tbuckley/cabot-search huggingface dataset:
Combined Treatment with Temozolomide and Methoxyamine: Blocking Apurininc/Pyrimidinic Site Repair Coupled with Targeting Topoisomerase IIα
Authors: Ling Yan, Alina Bulgar, Yanling Miao, Varun Mahajan, Jon R. Donze, Stanton L. Gerson, Lili Liu
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Methoxyamine has been shown to potentiate the cytotoxic effect of temozolomide both in vitro and in human tumor xenograft models. We postulate that the enhanced cytotoxicity is mediated by methoxyamine-bound apurininc/pyrimidinic (MX-AP) site, a key lesion formed by the combination of temozolomide and methoxyamine. When located within topoisomerase IIα (topo II) cleavage sites in DNA, MX-AP sites act as dual lethal targets, not only functionally disrupting the base excision repair (BER) pathway but also potentially poisoning topo II. Experimental Design: Using oligonucleotide substrates, in which a position-specific MX-AP site is located within topo II cleavage sites, we examined the effect of MX-AP site on both AP endonuclease– and topo II–mediated DNA cleavage in vitro. Results: MX-AP sites were refractory to the catalytic activity of AP endonuclease, indicating their ability to block BER. However, they were cleaved by either purified topo II or nuclear extracts from tumor cells expressing high levels of topo II, suggesting that MX-AP sites stimulate topo II–mediated DNA cleavages. In cells, treatment with temozolomide and methoxyamine increased the expression of topo II and enriched the formation of γH2AX foci, which were colocalized with up-regulated topo II, confirming that DNA double-strand breaks marked by γH2AX foci are associated with topo II in cells. Conclusions: Our findings identify a molecular mechanism of cell death whereby MX-AP sites that cumulated in cells due to resistance to BER potentially convert topo II into biotoxins, resulting in enzyme-mediated DNA scission and cell death.
Peter John Holmes Barron
Authors: T. B. M. Atkinson
Journal: BMJ (2009)

After house posts at University College Hospital London and Bury St Edmunds, Peter John Holmes Barron did two years’ service in the Royal Army Medical Corps doing obstetrics and gynaecology at Colchester. During this time he married Pat (Chippindale), a fellow student in his year and his wife for 59 …
Is lactic acidosis a cause of exercise induced hyperventilation at the respiratory compensation point?
Authors: T Meyer, O Faude, J Scharhag, A Urhausen, W Kindermann
Journal: British Journal of Sports Medicine (2004)

The respiratory compensation point (RCP) marks the onset of hyperventilation ("respiratory compensation") during incremental exercise. Its physiological meaning has not yet been definitely determined, but the most common explanation is a failure of the body's buffering mechanisms which leads to metabolic (lactic) acidosis. It was intended to test this experimentally.During a first ramp-like exercise test on a cycle ergometer, RCP (range: 2.51-3.73 l x min(-1) oxygen uptake) was determined from gas exchange measurements in five healthy subjects (age 26-42; body mass index (BMI) 20.7-23.9 kg x m(-2); Vo(2peak) 51.3-62.1 ml x min(-1) x kg(-1)). On the basis of simultaneous determinations of blood pH and base excess, the necessary amount of bicarbonate to completely buffer the metabolic acidosis was calculated. This quantity was administered intravenously in small doses during a second, otherwise identical, exercise test.In each subject sufficient compensation for the acidosis, that is, a pH value constantly above 7.37, was attained during the second test. A delay but no disappearance of the hyperventilation was present in all participants when compared with the first test. RCP occurred on average at a significantly (p = 0.043) higher oxygen uptake (+0.15 l x min(-1)) compared with the first test.For the first time it was directly demonstrated that exercise induced lactic acidosis is causally involved in the hyperventilation which starts at RCP. However, it does not represent the only additional stimulus of ventilation during intense exercise. Muscle afferents and other sensory inputs from exercising muscles are alternative triggering mechanisms.
A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054)
Authors: R. Rampling, M. Sanson, T. Gorlia, D. Lacombe, C. Lai, M. Gharib, W. Taal, C. Stoffregen, R. Decker, M. J. van den Bent
Journal: Neuro-Oncology (2012)

