tbuckley/cabot-search huggingface dataset:
An SRF/miR-1 axis regulates NCX1 and Annexin A5 protein levels in the normal and failing heart
Authors: Eva Tritsch, Youssef Mallat, Florence Lefebvre, Nicolas Diguet, Brigitte Escoubet, Jocelyne Blanc, Leon J. De Windt, Daniele Catalucci, Grégoire Vandecasteele, Zhenlin Li, Mathias Mericskay
Journal: Cardiovascular Research (2013)

The expression of the sodium/calcium exchanger NCX1 increases during cardiac hypertrophy and heart failure, playing an important role in Ca2+ extrusion. This increase is presumed to result from stress signalling induced changes in the interplay between transcriptional and post-transcriptional regulations. We aimed to determine the impact of the SRF transcription factor known to regulate the NCX1 promoter and microRNA genes, on the expression of NCX1 mRNA and protein and Annexin A5 (AnxA5), a Ca2+-binding protein interacting with NCX1 and increased during HF. NCX1 mRNA was decreased while the protein was increased in the failing heart of the cardiomyocyte-restricted SRF knock-out mice (SRFHKO). The induction of NCX1 mRNA by the pro-hypertrophic drug phenylephrine observed in control mice was abolished in the SRFHKO though the protein was strongly increased. AnxA5 protein expression profile paralleled the expression of NCX1 protein in the SRFHKO. MiR-1, a microRNA regulated by SRF, was decreased in the SRFHKO and repressed by phenylephrine. In vitro and in vivo manipulation of miR-1 levels and site-directed mutagenesis showed that NCX1 and AnxA5 mRNAs are targets of miR-1. AnxA5 overexpression slowed down Ca2+ extrusion during caffeine application in adult rat cardiomyocytes. Our study reveals the existence of a complex regulatory loop where SRF regulates the transcription of NCX1 and miR-1, which in turn functions as a rheostat limiting the translation of NCX1 and AnxA5 proteins. The decrease of miR-1 and increase of AnxA5 appear as important modulators of NCX1 expression and activity during heart failure.
Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4
Authors: R. Moucari, M.-P. Ripault, M. Martinot-Peignoux, H. Voitot, A.-C. Cardoso, C. Stern, N. Boyer, S. Maylin, M.-H. Nicolas-Chanoine, M. Vidaud, D. Valla, P. Bedossa, P. Marcellin
Journal: Gut (2009)

Hepatitis C virus (HCV) genotype 4 (HCV-4) is increasing in prevalence in Western countries. However, little is known about the severity of the disease and response to treatment. The aim of this study was to assess the predictors (logistic regression) of severe fibrosis (METAVIR score F3-F4), and sustained virological response (SVR) to peginterferon and ribavirin in 226 consecutive HCV-4 patients (Egyptians 40%, Europeans 35% and Africans 24%).Insulin resistance was assessed using the homeostasis model (HOMA-IR). Serum HCV-RNA level (bDNA) and subtypes of HCV (LiPA) were determined for all patients.Insulin resistance (HOMA-IR >3) was present in 105 patients (46%), and was associated with: age >45 years (OR, 2.614; 95% CI, 1.316 to 5.194), body mass index (BMI) >25 kg/m(2) (OR, 2.105; 95% CI, 1.048 to 4.229), serum HCV-RNA >800 000 IU/ml (OR, 3.143; 95% CI, 1.503 to 6.574), severe fibrosis (OR, 2.657; 95% CI, 1.214 to 5.818), and steatosis >30% (OR, 2.488; 95% CI, 1.105 to 5.602). Severe fibrosis was present in 67 patients (29%) and was associated with Egyptian origin (OR, 5.872; 95% CI, 2.747 to 12.553), excessive alcohol intake (OR, 5.311; 95% CI, 1.287 to 21.924), and HOMA-IR >3 (OR, 3.864; 95% CI, 1.859 to 8.034). 108 patients received a 48 week course of peginterferon plus ribavirin. SVR (undetectable serum HCV-RNA (TMA) 24 weeks after treatment stopping) was achieved in 59 patients (55%) and was associated with Egyptian origin (OR, 13.119; 95% CI, 3.089 to 55.706), HOMA-IR <2 (OR, 5.314; 95% CI, 1.953 to 14.459), and non-severe fibrosis (OR, 8.059; 95% CI, 2.512 to 25.855).Insulin resistance and geographical origin are major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4 patients. Insulin resistance is frequently encountered in these patients, and correlated independently with serum HCV-RNA.
Use of a Computerized Decision Aid for Developmental Surveillance and Screening
Authors: Aaron E. Carroll, Nerissa S. Bauer, Tamara M. Dugan, Vibha Anand, Chandan Saha, Stephen M. Downs
Journal: JAMA Pediatrics (2014)

