tbuckley/cabot-search huggingface dataset:
Taurine Prevents the Decrease in Expression and Secretion of Extracellular Superoxide Dismutase Induced by Homocysteine
Authors: Hidemi Nonaka, Takeshi Tsujino, Yasuhiro Watari, Noriaki Emoto, Mitsuhiro Yokoyama
Journal: Circulation (2001)

Background — Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Homocysteine has been shown to induce endoplasmic reticulum (ER) stress in vascular endothelial cells. ER stress is a condition in which glycoprotein trafficking is disrupted and unfolded proteins accumulate in the ER. ER molecular chaperons, such as GRP78, are induced and an ER resident kinase, PERK, is activated when cells are subjected to ER stress. Conversely, taurine is reported to have antiatherogenic effects by unknown mechanisms. To elucidate the mechanisms by which homocysteine induces atherosclerosis and taurine prevents it, we examined whether homocysteine and taurine affect the expression and secretion of extracellular superoxide dismutase (EC-SOD), a glycoprotein secreted from vascular smooth muscle cells (VSMCs) that protects the vascular wall from oxidative stress. Methods and Results — We assessed the expression of EC-SOD and GRP78 mRNA in cultured rat VSMCs by Northern blot analysis. The EC-SOD protein secreted into the culture medium was examined by Western blot analysis. Homocysteine (5 mmol/L) and other ER stress inducers, including A23187, were found to decrease EC-SOD mRNA expression and protein secretion. Furthermore, they upregulated GRP78 mRNA expression and activated PERK. Taurine (0.5 to 10 mmol/L), conversely, prevented these actions induced by homocysteine. Conclusions — Homocysteine induces ER stress and reduces the secretion and expression of EC-SOD in VSMCs, leading to increased oxidative stress in the vascular wall. Taurine restores the secretion and expression of EC-SOD by ameliorating ER stress induced by homocysteine.
Definitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet
Authors: Joëlle Guilhot, Michele Baccarani, Richard E. Clark, Francisco Cervantes, François Guilhot, Andreas Hochhaus, Sergei Kulikov, Jiri Mayer, Andreas L. Petzer, Gianantonio Rosti, Philippe Rousselot, Giuseppe Saglio, Susanne Saussele, Bengt Simonsson, Juan-Luis Steegmann, Andrey Zaritskey, Rüdiger Hehlmann
Journal: Blood (2012)
Sedentary behaviour and health: mapping environmental and social contexts to underpin chronic disease prevention
Authors: Neville Owen, Jo Salmon, Mohammad Javad Koohsari, Gavin Turrell, Billie Giles-Corti
Journal: British Journal of Sports Medicine (2014)

The time that children and adults spend sedentary-put simply, doing too much sitting as distinct from doing too little physical activity-has recently been proposed as a population-wide, ubiquitous influence on health outcomes. It has been argued that sedentary time is likely to be additional to the risks associated with insufficient moderate-to-vigorous physical activity. New evidence identifies relationships of too much sitting with overweight and obesity, type 2 diabetes, cardiovascular disease, some cancers and other adverse health outcomes. There is a need for a broader base of evidence on the likely health benefits of changing the relevant sedentary behaviours, particularly gathering evidence on underlying mechanisms and dose-response relationships. However, as remains the case for physical activity, there is a research agenda to be pursued in order to identify the potentially modifiable environmental and social determinants of sedentary behaviour. Such evidence is required so as to understand what might need to be changed in order to influence sedentary behaviours and to work towards population-wide impacts on prolonged sitting time. In this context, the research agenda needs to focus particularly on what can inform broad, evidence-based environmental and policy initiatives. We consider what has been learned from research on relationships of environmental and social attributes and physical activity; provide an overview of recent-emerging evidence on relationships of environmental attributes with sedentary behaviour; argue for the importance of conducting international comparative studies and addressing life-stage issues and socioeconomic inequalities and we propose a conceptual model within which this research agenda may be addressed.
OBSERVATIONS BY ELECTRON MICROSCOPY ON CONTRACTION OF SKELETAL MYOFIBRILS INDUCED WITH ADENOSINETRIPHOSPHATE
Authors: Charles A. Ashley, Keith R. Porter, Delbert E. Philpott, George M. Hass
Journal: The Journal of Experimental Medicine (1951)

