tbuckley/cabot-search huggingface dataset:
Visualizing the Dynamics of EGFR Activity and Antiglioma Therapies <i>In vivo</i>
Authors: Esther Arwert, Shawn Hingtgen, Jose-Luiz Figueiredo, Henry Bergquist, Umar Mahmood, Ralph Weissleder, Khalid Shah
Journal: Cancer Research (2007)

Abstract Many altered pathways in cancer cells depend on growth factor receptors. In primary malignant gliomas, the amplification/alteration of the epidermal growth factor receptor (EGFR) has been shown to play a significant role in enhancing glioma burden. In an effort to dissect the role of EGFR expression in glioma progression in vivo and evaluate targeted therapies for gliomas, we have genetically engineered glioma cells to visualize the dynamics of EGFR and targeted therapies in real time in vivo. Using engineered lentiviral vectors bearing fusions between EGFR and its exon 2 to 7 deleted variant (EGFRvIII) with green fluorescent protein (GFP) and Renilla luciferase (Rluc), we show that there is a direct correlation between EGFR expression and glioma cell proliferation in the initial stages of glioma progression. To monitor and evaluate EGFR-targeted therapies, we have engineered (a) short hairpin RNAs (shRNA) and (b) clinically used monoclonal antibody, cetuximab. Using EGFR-GFP-Rluc/firefly luciferase (Fluc)-DsRed2 glioma model, we show that both shRNAs and cetuximab result in a considerable reduction in glioma cell proliferation in culture and glioma burden in vivo that can be monitored in real time at a cellular resolution. This study serves as a template to follow the role of growth factor receptor expression in tumor progression and to image therapeutic efficacy of targeted therapies in cancer. [Cancer Res 2007;67(15):7335–42]
New-Onset Heart Failure in Children in the Absence of Structural Congenital Heart Disease
Authors: Steven A. Webber
Journal: Circulation (2008)

advances in the operative and perioperative care of children with major forms of congenital heart disease have resulted in excellent short-and medium-term outcomes for the most severe forms of heart disease, including those with so-called single-ventricle physiology.This represents one of the great advances in pediatrics over the last 3 decades.A corollary of these observations is that some of the worst outcomes for children with heart disease are now observed in those with cardiomyopathy (whether acquired or congenital).This fact has drawn focus on heart muscle disease as an important cause of morbidity and mortality in children. Article p 79Data from the Registry of the International Society for Heart and Lung Transplantation 1 emphasize that cardiomyopathies (notably the dilated form) remain the main indication for heart transplantation in childhood.This international report provides very limited information, however, on outcomes before transplantation.The Pediatric Heart Transplant Study, a multi-institutional research consortium from 3 countries, has focused (since 1993) on identifying risk factors for various outcomes from the time of listing for transplantation in children with end-stage heart disease, the majority of whom have cardiomyopathy. 2,3This has provided important information on pretransplantation morbidity and mortality rates in children with advanced heart disease but does not address the epidemiology or outcomes for children at first presentation with heart failure unrelated to structural heart disease.Recently, 2 groups have provided population-based data on pediatric cardiomyopathies, allowing ascertainment of incidence and spectrum of cardiomyopathy types.The prospective arm of the Pediatric Cardiomyopathy Registry sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health provided the first population data on the incidence and types of pediatric cardiomyopathy in the United States. 4The findings were remarkably similar to the results of a population-based study of primary pediatric cardiomyopathies from Australia. 5Both the Pediatric Cardio-
Associations of PM <sub>2.5</sub> Constituents and Sources with Hospital Admissions: Analysis of Four Counties in Connecticut and Massachusetts (USA) for Persons ≥ 65 Years of Age
Authors: Michelle L. Bell, Keita Ebisu, Brian P. Leaderer, Janneane F. Gent, Hyung Joo Lee, Petros Koutrakis, Yun Wang, Francesca Dominici, Roger D. Peng
Journal: Environmental Health Perspectives (2013)

