tbuckley/cabot-search huggingface dataset:
The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas
Authors: Beatrice Gini, Ciro Zanca, Deliang Guo, Tomoo Matsutani, Kenta Masui, Shiro Ikegami, Huijun Yang, David Nathanson, Genaro R. Villa, David Shackelford, Shaojun Zhu, Kazuhiro Tanaka, Ivan Babic, David Akhavan, Kelly Lin, Alvaro Assuncao, Yuchao Gu, Bruno Bonetti, Deborah S. Mortensen, Shuichan Xu, Heather K. Raymon, Webster K. Cavenee, Frank B. Furnari, C. David James, Guido Kroemer, James R. Heath, Kristen Hege, Rajesh Chopra, Timothy F. Cloughesy, Paul S. Mischel
Journal: Clinical Cancer Research (2013)

Abstract Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it. Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance. Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death. Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.
Vasodepressor reaction induced by inferior vena cava occlusion and isoproterenol in the rat. Role of beta 1- and beta 2-adrenergic receptors.
Authors: M B Waxman, J A Asta, D A Cameron
Journal: Circulation (1994)

BACKGROUND Testing for the susceptibility of vasodepressor reaction in humans involves the combination of restriction of venous return by passive upright tilting and the administration of isoproterenol. We developed an experimental rat model in which vasodepressor reactions are induced when the inferior vena cava is occluded during an infusion of isoproterenol. The reactions are characterized by the development of paradoxical bradycardia during the period of inferior vena cava occlusion. METHODS AND RESULTS Inferior vena cava occlusion was performed for 60 seconds, and the maximal changes in RR interval were measured during seven states as follows: (1) when inferior vena cava occlusion was performed under control conditions in 40 rats, the rate accelerated in all 40 rats (delta RR, -15.6 +/- 1.9 milliseconds in 25 rats, P &lt; .001; delta RR, -13.3 +/- 1.7 milliseconds in 10 rats, P &lt; .001); (2) when inferior vena cava occlusion was performed in 25 rats during an infusion of isoproterenol, a vasodepressor reaction was observed in all rats as the heart rate slowed (delta RR, +92.7 +/- 8.3 milliseconds, P &lt; .001); (3) when inferior vena cava occlusion was performed in 10 rats during an infusion of dobutamine, a selective beta 1-agonist, a vasodepressor reaction was observed in all rats as the heart rate slowed (delta RR, +63.3 +/- 10.6 milliseconds, P &lt; .001); (4) when inferior vena cava occlusion was performed in 5 rats during an infusion of salbutamol, a selective beta 2-agonist, vasodepressor reaction was not observed as the heart rate accelerated in all rats (delta RR, -11.4 +/- 2.8 milliseconds, P &lt; .002); (5) the vasodepressor reaction induced by either dobutamine or isoproterenol was inhibited by atenolol, a selective beta 1-adrenergic receptor antagonist; (6) the vasodepressor reaction induced by isoproterenol was inhibited by propranolol (lipophilic) and sotalol (nonlipophilic) beta-blockers and there was a dose-dependent attenuation by propranolol of the maximal RR interval slowing during inferior vena cava occlusion; and (7) butoxamine, a selective beta 2-adrenergic receptor antagonist, attenuated but did not block the vasodepressor reaction observed during an infusion of isoproterenol. CONCLUSIONS Reduced cardiac volume combined with beta 1-adrenergic stimulation can stimulate a vasodepressor reaction in rats. beta 2-Adrenergic receptors play little or no role in the reaction. The vasodepressor reaction can be blocked by selective or nonselective beta 1-adrenergic antagonists independent of the drug's ability to penetrate the central nervous system. The application of these findings to humans remains to be elucidated.
Treatment with atorvastatin partially protects the rat heart from harmful catecholamine effects
Authors: A. Schmechel, M. Grimm, A. El-Armouche, G. Hoppner, A. P. Schwoerer, H. Ehmke, T. Eschenhagen
Journal: Cardiovascular Research (2009)

