tbuckley/cabot-search huggingface dataset:
Abstract 2375: Regulation of Cardiac Myocyte Contractility by Phospholemman
Authors: Jianliang Song, Xue-Qian Zhang, JuFang Wang, Ellina Cheskis, Tung O Chan, Arthur M Feldman, Amy L Tucker, Joseph Y Cheung
Journal: Circulation (2008)

Phospholemman (PLM) regulates cardiac contractility by modulating Na + /Ca 2+ exchanger (NCX1) and/or Na + -K + -ATPase activities. PLM, when phosphorylated at serine68, disinhibits Na + -K + -ATPase but inhibits NCX1. In this study, we first demonstrated that adult mouse cardiac myocytes cultured for 48 hours had normal surface membrane area and t-tubule appearance, and exhibited near normal contractility. Contractile differences between wild-type (WT) and PLM knockout (KO) myocytes were preserved after 48h of culture. Infection with adenovirus overexpressing GFP did not affect contractility at 48h. When WT PLM was overexpressed in PLM-KO myocytes, part of PLM was phosphorylated, both Na + -K + -ATPase current (I pump ) and Na + /Ca 2+ exchange current (I NaCa ) were depressed, and contractility and [Ca 2+ ] i transients reverted back to those observed in cultured WT myocytes. Overexpressing PLMS68E mutant (phosphomimetic) in PLM-KO myocytes resulted in suppression of I NaCa but no effect on I pump . Contractility and [Ca 2+ ] i transient amplitudes in PLM-KO myocytes overexpressing PLMS68E mutant were depressed when compared to PLM-KO myocytes overexpressing GFP. Overexpressing PLMS68A mutant (mimicking unphosphorylated PLM) in PLM-KO myocytes had no effects on I NaCa but decreased I pump . Contractility and [Ca 2+ ] i transient amplitudes in PLM-KO myocytes overexpressing S68A mutant were similar to PLM-KO myocytes overexpressing GFP. Neither WT PLM nor its mutants had any effect on SR Ca 2+ uptake in KO myocytes. We conclude that at the single myocyte level, PLM affects cardiac contractility and [Ca 2+ ] i homeostasis primarily by its direct inhibitory effects on Na + /Ca 2+ exchange.
Abstract 3883: Thyroid cancer cells with low proteasome activity have therapeutic resistance
Authors: Takahito Fukusumi, Hideshi Ishii, Masamitsu Konno, Shimpei Nishikawa, Yoshihiro Kano, Shinichiro Hasegawa, Hisataka Ogawa, Atsushi Hamabe, Kozo Noguchi, Masaaki Miyo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hidenori Inohara
Journal: Cancer Research (2014)

Abstract Background Thyroid cancer is the most frequent endocrine malignancy with a global increasing incidence. Papillary, follicular, and anaplastic thyroid carcinomas arise from endodermal-derived follicular cells, which represent the most abundant cellular population of the thyroid gland. The recent discovery of cancer stem cells (CSCs) in a variety of tumors has changed the view of carcinogenesis and therapeutic resistance. Therefore, the identification of CSCs in thyroid cancer represents a crucial step to elucidate the mechanism of therapeutic resistance, and develop effective therapies. It was previously reported that low intrinsic proteasome activity in glioma, pancreas, prostate, and breast cancer cells correlated with therapeutic resistance and CSCs properties. We hypothesized that a therapeutic resistant cell population with intrinsically low 26S proteasome activity can also be found in thyroid cancer. Materials and Methods We engineered human thyroid cancer cell lines (TPC-1, FRO, and WRO) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase from a retroviral vector. The green fluorescence accumulates in a small population of these cells as a result of low activity of the 26S proteasome. Result We identified a small population of cells with intrinsically low 26S proteasome activity in all thyroid cell lines. These populations have cisplatin, 5-FU, and radio-resistance. To further investigate differences between thyroid cancer cells with high and low proteasome activity, we studied their self-renewal capacity and tumorigenicity using an in vitro sphere-forming assay and an in vivo xenograft transplantation assay. Conclusion We conclude that established thyroid cancer cell lines are heterogeneous with regard to their intrinsic proteasome activity and that they contain a therapeutic resistant subpopulation of cells that can be identified by low proteasome activity. Further studies are needed to elucidate the mechanism that thyroid cancer cells with low proteasome activity have these properties. Learning Objective We identified thyroid cancer cells with low proteasome activity have therapeutic resistance and CSCs properties. Citation Format: Takahito Fukusumi, Hideshi Ishii, Masamitsu Konno, Shimpei Nishikawa, Yoshihiro Kano, Shinichiro Hasegawa, Hisataka Ogawa, Atsushi Hamabe, Kozo Noguchi, Masaaki Miyo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hidenori Inohara. Thyroid cancer cells with low proteasome activity have therapeutic resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3883. doi:10.1158/1538-7445.AM2014-3883
Maintenance strategy with fluoropyrimidines (FP) plus Bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): A phase III non-inferiority trial (AIO KRK 0207).
Authors: Dirk Arnold, Ullrich Graeven, Christian A. Lerchenmuller, Brigitta Killing, Reinhard Depenbusch, Claus-Christoph Steffens, Salah-Eddin Al-Batran, Thoralf Lange, Georg Dietrich, Jan Stoehlmacher, Andrea Tannapfel, Hans-Joachim Schmoll, Anke Reinacher-Schick, Susanna Hegewisch-Becker
Journal: Journal of Clinical Oncology (2014)