IMPORTANCE Developmental delays and disabilities are common in children.Research has indicated that intervention during the early years of a child's life has a positive effect on cognitive development, social skills and behavior, and subsequent school performance.OBJECTIVE To determine whether a computerized clinical decision support system is an effective approach to improve standardized developmental surveillance and screening (DSS) within primary care practices. DESIGN, SETTING, AND PARTICIPANTSIn this cluster randomized clinical trial performed in 4 pediatric clinics from June 1, 2010, through December 31, 2012, children younger than 66 months seen for primary care were studied. INTERVENTIONSWe compared surveillance and screening practices after adding a DSS module to an existing computer decision support system. MAIN OUTCOMES AND MEASURESThe rates at which children were screened for developmental delay.RESULTS Medical records were reviewed for 360 children (180 each in the intervention and control groups) to compare rates of developmental screening at the 9-, 18-, or 30-month well-child care visits.The DSS module led to a significant increase in the percentage of patients screened with a standardized screening tool (85.0%vs 24.4%, P < .001).An additional 120 records (60 each in the intervention and control groups) were reviewed to examine surveillance rates at visits outside the screening windows.The DSS module led to a significant increase in the percentage of patients whose parents were assessed for concerns about their child's development (71.7% vs 41.7%, P = .04).CONCLUSIONS AND RELEVANCE Using a computerized clinical decision support system to automate the screening of children for developmental delay significantly increased the numbers of children screened at 9, 18, and 30 months of age.It also significantly improved surveillance at other visits.Moreover, it increased the number of children who ultimately were diagnosed as having developmental delay and who were referred for timely services at an earlier age.
The Safety Risks of Innovation
Authors: Thomas J. Moore, Curt D. Furberg
Journal: JAMA (2012)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Alcohol, obesity, and TNF-α
Authors: A POULLIS, M A MENDALL
Journal: Gut (2001)

Editor,—The conclusions reached by Wigg et al ((2001) Gut 48:206–11.[OpenUrl][1][Abstract/FREE Full Text][2]) about the origin and importance of tumour necrosis factor α (TNF-α) in non-alcoholic steatohepatitis (NASH) patients have failed to take into account the relationship between even modest alcohol consumption and TNF-α production and function. The authors found a lack of correlation between obesity and TNF-α levels in NASH patients and concluded that TNF-α, which they see as central to the pathogenesis of the condition, must have other sources. We first described the strong correlation between obesity and serum TNF-α in 1998.1 Adipose tissue synthesises a number of proinflammatory cytokines.2 The negative correlation found in the Adelaide study is surprising given the findings in larger studies of non-NASH subjects and may be due to the small study numbers and not correcting for modest alcohol intake. Alcohol consumption is considered a risk factor for the development and progression of liver disease in patients with fatty livers. We previously showed a strong negative … Dr AJ Wigg, Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia.alan.wigg{at}flinders.edu.au [1]: {openurl}?query=rft.jtitle%253DHeart%26rft.stitle%253DHeart%26rft.aulast%253DMendall%26rft.auinit1%253DM.%2BA.%26rft.volume%253D78%26rft.issue%253D3%26rft.spage%253D273%26rft.epage%253D277%26rft.atitle%253DRelation%2Bof%2Bserum%2Bcytokine%2Bconcentrations%2Bto%2Bcardiovascular%2Brisk%2Bfactors%2Band%2Bcoronary%2Bheart%2Bdisease.%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fhrt.78.3.273%26rft_id%253Dinfo%253Apmid%252F9391290%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=heartjnl&resid=78/3/273&atom=%2Fgutjnl%2F49%2F2%2F313.atom
The Unfolded Protein Response Induces the Angiogenic Switch in Human Tumor Cells through the PERK/ATF4 Pathway
Authors: Yugang Wang, Goleeta N. Alam, Yu Ning, Fernanda Visioli, Zhihong Dong, Jacques E. Nör, Peter J. Polverini
Journal: Cancer Research (2012)

