tbuckley/cabot-search huggingface dataset:
Atrophic phenotype of cultured COPD myotubes can be reversed by an antioxidant treatment
Authors: Pascal Pomiès, Marine Blaquière, Fares Gouzi, Jacques Mercier, Christian Préfaut, Maurice Hayot
Journal: European Respiratory Journal (2014)

Skeletal limb muscle atrophy is a clinically relevant manifestation of chronic obstructive pulmonary disease (COPD). Oxidative stress contributes to muscle atrophy and is considered as a major therapeutic target. We have recently developed an in vitro cellular model based on purified satellite cells from vastus lateralis muscle biopsies of COPD patients, and have shown that cultured COPD myotubes have a reduced diameter and an elevated oxidative stress compared to healthy subjects.

Our objective was to determine the signaling pathways involved in the reduced diameter of COPD myotubes, and to evaluate if an antioxidant molecule could reverse this phenotype.

Using cultured myoblasts and myotubes derived from satellite cells of 8 COPD patients and 8 healthy controls (CTL) (age: 59.0 vs. 62.0, p=0.44; FEV1 %pred: 31.5 vs. 102.0, p‹0.001, respectively), we examined the expression of 14 markers of the protein breakdown and protein synthesis pathways, and evaluated the effect of acid ascorbic on COPD myotube diameter.

Elevated expression of myostatin, associated with a decreased P-AKT/AKT ratio and an increased atrogin-1 expression, is observed in COPD vs. CTL myoblasts and/or myotubes (p‹0.05 in all instance). Furthermore, culture of COPD myotubes in presence of ascorbic acid showed a significant increase of the myotube diameter in a dose-response relationship (p‹0.05).

In conclusion, the reduced diameter of cultured COPD myotubes (i.e. atrophy) is associated with an increase of protein breakdown and a decrease of protein synthesis. This reduced diameter can be reversed by the addition of an antioxidant molecule, suggesting that oxidative stress is involved in the COPD atrophic phenotype.
Abstract IA15: Strategies to overcome acquired resistance to kinase inhibitors
Authors: Gideon Bollag
Journal: Clinical Cancer Research (2015)

Abstract Current therapies for oncogenic kinase-driven cancers often involve kinase inhibitors. While the efficacy of these therapies is often striking, eventual relapse due to acquired resistance is common. For example, first-generation BRAF inhibitors are making a major impact on the disease-course in BRAF-mutant cancers and metastatic melanoma in particular. Nonetheless, many patients relapse and relapsed tumors generally display BRAF pathway re-activation. In order to improve the durability and tolerability of therapy, Plexxikon has been pursuing multiple strategies. Since the well-documented RAF inhibitor paradox is implicated as a contributor to drug resistance as well as unwanted side effects, we have designed a series of compounds that exhibit potent anti-BRAF efficacy without causing paradoxical pathway activation in RAS mutant cells. These compounds, dubbed Paradox Breakers, are also active against certain BRAF isoforms that are resistant to inhibition by first-generation compounds. Furthermore, we believe that macrophages in the tumor microenvironment are likely to enable resistance to BRAF inhibition. Therefore, we are pursuing studies to co-target BRAF in tumors and macrophages in the tumor microenvironment. Furthermore, inhibiting oncogenic KIT mutations is a validated therapeutic approach to treat gastrointestinal stromal tumors (GIST). The use of clinically approved kinase inhibitors such as imatinib frequently reveals secondary or acquired mutations that render these first-generation KIT inhibitors ineffective. Some of the acquired mutations reside in exon 17, coding for amino acids in the activation loop of the folded protein. This set of mutations has been shown to constitutively activate the receptor. Using a scaffold-based drug discovery approach, we have successfully identified a novel KIT exon 17 mutant-targeted inhibitor that shows minimal cross-reactivity in a kinome wide screen. This inhibitor shows robust efficacy in a patient-derived, imatinib-resistant GIST xenograft (Molecular Response). Plans to develop these approaches into clinical projects will be discussed. Citation Format: Gideon Bollag (on behalf of the Plexxikon team). Strategies to overcome acquired resistance to kinase inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA15.
Outcome of respiratory distress syndrome at 28 days: a prospective longitudinal study
Authors: S Van Lierde, J Smith, H Devlieger, E Eggermont
Journal: European Respiratory Journal (1992)

