tbuckley/cabot-search huggingface dataset:
Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts
Authors: Gaspar J. Kitange, Brett L. Carlson, Mark A. Schroeder, Patrick T. Grogan, Jeff D. Lamont, Paul A. Decker, Wenting Wu, C. David James, Jann N. Sarkaria
Journal: Neuro-Oncology (2008)

Temozolomide (TMZ)-based therapy is the standard of care for patients with glioblastoma multiforme (GBM), and resistance to this drug in GBM is modulated by the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). Expression of MGMT is silenced by promoter methylation in approximately half of GBM tumors, and clinical studies have shown that elevated MGMT protein levels or lack of MGMT promoter methylation is associated with TMZ resistance in some, but not all, GBM tumors. In this study, the relationship between MGMT protein expression and tumor response to TMZ was evaluated in four GBM xenograft lines that had been established from patient specimens and maintained by serial subcutaneous passaging in nude mice. Three MGMT unmethylated tumors displayed elevated basal MGMT protein expression, but only two of these were resistant to TMZ therapy (tumors GBM43 and GBM44), while the other (GBM14) displayed a level of TMZ sensitivity that was similar in extent to that seen in a single MGMT hypermethylated line (GBM12). In tissue culture and animal studies, TMZ treatment resulted in robust and prolonged induction of MGMT expression in the resistant GBM43 and GBM44 xenograft lines, while MGMT induction was blunted and abbreviated in GBM14. Consistent with a functional significance of MGMT induction, treatment of GBM43 with a protracted low-dose TMZ regimen was significantly less effective than a shorter high-dose regimen, while survival for GBM14 was improved with the protracted dosing regimen. In conclusion, MGMT expression is dynamically regulated in some MGMT nonmethylated tumors, and in these tumors, protracted dosing regimens may not be effective.
Cardiac fibroblasts are major production and target cells of adrenomedullin in the heart in vitro
Authors: Y Tomoda
Journal: Cardiovascular Research (2001)

Objective: Adrenomedullin (AM) is a potent vasodilator peptide. Plasma AM concentration is increased in patients with various heart diseases, and both myocytes (MCs) and non-myocytes (NMCs) secrete AM and express its receptors. These facts suggest that cardiac cells possess an autocrine/paracrine capability mediated by AM. Methods: MCs and NMCs were prepared from cardiac ventricles of neonatal rats. AM and endothelin-1 concentrations were measured by radioimmunoassays, and interleukin-6 level by a specific bioassay. Total nitrite/nitrate contents were measured with a fluorescence assay kit. Results: A basal secretion rate of AM from NMCs was 2.8-fold higher than that from MCs. Interleukin-1β, tumor necrosis factor-α and lipopolysaccharide stimulated AM secretion from NMCs but not from MCs. AM stimulated interleukin-6 production in the presence of these cytokines or lipopolysaccharide, which was more prominent in NMCs. In the presence of interleukin-1β, AM augmented nitric oxide synthesis 2.7-fold in NMCs, but slightly in MCs. NMCs secreted endothelin-1 at a rate nine times higher than MCs, and AM inhibited endothelin-1 secretion from NMCs. Conclusion: This in vitro study suggests that AM in the heart is mainly produced in NMCs and exerts its effects through NMCs, especially under inflammatory conditions.
The Diffusion of Docetaxel in Patients With Metastatic Prostate Cancer
Authors: Joseph M. Unger, Dawn L. Hershman, Diane Martin, Ruth B. Etzioni, William E. Barlow, Michael LeBlanc, Scott R. Ramsey
Journal: JNCI Journal of the National Cancer Institute (2014)

Diffusion of new cancer treatments can be both inefficient and incomplete. The uptake of new treatments over time (diffusion) has not been well studied. We analyzed the diffusion of docetaxel in metastatic prostate cancer. We identified metastatic prostate cancer patients diagnosed from 1995 to 2007 using the Surveillance, Epidemiology, and End Results Program (SEER)–Medicare database. Medicare claims through 2008 were analyzed. We assessed cumulative incidence of docetaxel by socioeconomic, demographic, and comorbidity variables, and compared diffusion patterns to landmark events including release of phase III results and FDA approval dates. We compared docetaxel diffusion patterns in prostate cancer to those in metastatic breast, lung, ovarian, and gastric cancers. To model docetaxel use over time, we used the classic "mixed influence" deterministic diffusion model. All statistical tests were two-sided. We identified 6561 metastatic prostate cancer patients; 1350 subsequently received chemotherapy. Among patients who received chemotherapy, docetaxel use was 95% by 2008. Docetaxel uptake was statistically significantly slower (P < .01) for patients older than 65 years, blacks, patients in lower income areas, and those who experienced poverty. Eighty percent of docetaxel diffusion occurred prior to the May, 2004 release of phase III results showing superiority of docetaxel over standard-of-care. The maximum increase in the rate of use of docetaxel occurred nearly simultaneously for prostate cancer as for all other cancers combined (in 2000). Efforts to increase the diffusion of treatments with proven survival benefits among disadvantaged populations could lead to cancer population survival gains. Docetaxel diffusion mostly preceded phase III evidence for its efficacy in castration-resistant prostate cancer, and appeared to be a cancer-wide—rather than a disease-specific—phenomenon. Diffusion prior to definitive evidence indicates the prevalence of off-label chemotherapy use.
Safety of formoterol in asthma clinical trials: an update
Authors: Malcolm R. Sears, Finn Radner
Journal: European Respiratory Journal (2013)

