tbuckley/cabot-search huggingface dataset:
Effects of electrical stimulation on Vo<sub>2</sub>kinetics and delta efficiency in healthy young men
Authors: M Pérez, A Lucia, A Santalla, J L Chicharro
Journal: British Journal of Sports Medicine (2003)

Objective: To determine the effects of electrical stimulation (ES) on oxygen uptake (V o 2 ) kinetics and delta efficiency (DE) during gradual exercise. The hypothesis was that ES would attenuate the V o 2 -workload relation and improve DE. Methods: Fifteen healthy, untrained men (mean (SD) age 22 (5) years) were selected. Ten were electrostimulated on both quadriceps muscles with a frequency of 45–60 Hz, with 12 seconds of stimulation followed by eight seconds recovery for a total of 30 minutes a day, three days a week for six weeks. The remaining five subjects were assigned to a control group. A standardised exercise test on a cycle ergometer (ramp protocol, workload increases of 20 W/min) was performed by each subject before and after the experimental period. The slope of the V o 2 -power output (W) relation (ΔV o 2 /ΔW) and DE were calculated in each subject at moderate to high intensities (above the ventilatory threshold—that is, from 50–60% to 100% V o 2 max). Results: The mean (SEM) values for ΔV o 2 /ΔW and DE had significantly decreased and increased respectively after the six week ES programme (p&lt;0.05; 9.8 (0.2) v 8.6 (0.5) ml O 2 /W/min respectively and 27.7 (0.9) v 31.5 (1.4)% respectively). Conclusions: ES could be used as a supplementary tool to improve two of the main determinants of endurance capacity, namely V o 2 kinetics and work efficiency.
Preoperative Bevacizumab Does Not Significantly Increase Postoperative Complication Rates in Patients Undergoing Hepatic Surgery for Colorectal Cancer Liver Metastases
Authors: Susan B. Kesmodel, Lee M. Ellis, E. Lin, George J. Chang, Eddie K. Abdalla, Scott Kopetz, Jean-Nicolas Vauthey, Miguel A. Rodriguez-Bigas, Steven A. Curley, Barry W. Feig
Journal: Journal of Clinical Oncology (2008)

Purpose Although bevacizumab (BV) increases survival rates when used with chemotherapy (CTX) in patients who have metastatic colorectal cancer (CRC), an increase in wound complications has been observed in patients who undergo surgery while receiving BV. We therefore evaluated whether neoadjuvant BV is associated with an increase in postoperative complications in patients undergoing surgery for CRC liver metastases. Patients and Methods Two subgroups of patients who received neoadjuvant CTX + BV (n = 81) or CTX alone (n = 44) were identified from a database of patients who underwent surgery for CRC liver metastases. Univariate and multivariate logistic regression models were used to evaluate the association of patient and tumor characteristics, neoadjuvant therapy, and operative factors with postoperative complications. Results Postoperative complications developed in 40 patients (49%) who received CTX + BV and 19 patients (43%) who received CTX. The median time from BV discontinuation to surgery was 58 days (range, 31 to 117 days). No significant associations were identified between BV use and timing of BV discontinuation and postoperative complications. On multivariate analysis, lower serum albumin and concomitant surgical procedures were associated with an increased risk of developing any complication (P = .035 and .023, respectively), and lower serum albumin was associated with hepatobiliary complications (P = .016). Conclusion Neither the use of BV nor timing of BV administration was associated with an increase in complication rates. These data suggest that the combination of BV with neoadjuvant CTX in patients who have CRC liver metastases does not increase surgical complications. To determine the optimal timing of surgery in patients receiving neoadjuvant BV, confirmatory prospective studies are required.
Induction of Differentiation of Friend Murine Erythroleukemia Cells by Poly-&lt;sc&gt;l&lt;/sc&gt;-lysine and Daunorubicin-Poly-&lt;sc&gt;l&lt;/sc&gt;-lysine Conjugate&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Rosanna Supino, Nadia Gibelli, Franco Zunino
Journal: JNCI Journal of the National Cancer Institute (1986)