Skeletal myofibrils isolated either by tryptic digestion at 0 degrees C. or by a colloid mill and suspended in buffer solution (pH 7.0, micro; 0.154) containing 20 per cent glycerin and 0.0025 M adenosinetriphosphate at -5 degrees C. contracted slowly and progressively when the temperature was raised above 0 degrees C. Formalin fixation halted this contraction. With the aid of these procedures myofibrils in progressive stages of contraction were then studied with the electron microscope. Electron micrographs showed that uncontracted fibrils isolated by the colloid mill were structurally similar to those described by other workers. Treatment of fibrils with trypsin removed the Z bands and disorganized the I bands. This enzymatic modification of structure did not impair the contractile response. The principal structural changes during contraction consisted of a migration of dense material from the A band into the A-I junction or the Z band, a gradual increase in width of the fibril, a gradual decrease in length of sarcomeres, an apparent increase in the mean diameter of filaments, and a disorientation of these latter from their parallel arrangement.
A Novel Mechanism for Myocardial Stunning Involving Impaired Ca <sup>2+</sup> Handling
Authors: Song-Jung Kim, Raymond K. Kudej, Atsuko Yatani, Young-Kwon Kim, Gen Takagi, Ritsu Honda, David A. Colantonio, Jennifer E. Van Eyk, Dorothy E. Vatner, Randall L. Rasmusson, Stephen F. Vatner
Journal: Circulation Research (2001)

The mechanism of myocardial stunning has been studied extensively in rodents and is thought to involve a decrease in Ca 2+ responsiveness of the myofilaments, degradation of Troponin I (TnI), and no change in Ca 2+ handling. We studied the mechanism of stunning in isolated myocytes from chronically instrumented pigs. Myocytes were isolated from the ischemic (stunned) and nonischemic (normal) regions after 90-minute coronary stenosis followed by 60-minute reperfusion. Baseline myocyte contraction was reduced, P &lt;0.01, in stunned myocytes (6.3±0.4%) compared with normal myocytes (8.8±0.4%). The time for 70% relaxation was prolonged, P &lt;0.01, in stunned myocytes (131±8 ms) compared with normal myocytes (105±5 ms). The impaired contractile function was associated with decreased Ca 2+ transients (stunned, 0.33±0.04 versus normal, 0.49±0.05, P &lt;0.01). Action potential measurements in stunned myocytes demonstrated a decrease in plateau potential without a change in resting membrane potential. These changes were associated with decreased L-type Ca 2+ -current density (stunned, −4.8±0.4 versus normal, −6.6±0.4 pA/pF, P &lt;0.01). There were no differences in TnI, sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a), and phospholamban protein quantities. However, the fraction of phosphorylated phospholamban monomer was reduced in stunned myocardium. In rats, stunned myocytes demonstrated reduced systolic contraction but actually accelerated relaxation and no change in Ca 2+ transients. Thus, mechanisms of stunning in the pig are radically different from the widely held concepts derived from studies in rodents and involve impaired Ca 2+ handling and dephosphorylation of phospholamban, but not TnI degradation.
Alfuzosin and Symptoms of Chronic Prostatitis–Chronic Pelvic Pain Syndrome
Authors: J Curtis Nickel, John N Krieger, Mary McNaughton-Collins, Rodney U Anderson, Michel Pontari, Daniel A Shoskes, Mark S Litwin, Richard B Alexander, Paige C White, Richard Berger, Robert Nadler, Michael O'Leary, Men Long Liong, Scott Zeitlin, Shannon Chuai, J Richard Landis, John W Kusek, Leroy M Nyberg, Anthony J Schaeffer
Journal: New England Journal of Medicine (2008)