Abstract Neovascularization is a limiting factor in tumor growth and progression. It is well known that changes in the tumor microenvironment, such as hypoxia and glucose deprivation (GD), can induce VEGF production. However, the mechanism linking GD to tumor growth and angiogenesis is unclear. We hypothesize that GD induces the angiogenic switch in tumors through activation of the unfolded protein response (UPR). We report that UPR activation in human tumors results in elevated expression of proangiogenic mediators and a concomitant decrease in angiogenesis inhibitors. cDNA microarray results showed that GD-induced UPR activation promoted upregulation of a number of proangiogenic mediators (VEGF, FGF-2, IL-6, etc.) and downregulation of several angiogenic inhibitors (THBS1, CXCL14, and CXCL10). In vitro studies revealed that partially blocking UPR signaling by silencing protein kinase RNA–like ER kinase (PERK) or activating transcription factor 4 (ATF4) significantly reduced the production of angiogenesis mediators induced by GD. However, suppressing the alpha subunit of hypoxia-inducible factors had no effect on this process. Chromatin immunoprecipitation (ChIP) confirmed binding of ATF4 to a regulatory site in the VEGF gene. In vivo results confirmed that knockdown of PERK in tumor cells slows down tumor growth and decreases tumor blood vessel density. Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. Cancer Res; 72(20); 5396–406. ©2012 AACR.
Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Can Regulate Dendritic Cell–induced Activation and Cytotoxicity of CD8+ T Cells Independently of CD4+T Cell Help
Authors: Kathy D. McCoy, Ian F. Hermans, J. Henry Fraser, Graham Le Gros, Franca Ronchese
Journal: The Journal of Experimental Medicine (1999)

The mechanisms that regulate the strength and duration of CD8+ cytotoxic T cell activity determine the effectiveness of an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8+ T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8+ T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti–CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8+ T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4+ T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8+ T cells, indicating its potential for tumor immunotherapy even in situations in which CD4+ T cell help is limited or absent.
The Loss of Postprandial Glycemic Control Precedes Stepwise Deterioration of Fasting With Worsening Diabetes
Authors: Louis Monnier, Claude Colette, Gareth J. Dunseath, David R. Owens
Journal: Diabetes Care (2007)

The aim of the study was to determine whether the loss of fasting and postprandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes.In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (<6.5%, n = 30), 2 (6.5-6.9%, n = 17), 3 (7-7.9%, n = 32), 4 (8-8.9%, n = 25), and 5 (> or =9%, n = 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phenomenon states, respectively, were also compared.Glucose concentrations increased steadily from group 1 to 5 in a stepwise manner. The initial differences in mean glucose concentrations reaching statistical significance occurred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P = 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P = 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P < 0.0001) for nocturnal fasting periods.The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment.
Mechanized derivation of linear invariants.
Authors: J A Cavender
Journal: Molecular Biology and Evolution (1989)

