tbuckley/cabot-search huggingface dataset:
Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway
Authors: Martina Krüger, Christine Sachse, Wolfram H. Zimmermann, Thomas Eschenhagen, Stefanie Klede, Wolfgang A. Linke
Journal: Circulation Research (2007)

Titins, giant sarcomere proteins with major mechanical/signaling functions, are expressed in 2 main isoform classes in the mammalian heart: N2B (3000 kDa) and N2BA (>3200 kDa). A dramatic isoform switch occurs during cardiac development, from fetal N2BA titin (3700 kDa) expressed before birth to a mix of smaller N2BA/N2B isoforms found postnatally; adult rat hearts almost exclusively have N2B titin. The isoform switch, which can be reversed in chronic human heart failure, alters myocardial distensibility and mechanosignaling. Here we determined factors regulating this switch using, as a model system, primary cardiomyocyte cultures prepared from embryonic rats. In standard culture, the mean N2B percentage initially was 14% and increased by approximately 60% within 1 week, resembling the in vivo switching. The titin isoform transition was independent of endothelin-1-induced myocyte hypertrophy and was not altered by pacing, contractile arrest, or cell stretch; however, it was modestly impaired by decreasing substrate rigidity and strongly dependent on serum components. Angiotensin II significantly promoted the transition. The mean N2B proportion in 1-week-old cultures dropped 20% to 25% in hormone-reduced medium, but addition of 3,5,3'-triiodo-l-thyronine (T3) nearly restored the proportion to that found in standard culture. This T3 effect was not prevented by bisphenol A, a specific inhibitor of the classic genomic pathway of T3 action. In contrast, the titin switch could be stalled by the phosphatidylinositol 3-kinase inhibitor LY294002, which decreased the proportion of N2B mRNA transcripts within hours and suppressed a rapid T3-induced increase in Akt phosphorylation. Also, angiotensin II, but not endothelin-1 or cell stretch, enhanced Akt phosphorylation. Thus, although matrix stiffness modulates developmental titin isoform transitions, these transitions are mainly regulated through phosphatidylinositol 3-kinase/Akt-dependent signaling triggered particularly by T3 via a rapid action pathway.
Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy
Authors: Uta Griesenbach, Makoto Inoue, Cuixiang Meng, Raymond Farley, Mario Chan, Nikki K. Newman, Andrea Brum, Jun You, Angela Kerton, Amelia Shoemark, A. Christopher Boyd, Jane C. Davies, Tracy E. Higgins, Deborah R. Gill, Stephen C. Hyde, J. Alastair Innes, David J. Porteous, Mamoru Hasegawa, Eric W. F. W. Alton
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Ongoing efforts to improve pulmonary gene transfer thereby enabling gene therapy for the treatment of lung diseases, such as cystic fibrosis (CF), has led to the assessment of a lentiviral vector (simian immunodeficiency virus [SIV]) pseudotyped with the Sendai virus envelope proteins F and HN.Objectives: To place this vector onto a translational pathway to the clinic by addressing some key milestones that have to be achieved.Methods: F/HN-SIV transduction efficiency, duration of expression, and toxicity were assessed in mice. In addition, F/HN-SIV was assessed in differentiated human air–liquid interface cultures, primary human nasal epithelial cells, and human and sheep lung slices.Measurements and Main Results: A single dose produces lung expression for the lifetime of the mouse (∼2 yr). Only brief contact time is needed to achieve transduction. Repeated daily administration leads to a dose-related increase in gene expression. Repeated monthly administration to mouse lower airways is feasible without loss of gene expression. There is no evidence of chronic toxicity during a 2-year study period. F/HN-SIV leads to persistent gene expression in human differentiated airway cultures and human lung slices and transduces freshly obtained primary human airway epithelial cells.Conclusions: The data support F/HN-pseudotyped SIV as a promising vector for pulmonary gene therapy for several diseases including CF. We are now undertaking the necessary refinements to progress this vector into clinical trials.
Mammary Tumor Virus Activity in Red Blood Cells of BALB/c f. C3H Mice2
Authors: S. Nandi, D. Knox, K. B. DeOme, M. Handin, V. V. Finster, P. B. Pickett
Journal: JNCI Journal of the National Cancer Institute (1966)