In men with chronic prostatitis-chronic pelvic pain syndrome, treatment with alpha-adrenergic receptor blockers early in the course of the disorder has been reported to be effective in some, but not all, relatively small randomized trials.We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of alfuzosin, an alpha-adrenergic receptor blocker, in reducing symptoms in men with chronic prostatitis-chronic pelvic pain syndrome. Participation in the study required diagnosis of the condition within the preceding 2 years and no previous treatment with an alpha-adrenergic receptor blocker. Men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin per day or placebo. The primary outcome was a reduction of at least 4 points (from baseline to 12 weeks) in the score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (range, 0 to 43; higher scores indicate more severe symptoms). A 4-point decrease is the minimal clinically significant difference in the score.A total of 272 eligible participants underwent randomization, and in both study groups, 49.3% of participants had a decrease of at least 4 points in their total NIH-CPSI score (rate difference associated with alfuzosin, 0.1%; 95% confidence interval, -11.2 to 11.0; P=0.99). In addition, a global response assessment showed similar response rates at 12 weeks: 33.6% in the placebo group and 34.8% in the alfuzosin group (P=0.90). The rates of adverse events in the two groups were also similar.Our findings do not support the use of alfuzosin to reduce the symptoms of chronic prostatitis-chronic pelvic pain syndrome in men who have not received prior treatment with an alpha-blocker. (ClinicalTrials.gov number, NCT00103402.)
Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma
Authors: Peter M. Voorhees, Qing Chen, Deborah J. Kuhn, George W. Small, Sally A. Hunsucker, John S. Strader, Robert E. Corringham, Mohamed H. Zaki, Jeffrey A. Nemeth, Robert Z. Orlowski
Journal: Clinical Cancer Research (2007)

Inhibition of the proteasome leads to the activation of survival pathways in addition to those that promote cell death. We hypothesized that down-regulation of interleukin-6 (IL-6) signaling using the monoclonal antibody CNTO 328 would enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance.The cytotoxicity of bortezomib, CNTO 328, and the combination, along with the associated molecular changes, was assessed in IL-6-dependent and IL-6-independent multiple myeloma cell lines, both in suspension and in the presence of bone marrow stromal cells and in patient-derived myeloma samples.Treatment of IL-6-dependent and IL-6-independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion. This effect was additive to synergistic and was preserved in the presence of bone marrow stromal cells and in CD138(+) myeloma samples derived from patients with relative clinical resistance to bortezomib. CNTO 328 potentiated bortezomib-mediated activation of caspase-8 and caspase-9 and the common downstream effector caspase-3; attenuated bortezomib-mediated induction of antiapoptotic heat shock protein-70, which correlated with down-regulation of phosphorylated signal transducer and activator of transcription-1; and inhibited bortezomib-mediated accumulation of myeloid cell leukemia-1, an effect that was associated with down-regulation of phosphorylated signal transducer and activator of transcription-3.Taken together, our results provide a strong preclinical rationale for the clinical development of the bortezomib/CNTO 328 combination for patients with myeloma.
PI3Kp110-, Src-, FAK-dependent and DOCK2-independent migration and invasion of CXCL13-stimulated prostate cancer cells
Authors: Christelle P. El Haibi, Praveen K. Sharma, Rajesh Singh, Paul R. Johnson, Jill Suttles, Shailesh Singh, James W. Lillard
Journal: Molecular Cancer (2010)

Most prostate cancer (PCa)-related deaths are due to metastasis, which is mediated in part by chemokine receptor and corresponding ligand interaction. We have previously shown that PCa tissue and cell lines express high levels of the chemokine receptor CXCR5, than compared to their normal counterparts, and interaction of CXCR5 with its specific ligand (CXCL13) promoted PCa cell invasion, migration, and differential matrix metalloproteinase (MMP) expression. This study dissects some of the molecular mechanisms following CXCL13-CXCR5 interaction that mediate PCa cell migration and invasion.Using Western blot analysis, kinase-specific cell-based ELISAs, and migration and invasion assays, we show that PCa cell lines differentially express phosphoinositide-3 kinase (PI3K) catalytic subunit isoforms and dedicator of cytokinesis 2 (DOCK2). Specifically, we show that PC3 and normal prostatic epithelial (RWPE-1), but not LNCaP cell lines expressed DOCK2, while RWPE, PC3, and LNCaP cell lines expressed PI3K-p110alpha and -p110beta. Moreover, PC3 selectively expressed PI3K-p110gamma, but LNCaP and RWPE cell lines expressed PI3Kp110delta. CXCL13 caused CXCR5-dependent activation of the PI3Kp85alpha in LNCaP cells, and p85alpha as well as -p101 in PC3 cells. CXCL13-CXCR5 interaction regulated LNCaP and PC3 cell migration and invasion through extracellular signal-regulated kinase 1/2 (ERK1/2) activation that was primarily dependent on the PI3Kp110 isoform(s), Src, and focal adhesion kinase (FAK), but not DOCK2.While additional studies will be needed to determine the PI3K-independent (i.e., DOCK2-mediated) and -dependent events that dictate PCa cell responsiveness to CXCL13, these data provide evidence of the existence of cell type- and stimulus-specific signaling events that support migration and invasion of PCa cells.
Sebaceous gland hyperplasia and senile comedones: a prevalence study in elderly hospitalized patients
Authors: P. KUMAR, R. MARKS
Journal: British Journal of Dermatology (1987)