3503^ Background: The optimal maintenance strategy following combination chemotherapy plus Bev is still controversial. AIO KRK 0207 investigates whether after a 24-week standard induction with F//Ox/Bev, no continuation of therapy or continuation with Bev alone are non-inferior to FP plus Bev. Methods: Pts with mCRC and 'standard' eligibility criteria were enrolled. After 24 weeks of induction treatment with FP/Ox/Bev, pts without disease progression were randomized into one of the following arms: A) standard maintenance treatment with FP plus Bev; B) Bev alone; or C) no treatment. At first progression, re-induction of the initial treatment was planned. The primary endpoint was 'time to failure of strategy' (TFS), comprising maintenance plusre-induction after first progression. Sample size was calculated (one-sided alpha of 0.0125; power of 80%) to conclude non-inferiority compared with the FP plus Bev arm. Secondary endpoints included time to first progression (PFS1) and overall survival (OS). Results: 840 pts were enrolled, 473 randomized. Median follow-up is 27 months. After induction, 60% of pts had CR/PR, 40% SD. Median PFS1 in arms A, B, C were 6.2, 4.6 and 3.6 months (p< 0.0001; A vs C: HR 2.11, 95% CI 1.63-2.73; A vs B: HR 1.28, 95% CI 0.99-1.65; B vs C: HR 1.56, 95% CI 1.22-1.99), respectively. TFS favored arm A over arm C (HR 1.31, 95% CI 1.01-1.69, p=0.038) but without difference between arms A and B (HR 1.04,95% CI 0.81-1.36, p=0.74). However, upon first progression only 24% in arm A and 47 % in both arms B and C, received re-induction. After 200 documented events, preliminary OS is 23.4 months from randomization, without significant difference between treatment arms (p=0.69). Conclusions: Following 24 weeks of induction, active maintenance with both, FP plus Bev or Bev alone, show prolonged TFS over no treatment. Only a minority of patients received re-induction treatment as planned. With currently limited follow up, the different maintenance strategies had no impact on OS. Clinical trial information: NCT00973609.
Late-breaking abstract: A prospective study of central obesity, overall obesity and incident asthma in adults
Authors: Ben Brumpton, Arnulf Langhammer, Pål Romundstad, Yue Chen, Xiao-Mei Mai
Journal: European Respiratory Journal (2011)

Introduction:  Measures of body mass index (BMI) and waist circumference (WC) define overall obesity and central obesity respectively. While high BMI has been established as a risk factor for asthma in adults, WC has seldom been investigated.   Aims and objectives:  We conducted a prospective cohort study to investigate the individual and combined effect of central obesity and overall obesity on adult incident asthma.   Methods:  A total of 23,245 adults without asthma, 19-55 years of age from the second Norwegian Nord-Trondelag Health Study (HUNT), were followed for 11 years. WC and BMI were measured and categorised as central obesity (WC ≥88cm in women and ≥102cm in men) and overall obesity (BMI ≥30.0 kg/m 2 ). Incident asthma was self reported asthma during the follow up. Odds ratios (OR) were calculated by logistic regression models adjusted for age, smoking status, education, family history, physical activity, social benefit, economical difficulty and sex.   Results:  Of the 23,245 adults in the analysis, 12% (n=2,792) were overall obese, 13.6% (n=3,170) were centrally obese at baseline and 3.5% (n=818) had asthma during the 11-year at follow up. Central obesity in the absence of overall obesity was significantly associated with incident asthma (OR 1.44, 95% confidence interval (CI) 1.09-1.91). The OR for overall obesity in the absence of central obesity was 1.38 (95% CI 0.96-2.00), similar to central obesity alone. Central obesity combined with overall obesity (OR 1.81, 95% CI 1.48-2.23) is compatible with an additive effect of BMI and WC on asthma.   Conclusion:  Central obesity and overall obesity seem to have an individual effect on incident asthma in adults and an additive effect when in combination.
Safety of Cimetidine in Obstetric Patients
Authors: W A W McGowan
Journal: Journal of the Royal Society of Medicine (1979)