Linear invariants, discovered by Lake, promise to provide a versatile way of inferring phylogenies on the basis of nucleic acid sequences (the method that he called "evolutionary parsimony"). A semigroup of Markov transition matrices embodies the assumptions underlying the method, and alternative semigroups exist. The set of all linear invariants may be derived from the semigroup by using an algorithm described here. Under assumptions no stronger than Lake's, there are greater than 50 independent linear invariants for each of the 15 rooted trees linking four species.
Recurrence of Lupus Nephritis after Kidney Transplantation
Authors: Gabriel Contreras, Adela Mattiazzi, Giselle Guerra, Luis M. Ortega, Elaine C. Tozman, Hua Li, Leonardo Tamariz, Cristiane Carvalho, Warren Kupin, Marco Ladino, Baudouin LeClercq, Isabel Jaraba, Decio Carvalho, Efrain Carles, David Roth
Journal: Journal of the American Society of Nephrology (2010)

The frequency and outcome of recurrent lupus nephritis (RLN) among recipients of a kidney allograft vary among single-center reports. From the United Network for Organ Sharing files, we estimated the period prevalence and predictors of RLN in recipients who received a transplant between 1987 and 2006 and assessed the effects of RLN on allograft failure and recipients' survival. Among 6850 recipients of a kidney allograft with systemic lupus erythematosus, 167 recipients had RLN, 1770 experienced rejection, and 4913 control subjects did not experience rejection. The period prevalence of RLN was 2.44%. Non-Hispanic black race, female gender, and age <33 years each independently increased the odds of RLN. Graft failure occurred in 156 (93%) of those with RLN, 1517 (86%) of those with rejection, and 923 (19%) of control subjects without rejection. Although recipients with RLN had a fourfold greater risk for graft failure compared with control subjects without rejection, only 7% of graft failure episodes were attributable to RLN compared and 43% to rejection. During follow-up, 867 (13%) recipients died: 27 (16%) in the RLN group, 313 (18%) in the rejection group, and 527 (11%) in the control group. In summary, severe RLN is uncommon in recipients of a kidney allograft, but black recipients, female recipient, and younger recipients are at increased risk. Although RLN significantly increases the risk for graft failure, it contributes far less than rejection to its overall incidence; therefore, these findings should not keep patients with lupus from seeking a kidney transplant.
Immunoconjugates of Geldanamycin and Anti-HER2 Monoclonal Antibodies: Antiproliferative Activity on Human Breast Carcinoma Cell Lines
Authors: R. Mandler
Journal: JNCI Journal of the National Cancer Institute (2000)