The noduligenic test for mammary tumor virus (MTV) was used in investigations designed to ascertain which fraction of blood carries MTV activity in female BALB/c f. C3H mice of various ages and physiological states. Electron microscopic examination of red blood cells (RBC) and bone marrow cells, fluorocarbon extraction of blood, and potassium tartrate isopycnic density gradient centrifugation of whole blood and RBC from BALB/c f. C3H mice were also carriftl out to determine whether bloodborne MTV activity is associated with the presence of B particles. Biologically detectable MTV activity was always associated with the RBC fraction of blood. No such activity was associated with white blood cells (burfy coat) of 5-week-old females, or with plasma from donors of various physiological states except at lactation. Electron microscopically visible MTV particles (types A and B) were not observed in mature RBC, in bone marrow cells, or in pellets following fluorocarbon extraction of hemolyzed whole blood. The characteristic band for B particles was also absent after density gradient centrifugation of whole blood and of RBC from mice of the BALB/c f. C3H strain. Nodules in the mammary tissues of test mice inoculated with RBC from BALB/c f. C3H donors contained abundant A and B particles. The significance of these findings has been discussed and the suggestion was made that blood-borne MTV activity in BALB/c f. C3H mice may not be associated with B particles.
Contrasting Gene Expression Profiles in Two Canine Models of Atrial Fibrillation
Authors: Sophie Cardin, Eric Libby, Patricia Pelletier, Sabrina Le Bouter, Akiko Shiroshita-Takeshita, Nolwenn Le Meur, Jean Léger, Sophie Demolombe, André Ponton, Leon Glass, Stanley Nattel
Journal: Circulation Research (2007)

Gene-expression changes in atrial fibrillation patients reflect both underlying heart-disease substrates and changes because of atrial fibrillation-induced atrial-tachycardia remodeling. These are difficult to separate in clinical investigations. This study assessed time-dependent mRNA expression-changes in canine models of atrial-tachycardia remodeling and congestive heart failure. Five experimental groups (5 dogs/group) were submitted to atrial (ATP, 400 bpm x 24 hours, 1 or 6 weeks) or ventricular (VTP, 240 bpm x 24 hours or 2 weeks) tachypacing. The expression of approximately 21,700 transcripts was analyzed by microarray in isolated left-atrial cardiomyocytes and (for 18 genes) by real-time RT-PCR. Protein-expression changes were assessed by Western blot. In VTP, a large number of significant mRNA-expression changes occurred after both 24 hours (2209) and 2 weeks (2720). In ATP, fewer changes occurred at 24 hours (242) and fewer still (87) at 1 week, with no statistically-significant alterations at 6 weeks. Expression changes in VTP varied over time in complex ways. Extracellular matrix-related transcripts were strongly upregulated by VTP consistent with its pathophysiology, with 8 collagen-genes upregulated >10-fold, fibrillin-1 8-fold and MMP2 4.5-fold at 2 weeks (time of fibrosis) but unchanged at 24 hours. Other extracellular matrix genes (eg, fibronectin, lysine oxidase-like 2) increased at both time-points ( approximately 10, approximately 5-fold respectively). In ATP, mRNA-changes almost exclusively represented downregulation and were quantitatively smaller. This study shows that VTP-induced congestive heart failure and ATP produce qualitatively different temporally-evolving patterns of gene-expression change, and that specific transcriptomal responses associated with atrial fibrillation versus underlying heart disease substrates must be considered in assessing gene-expression changes in man.
The Role of p38α Mitogen-Activated Protein Kinase Activation in Renal Fibrosis
Authors: Cosimo Stambe, Robert C. Atkins, Greg H. Tesch, Takao Masaki, George F. Schreiner, David J. Nikolic-Paterson
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The p38 mitogen-activated protein kinase (MAPK) pathway transduces external stress stimuli and is important in extracellular matrix synthesis in cell types in vitro; however, its role in renal fibrosis is not known. Explored was the role the p38 MAPK pathway in rat unilateral ureteric obstruction (UUO), a model of renal fibrosis induced by a noninflammatory surgical insult. In a time-course study, a marked increase in phosphorylation (activation) of p38 in both interstitial myofibroblasts and tubules was shown. Rats were then treated daily with a specific inhibitor of p38α, NPC 31169, from the time of UUO surgery until being killed 7 d later. Compared with vehicle, NPC 31169–treated rats had a significant reduction in renal fibrosis assessed by interstitial volume, collagen IV deposition, and mRNA levels. This was primarily due to a reduction in the accumulation of interstitial myofibroblasts, as shown by a reduction in the area of immunostaining for alpha–smooth muscle actin and heat shock protein 47. The increase in renal TGF-β1 mRNA and protein levels in UUO was unaltered with NPC 31169 treatment; however, connective tissue growth factor mRNA was reduced. These results demonstrate that p38α MAPK plays an important role in renal fibrosis, acting downstream of TGF-β1. Blockade of p38 MAPK reduces extracellular matrix production and may be considered a potential therapeutic option in the treatment of renal fibrosis.
Ventral versus dorsal pathway: The source of the semantic object/event and the syntactic noun/verb distinction?
Authors: Markus Werning
Journal: Behavioral and Brain Sciences (2003)