Use of long-acting β-agonists (LABAs) in asthma remains controversial, and large safety trials are in progress. We have previously reported safety outcomes with formoterol in 117 AstraZeneca asthma trials (78 339 patients, 92% using inhaled corticosteroids) completed by December 2006, and have now added 32 trials with formoterol (26 124 patients, 100% using inhaled corticosteroids) completed by December 2011. The primary dataset of 79 randomised controlled trials includes 94 684 patients, 67 380 of whom were exposed to formoterol, while the complete dataset comprises 149 trials and 104 463 patients. There were no new asthma-related deaths in the expanded primary dataset, with eight asthma-related deaths among formoterol-randomised patients and two among non-LABA-randomised patients (relative risk 1.13, 95% CI 0.23–10.9), and 15 versus nine cardiac-related deaths (relative risk 0.47, 95% CI 0.19–1.22). Nonfatal asthma-related serious adverse events were significantly reduced with formoterol (relative risk 0.63, 95% CI 0.53–0.75), as were discontinuations due to adverse events. Examining 40 trials with direct formoterol versus non-LABA comparisons, Mantel–Haenszel relative risk for asthma-related death was 2.75 (95% CI 0.52–14.4) and for serious adverse events 0.83 (95% CI 0.68–1.02). We conclude that this enlarged dataset indicates no increased risk of asthma-related deaths among patients exposed to formoterol compared with non-LABA treatments, although the wide confidence interval precludes certainty.
Granulocyte transfusions in hematologic malignancy patients with invasive pulmonary aspergillosis: outcomes and complications
Authors: I.I. Raad, A.M. Chaftari, M.M. Al Shuaibi, Y. Jiang, W. Shomali, J.E. Cortes, B. Lichtiger, R.Y. Hachem
Journal: Annals of Oncology (2013)
CCCTC-Binding Factor Confines the Distal Action of Estrogen Receptor
Authors: Chang S. Chan, Jun S. Song
Journal: Cancer Research (2008)

Distal enhancers have recently emerged as a common mode of gene regulation for several transcription factors, including estrogen and androgen receptors, the two key regulators of breast and prostate cancer major subtypes. Despite the rapid success in genome-wide annotation of estrogen receptor-alpha (ERalpha) binding sites in cell lines, the precise mechanism governing the gene-to-enhancer association is still unknown and no quantitative model that can predict the estrogen responsiveness of genes has been hitherto proposed. This article presents an integrative genomics approach to construct a predictive model that can explain more than 70% of estrogen-induced expression profiles. The proposed method combines a recent map of the insulator protein CCCTC-binding factor (CTCF) with previous ER location studies and expression profiling in the presence of the translation inhibitor cycloheximide, providing evidence that CTCF partitions the human genome into distinct ER-regulatory blocks. It is shown that estrogen-responsive genes with a decreased transcription level (down-regulated genes) have a markedly different relative distribution of ER binding sites compared with those with an increased transcription level (up-regulated genes). Finally, Bayesian belief networks are constructed to quantify the effects of ER-binding distance from genes as well as the insulating effects of CTCF on the estrogen responsiveness of genes. This work thus represents a stride toward understanding and predicting the distal activities of steroid hormone nuclear receptors.
Testing Patient Comprehension of Medication Labeling Is Important
Authors: Julie Aker, Melissa Beck
Journal: JAMA Internal Medicine (2013)

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Survival and Functional Outcomes After Hip Fracture Among Nursing Home Residents
Authors: Mark D. Neuman, Jeffrey H. Silber, Jay S. Magaziner, Molly A. Passarella, Samir Mehta, Rachel M. Werner
Journal: JAMA Internal Medicine (2014)

