic, two non-alcoholic) with cirrhosis and portal hypertension. After the meal, the portosystemic gradient increased by 33% from mean (SEM) 15.6 (0.9) mm Hg to 20.7 (1.3) mm Hg, (p less than 0.01; Wilcoxon signed ranks test) within 30 minutes. Coincident with this increase in portosystemic gradient, estimated hepatic blood flow increased by 69.2% from 20.1 (1.7) ml/min/kg to 33.9 (2.5) ml/min/kg (p = 0.01), peak values occurring at 25 minutes, at which time the postsinusoidal hepatic vascular resistance had decreased by 31% from 1.10 (0.1) 10(-2) mm Hg/ml/min to 0.8 (0.5) 10(-2) mm Hg/ml/min (p = 0.01). These results suggest that the postprandial increase in portal venous pressure in patients with cirrhosis is mediated by an increase in hepatic blood flow and modified by a simultaneous decrease in postsinusoidal resistance.
Decreased Perivascular Fibrosis but Not Cardiac Hypertrophy in ROCK1 <sup>+/−</sup> Haploinsufficient Mice
Authors: Yoshiyuki Rikitake, Naotsugu Oyama, Chao-Yung C. Wang, Kensuke Noma, Minoru Satoh, Hyung-Hwan Kim, James K. Liao
Journal: Circulation (2005)

Rho GTPase and its downstream target, Rho-associated kinase (ROCK), have been implicated in diverse cardiovascular diseases such as cardiac hypertrophy. However, pharmacological inhibitors of ROCK are not entirely specific, nor can they discriminate between the ROCK isoforms ROCK1 and ROCK2. To determine the specific role of ROCK1 in the development of cardiac hypertrophy, we generated ROCK1(+/-) haploinsufficient mice and determined whether cardiac hypertrophy and remodeling are decreased in these mice.Litters of ROCK1(-/-) mice on C57Bl/6 background were markedly underrepresented, suggesting lethality in utero or postnatally. ROCK1(+/-) mice, however, are viable and fertile with no obvious phenotypic abnormalities. Basal blood pressure, heart rate, and cardiac dimension and function in ROCK1(+/-) mice were similar to those in wild-type (WT) littermates. Infusion of angiotensin II (400 ng.kg(-1).min(-1) for 28 days) or treatment with NG-nitro-L-arginine methyl ester (1 mg/mL in drinking water for 28 days) caused similar increases in systolic blood pressure, left ventricular wall thickness, left ventricular mass, ratio of heart weight to tibial length, and cardiomyocyte size in ROCK1(+/-) mice and WT littermates. In contrast, perivascular fibrosis in hearts was increased to a lesser extent in ROCK1(+/-) mice compared with WT littermates. This was associated with decreased expression of transforming growth factor-beta, connective tissue growth factor, and type III collagen. In addition, perivascular fibrosis induced by transaortic constriction or myocardial infarction was decreased in ROCK1(+/-) mice compared with WT littermates.These findings indicate ROCK1 is critical for the development of cardiac fibrosis, but not hypertrophy, in response to various pathological conditions and suggest that signaling pathways leading to the hypertrophic and profibrotic response of the heart are distinct.