Fifty eight newborn infants with respiratory distress syndrome (RDS) were prospectively studied, in order to determine clinical variables prognostic of poor outcome at 28 days. Twenty six infants survived without bronchopulmonary dysplasia (BPD), 13 had Type 1 BPD, 4 had Type 2 BPD and 15 infants died before 28 days. Survivors without BPD had higher birthweights and gestational ages. Among the other infants, severity of initial lung disease was the best discriminator between outcome groups: Type 1 BPD infants had the best lungs at onset, and the nonsurvivors had the worst lungs. Stepwise multiple logistic regression identified gestational age and the ventilatory index number 1 (VI1) (= respirator frequency x maximal inspiratory pressure) at day 3 as the most useful variables to predict "poor outcome" (nonsurvival or Type 2 BPD). Ninety five percent of the infants were correctly classified using a cut-off probability of 0.5. We conclude that RDS outcome at 28 days is determined at a very early stage and that poor outcome can be predicted with reasonable accuracy at three days of age.
Phase I Trial to Determine the Safety, Pharmacodynamics, and Pharmacokinetics of RSR13, a Novel Radioenhancer, in Newly Diagnosed Glioblastoma Multiforme
Authors: L. Kleinberg, S. A. Grossman, S. Piantadosi, J. Pearlman, H. Engelhard, G. Lesser, J. Ruffer, M. Gerber
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4-(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylproprionic acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues. PATIENTS AND METHODS: In this multi-institutional, dose frequency–seeking trial, 19 adult patients with newly diagnosed GBM received RSR13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over 1 hour by central venous access with 4 L/min of O 2 by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (PD) determinations were performed. The PD end point was shift in P50, the oxygen half-saturation pressure of HgB. RESULTS: Grade 3 dose-limiting toxicity occurred innone of the patients with every-other-day dosing and in two of the 10 patients with daily dosing. Grade 2 or greater toxicity occurred in three out of nine and six out of 10, respectively. PK and PD data demonstrate that a substantial PD effect was reliably achieved, that PD effect was related to RBC RSR13 concentration, and that there was no significant drug accumulation even with daily dosing. The mean shift in P50 was 9.24 ± 2.6 mmHg (a 34% increase from baseline), which indicates a substantial increase in tendency toward oxygen unloading. CONCLUSION: Daily RSR13 (100 mg/kg) during cranial RT is well tolerated and achieves the desired PD end point. A phase II trial of daily RSR13 for newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.
Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer.
Authors: A D Seidman, C A Hudis, J Albanell, J Albanel, W Tong, I Tepler, V Currie, M E Moynahan, M Theodoulou, M Gollub, J Baselga, L Norton
Journal: Journal of Clinical Oncology (1998)

PURPOSE To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at &lt; or = 100 mg/m2. CONCLUSION Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.
Activity of Thalidomide in AIDS-Related Kaposi’s Sarcoma
Authors: Richard F. Little, Kathleen M. Wyvill, James M. Pluda, Lauri Welles, Vickie Marshall, William D. Figg, Fonda M. Newcomb, Giovanna Tosato, Ellen Feigal, Seth M. Steinberg, Denise Whitby, James J. Goedert, Robert Yarchoan
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi’s sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS: Human immunodeficiency virus (HIV)–seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm 3 (range, 14 to 646 cells/mm 3 ) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.
NIV for acute respiratory failure: The role of patient selection in hospital mortality
Authors: Daniel Bech Rasmussen, Signe Høyer Schwaner, Helle Frost Andreassen, Ejvind Frausing Hansen, Jon Torgny Wilcke
Journal: European Respiratory Journal (2014)

Introduction  Hospital mortality among COPD patients receiving NIV for acute respiratory failure has shown to be significantly higher in clinical settings than in randomized trials in highly selected patients. This may be caused by low quality care and/or use of NIV for patients with terminal pulmonary disease with a do-not-intubate (DNI) and a do-not-resuscitate (DNR) order.  Objectives  The aim of this study was to determine the role of patient selection for in-hospital mortality among patients receiving NIV for acute respiratory failure.  Methods  Retrospective study including all patients receiving acute NIV due to COPD and acute respiratory failure on a respiratory ward in 2012.  Results  Thirty-nine of 68 patients (57%) had a DNI/DNR order. Overall in-hospital mortality rate was 35%. Thirty-day mortality rate was 41% and 1 year mortality rate was 56%. Average age at admission was 74 ± 12 years and average pH after initial treatment was 7.28. In-hospital mortality was 62% in 39 patients with a DNI/DNR order and 0% in 29 patients with no limitations in treatment.  We identified a subgroup of 11 (28%) patients who fulfilled the inclusion criteria of the known RCT (i.e. Plant, PK et al. Lancet 2000; 355(9219):1931-5). In this subgroup in-hospital mortality rate and 30-day mortality rate were 0% and 1 year mortality rate was 18%. Average age was 68 ± 14 years and average pH was 7.31.  Conclusion  High total mortality reflects that patient selection in clinical practice is very different from RCT. Quality of acute NIV treatment seems acceptable in clinical practice with very low mortality in a subgroup with inclusion criteria similar to the known RCT.
Incidence of Diabetes Following Ramipril or Rosiglitazone Withdrawal
Authors: Rury R. Holman, Bernie Zinman, Salim Yusuf, Patrick M. Sheridan, Sonia S. Anand, Jackie J. Bosch, Ignacio Conget, Melanie J. Davies, Valdis Pirags, Gilles R. Dagenais, Janice M. Pogue, Paul Z. Zimmet, Hertzel C. Gerstein
Journal: Diabetes Care (2011)