Two hundred and eighty-six patients over the age of 65 (age range 65-102, mean age 82 years), who were hospitalized in geriatric wards, were examined clinically for the presence of sebaceous gland hyperplasia and senile comedones. The degree of solar elastotic change present was scored on a visual analogue scale. The prevalence rate of sebaceous gland hyperplasia and of senile comedones was found to be 26% in each case. Approximately one third of patients had both lesions. Neither of these lesions was related to either the degree of solar elastotic change or the skin type with regard to tanning ability. It was concluded that chronic solar exposure was not a likely cause of these common conditions.
HMGA1 Inhibits the Function of p53 Family Members in Thyroid Cancer Cells
Authors: Francesco Frasca, Alessandra Rustighi, Roberta Malaguarnera, Sandro Altamura, Paolo Vigneri, Giannino Del Sal, Vincenzo Giancotti, Vincenzo Pezzino, Riccardo Vigneri, Guidalberto Manfioletti
Journal: Cancer Research (2006)

Abstract HMGA1 is an architectural transcription factor expressed at high levels in transformed cells and tumors. Several lines of evidence indicate that HMGA1 up-regulation is involved in the malignant transformation of thyroid epithelial cells. However, the mechanisms underlying the effect of HMGA1 on thyroid cancer cell phenotype are not fully understood. We now show that in thyroid cancer cells, HMGA1 down-regulation by small interfering RNA and antisense techniques results in enhanced transcriptional activity of p53, TAp63α, TAp73α, and, consequently, increased apoptosis. Coimmunoprecipitation and pull-down experiments with deletion mutants showed that the COOH-terminal oligomerization domain of p53 family members is required for direct interaction with HMGA1. Moreover, inhibition of HMGA1 expression in thyroid cancer cells resulted in increased p53 oligomerization in response to the DNA-damaging agent doxorubicin. Finally, electrophoretic mobility shift assay experiments showed that the p53-HMGA1 interaction results in reduced DNA-binding activity. These results indicate a new function of HMGA1 in the regulation of p53 family members, thus providing new mechanistic insights in tumor progression. (Cancer Res 2006; 66(6): 2980-89)
Protection against endotoxic shock by bactericidal/permeability-increasing protein in rats.
Authors: H Jin, R Yang, S Marsters, A Ashkenazi, S Bunting, M N Marra, R W Scott, J B Baker
Journal: Journal of Clinical Investigation (1995)

Bactericidal/permeability-increasing protein (BPI) is a neutrophil primary granule protein that inhibits effects of LPS in vitro. The current study examined the effects of BPI on hemodynamics, mortality, and circulating endotoxin and cytokines in conscious rats with endotoxic shock. Catheters were implanted into the right femoral artery and vein. 1 d later, human recombinant BPI (10 mg/kg) or vehicle was intravenously injected immediately, 30 min, or 2 h after intravenous injection of LPS (7.5 mg/kg). Mean arterial pressure (MAP) and heart rate were monitored and blood was collected before and after injection. BPI given immediately or 30 min after LPS prevented the LPS-induced reduction in MAP at 4-8 h and markedly reduced mortality. BPI given 2 h after LPS injection had no protective effect. BPI treated immediately after LPS reduced the circulating levels of endotoxin and IL-6 but increased the circulating levels of TNF. We propose that BPI exerts its protective effect through a TNF-independent mechanism, by inhibiting endotoxin-stimulated production of IL-6.
Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells
Authors: Martin Michaelis, Denise Klassert, Susanne Barth, Tatyana Suhan, Rainer Breitling, Bernd Mayer, Nora Hinsch, Hans W Doerr, Jaroslav Cinatl, Jindrich Cinatl
Journal: Molecular Cancer (2009)

