tbuckley/cabot-search huggingface dataset:
Mechanical Stretch and Angiotensin II Differentially Upregulate the Renin-Angiotensin System in Cardiac Myocytes In Vitro
Authors: Ricky Malhotra, Junichi Sadoshima, Frank C. Brosius, Seigo Izumo
Journal: Circulation Research (1999)

Abstract —Pressure overload in vivo results in left ventricular hypertrophy and activation of the renin-angiotensin system in the heart. Mechanical stretch of neonatal rat cardiac myocytes in vitro causes secretion of angiotensin II (Ang II), which in turn plays a pivotal role in mechanical stretch–induced hypertrophy. Although in vivo data suggest that the stimulus of hemodynamic overload serves as an important modulator of cardiac renin-angiotensin system (RAS) activity, it is not clear whether observed upregulation of RAS genes is a direct effect of hemodynamic stress or is secondary to neurohumoral effects in response to hemodynamic overload. Moreover, it is unclear whether activation of the local RAS in response to hemodynamic overload predominantly occurs in cardiac myocytes or fibroblasts or both. In the present study, we examined the effect of mechanical stretch on expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and Ang II receptor (AT 1A , AT 1B , and AT 2 ) genes in neonatal rat cardiac myocytes and cardiac fibroblasts in vitro. The level of expression of angiotensinogen, renin, ACE, and AT 1A genes was low in unstretched cardiac myocytes, but stretch upregulated expression of these genes at 8 to 24 hours. Stimulation of cardiac myocytes with Ang II also upregulated expression of angiotensinogen, renin, and ACE genes, whereas it downregulated AT 1A and did not affect AT 1B gene expression. Although losartan, a specific AT 1 antagonist, completely inhibited Ang II–induced upregulation of angiotensinogen, renin, and ACE genes, as well as stretch-induced upregulation of AT 1A expression, it did not block upregulation of angiotensinogen, renin, and ACE genes by stretch. Western blot analyses showed increased expression of angiotensinogen and renin protein at 16 to 24 hours of stretch. The ACE-like activity was also significantly elevated at 24 hours after stretch. Radioligand binding assays revealed that stretch significantly upregulated the AT 1 density on cardiac myocytes. Interestingly, stretch of cardiac fibroblasts did not result in any discernible increases in the expression of RAS genes. Our results indicate that mechanical stretch in vitro upregulates both mRNA and protein expression of RAS components specifically in cardiac myocytes. Furthermore, components of the cardiac RAS are independently and differentially regulated by mechanical stretch and Ang II in neonatal rat cardiac myocytes.
FoxM1B Regulates NEDD4-1 Expression, Leading to Cellular Transformation and Full Malignant Phenotype in Immortalized Human Astrocytes
Authors: Bingbing Dai, Russell O. Pieper, Dawei Li, Ping Wei, Mingguang Liu, Shiao Y. Woo, Kenneth D. Aldape, Raymond Sawaya, Keping Xie, Suyun Huang
Journal: Cancer Research (2010)