To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3 months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone.Following median (interquartile range) 71 (63-86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo.In people allocated to ramipril compared with those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped.
NUTRITIONAL AND HORMONAL REGULATION OF ENZYMES IN FAT SYNTHESIS: Studies of Fatty Acid Synthase and Mitochondrial Glycerol-3-Phosphate Acyltransferase Gene Transcription
Authors: Hei Sook Sul, Dong Wang
Journal: Annual Review of Nutrition (1998)

▪ Abstract The activities of critical enzymes in fatty acid and triacylglycerol biosynthesis are tightly controlled by different nutritional, hormonal, and developmental conditions. Feeding previously fasted animals high-carbohydrate, low-fat diets causes a dramatic induction of enzymes—such as fatty acid synthase (FAS) and mitochondrial glycerol-3-phosphate acyltransferase (GPAT)—involved in fatty acid and triacylglycerol synthesis. During fasting and refeeding, transcription of these two enzymes is coordinately regulated by nutrients and hormones, such as glucose, insulin, glucagon, glucocorticoids, and thyroid hormone. Insulin stimulates transcription of the FAS and mitochondrial GPAT genes, and glucagon antagonizes the insulin effect through the cis-acting elements within the promoters and their bound trans-acting factors. This review discusses advances made in the understanding of the transcriptional regulation of FAS and mitochondrial GPAT genes, with emphasis on elucidation of the mechanisms by which multiple nutrients and hormones achieve their effects.
Accurate monitoring of the right ventricular ejection fraction by echocardiography in pulmonary hypertension
Authors: Takahiro Sato, Ichizo Tsujino, Noriko Oyama-Manabe, Hiroshi Ohira, Taku Watanabe, Masaharu Nishimura
Journal: European Respiratory Journal (2013)

Background  Right ventricular ejection fraction (RVEF) is an emerging prognostic predictor of patients with pulmonary hypertension (PH).   Aim  We sought to evaluate the accuracy and suitability of two echocardiographic parameters of right ventricular systolic function: tricuspid annular plane systolic excursion (TAPSE) and systolic lateral tricuspid annular motion velocity (TVlat) in the monitoring of RVEF of PH patients.   Methods  Consecutive 37 patients with PH (median pulmonary arterial pressure 36 (28 -43) mmHg) were studied. We measured TAPSE and TVlat as echocardiographic indices of RVEF. TAPSE and TVlat measured at baseline and at follow-up, and the changes during follow-up were compared with those of magnetic resonance imaging (MRI)-derived RVEF. Receiver operating characteristic (ROC) analysis was conducted to calculate the cut-off levels of TAPSE and TVlat for the identification of patients with improved RVEF.   Results  TAPSE and TVlat were significantly correlated with MRI-derived RVEF at baseline (TAPSE: r=0.90, TVlat: r=0.69) and at follow-up (TAPSE: r=0.87, TVlat: r=0.64). The changes during follow-up were also significantly correlated with that of MRI-derived RVEF for TAPSE (r=0.80) and for TVlat (r=0.71). Twenty-seven of 29 patients (78%) exhibited improved RVEF at follow-up by MRI, and the ROC analysis showed that ΔTAPSE > -0.9 mm and ΔTVlat > 0.1 cm/sec identified PH patients with improved RVEF with high sensitivity (TAPSE 90%, TVlat 90%) and specificity (TAPSE 88%, TVlat 100%), and with high AUC (TAPSE 0.95, TVlat 0.97).   Conclusion  TAPSE and TVlat are accurate indices of RVEF that allows for identifying PH patients with improved RVEF by PH-targeted therapy.
High expression of Hsp90-beta and GRP 94 association with poor survival in resected non-small cell lung cancer patients.
Authors: Shang-Hung Chen, Ching-Chuan Kuo, Chien-Feng Li, Tsui-Chun Tsou, Huai-Chih Chiang, Kwang-Yu Chang, Chun-Hei Antonio Cheung, Li-Tzong Chen, Jang-Yang Chang
Journal: Journal of Clinical Oncology (2014)