We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m(2) for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels.
Integration of Host-Related Signatures with Cancer Cell–Derived Predictors for the Optimal Management of Anticancer Chemotherapy
Authors: Laurence Zitvogel, Oliver Kepp, Laetitia Aymeric, Yuting Ma, Clara Locher, Nicolas F. Delahaye, Fabrice André, Guido Kroemer
Journal: Cancer Research (2010)

Abstract Current cancer management aims to integrate molecular signatures into the design of personalized therapies. Recent advances in “omics” done on tumor specimens have led to the identification of factors that either recognize cancers of dismal prognosis or pinpoint “druggable” signaling pathways, which can be interrupted by targeted therapies. However, accumulating evidence underscores the biological and clinical significance of immune predictors in several compartments (blood, serum, tumor) in a variety of malignancies. An additional aspect that has been overlooked is the bidirectional, tumor-host interaction during therapeutic intervention, suggesting that dynamic molecular, biochemical, and metabolic signatures should be developed in the future. We review immune parameters of prognostic or predictive value during cancer therapy, and highlight existing “descriptive-prognostic” and “functional-therapeutic” molecular signatures, with the hindsight of designing appropriate compensatory therapies. Cancer Res; 70(23); 9538–43. ©2010 AACR.
Coronary Heart Disease in Smokers
Authors: Philipp A. Kaufmann, Tomaso Gnecchi-Ruscone, Marco di Terlizzi, Klaus P. Schäfers, Thomas F. Lüscher, Paolo G. Camici
Journal: Circulation (2000)

Background —Coronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. Methods and Results —We used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects ( P &lt;0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects. Conclusions —The present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.
Metformin as adjunct antituberculosis therapy
Authors: Amit Singhal, Liu Jie, Pavanish Kumar, Gan Suay Hong, Melvin Khee-Shing Leow, Bhairav Paleja, Liana Tsenova, Natalia Kurepina, Jinmiao Chen, Francesca Zolezzi, Barry Kreiswirth, Michael Poidinger, Cynthia Chee, Gilla Kaplan, Yee Tang Wang, Gennaro De Libero
Journal: Science Translational Medicine (2014)

The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate-activated protein kinase)-dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.
Cocoa and Cardiovascular Health
Authors: Roberto Corti, Andreas J. Flammer, Norman K. Hollenberg, Thomas F. Lüscher
Journal: Circulation (2009)

Epidemiological data demonstrate that regular dietary intake of plant-derived foods and beverages reduces the risk of coronary heart disease and stroke. Among many ingredients, cocoa might be an important mediator. Indeed, recent research demonstrates a beneficial effect of cocoa on blood pressure, insulin resistance, and vascular and platelet function. Although still debated, a range of potential mechanisms through which cocoa might exert its benefits on cardiovascular health have been proposed, including activation of nitric oxide and antioxidant and antiinflammatory effects. This review summarizes the available data on the cardiovascular effects of cocoa, outlines potential mechanisms involved in the response to cocoa, and highlights the potential clinical implications associated with its consumption.
Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease
Authors: Lucia Pacifico, Michele Di Martino, Antonio De Merulis, Mario Bezzi, John Frederick Osborn, Carlo Catalano, Claudio Chiesa
Journal: Hepatology (2013)

Nonalcoholic fatty liver disease (NAFLD) may increase the risk for cardiac dysfunction. The present study aimed to determine whether, in children, NAFLD is associated with subclinical left ventricular (LV) structural and functional abnormalities independently of metabolic risk factors. We performed a complete echocardiographic study including tissue Doppler imaging, magnetic resonance imaging (MRI) for measurement of hepatic fat fraction (HFF) and abdominal fat mass distribution, along with lipid profile, insulin sensitivity, and high-sensitivity C-reactive protein in 108 obese children, 54 with (HFF ≥5%) and 54 without NAFLD, and 18 lean healthy subjects. The three groups were matched for age, gender, and pubertal status, and obese children with NAFLD were matched for body mass index/standard deviation score with those without NAFLD. Forty-one of the children with NAFLD underwent liver biopsy. Compared to controls and children without liver involvement, those with NAFLD had features of LV diastolic dysfunction, including higher E-to-e' ratio and lower e' tissue velocity. The Tei index (reflecting the combined systolic and diastolic LV function) was also significantly higher in NAFLD children. Among children with biopsy-proven NAFLD, 26 had definite nonalcoholic steatohepatitis (NASH) and 15 were not-NASH. Patients with definite-NASH had significantly lower e' velocity and significantly higher E-to-e' and Tei index ( P &lt; 0.001, respectively) than those without NASH. In multiple logistic regression analysis, NAFLD was the only statistically significant variable associated with increased E-to-e' ratio, whereas NAFLD and systolic blood pressure were significantly associated with increased Tei index. Conclusion : Asymptomatic obese children with NAFLD exhibit features of early LV diastolic and systolic dysfunction, and these abnormalities are more severe in those with NASH. (Hepatology 2014;59:461–470)
Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function
Authors: Sergei D. Rybalkin, Chen Yan, Karin E. Bornfeldt, Joseph A. Beavo
Journal: Circulation Research (2003)