Our recent studies have shown that the FoxM1B transcription factor is overexpressed in human glioma tissues and that the level of its expression correlates directly with glioma grade. However, whether FoxM1B plays a role in the early development of glioma (i.e., in transformation) is unknown. In this study, we found that the FoxM1B molecule causes cellular transformation and tumor formation in normal human astrocytes (NHA) immortalized by p53 and pRB inhibition. Moreover, brain tumors that arose from intracranial injection of FoxM1B-expressing immortalized NHAs displayed glioblastoma multiforme (GBM) phenotypes, suggesting that FoxM1B overexpression in immortalized NHAs not only transforms the cells but also leads to GBM formation. Mechanistically, our results showed that overexpression of FoxM1B upregulated NEDD4-1, an E3 ligase that mediates the degradation and downregulation of phosphatase and tensin homologue (PTEN) in multiple cell lines. Decreased PTEN in turn resulted in the hyperactivation of Akt, which led to phosphorylation and cytoplasmic retention of FoxO3a. Blocking Akt activation with phosphoinositide 3-kinase/Akt inhibitors inhibited the FoxM1B-induced transformation of immortalized NHAs. Furthermore, overexpression of FoxM1B in immortalized NHAs increased the expression of survivin, cyclin D1, and cyclin E, which are important molecules for tumor growth. Collectively, these results indicate that overexpression of FoxM1B, in cooperation with p53 and pRB inhibition in NHA cells, promotes astrocyte transformation and GBM formation through multiple mechanisms.
Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer
Authors: Christopher G. Slatore, Alyson J. Littman, David H. Au, Jessie A. Satia, Emily White
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Lung cancer is the leading cause of cancer-related mortality in the United States. Although supplements are used by half the population, limited information is available about their specific effect on lung cancer risk.
Role of the Atrium in Determining the Functional and Effective Refractory Periods and the Conductivity of the Atrioventricular Transmission System
Authors: GREGORY R. FERRIER, PETER E. DRESEL
Journal: Circulation Research (1973)

Relative contributions of the atria and the atrioventricular (AV) node to AV conduction were studied in isolated, blood-perfused dog hearts. The functional refractory period of the atria, although shorter than that of the AV node, determined the functional refractory period of the entire transmission system in 50% of the hearts. Slow atrial conduction of early beats greatly influenced the shape of the curve used to determine the functional refractory period of the transmission system. The atrial effective refractory period was also shorter than the effective refractory period of the AV node. However, the effective refractory period of the entire transmission system was equal to that of the atrium when the driving interval was longer than 320 msec, and it decreased as the driving interval was shortened. At driving intervals of 320 msec or less, the effective refractory period of the AV transmission system abruptly increased and became equal to the effective refractory period of the node. Conduction of early premature responses from near the sinoatrial node to the AV node was supernormal in 50% of the hearts. Supernormal conduction of premature atrial responses in the ventricles was also observed. The period of supernormal conduction in both tissues shifted toward greater prematurity as heart rate increased. The importance of the atrium in determining the functional properties of the AV transmission system has been previously underestimated.
YM-359445, an Orally Bioavailable Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor, Has Highly Potent Antitumor Activity against Established Tumors
Authors: Nobuaki Amino, Yukitaka Ideyama, Mayumi Yamano, Sadao Kuromitsu, Katsuinori Tajinda, Kiyohiro Samizu, Hiroyuki Hisamichi, Akira Matsuhisa, Kenna Shirasuna, Masafumi Kudoh, Masayuki Shibasaki
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a (3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase. The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo. Experimental Design: We tested the effects of YM-359445 on VEGFR2 tyrosine kinase activity, cell proliferation, and angiogenesis. The antitumor activity of YM-359445 was also tested in nude mice bearing various established tumors and compared with other VEGFR2 tyrosine kinase inhibitors (ZD6474, CP-547632, CGP79787, SU11248, and AZD2171), a cytotoxic agent (paclitaxel), and an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib). Results: The IC50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 μmol/L. In human vascular endothelial cells, the compound inhibited VEGF-dependent proliferation, VEGFR2 autophosphorylation, and sprout formation at concentrations of 0.001 to 0.003 μmol/L. These concentrations had no direct cytotoxic effect on cancer cells. In mice bearing various established tumors, including paclitaxel-resistant tumors, once daily oral administration of YM-359445 at doses of 0.5 to 4 mg/kg not only inhibited tumor growth but also reduced its vasculature. YM-359445 had greater antitumor activity than other VEGFR2 tyrosine kinase inhibitors. Moreover, in human lung cancer A549 xenografts, YM-359445 markedly regressed the tumors (73%) at a dose of 4 mg/kg, whereas gefitinib caused no regression even at 100 mg/kg. Conclusion: Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.
Improvement of respiratory failure with NIV
Authors: G J Gibson
Journal: Thorax (2006)

