tbuckley/cabot-search huggingface dataset:
Randomized Phase II Study of Ixabepilone or Paclitaxel Plus Carboplatin in Patients With Non–Small-Cell Lung Cancer Prospectively Stratified by Beta-3 Tubulin Status
Authors: Martin J. Edelman, Claus-Peter Schneider, Chun-Ming Tsai, Heung-Tae Kim, Elisabeth Quoix, Alexander V. Luft, Remigiusz Kaleta, Pralay Mukhopadhyay, Ovidiu C. Trifan, Laura Whitaker, Martin Reck
Journal: Journal of Clinical Oncology (2013)

Purpose Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) isoform is an unfavorable prognostic factor in non–small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including β3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for β3T expression. Patients and Methods Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m 2 ) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m 2 ) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup. Results Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies. Conclusion There was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.
2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer
Authors: Tara E. Sutherland, Michael Schuliga, Trudi Harris, Bedrich L. Eckhardt, Robin L. Anderson, Lilly Quan, Alastair G. Stewart
Journal: Clinical Cancer Research (2005)

Abstract Purpose: 2-Methoxyestradiol (2MEO) is being developed as a novel antitumor agent based on its antiangiogenic activity, tumor cell cytotoxicity, and apparent lack of toxicity. However, pharmacologic concentrations of 2MEO bind to estrogen receptors (ER). We have therefore examined the ER activity of 2MEO. Experimental Design: Estrogenic actions of 2MEO were evaluated by changes in gene expression of the ER-positive (MCF7) breast tumor cell line and, in vivo, estrogenicity was assessed in breast tumor xenograft models and by measuring endocrine responses in uterus and liver. Results: In the ER-positive breast tumor cell line (MCF7), microarray experiments revealed that 269 of 279 changes in gene expression common to 2MEO and estradiol were prevented by the ER antagonist, ICI 182,780. Changes in the expression of selected genes and their sensitivity to inhibition by ICI 182,780 were confirmed by quantitative reverse transcription–PCR measurement. Activation of ER in MCF7 cells by 2MEO was further confirmed by stimulation of an estrogen response element–dependent reporter gene that was blocked by ICI 182,780 (1 μmol/L). Doses of 2MEO (15-150 mg/kg) that had no antitumor efficacy in either nu/nu BALB/c or severe combined immunodeficient mice bearing ER-negative MDA-MB-435 tumors had uterotropic and hepatic estrogen-like actions. In female nu/nu BALB/c mice inoculated with the estrogen-dependent MCF7 tumor cells, 2MEO (50 mg/kg/d) supported tumor growth. Conclusions: Tumor growth enhancement by 2MEO at doses generating serum levels (100-500 nmol/L) that have estrogenic activity suggests that a conservative approach to the further clinical evaluation of this agent should be adopted and that its evaluation in breast cancer is inappropriate.
JAK2/STAT3 targeted therapy suppresses tumor invasion via disruption of the EGFRvIII/JAK2/STAT3 axis and associated focal adhesion in EGFRvIII-expressing glioblastoma
Authors: Q. Zheng, L. Han, Y. Dong, J. Tian, W. Huang, Z. Liu, X. Jia, T. Jiang, J. Zhang, X. Li, C. Kang, H. Ren
Journal: Neuro-Oncology (2014)

As a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood. Through gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells. The activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models. Taken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors.
Complexome Profiling Identifies TMEM126B as a Component of the Mitochondrial Complex I Assembly Complex
Authors: Heinrich Heide, Lea Bleier, Mirco Steger, Jörg Ackermann, Stefan Dröse, Bettina Schwamb, Martin Zörnig, Andreas S. Reichert, Ina Koch, Ilka Wittig, Ulrich Brandt
Journal: Cell Metabolism (2012)
A Pegylated Leptin Antagonist Ameliorates CKD-Associated Cachexia in Mice
Authors: Wai W. Cheung, Wei Ding, Sujana S. Gunta, Yong Gu, Rinat Tabakman, Leah N. Klapper, Arieh Gertler, Robert H. Mak
Journal: Journal of the American Society of Nephrology (2013)

Elevated serum leptin levels correlate with inflammation and predict changes in lean body mass in patients with CKD, and activation of the melanocortin system by leptin signaling mediates the pathophysiology of CKD-associated cachexia. We tested whether treatment with a pegylated leptin receptor antagonist (PLA) attenuates cachexia in mice with CKD. CKD and Sham mice received vehicle or PLA (2 or 7 mg/kg per day). At these doses, PLA did not influence serum leptin levels in mice. Treatment with 7 mg/kg per day PLA stimulated appetite and weight gain, improved lean mass and muscle function, reduced energy expenditure, and normalized the levels of hepatic TNF-α and IL-6 mRNA in mice with CKD. Furthermore, treatment with 7 mg/kg per day PLA attenuated the CKD-associated increase in the transcriptional and protein abundance of uncoupling proteins that mediates thermogenesis, and it normalized the molecular signatures of processes associated with muscle wasting in CKD, including proteolysis, myogenesis and muscle regeneration, and expression of proinflammatory muscle cytokines, such as IL-1α, -1β, and -6 and TNF-α. Our results suggest that leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.
Effect of Amlodipine on the Progression of Atherosclerosis and the Occurrence of Clinical Events
Authors: Bertram Pitt, Robert P. Byington, Curt D. Furberg, Donald B. Hunninghake, G. B. John Mancini, Michael E. Miller, Ward Riley, None (for the PREVENT Investigators)
Journal: Circulation (2000)