Little is known regarding outcomes after hip fracture among long-term nursing home residents.To describe patterns and predictors of mortality and functional decline in activities of daily living (ADLs) among nursing home residents after hip fracture.Retrospective cohort study of 60,111 Medicare beneficiaries residing in nursing homes who were hospitalized with hip fractures between July 1, 2005, and June 30, 2009.Data sources included Medicare claims and the Nursing Home Minimum Data Set. Main outcomes included death from any cause at 180 days after fracture and a composite outcome of death or new total dependence in locomotion at the latest available assessment within 180 days. Additional analyses described within-residents changes in function in 7 ADLs before and after fracture.Of 60,111 patients, 21,766 (36.2%) died by 180 days after fracture; among patients not totally dependent in locomotion at baseline, 53.5% died or developed new total dependence within 180 days. Within individual patients, function declined substantially after fracture across all ADL domains assessed. In adjusted analyses, the greatest decreases in survival after fracture occurred with age older than 90 years (vs ≤75 years: hazard ratio [HR], 2.17; 95% CI, 2.09-2.26 [P < .001]), nonoperative fracture management (vs internal fixation: HR for death, 2.08; 95% CI, 2.01-2.15 [P < .001]), and advanced comorbidity (Charlson score of ≥5 vs 0: HR, 1.66; 95% CI, 1.58-1.73 [P < .001]). The combined risk of death or new total dependence in locomotion within 180 days was greatest among patients with very severe cognitive impairment (vs intact cognition: relative risk [RR], 1.66; 95% CI, 1.56-1.77 [P < .001]), patients receiving nonoperative management (vs internal fixation: RR, 1.48; 95% CI, 1.45-1.51 [P < .001]), and patients older than 90 years (vs ≤75 years: RR, 1.42; 95% CI, 1.37-1.46 [P < .001]).Survival and functional outcomes are poor after hip fracture among nursing home residents, particularly for patients receiving nonoperative management, the oldest old, and patients with multiple comorbidities and advanced cognitive impairment. Care planning should incorporate appropriate prognostic information related to outcomes in this population.
Long term treatment with theophylline increases malonyl dialdehyde plasma concentrations.
Authors: P Godard, J Chaintreuil, J Bensadoun, G Parelon, A C de Paulet, F B Michel
Journal: Thorax (1984)

As theophylline is known to stimulate lipolysis and lipid mobilisation, plasma concentrations of malonyl dialdehyde were studied in asthmatic patients being treated with sustained release theophylline. Malonyl dialdehyde was assessed as malonyl dialdehyde like material (MDA-LM) by the thiobarbituric acid assay. In a kinetic study (eight patients) plasma MDA-LM concentrations were found to be significantly higher after 30 than after eight days' treatment or before treatment, but not significantly different after 90 than after 30 days. In a comparative study (29 patients and 29 healthy volunteers) the mean plasma MDA-LM concentration was shown to be very significantly higher in the asthmatic group. The results are probably explained by an effect of theophylline on lipid peroxidation, and the effect of long term treatment on plasma MDA-LM merits further investigation.
Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Frank C. Gibson, Charlie Hong, Hsin-Hua Chou, Hiromichi Yumoto, Jiqiu Chen, Egil Lien, Jodie Wong, Caroline Attardo Genco
Journal: Circulation (2004)

Background— Infectious diseases have emerged as potential risk factors for cardiovascular disease (CVD). Epidemiological studies support a connection between periodontal disease, a chronic inflammatory disease of the supporting tissues of the teeth, and CVD. Methods and Results— To directly test the connection between periodontal disease and atherosclerosis, apoE −/− mice were orally challenged with the periodontal disease pathogen Porphyromonas gingivalis or an invasion-impaired P gingivalis fimbriae-deficient mutant (FimA−). Both wild-type P gingivalis and the FimA− mutant were detected in blood and aortic arch tissue of apoE −/− mice by PCR after challenge. ApoE −/− mice challenged with wild-type P gingivalis presented with increased atherosclerotic plaque and expressed the innate immune response markers Toll-like receptor (TLR)-2 and TLR-4 in aortic tissue. Despite detection of the FimA− mutant in the blood and in aortic arch tissue, apoE −/− mice challenged with the FimA− mutant did not present with periodontal disease, upregulation of TLRs, or accelerated atherosclerosis. Furthermore, we demonstrate that immunization to control P gingivalis -elicited periodontal disease concomitantly prevents P gingivalis -accelerated atherosclerosis. Conclusions— We conclude that invasive P gingivalis accelerates atherosclerosis.
Characterization of a Folate Transporter in HeLa Cells with a Low pH Optimum and High Affinity for Pemetrexed Distinct from the Reduced Folate Carrier
Authors: Yanhua Wang, Rongbao Zhao, I. David Goldman
Journal: Clinical Cancer Research (2004)