HER2 is a membrane receptor whose overexpression is strongly associated with poor prognosis in breast carcinomas. Inhibition of HER2 activity can reduce tumor growth, which led to the development of Herceptin, an anti-HER2 monoclonal antibody (MAb) that is already in clinical use. However, the objective response rate to Herceptin monotherapy is quite low. HER2 activity can also be inhibited by the highly cytotoxic antibiotic geldanamycin (GA). However, GA is not used clinically because of its adverse toxicity. Our purpose was to enhance the inhibitory activity of anti-HER2 MAb by coupling it to GA.We synthesized 17-(3-aminopropylamino)GA (17-APA-GA) and conjugated it to the anti-HER2 MAb e21, to form e21 : GA. The noninternalizing anti-HER2 MAb AE1 was used as a control. Internalization assays and western blot analyses were used to determine whether the anti-HER2 MAbs and their immunoconjugates were internalized into HER2-expressing cells and reduced HER2 levels. All statistical tests were two-sided.The immunoconjugate e21 : GA inhibited the proliferation of HER2-overexpressing cell lines better than unconjugated e21 (concentration required for 50% inhibition = 40 versus 1650 microg/mL, respectively). At 15 microg/mL, e21 : GA reduced HER2 levels by 86% within 16 hours, whereas unconjugated e21, 17-APA-GA, or AE1 : GA reduced HER2 levels by only 20%. These effects were not caused by release of 17-APA-GA from the immunoconjugate because immunoconjugates containing [(3)H]GA were stable in serum at 37 degrees C. Furthermore, e21 : GA did not significantly inhibit proliferation of the adult T-cell leukemia cell line HuT102, which is HER2 negative yet highly sensitive to GA.Our findings suggest that conjugating GA to internalizing MAbs enhances the inhibitory effect of the MAbs. This approach might also be applied in cellular targeting via growth factors and may be of clinical interest.
Endothelin-1 Impairs Alveolar Epithelial Function via Endothelial ET<sub>B</sub> Receptor
Authors: Alejandro P. Comellas, Arturo Briva, Laura A. Dada, Maria L. Butti, Humberto E. Trejo, Cecilia Yshii, Zaher S. Azzam, Juan Litvan, Jiwang Chen, Emilia Lecuona, Liuska M. Pesce, Masashi Yanagisawa, Jacob I. Sznajder
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR).To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation.Isolated perfused rat lung, transgenic rats deficient in ETB receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive 86Rb+ uptake.The ET-1-induced decrease in AFR was prevented by blocking the endothelin receptor ETB, but not ETA. Endothelial-epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Exposing transgenic rats deficient in ETB receptors in the pulmonary vasculature (ET-B(-/-)) to ET-1 did not decrease AFR or Na,K-ATPase protein abundance at the plasma membrane of AECs. Exposing HMVEC-L to ET-1 led to increased NO, and the ET-1-induced down-regulation of Na,K-ATPase was prevented by the NO synthase inhibitor l-NAME, but not by a guanylate cyclase inhibitor.We provide the first evidence that ET-1, via an endothelial-epithelial interaction, leads to decreased AFR by a mechanism involving activation of endothelial ETB receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.
STUDIES ON INFLAMMATION
Authors: Valy Menkin, Miriam F. Menkin
Journal: The Journal of Experimental Medicine (1930)

1. By means of a colorimetric method the concentration of trypan blue in capillaries can be estimated by direct observation and its changes followed as the dye passes out of the circulating blood stream. 2. The change in concentration of trypan blue in the capillaries of both the normal and the inflamed mesentery of frogs can be described by two separate exponential equations of the type: y = be(-ax). 3. From these equations it is found that the rate of fall of concentration following intraventricular injection of the dye is almost twice as great in the capillaries of the inflamed as in those of the normal mesentery. This difference is a measure of increased permeability with inflammation.
Diesel Exhaust Particles Enhance Antigen-induced Airway Inflammation and Local Cytokine Expression in Mice
Authors: HIROHISA TAKANO, TOSHIKAZU YOSHIKAWA, TAKAMICHI ICHINOSE, YUICHI MIYABARA, KOICHI IMAOKA, MASARU SAGAI
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Previous experimental studies have suggested that nasal instillation of diesel exhaust particles (DEP) can enhance nasal IgE response and cytokine production. However, there is no experimental evidence for the relation of DEP to allergic asthma. We investigated the effects of DEP inoculated intratracheally on antigen-induced airway inflammation, local expression of cytokine proteins, and antigen-specific immunoglobulin production in mice. DEP aggravated ovalbumin-induced airway inflammation characterized by infiltration of eosinophils and lymphocytes and an increase in goblet cells in bronchial epithelium. DEP with antigen markedly increased interleukin-5 (IL-5) protein levels in lung tissue and bronchoalveolar lavage supernatants compared with either antigen or DEP alone. The combination of DEP and antigen induced significant increases in local expression of IL-4, granulocyte macrophage-colony stimulating factor (GM-CSF), and IL-2, whereas expression of interferon-gamma was not affected. In addition, DEP exhibited adjuvant activity for the antigen-specific production of IgG and IgE. These results provide the first experimental evidence that DEP can enhance the manifestations of allergic asthma. The enhancement may be mediated mainly by the increased local expression of IL-5, and also by the modulated expression of IL-4, GM-CSF, and IL-2.