In their recent paper Nickol et al 1 studied the possible mechanisms by which non-invasive ventilation (NIV) improves ventilatory failure in patients with a restrictive defect due to either neuromuscular disease or kyphoscoliosis. They investigated three possible hypotheses for reduction in daytime hypercapnia—namely, increased ventilatory sensitivity to CO2, improved respiratory muscle function, and increased respiratory system compliance. They showed that the reduction in diurnal Paco2 after treatment was accompanied by an increase in hypercapnic ventilatory response (HCVR), with no changes in non-volitional tests of respiratory muscle strength or respiratory mechanics. They conclude that an increased ventilatory response to CO2 is the principal mechanism underlying the long term improvement in gas exchange associated with NIV.

Interpretation of HCVR in patients with lung disease is often difficult and, as the authors point out, the measurement is highly variable. In attempting to minimise this variability they report the mean of two tests, but the finding of no significant difference between the first and second test is insufficient evidence to …
Heterogeneity in the Helicobacter pylori vacA and cagA genes: association with gastroduodenal disease in South Africa?
Authors: M Kidd, A J Lastovica, J C Atherton, J A Louw
Journal: Gut (1999)

Helicobacter pylori infection is universally associated with gastritis, but only sometimes with clinically significant disease. Candidate virulence markers seem to be useful in identifying the pathogenic infections in some populations.To investigate the association between putative virulence markers and disease in an African population.Fifty nine H pylori strains isolated from dyspeptic patients (11 with peptic ulceration, eight with gastric adenocarcinoma, and 28 with no pathology other than gastritis) were studied for differences in the genes vacA and cagA.Forty seven (80%) of 59 strains had the vacA signal sequence genotype s1 (one s1a, 46 s1b) and 12 (20%) had subtype s2. vacA mid-region analysis revealed that 40 (68%) strains were vacA m1 and 19 (32%) were m2. All 14 strains from patients with peptic ulceration were vacA s1, in contrast to 23 (66%) of 35 strains from patients with gastritis alone (p<0.01). vacA s2 was found exclusively in patients with gastritis alone (p<0.01). All strains isolated from patients with gastric adenocarcinoma were s1b/m1 (p<0. 005 versus gastritis alone). cagA was detectable in 56 (95%) of 59 isolates. Strains from patients with peptic ulceration (12/13 versus 19/30 with gastritis alone, p=0.05) had the shortest fragment length in the 3' region of cagA, while 4/10 strains from patients with gastric cancer had the longest fragment length in this region (p<0. 02 versus gastritis alone).In this study, the vacA s1 genotype, and fragment length of the 3' region of cagA identified isolates associated with significant clinical disease. The vacA s1bm1 genotype seems to be strongly associated with gastric cancer.
Unprecedented Heterogeneity in the Synonymous Substitution Rate within a Plant Genome
Authors: Andan Zhu, Wenhu Guo, Kanika Jain, Jeffrey P. Mower
Journal: Molecular Biology and Evolution (2014)

The synonymous substitution rate varies widely among species, but it is generally quite stable within a genome due to the absence of strong selective pressures. In plants, plastid genes tend to evolve faster than mitochondrial genes, rate variation among species generally correlates between the mitochondrial and plastid genomes, and few examples of intragenomic rate heterogeneity exist. To study the extent of substitution rate variation between and within plant organellar genomes, we sequenced the complete mitochondrial and plastid genomes from the bugleweed, Ajuga reptans, which was previously shown to exhibit rate heterogeneity for several mitochondrial genes. Substitution rates were accelerated specifically in the mitochondrial genome, which contrasts with correlated plastid and mitochondrial rate changes in most other angiosperms. Strikingly, we uncovered a 340-fold range of synonymous substitution rate variation among Ajuga mitochondrial genes. This is by far the largest amount of synonymous rate heterogeneity ever reported for a genome, but the evolutionary forces driving this phenomenon are unclear. Selective effects on synonymous sites in plant mitochondria are generally weak and thus unlikely to generate such unprecedented intragenomic rate heterogeneity. Quickly evolving genes are not clustered in the genome, arguing against localized hypermutation, although it is possible that they were clustered ancestrally given the high rate of genomic rearrangement in plant mitochondria. Mutagenic retroprocessing, involving error-prone reverse transcription and genomic integration of mature transcripts, is hypothesized as another potential explanation.
Induced pluripotent stem cells in hematology: current and future applications
Authors: D Focosi, G Amabile, A Di Ruscio, P Quaranta, D G Tenen, M Pistello
Journal: Blood Cancer Journal (2014)