Cimetidine has been suggested as a new approach to the prevention of the acid pulmonary aspiration syndrome in obstetric anaesthesia. In 20 patients in labour cimetidine 200 mg intravenously did not prolong labour or alter the pattern or strength of uterine contractions. The fetal heart rate did not show any alteration in rate or pattern and it was confirmed that cimetidine crosses the placenta. These findings suggest that further studies of cimetidine in obstetric patients would be safe.
Carbon dioxide monitoring during polygraphy in children with sleep-disordered breathing: Is it necessary?
Authors: Sonia Khirani, Jade Pautrat, Michèle Boulé, Nicole Beydon, Brigitte Fauroux
Journal: European Respiratory Journal (2013)

Introduction   Most adult sleep laboratories do not measure carbon dioxide (CO 2 ) routinely during polygraphy (PG). In children, CO 2  measurements are “recommended” but few studies have analyzed systematic CO 2  monitoring during PG.   Objectives   The aim of the study was to assess the prevalence and predictors of nocturnal hypercapnia in children with sleep-disordered breathing (SDB).   Methods   Systematic transcutaneous CO 2  (PtcCO 2 ) monitoring was performed during overnight PG. Three definitions of nocturnal hypercapnia were used: a maximal PtcCO 2 >50 mmHg, percentage of sleep time with PtcCO 2 >50 mmHg >2%, and a PtcCO 2 >10 mmHg above waking baseline level. PtcCO 2  indices were correlated to the apnoea-hypopnoea index (AHI) and oxygenation indices (desaturation index, minimal SpO 2  and percentage of time with SpO 2    Results   221 PGs from patients with suspicion of obstructive sleep apnoea (72%), neuromuscular (21%) and lung diseases (7%) were analyzed. The percentage of hypercapnic patients ranged between 20 and 60%, and was not different between groups whatever the definition of hypercapnia. Significant but weak correlations were observed between hypercapnia according to the 3 definitions and the AHI (r=0.137, p=0.047 for maximal PtcCO 2 ) and oxygenation indices. The Receiver operating characteristic curves showed a poor sensitivity and specificity of the AHI and SpO 2  to predict nocturnal hypercapnia.   Conclusion   This study shows that 20 to 60% of children undergoing an overnight PG for SDB have nocturnal hypercapnia which is poorly correlated to the AHI and oxygenation indices. A systematic nocturnal CO 2  recording is useful in all children presenting with SDB, whatever the underlying disease.
Management of Spontaneous Rupture of Hepatocellular Carcinoma: Single-Center Experience
Authors: Chi-Leung Liu, Sheung-Tat Fan, Chung-Mau Lo, Wai-Kuen Tso, Ronnie Tung-Ping Poon, Chi-Ming Lam, John Wong
Journal: Journal of Clinical Oncology (2001)

To report the management of patients with spontaneous rupture of hepatocellular carcinoma (HCC) in a single center over a 10-year period and to evaluate a two-stage therapeutic approach.A retrospective study was performed on all 1,716 patients with HCC who presented from 1989 to 1998. The two-stage therapeutic approach to manage ruptured HCC consisted of initial management by conservative method, hemostasis by transarterial embolization (TAE) or surgical means, followed by second-stage hepatic resection or transarterial oily chemoembolization (TOCE). Results of definitive treatment were compared with patients with no history of rupture during the same study period.During the study period, 154 patients (9%) had spontaneous HCC rupture. Initial intervention to control bleeding included TAE in 42 patients, surgical hemostasis in 35 patients, and conservative management only in 53 patients. The 30-day mortality rate was 38%. Independent factors on presentation affecting 30-day mortality were shock on admission, hemoglobin, serum total bilirubin, and known diagnosis of inoperable tumor. After initial stabilization and clinical evaluation, 33 patients underwent hepatic resection and 30 patients received TOCE. Median survival of the hepatectomy patients was 25.7 months; that of the TOCE patients was 9.7 months. Compared with patients with no rupture, survival after hepatectomy (25.7 months v 49.2 months, P =.003) was inferior but still substantially long, whereas survival after TOCE was comparable (9.7 months v 8.7 months, P =.904).Early mortality of spontaneous rupture of HCC was dependent on prerupture disease state, liver function, and severity of bleeding. Although it was a catastrophic presentation, prolonged survival could be achieved in selected patients with second-stage hepatic resection or TOCE.
Diagnostic value of non-specific humoral immune changes in children investigated for tuberculosis by skin test and bacteriology
Authors: Marina Spinu, Carmen Monica Pop, Carmen Dana Sandru, Daniel Cadar, Mihaela Niculae, Pompei Bolfa
Journal: European Respiratory Journal (2011)