Abstract Background Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. Results Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. Conclusion A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target.
Body Fat Distribution and 5-Year Risk of Death in Older Women
Authors: Aaron R. Folsom
Journal: JAMA (1993)

<h3>Objective.</h3> —To test the hypothesis that both body mass index (expressed as the ratio of weight in kilograms per height in meters squared) and the ratio of waist circumference to hip circumference are positively associated with mortality risk in older women. <h3>Design.</h3> —Prospective cohort study with a 5-year follow-up period. <h3>Setting.</h3> —General community. <h3>Participants.</h3> —Random sample of 41 837 Iowa women aged 55 to 69 years. <h3>Main Outcome Measure.</h3> —Total mortality (1504 deaths). <h3>Main Results.</h3> —Body mass index, an index of relative weight, was associated with mortality in a J-shaped fashion: rates were elevated in the leanest as well as in the most obese women. In contrast, waist/hip circumference ratio was strongly and positively associated with mortality in a dose-response manner. Adjusted for age, body mass index, smoking, education level, marital status, estrogen use, and alcohol use, a 0.15-unit increase in waist/hip circumference ratio (eg, a 15-cm [6-in] increase in waist measurement in a woman with 100-cm [40-in] hips) was associated with a 60% greater relative risk of death. The observed associations were not explained to any great degree by bias from weight loss prior to baseline or higher early deaths among lean participants. <h3>Conclusions.</h3> —Waist/hip circumference ratio is a better marker than body mass index of risk of death in older women. Waist/hip circumference ratio should be measured as part of routine surveillance and risk monitoring in medical practice. <i>JAMA</i>. 1993;269:483-487)
Identification of a Novel Macrophage Phenotype That Develops in Response to Atherogenic Phospholipids via Nrf2
Authors: Alexandra Kadl, Akshaya K. Meher, Poonam R. Sharma, Monica Y. Lee, Amanda C. Doran, Scott R. Johnstone, Michael R. Elliott, Florian Gruber, Jenny Han, Wenshu Chen, Thomas Kensler, Kodi S. Ravichandran, Brant E. Isakson, Brian R. Wamhoff, Norbert Leitinger
Journal: Circulation Research (2010)

Rationale: Macrophages change their phenotype and biological functions depending on the microenvironment. In atherosclerosis, oxidative tissue damage accompanies chronic inflammation; however, macrophage phenotypic changes in response to oxidatively modified molecules are not known. Objective: To examine macrophage phenotypic changes in response to oxidized phospholipids that are present in atherosclerotic lesions. Methods and Results: We show that oxidized phospholipid-treated murine macrophages develop into a novel phenotype (Mox) that is strikingly different from the conventional M1 and M2 macrophage phenotypes. Compared to M1 and M2, Mox macrophages show a different gene expression pattern, as well as decreased phagocytotic and chemotactic capacity. Treatment with oxidized phospholipids induces both M1 and M2 macrophages to switch to the Mox phenotype. Whole-genome expression array analysis and subsequent gene ontology clustering revealed that the Mox phenotype was characterized by abundant overrepresentation of Nrf2-mediated expression of redox-regulatory genes. In macrophages isolated from Nrf2 −/− mice, oxidized phospholipid-induced gene expression and regulation of redox status were compromised. Moreover, we found that Mox macrophages comprise 30% of all macrophages in advanced atherosclerotic lesions of low-density lipoprotein receptor knockout (LDLR −/− ) mice. Conclusions: Together, we identify Nrf2 as a key regulator in the formation of a novel macrophage phenotype (Mox) that develops in response to oxidative tissue damage. The unique biological properties of Mox macrophages suggest this phenotype may play an important role in atherosclerotic lesion development as well as in other settings of chronic inflammation.