The ability of the synthetic cationic polypeptide Poly-l-lysine (PLL) to induce differentiation of Friend murine erythroleukemia cells was examined with the use of polymers of different molecular weights. Like other membrane-interacting agents (polar solvents), all the polymers tested were effective in inducing cell differentiation. This effect was found to be molecular weight dependent, as already reported for other membrane-related actions of these polymers. Since anthracyclines also exert direct effects on the cell membrane, the activity of the daunorubicin-PLL conjugate was also examined. The covalent linking of the drug to the polyamino acid somewhat reduced, the differentiation-inducing activity in this system. Indeed, free daunorubicin was found to inhibit the maturational process. Although the inducing effect was observed when the free PLL or daunorubicin-linked PLL was added alone, polymers enhanced differentiation produced by suboptimal concentrations of dimethyl sulfoxide (DMSO). Since PLL was inactive as an initiator of the maturation of a DMSO-resistant line, it is likely that some events (presumably membrane-related effects) involved in the multistep stimulation process are common to polar-planar solvents and the polycationic polymer.
One Hundred Years in the Making: The Global Tobacco Epidemic
Authors: Heather Wipfli, Jonathan M. Samet
Journal: Annual Review of Public Health (2015)

Today's global tobacco epidemic may represent one of the first instances of the globalization of a noninfectious cause of disease. This article focuses on the first century of the global tobacco epidemic and its current status, reviewing the current and projected future of the global tobacco epidemic and the steps that are in progress to end it. In the United States and many countries of Western Europe, tobacco consumption peaked during the 1960s and 1970s and declined as tobacco control programs were initiated, motivated by the evidence indicting smoking as a leading cause of disease. Despite this policy advancement and the subsequent reductions in tobacco consumption, the global tobacco epidemic continued to grow exponentially in the later years of the twentieth century, as the multinational companies sought new markets to replace those shrinking in high-income countries. In response, between 2000 and 2004, the World Health Organization developed its first public health treaty, the Framework Convention on Tobacco Control, which entered into force in 2005. An accompanying package of interventions has been implemented. New approaches to tobacco control, including plain packaging and single representation of brands, have been implemented by Australia and Uruguay, respectively, but have been challenged by the tobacco industry.
S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer
Authors: Patrick C. Mahon, Patrick Baril, Vipul Bhakta, Claude Chelala, Krishna Caulee, Tomohiko Harada, Nicholas R. Lemoine
Journal: Cancer Research (2007)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that is characterized by a particularly marked resistance to chemotherapy. We previously showed an association between decreased expression of BNIP3 and chemoresistance in PDAC cell lines. To further explore the molecular basis of chemoresistance in PDAC, we analyzed microarray data obtained from normal pancreas and PDAC tumor samples to identify genes exhibiting a negative correlation with the expression profile of BNIP3. This analysis identified several S100 family proteins, of which two, S100A2 and S100A4, showed in vitro the ability to repress exogenous BNIP3 promoter activity. We subsequently showed that RNA interference–mediated S100A4 knockdown resulted in an elevated expression of BNIP3 in PDAC cell lines that possess an unmethylated BNIP3 promoter, suggesting that, in addition to hypermethylation, S100A4 overexpression may represent an alternative mechanism for inhibiting BNIP3 function in PDAC. S100A4 knockdown also resulted in an increased sensitivity of PDAC cell lines to gemcitabine treatment, which was coupled with an increase in apoptosis and cell cycle arrest. To investigate the underlying mechanisms mediating these effects, we studied the effect of silencing the expression of S100A4 on the induction of apoptosis, cell cycle arrest, and the activation of apoptotic mediators. Knockdown of S100A4 clearly induced apoptosis with increased fragmentation of DNA and phosphatidyl serine externalization; activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase; and release of cytochrome c into the cytosol. These findings provide evidence that supports a novel role for S100A4 as a prosurvival factor in pancreatic cancer. [Cancer Res 2007;67(14):6786–95]
Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression
Authors: Candace A. Gilbert, Joyce M. Slingerland
Journal: Annual Review of Medicine (2012)