Atorvastatin blunts the response of cardiomyocytes to catecholamines by reducing isoprenylation of G gamma subunits. We examined whether atorvastatin exerts similar effects in vivo and protects the rat heart from harmful effects of catecholamines.Rats were treated with atorvastatin (1 or 10 mg/kg x day) or H(2)O for 14 days per gavage. All three animal groups were subjected to restraint stress on day 10 and to infusions of isoprenaline (ISO; 1 mg/kg x day) or NaCl via minipumps for the last 4 days. Heart rate was measured by telemetry, left ventricular atrial natriuretic peptide (ANP) transcript levels by RT-PCR, and left atrial contractile function in organ baths. Heart rate was similar in all six study groups. In animals pre-treated with water, infusion of ISO induced an increase in heart-to-body weight ratio (HW/BW) by approximately 20%, an increase in ANP mRNA by approximately 350%, and a reduction in the inotropic effect of isoprenaline in left atrium by approximately 50%. In animals pre-treated with high-dose atorvastatin, the effects of ISO on HW/BW, ANP, and left atrial force were approximately 40, 50, and 40% smaller, respectively. Low dose atorvastatin had similar, albeit smaller effects. Atorvastatin treatment of NaCl-infused rats had only marginal effects. In cardiac homogenates from atorvastatin-treated rats (both NaCl- and ISO-infused), G gamma and G alpha(s) were partially translocated from the membrane to the cytosol.In the rat heart, treatment with atorvastatin results in translocation of cardiac membrane G gamma and G alpha(s) to the cytosol. This mechanism might contribute to protecting the heart from harm induced by chronic isoprenaline infusion without affecting heart rate.
Adaptation of pulmonary receptors in the spontaneously breathing anaesthetized rat
Authors: A Davies, L Pirie, RA Eyre-Todd
Journal: European Respiratory Journal (1996)

It has been suggested that species with high breathing frequencies have pulmonary stretch receptors which adapt more rapidly than species with low breathing frequencies. This has proved not to be so. Our hypothesis is that this theory is in fact correct if modified so that overall rate of adaptation of afferent vagal activity, i.e. the sum of stretch and rapidly adapting receptors, is considered. A rapidly breathing species, such as the rat, would thus have a greater proportion of rapidly adapting receptors, than a more slowly breathing species. To test this hypothesis, we measured the proportion of rapidly adapting pulmonary mechanoreceptors in spontaneously breathing rats for comparison with existing results from more slowly breathing species. We found there to be one rapidly adapting receptor for every three slowly adapting receptors present. This measurement has not previously been made in spontaneously breathing rats. The ratio of rapidly to slowly adapting pulmonary receptors in the species sequence cat-rabbit-rat is the same as the ratio of their breathing frequencies (3:4:10). We propose that the difference in proportion of slowly to rapidly adapting pulmonary receptors in different species may be related to their eupnoeic breathing frequency.
Intermittent Preventive Therapy for Malaria During Pregnancy Using 2 vs 3 or More Doses of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in Africa
Authors: Kassoum Kayentao, Paul Garner, Anne Maria van Eijk, Inbarani Naidoo, Cally Roper, Abdunoor Mulokozi, John R. MacArthur, Mari Luntamo, Per Ashorn, Ogobara K. Doumbo, Feiko O. ter Kuile
Journal: JAMA (2013)

Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain.To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens.ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy.Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models.Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events.Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.
PTU-111 A Prospective Study of Intravenous Paracetamol Prescribing and its use in Patients at Risk of Iatrogenic Paracetamol Induced Hepatotoxicity
Authors: J A Evans, F Sampaziotis, D Ismail, S Baillie, J McGrath
Journal: Gut (2013)

<h3>Introduction</h3> Intravenous (iv) paracetamol can cause severe hepatotoxicity and lead to death if inappropriately prescribed<sup>1</sup>. It is increasingly being used for post-operative pain and pyrexia<sup>2</sup>. There is a lack of awareness that paracetamol should be prescribed by weight when used in certain higher risk groups<sup>1,2</sup>; including those weighing less than 50kilos and in malnourished patients<sup>3</sup>. This study assessed iv paracetamol prescribing in patients at increased risk of hepatotoxicity. <h3>Methods</h3> Drug charts and medical records from 5 wards (3 surgical and 2 medical including 1 gastroenterology ward) were assessed prospectively over 3 days. All patients prescribed paracetamol were identified; those receiving iv preparations were included. The age, sex and weight were recorded in conjunction with the dose, route and number of paracetamol doses received by each patient. Intravenous doses were identified by countersignatures on drug charts or where iv was the only route indicated. Medical records were reviewed for a history of alcohol excess, chronic liver disease, chronic kidney disease (CKD), eating disorders, and those taking CYP450 inducing medications. <h3>Results</h3> 59 patients were receiving paracetamol via any route. The average age was 74.6 years old (range 32–86). 25 patients had received iv paracetamol with 12/25 (48%) receiving the drug only via the iv route. The mean number of consecutive doses was 4.44 (range 1–28). 3 patients had CKD, 3 patients were on the CYP450 inducer Rifampicin and 1 patient had an eating disorder and CKD. 2 patients receiving iv doses were under 50 kg, one of which had CKD. Of the 9 patients deemed to be at risk of iatrogenic paracetamol induced hepatotoxicity, 0% had paracetamol prescribed at the recommended reduced dose of 3g per day. <h3>Conclusion</h3> This study demonstrates that intravenous paracetamol was not being prescribed appropriately. Intravenous paracetamol should be reduced in high risk groups to 3g per day (15mg/kg/24 hours). With 25–37% of all hospital inpatients being deemed at risk of malnourishment4 a large patient cohort is at risk of paracetamol induced liver injury. Assessment of nutritional status and improved awareness of higher risk patients is needed to avoid iatrogenic paracetamol induced hepatotoxicity through poor prescribing. <h3>Disclosure of Interest</h3> None Declared <h3>References</h3> Fatal Accident Inquiry into the death of Danielle Welsh.<i></i> Available at: http://www.scotland-judiciary.org.uk/10/715/[Accessed15 Nov 2012] Gray T, Hoffman R, Bateman D. Intravenous paracetamol – an international perspective of toxicity. Clinical Toxicology 2011; 49 : 150–152. British National Formulary. Sept 2012.64 : 264–265 BAPEN 2012 -http://www.bapen.org.uk/about-malnutrition/introduction-to malnutrition?showall = &amp;start = 4, [Accessed 3rd Jan 2013].
Squamous cell carcinoma of the nail bed: a clinicopathological study of 12 cases
Authors: JOAN GUITART, WILMA F. BERGFELD, R.J. TUTHILL, R.R. TUBBS, R. ZIENOWICZ, E.J. FLEEGLER
Journal: British Journal of Dermatology (1990)