Cyclic GMP (cGMP) made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an important regulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals. The ability of smooth muscle cells (SMCs) to utilize different combinations of phosphodiesterase (PDE) isozymes allows cGMP to mediate these multiple processes. For example, PDE5 as a major cGMP-hydrolyzing PDE effectively controls the development of smooth muscle relaxation. In order for contraction to occur, PDE5 is activated and cGMP falls. Conversely, blockade of PDE5 activity allows the relaxation cycle to be prolonged and enhanced. A recently shown direct activation of PDE5 by cGMP binding to the GAF A domain suggests that this regulatory site might be a target for new drug development. The calcium surge associated with vasoconstrictor initiated contraction also activates a calcium/calmodulin-dependent PDE (PDE1A). Together, PDE5 and PDE1A lower cGMP sufficiently to allow contraction. Longer term, both PDE5 and PDE1A mRNA are induced by chronic stimulation of guanylyl cyclase. This induction is a major cause of the tolerance that develops to NO-releasing drugs. Finally, high levels of cGMP or cAMP also act as a brake to attenuate the proliferative response of SMCs to many mitogens. After vessel damage, in order for SMC proliferation to occur, the levels of cGMP and cAMP must be decreased. In humans, this decrease is caused in large part by induction of another Ca 2+ /calmodulin-dependent PDE (PDE1C) that allows the brake to be released and proliferation to start.
Cerebral thrombosis and oral contraceptives.
Authors: W. B. Jennett
Journal: BMJ (1969)

Among 146 patients with carotid territory ischemia (aged 15 to 45 years) the proportion of nonpregnant women was the same as in former years even though the number of referrals had doubled from the year 1956 to 1965.  The increase was exactly balanced by more men in the age group under study.  Of the 42 nonpregnant women 40 had never used oral contraceptives.  The mortality rate for pregnant and puerperal women was 3 times as great as for nonpregnant women.  The middle cerebral artery was more often affected in the pregnant group the internal carotid in the neck in the nonpregnant group.
Treatment of poisoning by antidepressants
Authors: A. B. Baker
Journal: BMJ (1967)

plicity of new drugs can hardly be taken for granted.Should there be any parallel with the effects of alcohol, for example, in a few years' time there could be a crop of iatrogenic delirium tremens and liver cirrhosis which would hardly bear contemplation.We should not forget that the present stupendous amphetamine consumption, legiti- mate and otherwise, was initiated by ourselves, just as the overconsumption of barbiturates is a legacy of the sedative era.Past experience gives a clear warning.Our collective therapeutic machine is very sensitive to the accelerator and we are driving without brakes.-Iam, etc., Sheffield.
A Clinicobiological Model Predicting Survival in Medulloblastoma
Authors: Amit Ray, Michael Ho, Jing Ma, Robert K. Parkes, Todd G. Mainprize, Shigeo Ueda, John McLaughlin, Eric Bouffet, James T. Rutka, Cynthia E. Hawkins
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to determine the relative contributions of biological and clinical predictors of survival in patients with medulloblastoma (MB). Experimental Design: Clinical presentation and survival information were obtained for 119 patients who had undergone surgery for MB at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1985 and 2001. A tissue microarray was constructed from the tumor samples. The arrays were assayed for immunohistochemical expression of MYC, p53, platelet-derived growth factor receptor-α, ErbB2, MIB-1, and TrkC and for apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling). Both univariable and multivariable analyses were conducted to characterize the association between survival and both clinical and biological markers. For the strongest predictors of survival, a weighted predictive score was calculated based on their hazard ratios (HRs). The sum of these scores was then used to give an overall prediction of survival using a nomogram. Results: The four strongest predictors of survival in the final multivariable model were the presence of metastatic disease at presentation (HR, 2.02; P = 0.01) and p53 (HR, 2.29; P = 0.02), TrkC (HR, 0.65; P = 0.14), and ErbB2 (HR, 1.51; P = 0.21) immunopositivity. A linear prognostic index was derived, with coefficients equal to the logarithm of these HRs. The 5-year survival rate for patients at the 10th, 50th, and 90th percentiles of the score distribution was 80.0%, 71.0%, and 35.7%, respectively, with radiation therapy and 70.5%, 58.5%, and 20.0%, respectively, without radiation therapy. Conclusions: In this study, we demonstrate an approach to combining both clinical and biological markers to quantify risk in MB patients. This provides further prognostic information than can be obtained when either clinical factors or biological markers are studied separately and establishes a framework for comparing prognostic markers in future clinical studies.
Acid-Base Disorders in Critical Care Medicine
Authors: V Fencl, T H Rossing
Journal: Annual Review of Medicine (1989)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Sex-Linked Attenuation of the Graft-Versus-Host Reaction: Effect on Pathologic Features, Including Tumor Induction 2
Authors: Eugene A. Cornelius
Journal: JNCI Journal of the National Cancer Institute (1974)