Experimental data suggest that the division between the visual ventral and dorsal pathways may indeed indicate that static and dynamical information is processed separately. Contrary to Hurford, it is suggested that the ventral pathway primarily generates representations of objects, whereas the dorsal pathway produces representations of events. The semantic object/event distinction may relate to the morpho-syntactic noun/verb distinction.
Expression and distribution of PPP2R5C gene in leukemia
Authors: Haitao Zheng, Yu Chen, Shaohua Chen, Yuzhe Niu, Lijian Yang, Bo Li, Yuhong Lu, Suxia Geng, Xin Du, Yangqiu Li
Journal: Journal of Hematology & Oncology (2011)

Abstract Background Recently, we clarified at the molecular level novel chromosomal translocation t(14;14)(q11;q32) in a case of Sézary syndrome, which caused a rearrangement from TRAJ7 to the PPP2R5C gene. PPP2R5C is one of the regulatory B subunits of protein phosphatase 2A (PP2A). It plays a crucial role in cell proliferation, differentiation, and transformation. To characterize the expression and distribution of five different transcript variants of the PPP2R5C gene in leukemia, we analyzed the expression level of PPP2R5C in peripheral blood mononuclear cells from 77 patients with de novo leukemia, 26 patients with leukemia in complete remission (CR), and 20 healthy individuals by real-time PCR and identified the different variants of PPP2R5C by RT-PCR. Findings Significantly higher expression of PPP2R5C was found in AML, CML, T-ALL, and B-CLL groups in comparison with healthy controls. High expression of PPP2R5C was detected in the B-ALL group; however, no significant difference was found compared with the healthy group. The expression level of PPP2R5C in the CML-CR group decreased significantly compared with that in the de novo CML group and was not significantly different from the level in the healthy group. By using different primer pairs that covered different exons, five transcript variants of PPP2R5C could be identified. All variants could be detected in healthy samples as well as in all the leukemia samples, and similar frequencies and distributions of PPP2R5C were indicated. Conclusions Overexpression of PPP2R5C in T-cell malignancy as well as in myeloid leukemia cells might relate to its proliferation and differentiation. Investigation of the effect of target inhibition of this gene might be beneficial to further characterization of molecular mechanisms and targeted therapy in leukemia.
RNA Interference Targeting Aurora Kinase A Suppresses Tumor Growth and Enhances the Taxane Chemosensitivity in Human Pancreatic Cancer Cells
Authors: Tatsuo Hata, Toru Furukawa, Makoto Sunamura, Shinichi Egawa, Fuyuhiko Motoi, Noriyuki Ohmura, Tomotoshi Marumoto, Hideyuki Saya, Akira Horii
Journal: Cancer Research (2005)