Epidemiological studies have demonstrated associations between short-term exposure to PM2.5 and hospital admissions. The chemical composition of particles varies across locations and time periods. Identifying the most harmful constituents and sources is an important health and regulatory concern.We examined pollutant sources for associations with risk of hospital admissions for cardiovascular and respiratory causes.We obtained PM2.5 filter samples for four counties in Connecticut and Massachusetts and analyzed them for PM2.5 elements. Source apportionment was used to estimate daily PM2.5 contributions from sources (traffic, road dust, oil combustion, and sea salt as well as a regional source representing coal combustion and other sources). Associations between daily PM2.5 constituents and sources and risk of cardiovascular and respiratory hospitalizations for the Medicare population (> 333,000 persons ≥ 65 years of age) were estimated with time-series analyses (August 2000-February 2004).PM2.5 total mass and PM2.5 road dust contribution were associated with cardiovascular hospitalizations, as were the PM2.5 constituents calcium, black carbon, vanadium, and zinc. For respiratory hospitalizations, associations were observed with PM2.5 road dust, and sea salt as well as aluminum, calcium, chlorine, black carbon, nickel, silicon, titanium, and vanadium. Effect estimates were generally robust to adjustment by co-pollutants of other constituents. An interquartile range increase in same-day PM2.5 road dust (1.71 μg/m3) was associated with a 2.11% (95% CI: 1.09, 3.15%) and 3.47% (95% CI: 2.03, 4.94%) increase in cardiovascular and respiratory admissions, respectively.Our results suggest some particle sources and constituents are more harmful than others and that in this Connecticut/Massachusetts region the most harmful particles include black carbon, calcium, and road dust PM2.5.
Recent developments in capsule endoscopy
Authors: J. P. Galmiche, E. Coron, S. Sacher-Huvelin
Journal: Gut (2008)

<h3>Background</h3> Smoking is widely known to be damaging to health. It greatly increases the risk of various cancers, cardiovascular and respiratory diseases, and remains the leading preventable cause of morbidity and mortality in the UK. The article tested the hypothesis that smoking behaviour (either smoking or non-smoking) is associated with physical function, and assessed inferred causality using genetic predisposition to smoking behaviour as an instrumental variable. <h3>Methods and findings</h3> Data were drawn from the English Longitudinal Study of Ageing, waves 1–9 (mean age 65.8 years). Physical function was assessed by means of the body mobility and the activity of daily living indices. Polygenic scores for smoking behaviour were used as instrumental variables in a Mendelian randomisation framework. Instrumental variable estimators were used to examine causal effects. Among UK older adults (n=29 139), impaired physical function was significantly higher in (current) smokers compared with non-smokers. Relatively to non-smokers, smokers reported a higher level of impairment both in the body mobility index (β=5.553; 95% CI 1.029 to 10.077) and in the activities of daily living index (β=1.908; 95% CI 0.196 to 3.619). <h3>Conclusions</h3> This study demonstrates smoking behaviour to be a potential causal risk factor for physical function during ageing in the UK population. Accordingly, the benefits of smoking cessations may extend to physical function.
Assessing the potential for AAV vector genotoxicity in a murine model
Authors: Hojun Li, Nirav Malani, Shari R. Hamilton, Alexander Schlachterman, Giulio Bussadori, Shyrie E. Edmonson, Rachel Shah, Valder R. Arruda, Federico Mingozzi, J. Fraser Wright, Frederic D. Bushman, Katherine A. High
Journal: Blood (2010)

Abstract Gene transfer using adeno-associated virus (AAV) vectors has great potential for treating human disease. Recently, questions have arisen about the safety of AAV vectors, specifically, whether integration of vector DNA in transduced cell genomes promotes tumor formation. This study addresses these questions with high-dose liver-directed AAV-mediated gene transfer in the adult mouse as a model (80 AAV-injected mice and 52 controls). After 18 months of follow-up, AAV-injected mice did not show a significantly higher rate of hepatocellular carcinoma compared with controls. Tumors in mice treated with AAV vectors did not have significantly different amounts of vector DNA compared with adjacent normal tissue. A novel high-throughput method for identifying AAV vector integration sites was developed and used to clone 1029 integrants. Integration patterns in tumor tissue and adjacent normal tissue were similar to each other, showing preferences for active genes, cytosine-phosphate-guanosine islands, and guanosine/cysteine-rich regions. Gene expression data showed that genes near integration sites did not show significant changes in expression patterns compared with genes more distal to integration sites. No integration events were identified as causing increased oncogene expression. Thus, we did not find evidence that AAV vectors cause insertional activation of oncogenes and subsequent tumor formation.
Association of Treatment With Losartan vs Candesartan and Mortality Among Patients With Heart Failure
Authors: Henrik Svanström, Björn Pasternak, Anders Hviid
Journal: JAMA (2012)