It was suggested that repeated skin tests (IDR) used to diagnose childhood tuberculosis (TB) potentially change the immune response of the host. Adaptive cell-mediated immunity is the most important in protection against TB, but there is no information on the changes in the dynamics of immune globulins (Ig) and circulating immune complexes (CIC) in these patients. We hypothesized that the changes would be dependent on both the skin test results and bacteriological (BK) category of the subjects. The study was carried out in three groups of children, 1 to 17 years old, positive to both skin test and bacteriology (IDR+BK+, n=18), positive to the skin test but negative for bacteriology (IDR+BK+, n=12) and negative to skin test, but positive for bacteriology (IDR-BK+, n= 9). Serum samples were subjected to total immunoglobulin (Ig) and immune complexes measurements (CIC), carried out by 0.24% zinc sulphate and 4.2% polyethylene glycol precipitation tests, respectively. Optical densities (optical density units, ODU) were red spectrophotometrically. The statistical significance of the results was estimated by Student9s t test.  The highest concentration of immune globulins and circulating immune complexes, statistically significantly different (p
Effects of aclidinium bromide on exercise endurance, dynamic hyperinflation, physical activity and exertional dyspnoea in patients with moderate to severe COPD
Authors: Kai M. Beeh, Henrik Watz, Helgo Magnussen, Luis Puente-Maestu, Diana Jarreta, Cynthia Caracta, Esther Garcia Gil
Journal: European Respiratory Journal (2013)

INTRODUCTION: Lung hyperinflation is related to exertional dyspnoea, exercise intolerance and reduced physical activity in COPD patients.

AIMS: To investigate the effects of aclidinium on dynamic hyperinflation, exercise endurance time, physical activity and dyspnoea in COPD patients . 

METHODS: This double-blind, randomized, crossover study compared aclidinium bromide 400 µg BID (metered dose; equivalent to aclidinium 322 µg delivered dose) with placebo, each for 3 weeks, in 112 patients with moderate to severe stable COPD (FEV1 1.50 L, 56.7% pred). Patients performed constant load exercise at 75% of peak incremental exercise work rate. The primary endpoint was change from baseline in endurance time at Week 3. Other assessments were dyspnoea (Borg scale), dynamic inspiratory capacity (dIC) and parameters of physical activity (SenseWear® accelerometer).

RESULTS: see table

View this table:

Change from baseline





CONCLUSIONS: Aclidinium significantly improved dynamic hyperinflation, exercise tolerance, physical activity and dyspnoea compared with placebo in COPD patients.
Patterns of genetic variability at individual minisatellite loci in minke whale Balaenoptera acutorostrata populations from three different oceans.
Authors: I A van Pijlen, B Amos, T Burke
Journal: Molecular Biology and Evolution (1995)

The genetic variability at six cloned minisatellite loci was analyzed in minke whale populations from the North Atlantic, North Pacific, and Antarctic Oceans. Three loci displayed only a few different alleles in each of the three populations, with heterozygosity ranging from 0.00 to 0.47, and three loci revealed many different alleles in at least two fo the three populations, with heterozygosity ranging up to 0.98. Using small sample sizes, samples from two adjacent Antarctic Management Areas were not found to differ significantly in allele frequencies at any of the six loci. The use of principal coordinate analysis to detect multilocus disequilibria was explored. No significant evidence was found of intrapopulation heterogeneity within the pooled Antarctic sample. Pronounced interoceanic differences were observed at every locus, confirming the existence of genetic isolation found earlier using more conventional marker systems. The populations from the three oceans appear to have diverged to such a degree that the hypervariable loci have had time to evolve independently and arrive at different evolutionary stages in different populations. The frequency of undetected "null" alleles is remarkably high in minke whale populations compared to human populations and is probably a result of the cloning protocol used. Minisatellite loci are shown to provide a powerful population genetic tool, supplying levels of resolution appropriate to different degrees of evolutionary divergence.
Effect of Cytochalasin B and D on Groups of Insulin Receptors and on Insulin Action in Rat Adipocytes
Authors: Leonard Jarett, Robert M. Smith
Journal: Journal of Clinical Investigation (1979)