Male and female (C57BL/l × SJL/J)F1 mice were given injections of spleen cells from male SJLjJ donors. The male F1 recipients exhibited a typical graft-versushost reaction (GVHR), with a 36% mortality by the 40th day; the F1 females, by contrast, appeared healthy. Autopsy studies revealed severe pathologic changes characteristic of the GVHR in the Fl males, as well as premalignant and lymphomatous changes in most of them. The Fl females demonstrated only minimal evidence of a GVHRthere was slight lymphocytic depletion of the lymph nodes and spleen,with premalignant and lymphomatous changes in only a small proportion of the animals.
Human hepatocytes are more resistant than rat hepatocytes to Anoxia-reoxygenation injury
Authors: Paolo Caraceni, Antonio Gasbarrini, Andreas Nussler, Mauricio Di Silvio, Fabio Bartoli, Andre B. Borle, David H. Van Thiel
Journal: Hepatology (1994)

We performed this study to determine whether perfused isolated human and rat hepatocytes have different sensitivities to anoxia-reoxygenation injury. Oxygen free radicals were detected by lucigenin-enhanced chemiluminescence. Lipid peroxidation was assessed by measuring malondialdehyde release. Cell injury was evaluated by measuring lactate dehydrogenase release and trypan blue uptake. During the control period, lucigenin-enhanced chemiluminescence, malondialdehyde and lactate dehydrogenase release and trypan blue uptake were similar in rat and human hepatocytes. During 3.5 hr of anoxia, lucigenin-enhanced chemiluminescence decreased to background levels and malondialdehyde release remained constant in both groups. In contrast, lactate dehydrogenase release increased eightfold in rat hepatocytes but only threefold in human hepatocytes. With reoxygenation after 2.5 hr of anoxia, in rat hepatocytes lucigenin-enhanced chemiluminescence increased 13-fold within 15 min and then declined toward control levels. Malondialdehyde release doubled after 1 hr of reoxygenation. The rate of lactate dehydrogenase release increased to a level almost twice that observed in cells kept continuously anoxic. In contrast, with human hepatocytes lucigenin-enhanced chemiluminescence increased only fourfold, whereas malondialdehyde and lactate dehydrogenase releases did not differ significantly from those levels measured in cells perfused continuously under anoxic conditions. At the end of the experiment, the increase in trypan blue uptake was significantly greater with rat hepatocytes than with human hepatocytes. These results demonstrate that (a) during reoxygenation following 2.5 hr of anoxia, isolated human hepatocytes generate fewer oxygen free radical, and lipoperoxides than do rat hepatocytes, and (b) human hepatocytes are more resistant to cell injury during anoxia-reoxygenation than are rat hepatocytes.
Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study
Authors: B. Gwilliam, V. Keeley, C. Todd, M. Gittins, C. Roberts, L. Kelly, S. Barclay, P. C. Stone
Journal: BMJ (2011)

To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival.Prospective multicentre observational cohort study.18 palliative care services in the UK (including hospices, hospital support teams, and community teams).1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services.Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions.On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival.In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.