Abstract AURKA/STK15/BTAK, the gene encoding Aurora A kinase that is involved in the regulation of centrosomes and segregation of chromosomes, is frequently amplified and overexpressed in various kinds of human cancers, including pancreatic cancer. To address its possibility as a therapeutic target for pancreatic cancer, we employed the RNA interference technique to knockdown AURKA expression and analyzed its phenotypes. We found that the specific knockdown of AURKA in cultured pancreatic cancer cells strongly suppressed in vitro cell growth and in vivo tumorigenicity. The knockdown induced the accumulation of cells in the G2-M phase and eventual apoptosis. Furthermore, we observed a synergistic enhancement of the cytotoxicity of taxanes, a group of chemotherapeutic agents impairing G2-M transition, by the RNA interference–mediated knockdown of AURKA. These results indicate that inhibition of AURKA expression can result in potent antitumor activity and chemosensitizing activity to taxanes in human pancreatic cancer.
Role of biological therapy for inflammatory bowel disease in developing countries
Authors: Gerhard Rogler, Charles N Bernstein, Ajit Sood, Khean Lee Goh, Jesús K Yamamoto-Furusho, Zaigham Abbas, Michael Fried
Journal: Gut (2011)

Inflammatory bowel disease (IBD) has become a global disease. Its incidence in developing countries is rising. In Asia, this has been attributed to the rapid modernisation and westernisation of the population. As IBD emerges in developing nations, there is a need to reconcile the most appropriate treatment for these patient populations from the perspectives of both disease presentation and cost. In the West, biological agents are the fastest-growing segment of the prescription drug market. They typically cost several thousand to several tens of thousands of dollars per patient per year. The healthcare systems in developing countries will struggle to afford such expensive treatments. Developing countries cover two-thirds of the earth9s surface and are home to 3–5 billion inhabitants, constituting three-quarters of all humanity. If IBD emerges to the same extent in those countries as it has in the West, the need for biological therapy will increase dramatically, and the pharmaceutical industry, healthcare providers, patient advocate groups, governments and non-governmental organisations will have to discuss how to handle this. The authors propose that this dialogue should begin now with regard to (1) the major needs of patients with complicated IBD in developing countries, (2) the potential need for biological therapy in developing countries to treat IBD, (3) the necessary infrastructure for selecting patients with IBD who need biological therapy, and (4) medical/ethical issues limiting the use of biological therapy.
Predictors of Sexual Functioning in Ovarian Cancer Patients
Authors: Cindy L. Carmack Taylor, Karen Basen-Engquist, Eileen H. Shinn, Diane C. Bodurka
Journal: Journal of Clinical Oncology (2004)

To characterize sexual functioning of ovarian cancer patients and identify factors predicting sexual activity, functioning or satisfaction, discomfort, and habit or frequency.Data were collected on 232 women with epithelial ovarian cancer, 47% of whom were receiving treatment.Fifty percent of the patients had engaged in sexual activity in the past month. Of those who were sexually active, 47% reported no or little desire, 80% reported problems with vaginal dryness, and 62% reported pain or discomfort during penetration. Of those who were sexually inactive, reasons included no partner (44.1%), lack of interest (38.7%), physical problems making sex difficult (23.4%), and fatigue (10.8%). Partner factors also were identified, including physical problems (16.2%), lack of interest (15.3%), and fatigue (5.4%). A multivariate model was used to predict sexual activity and included demographic, medical, and psychosocial factors as predictors. Women who were married (P <.001), were younger than 56 years (P <.001), were not receiving active treatment (P <.01), had a longer time since original diagnosis (P =.104), and liked the appearance of their bodies (P =.004) were more likely to be sexually active. Univariate analyses indicated that demographic, medical, and psychosocial factors are significantly associated with sexual functioning or satisfaction, sexual discomfort, and sexual frequency or habit.Sexual rehabilitation for ovarian cancer patients should address management of physical and psychologic symptoms and include the patient's partner when appropriate.
Cerebral Venous Thrombosis in Children
Authors: Christine Heller, Achim Heinecke, Ralf Junker, Ralf Knöfler, Andrea Kosch, Karin Kurnik, Rosemarie Schobess, Arnold von Eckardstein, Ronald Sträter, Barbara Zieger, Ulrike Nowak-Göttl
Journal: Circulation (2003)