The benefit of angiotensin II-receptor blockers (ARBs) in heart failure is thought to be a class effect, but no head-to-head randomized trials have compared individual ARBs. Results from observational studies suggest that losartan may be associated with increased mortality in patients with heart failure compared with other ARBs.To assess the hypothesis that losartan use is associated with increased all-cause mortality in heart failure patients as compared with candesartan.We conducted a nationwide Danish registry-based cohort study, linking individual-level information on hospital contacts, filled prescriptions, and potential confounders. Patients aged 45 years and older with first-time hospitalization for heart failure in 1998-2008 were identified from the Danish National Patient Registry. New users of losartan and candesartan were selected for inclusion in the study cohort.We used Cox proportional hazards regression to compare the risk of all-cause mortality in users of losartan and candesartan.Among 4397 users of losartan, 1212 deaths occurred during 11,347 person-years of follow-up (unadjusted incidence rate [IR]/100 person-years, 10.7; 95% CI, 10.1-11.3) compared with 330 deaths during 3675 person-years among 2082 users of candesartan (unadjusted IR/100 person-years, 9.0; 95% CI, 8.1-10.0). Compared with candesartan, losartan was not associated with increased all-cause mortality (adjusted hazard ratio [HR], 1.10; 95% CI, 0.96-1.25) or cardiovascular mortality (adjusted HR, 1.14; 95% CI, 0.96-1.36). Compared with high doses of candesartan (16-32 mg), low-dose (12.5 mg) and medium-dose losartan (50 mg) were associated with increased mortality (HR, 2.79; 95% CI, 2.19-3.55 and HR, 1.39; 95% CI, 1.11-1.73, respectively); use of high-dose losartan (100 mg) was similar in risk (HR, 0.71; 95% CI, 0.50-1.00).Among patients with heart failure, overall use of losartan compared with candesartan was not associated with an increased mortality risk. Although low doses of losartan were associated with increased mortality, there was no increased mortality comparing high-dose losartan against the highest doses of candesartan.
[677] CHOLESTASIS BUT NOT STEATOSIS POTENTIATES LIVER INJURY BY ACTIVATED KUPFFER CELLS: EVIDENCE FOR A ROLE FOR CYCLOOXYGENASE-2
Authors: C.J. Steib, F. Roggel, T. Grote, M. Bystron, J. Haertl, C. Opelz, B. Goeke, A.L. Gerbes, M. Bilzer
Journal: Journal of Hepatology (2007)
SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status
Authors: Ayad M Al-Katib, Yuan Sun, Anton Scott Goustin, Asfar Sohail Azmi, Ben Chen, Amro Aboukameel, Ramzi M Mohammad
Journal: Journal of Hematology & Oncology (2009)

The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165–320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation.
Predicting Future Functional Status for Seriously Ill Hospitalized Adults: The SUPPORT Prognostic Model
Authors: Albert W. Wu
Journal: Annals of Internal Medicine (1995)

To develop a model estimating the probability of an adult patient having severe functional limitations 2 months after being hospitalized with one of nine serious illnesses.Prospective cohort study.Five teaching hospitals in the United States.1746 patients (model development) who survived 2 months and completed an interview, selected from 4301 patients in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT); independent validation sample of 2478 patients.Patient function 2 months after admission categorized as absence or presence of severe functional limitations (defined as Sickness Impact Profile scores > or = 30 or as activities of daily living scores > or = 4 [levels that require near-constant personal assistance]). A logistic regression model was constructed to predict severe functional limitation.One third (n = 590) of patients who were interviewed at 2 months had severe functional limitations. Changes in functional status were common: Of those with no baseline dependencies (not dependent on personal assistance), 21% were severely limited at 2 months; of those with 4 or more baseline limitations, 30% had improved. The patient's ability to do activities of daily living was the most important predictor of functional status. Physiologic abnormalities, diagnosis, days in hospital, age, quality of life, and previous exercise capacity also contributed substantially. Model performance, assessed using receiver-operating characteristic curves, was 0.79 for the development sample and 0.75 for the validation sample. The model was well calibrated for the entire risk range.Functional outcome varied substantially after hospitalization for a serious illness. A small amount of readily available clinical information can estimate the probability of severe functional limitations.
DEVELOPMENT AND BIOMEDICAL TESTING OF MILITARY OPERATIONAL RATIONS
Authors: Karl E. Friedl, Reed W. Hoyt
Journal: Annual Review of Nutrition (1997)

▪ Abstract This article gives a brief history of military nutrition research in this century and reviews recent advances made through field testing. Although modern rations are nutritionally complete, ration developers are challenged to improve palatability to promote increased intakes in field training and combat settings. The principal goal for military nutritionists is to identify the optimal macronutrient mix and specific ration components that sustain a soldier's performance in the face of operational stressors such as sleep deprivation, intense physical activity, climatic extremes, and hypobaric hypoxia. Energy expenditures during typical field-training exercises average approximately 4000 kcal/day, whereas energy intakes are usually 3000 kcal/day or less when operational rations are consumed. One way to ameliorate the effects of this shortfall is to provide soldiers with a carbohydrate beverage supplement.
Effects of Blood Pressure Reduction in Mild Hypertension
Authors: Johan Sundström, Hisatomi Arima, Rod Jackson, Fiona Turnbull, Kazem Rahimi, John Chalmers, Mark Woodward, Bruce Neal
Journal: Annals of Internal Medicine (2014)