Twelve cases were reviewed of squamous cell carcinoma of the nail bed, with emphasis on the aetiological role of human papillomavirus (HPV) infection and radiation damage. Using a hybridization technique, similar HPV genomes were detected in a uterine cervical neoplasia and a subungual squamous cell carcinoma in the same patient.
Press: Dutch doctors supported by media
Authors: G. van Heteren
Journal: BMJ (2000)

British doctors may feel all alone in the trenches as they continue to be hit by a relentless series of scandals in the press. Professional demoralisation, however, seems to be a much more widespread phenomenon, currently affecting many European healthcare settings, hinting at deeper and perhaps more common roots of professional unease. What clearly varies, however, are professional strategies to deal with the media.

Take the Netherlands. Here, too, healthcare provision has come under fire. But rather than pillorying doctors, most journalists aim their critical arrows elsewhere: at government, insurers, and hospital administrators. In the process, professionals have become the media's best friends, as victims of a failing system.

This peculiar state of affairs became visible again recently, when one of the senior commentators of De Telegraaf , the most widely read Dutch populist national morning paper, filled a column with his personal selection of headlines on health care from the previous few months ( De Telegraaf , 29 July). These included: “Many demented elderly without care” ( Haarlems Dagblad ); “Shortage of doctors to check up on children” ( Tubantia ); “Too little radiotherapy available for cancer patients” ( NRC Handelsblad ); “GPs sick of workload” ( Drentse Courant ); “A third of GPs will stop this year” ( Het Parool ); “Pregnant women without midwives” ( Noordhollands Dagblad ); “Day-budget finished, patients sent home” ( De Limburger ); and “Waiting …
Characterisation of T cell clonotypes that accumulated in multiple joints of patients with rheumatoid arthritis
Authors: M. Kurokawa, T. Kato, K. Masuko-Hongo, S.-i. Ueda, T. Kobata, M. Okubo, T. Nishimaki, T. Akaza, S.-i. Yoshino, R. Kasukawa, K. Nishioka, K. Yamamoto
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> To investigate whether identical T cell clonotypes accumulate in multiple rheumatoid joints, the clonality of T cells that had infiltrated into synovial tissue (ST) samples simultaneously obtained from multiple joints of patients with rheumatoid arthritis (RA) was analysed. <h3>METHODS</h3> T cell receptor (TCR) β gene transcripts, amplified by reverse transcription-polymerase chain reaction from ST and peripheral blood lymphocytes of five RA patients, were subjected to single strand conformation polymorphism analysis and DNA sequencing. <h3>RESULTS</h3> Approximately 40% of accumulated T cell clonotypes found in one joint of a patient were found in multiple joints in the same patient. Furthermore, identical amino acid sequences were found in TCR β junctional regions of these clonotypes from different patients with at least one HLA molecule match. <h3>CONCLUSIONS</h3> The T cell clonotypes accumulating in multiple rheumatoid joints may be involved in the perpetuation of polyarthritis by reacting to antigens common to these multiple joints.
Exposure-adjusted incidence rates and severity of competition injuries in Australian amateur taekwondo athletes: a 2-year prospective study
Authors: Reidar P Lystad, Petra L Graham, Roslyn G Poulos
Journal: British Journal of Sports Medicine (2012)