Obesity is a problem of epidemic proportions in many developed nations. Increased body mass index and obesity are associated with a significantly worse outcome for many cancers. Breast cancer risk in the postmenopausal setting and poor disease outcome for all patients is significantly augmented in overweight and obese individuals. The expansion of fat tissue involves a complex interaction of endocrine factors known as adipokines and cytokines. High cytokine levels in primary breast cancers and in the circulation of affected patients have been associated with poor outcome. This review summarizes the how cytokine production in obese adipose tissue creates a chronic inflammatory microenvironment that favors tumor cell motility, invasion, and epithelial-mesenchymal transition to enhance the metastatic potential of tumor cells. Many of the cytokines associated with a proinflammatory state are not only upregulated in obese adipose tissue but may also stimulate the self-renewal of cancer stem cells. Thus, enhanced cytokine production in obese adipose tissue may serve both as a chemoattractant for invading cancers and to augment their malignant potential. These new mechanistic insights suggest that the current obesity epidemic will presage a significant increase in cancer incidence, morbidity, and mortality in the next few decades.
Activation of phosphatidylinositol-3 kinase by ligation of the interleukin-7 receptor on human thymocytes.
Authors: H K Dadi, C M Roifman
Journal: Journal of Clinical Investigation (1993)

Interleukin-7 (IL-7) is a glycoprotein that regulates lymphocyte precursor growth and differentiation. However, the exact mechanism whereby the IL-7 receptor (IL-7R) mediates these cell growth signals remains unknown. One of the earliest metabolic events linked to mitogenic responses in other growth factor receptor systems is the activation of phosphatidylinositol-3 kinase (PI-3 kinase). We demonstrate here that ligation of the IL-7R results in dose- and time-dependent increases in PI-3 kinase activity. These results suggest that PI-3 kinase is involved in signal transduction via the IL-7R in human thymocytes.
Postchallenge Glucose, A1C, and Fasting Glucose as Predictors of Type 2 Diabetes and Cardiovascular Disease
Authors: Henna Cederberg, Tuula Saukkonen, Mauri Laakso, Jari Jokelainen, Pirjo Härkönen, Markku Timonen, Sirkka Keinänen-Kiukaanniemi, Ulla Rajala
Journal: Diabetes Care (2010)

A1C has been proposed as a new indicator for high risk of type 2 diabetes. The long-term predictive power and comparability of elevated A1C with the currently used high-risk indicators remain unclear. We assessed A1C, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) as predictors of type 2 diabetes and cardiovascular disease (CVD) at 10 years.This prospective population-based study of 593 inhabitants from northern Finland, born in 1935, was conducted between 1996 and 2008. An oral glucose tolerance test (OGTT) was conducted at baseline and follow-up, and A1C was determined at baseline. Those with a history of diabetes were excluded from the study. Elevated A1C was defined as 5.7-6.4%. Incident type 2 diabetes was confirmed by two OGTTs. Cardiovascular outcome was measured as incident CVD or CVD mortality. Multivariate log-binomial regression models were used to predict diabetes, CVD, and CVD mortality at 10 years. Receiver operating characteristic curves compared predictive values of A1C, IGT, and IFG.Incidence of diabetes during the follow-up was 17.1%. Two of three of the cases of newly diagnosed diabetes were predicted by a raise in >or=1 of the markers. Elevated A1C, IGT, or IFG preceded diabetes in 32.8, 40.6, and 21.9%, respectively. CVD was predicted by an intermediate and diabetic range of 2-h glucose but only by diabetic A1C levels in women.A1C predicted 10-year risk of type 2 diabetes at a range of A1C 5.7-6.4% but CVD only in women at A1C >or=6.5%.
Sorafenib Enhances Pemetrexed Cytotoxicity through an Autophagy-Dependent Mechanism in Cancer Cells
Authors: M. Danielle Bareford, Margaret A. Park, Adly Yacoub, Hossein A. Hamed, Yong Tang, Nichola Cruickshanks, Patrick Eulitt, Nisan Hubbard, Gary Tye, Matthew E. Burow, Paul B. Fisher, Richard G. Moran, Kenneth P. Nephew, Steven Grant, Paul Dent
Journal: Cancer Research (2011)