e13522 Background: O6-methylguanine–DNA methyltransferase (MGMT), a DNA repair enzyme, has been well-characterized to be a therapeutic determinant of O6-alkyalting drugs. Recently, we and others found that the expression level of MGMT is correlated to cisplatin (CDDP) sensitivity, however, the underlying mechanism and clinical relevance between MGMT and CDDP remains poorly defined. Methods: The Tet-On and RNA interference system were used in order to evaluate the regulations and interactions between MGMT expression and CDDP in cultured cells. The relationship between MGMT expression and clinical survivals in 83 nasopharyngeal carcinoma (NPC) patients receiving CDDP-based concurrent chemoradiotherapy (CCRT) was analyzed. Results: MGMT-proficient cells were highly resistance to the cytotoxic effects of CDDP as compared to MGMT-deficient cells. Further studies showed that the number of platinum-DNA adducts and double-strand DNA breaks after CDDP exposure were significantly lower in MGMT-proficient cells than in MGMT-deficient cells. Host cell reactivation assay revealed that MGMT protected cells from CDDP-induced DNA damage by enhancing global DNA repair capacity. Importantly, we demonstrated for the first time that MGMT protein directly repaired CDDP-induced DNA damage. CDDP-bound MGMT protein became ubiquitinated and was degraded through ubiquitin-mediated proteasome system. NPC patients receiving CDDP-based CCRT, with lower levels of MGMT expression, exhibited more satisfactory progression-free survival (P=.022) and overall survival (P=.015), than patients with higher levels of MGMT expression did. Conclusions: We first time demonstrate that MGMT not only plays a major role in determining the efficacy of CDDP, but also is a potential therapeutic target in the clinical use of this agent.
Abstract 2524: Long-Term (4 year) Outcome following Drug Eluting Stent Implantation versus Coronary Artery By-pass Surgery in Unprotected Left Main Coronary artery Lesions
Authors: Alaide Chieffo, Valeria Magni, Francesco Maisano, Alfonso Ielasi, Azeem Latib, Matteo Montorfano, Mauro Carlino, Giuseppe M Sangiorgi, Luca Ferri, Giorgio Bassanelli, Angela Ferrari, Cosmo Godino, Ottavio Alfieri, Antonio Colombo
Journal: Circulation (2008)

One-year outcome following drug-eluting stent (DES) implantation versus coronary artery by-pass grafting (CABG) in unprotected LMCA lesions have been previously reported from our center. Methods and results Two hundred forty-nine consecutive patients with an unprotected LMCA stenosis electively treated (107 with PCI and DES implantation and 142 with CABG) in our Center, between March 2002 and July 2004, were analysed. Hierarchical study end points were occurrence at 4 years of: death; death and/or myocardial infarction (MI); death, MI and/or stroke; target vessel revascularization (TVR, defined as any revascularization in left coronary system); and major cardiac cerebrovascular events (MACCE). A propensity analysis was performed to adjust for baseline differences between the two cohorts. At 4 year-clinical follow-up, no difference was found between PCI and CABG in the occurrence of death (respectively 12.0% vs. 14.1%; unadjusted odds ratio- OR=0.845; 95% confidence interval-CI=0.365 to 1.890; P=0.80; adjusted OR=0.652; 95% CI=0.254 to 1.620; P=0.42). At adjusted analysis, PCI group showed a trend toward a lower occurrence of the composite endpoint of death and myocardial infarction (13.0% vs. 19.7%; adjusted OR=0.461; 95% CI=0.180 to 1.088; P=0.08). PCI was associated with a lower rate of the composite endpoint of death, MI and/or stroke (respectively 14.0% vs. 22.5%; unadjusted OR=0.519; 95% CI=0.238to 1.071; P=0.07; adjusted OR=0.431; 95% CI=0.175 to 0.971; P=0.04). Indeed, CABG was correlated to lower TVR (8.4% vs. 28% ; unadjusted OR= 5.018; 95% CI= 1.990-23.8; p=0.0001; adjusted OR= 5.928; 95% CI= 1.933 – 38.0; p= 0.0003). No difference was detected in the occurrence of MACCE ( in PCI 36.4% vs. 28.1% in CABG, unadjusted OR=1.409; 95% CI=0.798 to 2.509 P=0.259; adjusted OR=1.438; 95% CI=0.754 to 2.766; P=0.3007). Conclusions At 4 year-clinical follow-up, in this single-center experience, there was still no difference in the occurrence of MACCE between elective PCI with DES implantation and CABG in LMCA lesions. There was an advantage of PCI in the composite endpoint of death, MI and/or stroke, while a benefit in the need for reintervention was still found in CABG. :