Studies were undertaken to characterize a low pH transport activity in a reduced folate carrier (RFC)-null HeLa-derived cell line (R5). This transport activity has a 20-fold higher affinity for pemetrexed (PMX; Kt, approximately 45 nmol/L) than methotrexate (MTX; Kt, approximately 1 micromol/L) with comparable Vmax values. The Ki values for folic acid, ZD9331, and ZD1694 were approximately 400-600 nmol/L, and the Ki values for PT523, PT632, and trimetrexate were >50 micromol/L. The transporter is stereospecific and has a 7-fold higher affinity for the 6S isomer than the 6R isomer of 5-formyltetrahydrofolate but a 4-fold higher affinity for the 6R isomer than the 6S isomer of dideazatetrahydrofolic acid. Properties of RFC-independent transport were compared with transport mediated by RFC at low pH using HepG2 cells, with minimal constitutive low pH transport activity, transfected to high levels of RFC. MTX influx Kt was comparable at pH 7.4 and pH 5.5 (1.7 versus 3.8 micromol/L), but Vmax was decreased 4.5-fold. There was no difference in the Kt for PMX (approximately 1.2 micromol/L) or the Ki for folic acid (approximately 130 micromol/L) or PT523 ( approximately 0.2 micromol/L) at pH 7.4 and pH 5.5. MTX influx in R5 and HepG2 transfectants at pH 5.5 was trans-stimulated in cells loaded with 5-formyltetrahydrofolate, inhibited by Cl- (HepG2-B > R5), Na+ independent, and uninhibited by energy depletion. Hence, RFC-independent low pH transport activity in HeLa R5 cells is consistent with a carrier-mediated process with high affinity for PMX. Potential alterations in protonation of RFC or the folate molecule as a function of pH do not result in changes in affinity constants for antifolates. Whereas both activities at low pH have similarities, they can be distinguished by folic acid and PT523, agents for which they have very different structural specificities.
<i>MEFV</i>mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease
Authors: Monique Stoffels, Agata Szperl, Anna Simon, Mihai G Netea, Theo S Plantinga, Marcel van Deuren, Sylvia Kamphuis, Helen J Lachmann, Edwin Cuppen, Wigard P Kloosterman, Joost Frenkel, Cleo C van Diemen, Cisca Wijmenga, Marielle van Gijn, Jos W M van der Meer
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome. We aimed to unravel the genetic cause of the symptoms. <h3>Methods</h3> Whole exome sequencing was used to screen for novel sequence variants, which were validated by direct Sanger sequencing. Ex vivo stimulation with peripheral blood mononuclear cells was performed to study the functional consequences of the mutation. mRNA and cytokine levels were measured by quantitative PCR and ELISA, respectively. <h3>Results</h3> Whole exome sequencing revealed a novel missense sequence variant, not seen in around 6800 controls, mapping to exon 8 of the <i>MEFV</i> gene (c.1730C&gt;A; p.T577N), co-segregating perfectly with disease in this family. Other mutations at the same amino acid (c.1730C&gt;G; p.T577S and c.1729A&gt;T; p.T577S) were found in a family of Turkish descent, with autosomal dominant inheritance of familial Mediterranean fever (FMF)-like phenotype, and a Dutch patient, respectively. Moreover, a mutation (c.1729A&gt;G; p.T577A) was detected in two Dutch siblings, who had episodes of inflammation of varying severity not resembling FMF. Peripheral blood mononuclear cells from one patient of the index family showed increased basal interleukin 1β mRNA levels and cytokine responses after lipopolysaccharide stimulation. Responses normalised with colchicine treatment. <h3>Conclusions</h3> Heterozygous mutations at amino acid position 577 of pyrin can induce an autosomal dominant autoinflammatory syndrome. This suggests that T577, located in front of the C-terminal B30.2/SPRY domain, is crucial for pyrin function.
TCT-93 Relationship of Transcatheter and Surgical Aortic Valve Replacement with Left Ventricular Function in High-Risk Patients with Aortic Stenosis
Authors: Sammy Elmariah, Jonathan Passeri, Irene Hueter, Ronan Margey, Ignacio Inglessis, Joshua Baker, Maureen Daher, Susheel Kodali, Praveen Mehrotra, Martin Leon, Lars Svensson, Arvind Agnihotri, Gus Vlahakes, Philippe Pibarot, Pamela Douglas, Igor Palacios
Journal: Journal of the American College of Cardiology (2012)
Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia
Authors: Tamera J. Corte, Gregory J. Keir, Konstantinos Dimopoulos, Luke Howard, Paul A. Corris, Lisa Parfitt, Claire Foley, Monica Yanez-Lopez, Daphne Babalis, Philip Marino, Toby M. Maher, Elizabeth A. Renzoni, Lisa Spencer, Charlie A. Elliot, Surinder S. Birring, Katherine O’Reilly, Michael A. Gatzoulis, Athol U. Wells, Stephen J. Wort
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality.Objectives: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group.Methods: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks.Measurements and Main Results: Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m2 and reduced cardiac index of 2.21 (± 0.5) L/min/m2 were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group).Conclusions: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP.Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).