Pemetrexed (ALIMTA, Lilly) is a folate antimetabolite that has been approved by the U.S. Food and Drug Administration for the treatment of non-small cell lung cancer and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (Nexavar, Bayer), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K, and/or phosphorylated mTOR, in addition to class III receptor tyrosine kinases such as platelet-derived growth factor receptor beta and VEGF receptors, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.
The Cell Death–Inducing Activity of the Peptide Containing Noxa Mitochondrial-Targeting Domain Is Associated with Calcium Release
Authors: Young-Woo Seo, Ha-Na Woo, Sujan Piya, Ae Ran Moon, Jae-Wook Oh, Cheol-Won Yun, Kyung-Keun Kim, Ji-Young Min, Seon-Yong Jeong, Seyung Chung, Peter I. Song, Seong-Yun Jeong, Eun Kyung Choi, Dai-Wu Seol, Tae-Hyoung Kim
Journal: Cancer Research (2009)

DNA damage stabilizes the p53 tumor suppressor protein that determines the cell fate by either cell cycle arrest or cell death induction. Noxa, the BH3-only Bcl-2 family protein, was shown to be a key player in p53-induced cell death through the mitochondrial dysfunction; however, the molecular mechanism by which Noxa induces the mitochondrial dysfunction to cause cell death in response to genotoxic agents is largely unknown. Here, we show that the mitochondrial-targeting domain (MTD) of Noxa is a prodeath domain. Peptide containing MTD causes massive necrosis in vitro through cytosolic calcium increase; it is released from the mitochondria by opening the mitochondrial permeability transition pore. MTD peptide-induced cell death can be inhibited by calcium chelator BAPTA-AM. Moreover, MTD peptide shows the potent tumor-killing activities in mice by joining with tumor-homing motifs.
Integrated care prevents hospitalisations for exacerbations in COPD patients
Authors: A. Casas
Journal: European Respiratory Journal (2006)

Hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations have a major impact on the disease evolution and costs. The current authors postulated that a simple and well-standardised, low-intensity integrated care intervention can be effective to prevent such hospitalisations. Therefore, 155 exacerbated COPD patients (17% females) were recruited after hospital discharge from centres in Barcelona (Spain) and Leuven (Belgium). They were randomly assigned to either integrated care (IC; n = 65; age mean±sd 70±9 yrs; forced expiratory volume in one second (FEV<sub>1</sub>) 1.1±0.5 L, 43% predicted) or usual care (UC; n = 90; age 72±9 yrs; FEV<sub>1</sub> 1.1±0.05 L, 41% pred). The IC intervention consisted of an individually tailored care plan upon discharge shared with the primary care team, as well as accessibility to a specialised nurse case manager through a web-based call centre. After 12 months' follow-up, IC showed a lower hospitalisation rate (1.5±2.6 <i>versus</i> 2.1±3.1) and a higher percentage of patients without re-admissions (49 <i>versus</i> 31%) than UC without differences in mortality (19 <i>versus</i> 16%, respectively). In conclusion, this trial demonstrates that a standardised integrated care intervention, based on shared care arrangements among different levels of the system with support of information technologies, effectively prevents hospitalisations for exacerbations in chronic obstructive pulmonary disease patients.
Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL
Authors: A.I. de Vos, K. Nooter, J. Verweij, W.J. Loos, E. Brouwer, P. de Bruijn, E.J. Ruijgrok, M.E.L. van der Burg, G. Stoter, A. Sparreboom
Journal: Annals of Oncology (1997)
F16, a Mitochondriotoxic Compound, Triggers Apoptosis or Necrosis Depending on the Genetic Background of the Target Carcinoma Cell
Authors: Valeria R. Fantin, Philip Leder
Journal: Cancer Research (2004)