Reprogramming somatic cells into induced pluripotent stem (iPS) cells is nowadays approaching effectiveness and clinical grade. Potential uses of this technology include predictive toxicology, drug screening, pathogenetic studies and transplantation. Here, we review the basis of current iPS cell technology and potential applications in hematology, ranging from disease modeling of congenital and acquired hemopathies to hematopoietic stem and other blood cell transplantation.
UKPDS 59: Hyperglycemia and Other Potentially Modifiable Risk Factors for Peripheral Vascular Disease in Type 2 Diabetes
Authors: Amanda I. Adler, Richard J. Stevens, Andrew Neil, Irene M. Stratton, Andrew J. M. Boulton, Rury R. Holman
Journal: Diabetes Care (2002)

To determine the role of hyperglycemia in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors.Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. PVD was defined as two of the following: ankle-arm blood pressure index < 0.8, absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs, and intermittent claudication. Logistic regression was used to estimate the association between potential risk factors measured 3-4 months after diagnosis of diabetes and incident PVD. The prevalence of PVD at 3-year intervals to 18 years was determined.Hyperglycemia, assessed as HbA(1c), was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1% increase in HbA(1c) was associated with a 28% increased risk of PVD (95% CI 12-46), and each 10-mmHg increase in systolic blood pressure with a 25% increase in risk (95% CI 10-43).Hyperglycemia, as well as smoking, dyslipidemia, and blood pressure are potentially modifiable risk factors for the development of PVD.
Pet- and pollen-induced upper airway symptoms in farmers and in nonfarmers
Authors: H.O. Koskela, K.K. Iivanainen, S.T. Remes, J. Pekkanen
Journal: European Respiratory Journal (2003)

The effect of farming on the risk of upper airway symptoms is not clear. In this cross-sectional, population-based study, 198 female farmers, 50 nonfarmers living on a farm, and 218 nonfarmers not living on a farm, filled in a symptom questionnaire and underwent skin-prick testing with common and agricultural allergens. In the logistic regression analysis, the latter group served as a control. Several adjustments were made, including childhood farming environment. Current farming was found to decrease the risks of pet- and pollen-induced upper airway symptoms, dose-dependently with the intensity and duration of animal husbandry. Including skin-test positivity to pets in the regression models did not affect the negative association between farming and pet-induced symptoms. In contrast, animal husbandry increased the risk of farm work-induced upper airway symptoms. Animal husbandry often induces work-related upper airway symptoms. However, the present study among female adults suggests that it may also decrease the risk of pet- and pollen-induced upper airway symptoms.
Activated ERBB2/HER2 Licenses Sensitivity to Apoptosis upon Endoplasmic Reticulum Stress through a PERK-Dependent Pathway
Authors: Rosa Martín-Pérez, Carmen Palacios, Rosario Yerbes, Ana Cano-González, Daniel Iglesias-Serret, Joan Gil, Mauricio J. Reginato, Abelardo López-Rivas
Journal: Cancer Research (2014)