The possible physiological importance of the groups of insulin receptors on rat adipocytes and the relationship of these groups to insulin action were investigated. The effect of cytochalasin B and D on biological actions of insulin was measured and compared with the effect of these agents on the ultrastructural distribution of groups of insulin receptors. Cytochalasin B had no effect on epinephrine-stimulated lipolysis, insulin inhibition of epinephrine-stimulated lipolysis, or insulin stimulation of protein synthesis. Cytochalasin B, over a concentration range of 50 nM to 5 muM, progressively inhibited the basal glucose transport system, as measured by glucose oxidation, 2-deoxyglucose transport, and 3-O-methylglucose transport. Insulin was capable of fully stimulating remaining basal transport at submaximal concentrations of cytochalasin B. Insulin pretreatment of adipocytes partially protected the glucose transport system from inhibition by cytochalasin B. Cytochalasin B markedly altered the distribution pattern of insulin receptors, which caused an increase in the number of single receptor molecules by decreasing the number of larger groups. A significant correlation (r = 0.964; P < 0.001) was found between the percent increase in single receptors and the percent decrease in glucose transport. Ferritin-insulin pretreatment of adipocytes prevented disruption of the groups of insulin receptors by cytochalasin B. Cytochalasin D had no effect on the biological actions of insulin or on the groups of insulin receptors. These data suggest that the ability of insulin to affect adipocyte metabolism is independent of the hormone occupying adjacent, grouped receptor sites. The marked contrast in effects of cytochalasin B and D on groups of insulin receptors and glucose transport suggests that the microfilament system is not involved in insulin action or in holding the groups of insulin receptors together, as both agents are known disrupters of microfilaments and inhibitors of actin gelation. The correlation between the effects of cytochalasin B on insulin receptor distribution and glucose transport leads to the speculation that the glycoprotein molecules containing the insulin receptor are functionally linked with the glucose transport system.
Heterogeneity of EGFR and HER2 gene status by fluorescent in situ hybridization in colorectal cancer
Authors: Nicola Personeni, Gert De Hertogh, Maria Debiec-Rychter, Jef De Schutter, Karel Geboes, Eric Van Cutsem, Sabine Tejpar
Journal: Clinical Cancer Research (2006)

B80   Background: Recent studies suggest that the epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (FISH) might predict response to anti-EGFR antibodies in advanced colorectal cancer (CRC) patients. Additionally, preclinical data indicate that HER2, a member of the EGFR family, could enhance sensitivity to tyrosine kinase inhibition. However, in CRC it is still unknown whether EGFR and HER2 gene status is stable during disease progression. Methods: EGFR and HER2 gene status is being analysed by FISH on 30 paired samples collected from patients with either: 1) a primary CRC and at least one related distant metastatic lesion; or 2) a primary CRC and a subsequent local relapse; or 3) two metachronous metastatic lesions. Evaluation of EGFR and HER2 status was based on two parameters: the specific copy numbers of both gene and chromosome  centromere, and their frequencies in tumor cells. For both genes, a FISH-positive status was retained when either a high level of  trisomy or  polysomy (≥3 copies of the gene in ≥40% of cells), or an amplification pattern were observed. EGFR protein expression by immunohistochemistry (IHC) was assessed and was further correlated to gene status. Results: 2 of 11 cases (18%) were discordant for EGFR status, but not for HER2: both cases represented paired metachronous metastatic lesions showing EGFR disomy in one sample and high level polysomy in the other one. Conversely, 3 of 11 cases (27%) were discordant for HER2 status, but not for EGFR: 2 cases showed high level polysomy in the primary tumor, being lost in the related metastasis, whilst 1 case exhibited high level polysomy in the metastasis, but not in the related primary tumor. By IHC analysis, EGFR expression was virtually absent in 2 of 9 samples bearing a FISH-positive status. The study is ongoing and final results will be presented at the meeting. Conclusions: Our preliminary results suggest for the first time that EGFR and HER2 gene status is not stable during disease progression, and they question whether the observed changes of EGFR and HER2 status are the result of any selective pressure in CRC. Moreover, our results further highlight the potential inconsistencies of EGFR assessment by IHC in a non negligible proportion of CRC. We anticipate that these findings have to be considered in future prospective studies.