Effects of blood pressure reduction in persons with grade 1 hypertension are unclear.To investigate whether pharmacologic blood pressure reduction prevents cardiovascular events and deaths in persons with grade 1 hypertension.Trials included in the BPLTTC (Blood Pressure Lowering Treatment Trialists' Collaboration) and trials identified from a previous review and electronic database searches.Patients without cardiovascular disease with blood pressures in the grade 1 hypertension range (140 to 159/90 to 99 mm Hg) who were randomly assigned to an active (antihypertensive drug or more intensive regimen) or control (placebo or less intensive regimen) blood pressure-lowering regimen.Individual-patient data from BPLTTC trials and aggregate data from other trials were extracted. Risk of bias was assessed for all trials.Individual-patient data involved 10 comparisons from trials where most patients had diabetes, and aggregate data involved 3 comparisons from trials of patients without diabetes. The average blood pressure reduction was about 3.6/2.4 mm Hg. Over 5 years, odds ratios were 0.86 (95% CI, 0.74 to 1.01) for total cardiovascular events, 0.72 (CI, 0.55 to 0.94) for strokes, 0.91 (CI, 0.74 to 1.12) for coronary events, 0.80 (CI, 0.57 to 1.12) for heart failure, 0.75 (CI, 0.57 to 0.98) for cardiovascular deaths, and 0.78 (CI, 0.67 to 0.92) for total deaths. Results were similar in secondary analyses. Withdrawal from treatment due to adverse effects was more common in the active groups.Blood pressure reductions and numbers of events were small.Blood pressure-lowering therapy is likely to prevent stroke and death in patients with uncomplicated grade 1 hypertension.Swedish Heart-Lung Foundation, Swedish Research Council, Australian Research Council, and National Health and Medical Research Council of Australia.
Measurement of blood and iron loss in colitis with a whole-body counter
Authors: B. H. R. Stack, T. Smith, J. H. Jones, J. Fletcher
Journal: Gut (1969)

Estimation with a whole-body counter of the fall in total body radioactivity due to loss of parenterally administered <sup>59</sup>Fe has been used to measure blood loss in 17 patients with ulcerative colitis. It was shown that blood loss was related to the activity of disease as judged by sigmoidoscopic changes and less obviously to the extent of involvement of the colon. Blood losses of 50 to 150 ml per week were observed when the patient saw no blood in the stools and the rectal mucosa did not appear haemorrhagic. Some patients lost more than 0·5 g iron during the few weeks following an exacerbation of ulcerative colitis suggesting that repeated replacement of the body9s iron stores is often necessary in this disease.
Gene expression screening of human mast cells and eosinophils using high-density oligonucleotide probe arrays: abundant expression of major basic protein in mast cells
Authors: Toshiharu Nakajima, Kenji Matsumoto, Hajime Suto, Kazuko Tanaka, Motohiro Ebisawa, Hisashi Tomita, Keisuke Yuki, Toshio Katsunuma, Akira Akasawa, Ryoichi Hashida, Yuji Sugita, Hideoki Ogawa, Chisei Ra, Hirohisa Saito
Journal: Blood (2001)
Mammalian Target of Rapamycin Complex 2 (mTORC2) Coordinates Pulmonary Artery Smooth Muscle Cell Metabolism, Proliferation, and Survival in Pulmonary Arterial Hypertension
Authors: Dmitry A. Goncharov, Tatiana V. Kudryashova, Houman Ziai, Kaori Ihida-Stansbury, Horace DeLisser, Vera P. Krymskaya, Rubin M. Tuder, Steven M. Kawut, Elena A. Goncharova
Journal: Circulation (2013)

Enhanced proliferation, resistance to apoptosis, and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (PAH). The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown.Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly upregulated in small remodeled pulmonary arteries and isolated distal PAVSMCs from subjects with idiopathic PAH that have increased ATP levels, proliferation, and survival that depend on glycolytic metabolism. Small interfering RNA- and pharmacology-based analysis showed that although both mTORC1 and mTORC2 contribute to proliferation, only mTORC2 is required for ATP generation and survival of idiopathic PAH PAVSMCs. mTORC2 downregulated the energy sensor AMP-activated protein kinase, which led to activation of mTORC1-S6 and increased proliferation, as well as a deficiency of the proapoptotic protein Bim and idiopathic PAH PAVSMC survival. NADPH oxidase 4 (Nox4) protein levels were increased in idiopathic PAH PAVSMCs, which was necessary for mTORC2 activation, proliferation, and survival. Nox4 levels and mTORC2 signaling were significantly upregulated in small pulmonary arteries from hypoxia-exposed rats at days 2 to 28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15 to 28 suppressed mTORC2 but not Nox4, induced smooth muscle-specific apoptosis in small pulmonary arteries, and reversed hypoxia-induced pulmonary vascular remodeling in rats.These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via the energy sensor AMP-activated protein kinase to increased proliferation and survival of PAVSMCs in PAH, which suggests a new potential pathway for therapeutic interventions.