HER2/Neu/ERBB2 is a receptor tyrosine kinase overexpressed in approximately 20% of human breast tumors. Truncated or mutant isoforms that show increased oncogenicity compared with the wild-type receptor are found in many breast tumors. Here, we report that constitutively active ERBB2 sensitizes human breast epithelial cells to agents that induce endoplasmic reticulum stress, altering the unfolded protein response (UPR) of these cells. Deregulation of the ERK, AKT, and mTOR activities elicited by mutant ERBB2 was involved in mediating this differential UPR response, elevating the response to endoplasmic reticulum stress, and apoptotic cell death. Mechanistic investigations revealed that the increased sensitivity of mutant ERBB2-expressing cells to endoplasmic reticulum stress relied upon a UPR effector signaling involving the PERK-ATF4-CHOP pathway, upregulation of the proapoptotic cell surface receptor TRAIL-R2, and activation of proapoptotic caspase-8. Collectively, our results offer a rationale for the therapeutic exploration of treatments inducing endoplasmic reticulum stress against mutant ERBB2-expressing breast tumor cells.
Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor <i>Prdx1</i> with Apoptosis Induction in Esophageal Cancer Cells
Authors: Isamu Hoshino, Hisahiro Matsubara, Naoyuki Hanari, Mikito Mori, Takanori Nishimori, Yasuo Yoneyama, Yasunori Akutsu, Haruhito Sakata, Kazuyuki Matsushita, Naohiko Seki, Takenori Ochiai
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The histone deacetylase inhibitor FK228 shows strong activity as a potent antitumor drug but its precise mechanism is still obscure. The purpose of this study is to reveal the effect of FK228 on gene expression in the cell and to determine the mechanism of the antitumor activity of FK228 for further clinical applications. Experimental Design and Results: Microarray analysis was applied to verify the gene expression profiles of 4,608 genes after FK228 treatment using human esophageal squamous cell cancer cell lines T.Tn and TE2. Among them, peroxiredoxin 1 (Prdx1), a member of the peroxiredoxin family of antioxidant enzymes having cell growth suppression activity, as well as p21WAF1, were significantly activated by FK288. In addition, FK228 strongly inhibited the cell growth of T.Tn and TE2 by the induction of apoptosis. Further, chromatin immunoprecipitation analysis revealed that FK228 induced the accumulation of acetylated histones H3 and H4 in Prdx1 promoter, including the Sp1-binding site. In mouse xenograft models of T.Tn and TE2 cells, FK228 injection resulted in significant tumor regression as well as activated Prdx1 expression in tumor tissues. Prdx1 suppression by RNA interference hindered the antitumor effect of FK228. Conclusion: Our results indicate that the antitumor effect of FK228 in esophageal cancer cells is shown at least in part through Prdx1 activation by modulating acetylation of histones in the promoter, resulting in tumor growth inhibition with apoptosis induction.
Non-invasive monitoring of CO2 levels in patients using NIV for AECOPD
Authors: M Cox
Journal: Thorax (2006)

Non-invasive ventilation (NIV) is the treatment of choice for persistent hypercapnic ventilatory failure during acute exacerbations of chronic obstructive pulmonary disease (AECOPD), despite optimal medical treatment.1,2 Assessment of the partial arterial pressure of carbon dioxide (Paco2) is the “gold standard” for the evaluation of the adequacy of alveolar ventilation in this setting. However, repeated intermittent invasive arterial puncture carries inherent risks, including pain.3 Transcutaneous measurement of carbon dioxide (TcPco2) theoretically appears more appropriate for monitoring Paco2. This measurement is based on the observation that CO2 has a high tissue solubility and diffuses through the skin. While available data as to the precision of TcPco2 measurements have given conflicting results,4–6 no study has attempted to assess simultaneous recordings of TcPco2 and Paco2 in patients requiring NIV for AECOPD.

We prospectively studied the agreement between TcPco2 …
Systemic safety of fluticasone furoate/vilanterol combination
Authors: Brian Lipworth
Journal: Thorax (2013)

The recent article by Busse et al 1 on the safety of fluticasone furoate/vilanterol combination (FF/VI) in asthma reported no significant changes in geometric mean 24 h urinary cortisol (24UC) compared with baseline, perhaps giving a false impression that FF is devoid of systemic adverse effects. The interpretation of these data should be put in context of the patients who were already taking inhaled corticosteroids (ICS 500–1000μg/day) and, as such, would have suppressed adrenal function prior to randomisation …