Background/aim The main purposes of this study were to determine the injury incidence and severity in Australian amateur taekwondo athletes, and to investigate potential risk factors for injury in competition taekwondo. Methods Data were collected at New South Wales State Championships in 2010 and 2011. Injuries were diagnosed by onsite sports medicine personnel and the actual number of days lost from full participation was used to determine injury severity. Injury incidence rates were calculated per 1000 athlete-exposures (injury incidence rate (IIR AE )) and per 1000 min of exposure (IIR ME ) and presented with 95% CI. Results The overall IIR AE and IIR ME were 59.93 (95% CI 51.16 to 69.77) and 16.32 (95% CI 13.93 to 19.00), respectively. Children under 10 years had significantly lower IIR AE compared with older age groups and black belts had significantly higher IIR AE compared with yellow belts, however, after accounting for the exposure time it was revealed that 10-year-olds to 14-year-olds and red belts incurred higher IIR ME . This study highlights the importance of including IIRs that account for exposure-time. In contrast with previous estimates, the current data indicated that one-third of injuries were moderate to severe. Relative to other body regions the upper limb had a higher proportion of moderate-to-severe injuries, and compared with the lower limb there was a disproportionate number of upper limb injuries resulting in fractures. Conclusions The findings suggest that the impact of injury on taekwondo athletes is significant, and should serve as an impetus to stakeholders to develop and implement injury prevention activities within the sport.
Anti‐tumor mechanisms of valproate: A novel role for an old drug
Authors: Roman A. Blaheta, Jindrich Cinatl
Journal: Medicinal Research Reviews (2002)

Abstract Valproic acid (VPA, 2‐propylpentanoic acid) is an established drug in the long‐term therapy of epilepsy. During the past years, it has become evident that VPA is also associated with anti‐cancer activity. VPA not only suppresses tumor growth and metastasis, but also induces tumor differentiation in vitro and in vivo. Several modes of action might be relevant for the biological activity of VPA: (1) VPA increases the DNA binding of activating protein‐1 (AP‐1) transcription factor, and the expression of genes regulated by the extracellular‐regulated kinase (ERK)‐AP‐1 pathway; (2) VPA downregulates protein kinase C (PKC) activity; (3) VPA inhibits glycogen synthase kinase‐3β (GSK‐3β), a negative regulator of the Wnt signaling pathway; (4) VPA activates the peroxisome proliferator‐activated receptors PPARγ and †; (5) VPA blocks HDAC (histone deacetylase), causing hyperacetylation. The findings elucidate an important role of VPA for cancer therapy. VPA might also be useful as low toxicity agent given over long time periods for chemoprevention and/or for control of residual minimal disease. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 492–511, 2002; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10017
Evaluation of a Wildfire Smoke Forecasting System as a Tool for Public Health Protection
Authors: Jiayun Yao, Michael Brauer, Sarah B. Henderson
Journal: Environmental Health Perspectives (2013)

Exposure to wildfire smoke has been associated with cardiopulmonary health impacts. Climate change will increase the severity and frequency of smoke events, suggesting a need for enhanced public health protection. Forecasts of smoke exposure can facilitate public health responses.We evaluated the utility of a wildfire smoke forecasting system (BlueSky) for public health protection by comparing its forecasts with observations and assessing their associations with population-level indicators of respiratory health in British Columbia, Canada.We compared BlueSky PM2.5 forecasts with PM2.5 measurements from air quality monitors, and BlueSky smoke plume forecasts with plume tracings from National Oceanic and Atmospheric Administration Hazard Mapping System remote sensing data. Daily counts of the asthma drug salbutamol sulfate dispensations and asthma-related physician visits were aggregated for each geographic local health area (LHA). Daily continuous measures of PM2.5 and binary measures of smoke plume presence, either forecasted or observed, were assigned to each LHA. Poisson regression was used to estimate the association between exposure measures and health indicators.We found modest agreement between forecasts and observations, which was improved during intense fire periods. A 30-μg/m3 increase in BlueSky PM2.5 was associated with an 8% increase in salbutamol dispensations and a 5% increase in asthma-related physician visits. BlueSky plume coverage was associated with 5% and 6% increases in the two health indicators, respectively. The effects were similar for observed smoke, and generally stronger in very smoky areas.BlueSky forecasts showed modest agreement with retrospective measures of smoke and were predictive of respiratory health indicators, suggesting they can provide useful information for public health protection.