Mutations that lead to the emergence of resistance to apoptosis are commonly observed among tumor cells. Some of the proteins affected are integral parts of the apoptotic cascade such as pro- and antiapoptotic members of the Bcl-2 family. F16 is a small molecule that accumulates in mitochondria of a variety of tumor cells and interferes with their physiological function. Because this interference ultimately triggers apoptosis in many affected cell lines, we examined the effect of antiapoptotic Bcl-2 overexpression on the response of cells to F16. Our results showed that high levels of Bcl-2 did not block the ability of F16 to induce cell death. However, unlike the apoptotic response that followed F16 treatment of cells with moderate Bcl-2 levels, cells resistant to a variety of apoptotic stimuli by virtue of Bcl-2 overexpression succumbed to F16 by necrosis. Thus, this dual ability of the mitochondriotoxic compound F16 to induce apoptosis and necrosis may represent an added advantage by expanding its spectrum of action toward genetically altered tumor cells incapable of apoptosis.
Malignant Ovarian Germ Cell Tumors: Identification of Novel Prognostic Markers and Long-Term Outcome After Multimodality Treatment
Authors: Nirupa Murugaesu, Peter Schmid, Gairin Dancey, Roshan Agarwal, Lydia Holden, Iain McNeish, Philip M. Savage, Edward S. Newlands, Gordon J.S. Rustin, Michael J. Seckl
Journal: Journal of Clinical Oncology (2006)

Purpose Malignant ovarian germ cell tumors are rare and knowledge about prognostic parameters currently is limited. This study was undertaken to evaluate long-term outcome of patients with malignant ovarian germ cell tumors (MOGCTs) after chemotherapy and to assess prognostic parameters. Patients and Methods A total of 113 patients with stage IC to IV MOGCTs were included into this retrospective study. Patients were treated at two large regional cancer centers between 1977 and 2003. Results Ten-year recurrence-free and overall survival rates were 82% and 81%, respectively. A total of 20 patients experienced relapse, all within the first 8 years. Outcome after relapse was poor, with only 10% of patients achieving long-term survival. Univariate and multivariate analyses demonstrated that initial stage of disease (relative risk [RR], 5.96; 95% CI, 3.47 to 10.22; P = .03) and elevation of serum markers β-human chorionic gonadotropin and alpha-fetoprotein (RR, 3.90; 95% CI, 1.40 to 10.9; P = .009) were significant predictors of overall survival, whereas age at diagnosis was of no prognostic value. Conclusion This is the first study to identify stage and tumor markers as prognostic parameters for patients with MOGCTs. This might help to select patients for risk-adapted treatment. There is need for improvement of therapeutic strategies after relapse.
Regulation of glycolytic enzyme activity during chronic hypoxia by changes in rate-limiting enzyme content. Use of monoclonal antibodies to quantitate changes in pyruvate kinase content.
Authors: A J Hance, E D Robin, L M Simon, S Alexander, L A Herzenberg, J Theodore
Journal: Journal of Clinical Investigation (1980)

Monoclonal antibodies were prepared against pyruvate kinase (PyKi; ATP: pyruvate phosphotransferase, EC 2.7.1.40) and used to quantitate PyKi content in L2 lung cells and WI-38 fibroblasts cultivated under hypoxic and normoxic conditions. After 96 h of hypoxic cultivation, PyKi activity was significantly increased in both cell types (L2: normoxia [Po2 = 142 torr], 0.11 +/- 0.01 [SD]; hypoxia [Po2 = 14 torr], 0.25 +/- 0.04 U/microgram DNA, P < 0.01). PyKi content increased proportionately in both cell lines (L2: normoxia, 0.44 +/- 0.13; hypoxia, 0.94 +/- 0.13 microgram enzyme protein/microgram DNA). Specific activity was not significantly different after 96 h (L2: normoxia, 261 +/- 11; hypoxia, 261 +/- 14 U/mg enzyme protein). These results indicate that regulation of glycolysis during chronic hypoxia occurs at the level of enzyme content. Chronic O2 depletion leads to either an increased rate of biosynthesis or a decreased rate of biodegradation of PyKi, causing augmented glycolytic capacity. Monoclonal antibodies provide a highly specific, convenient approach to charcterizing enzymes, as well as quantitating cellular enzyme content.
Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study
Authors: Michael J Blaha, Matthew J Budoff, Andrew P DeFilippis, Ron Blankstein, Juan J Rivera, Arthur Agatston, Daniel H O'Leary, Joao Lima, Roger S Blumenthal, Khurram Nasir
Journal: The Lancet (2011)