The present study was performed to assess the association of prothrombotic risk factors and underlying conditions (infections, vascular trauma, immobilization, malignancies, autoimmune diseases, renal diseases, metabolic disorders, obesity, birth asphyxia, cardiac malformations, and use of prothrombotic drugs) with cerebral venous thrombosis (CVT) in children.From 1995 to 2002, 149 pediatric patients aged newborn to <18 years (median 6 years) with CVT were consecutively enrolled. In patients and in 149 age- and gender-matched children with similar underlying clinical conditions but without CVT, the factor V G1691A mutation, the factor II G20210A variant, lipoprotein(a) [Lp(a)], protein C, protein S, antithrombin, and antiphospholipid antibodies, as well as associated clinical conditions, were investigated. Eighty-four (56.4%) of the patients had at least 1 prothrombotic risk factor compared with 31 control children (20.8%; P<0.0001). In addition, 105 (70.5%) of 149 patients with CVT presented with an underlying predisposing condition. On univariate analysis, factor V, protein C, protein S, and elevated Lp(a) were found to be significantly associated with CVT. However, in multivariate analysis, only the combination of a prothrombotic risk factor with an underlying condition (OR 3.9, 95% CI 1.8 to 8.6), increased Lp(a) (OR 4.1, 95% CI 2.0 to 8.7), and protein C deficiency (OR 11.1, 95% CI 1.2 to 104.4) had independent associations with CVT in the children investigated.CVT in children is a multifactorial disease that, in the majority of cases, results from a combination of prothrombotic risk factors and/or underlying clinical condition.
His Bundle Electrograms of Dog
Authors: P. JACOB VARGHESE, MARCELLO V. ELIZARI, SUN H. LAU, ANTHONY N. DAMATO
Journal: Circulation (1973)

Transmembrane potentials from the penetrating and branching portions of the bundle of His were simultaneously recorded along with bipolar extracellular electrograms. Recordings were obtained during periods of normal antegrade and retrograde conduction and also during various degrees of conduction delay and block within and distal to the bundle of His. The onset and termination of extracellular electrogram coincided with the upstrokes of the transmembrane action potentials recorded from the penetrating and branching portions respectively and the duration of the extracellular electrogram equaled the interelectrode conduction time. Thus, the extracellular electrogram accurately reflected the timing and duration of the electrical activity of the entire bundle of His (penetrating and branching portions). Intra-His bundle conduction delay as determined by an increase in interelectrode conduction time and a decrease in the upstroke velocity of phase O of the action potentials, resulted in a decrease in the amplitude and an increase in the duration of the extracellular recording. Significant intra-His bundle conduction delay resulted in two His bundle deflections (H and H') in the extracellular electrogram recordings. The onset of the two His deflections coincided with the upstrokes of the two transmembrane potential recordings. When intra-His bundle block occurred the action potential distal to the block and the corresponding deflection on the extracellular recording disappeared. The results of this study provide further evidence supporting the validity of clinical electrode-catheter recordings of His bundle activity.
Plasma Albumin Concentration Is a Predictor of HbA1c Among Type 2 Diabetic Patients, Independently of Fasting Plasma Glucose and Fructosamine
Authors: Santiago Rodríguez-Segade, Javier Rodríguez, Dolores Mayan, Felix Camiña
Journal: Diabetes Care (2005)

The importance of the HbA1c assay for evaluation of long-term glucose control is well established (1–3). However, data for HbA1c and average plasma glucose, in spite of their strong correlation (4–7), show considerable scatter: for a given HbA1c level, average blood glucose generally varies by ∼5 mmol/l (7). This hampers interpretation of the HbA1c values of individual patients.

In this study of a large sample of type 2 diabetic patients, we investigated the possibility of statistical association between HbA1c concentration and levels of the main glycatable circulating proteins other than hemoglobin (albumin and globulins).

The diabetes outpatient clinics of our center are attended by most local diabetic patients requiring insulin or oral antidiabetics. We enrolled 4,158 diabetic patients who, in this complex in the years 1998–2003, were prescribed insulin or oral antidiabetics for type 2 diabetes diagnosed using American Diabetes Association criteria (8) and who, for glucose control monitoring, underwent regular determination of fasting HbA1c accompanied, for research purposes, by determination of total protein concentration, albumin, globulins, creatinine, hemoglobin, fructosamine, and glucose; age, sex, duration of diabetes, and type of therapy were also recorded. For this report, we considered for each patient the first such profile obtained within the study period. Urinary albumin excretion (normal range …