The results of angiographic studies have suggested that calcium channel-blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both.The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively (P:=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0. 0126-mm decrease in the amlodipine group (P:=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization.Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.
PTH-167 The Investigation of Dyspepsia in Primary Care- The Burning Truth
Authors: S Beg, M Hughes, M Raza, D L Morris
Journal: Gut (2013)

<h3>Introduction</h3> Dyspepsia is a common symptom, thought to affect up to 46% of the population<sup>1</sup>. In order to streamline investigation and management in primary care, guidelines have been formulated by both the BSG and NICE. These advocate that prior to endoscopy patients are reviewed with respect to precipitating medications, helicobacter pylori (HP) status and are trialled on a proton pump inhibitor (PPI)<sup> 1, 2</sup>. <h3>Methods</h3> Using our computer based endoscopy database we retrospectively reviewed the direct access GP referrals for the endoscopic investigation of dyspepsia and reflux. We examined 260 cases referred to the North and East Hertfordshire NHS trust between January and December 2012 looking for adherence to guidelines. <h3>Results</h3> In our cohort 56% were female, with the average age of patients being 55.8 years old. 10% were considered to be urgent referrals, whilst 16.5% were referred via the two week wait. Only 30% patients were tested for HP status prior to investigation, with 10 patients having had serology and 80 tested using stool antigen testing. Just 15 patients (6%) in the cohort tested positive for HP by either serology, stool antigen, CLO or gastric biopsy. A greater proportion received a trial of a PPI, 53.8% receiving a full course, whilst 36.5% had used a PPI inconsistently and 9.6% had never tried a PPI. Only 45 patients (17%) had both HP testing and a trial of a PPI. An alternate cause of pathology was considered in 12 patients with investigation with an abdominal ultrasound, in 3 cases this was as a consequence of the endoscopist’s suggestion. The most common findings on endoscopy were oesophagitis, gastritis and duodenitis, 21% of examinations were entirely normal. Four cancers were identified within the 46 two week wait referrals. <h3>Conclusion</h3> Our data has confirmed that the patients in this cohort received inadequate work up in primary care, leading to unnecessary endoscopic investigation. The average age of the patients in this group indicates that many were at an age where pathology such as malignancy would be highly unlikely. Lack of adherence to guidelines is likely to be the reason for the low diagnostic yield of significant pathology, although our endoscopic findings are consistent with those of previous studies1. The low prevalence of helicobacter may represent a reduction in its prevalence, although it is difficult to know whether this is a consequence of inappropriate testing whilst on PPI therapy, the socioeconomics of our cohort or due to HP patient positive patients treated in primary care rather than referred for endoscopy. Improved use of guidelines and dialogue between primary and secondary care should improve patient selection for the endoscopic investigation of dyspepsia. <h3>Disclosure of Interest</h3> None Declared. <h3>References</h3> Dyspepsia: management of dyspepsia in adults in primary care, 2004 BSG: Dyspepsia management guidelines, 2002
Mesenchymal Progenitor Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Rat Cellular Cardiomyoplasty Model
Authors: Siamak Davani, Aliette Marandin, Nursen Mersin, Bernard Royer, Bernadette Kantelip, Patrick Hervé, Joseph-Philippe Etievent, Jean-Pierre Kantelip
Journal: Circulation (2003)

Background— Cellular cardiomyoplasty is a promising approach to improve postinfarcted cardiac function. The differentiation pathways of engrafted mesenchymal progenitor cells (MPCs) and their effects on the left ventricular function in a rat myocardial infarct heart model were analyzed. Methods and Results— A ligation model of left coronary artery of Lewis rats was used. MPCs were isolated by bone marrow cell adherence. Seven days after ligation, MPCs labeled with 4′,6-diamidino-2′-phenylindole were injected into the infarcted myocardium (n=8). Culture medium was injected in the infarcted myocardium of control animals (n=8). Thirty days after implantation, immunofluorescence studies revealed some engrafted cells expressing a smooth muscle phenotype (α SM actin + ), as similarly observed in culture. Other engrafted cells lost their smooth muscle phenotype and acquired an endothelial phenotype (CD31 + ). Furthermore, vessel density was augmented in the MPC group in comparison with the control group. After 30 days, echocardiography showed an improvement on left ventricular performance in the MPCs compared with the control group. Conclusions— In vivo administration of syngenic MPCs into a rat model of myocardial infarcted heart was safety demonstrated. Some engrafted cells appeared to differentiate into endothelial cells and loss their smooth muscle phenotype. MPC engraftment might to contribute to the improvement on the cardiac function in such a setting.
Development and validation of a rapid and sensitive UHPLC–MS/MS method for the determination of paliperidone in beagle dog plasma
Authors: Hongming Chen, Longshan Zhao, Guangjing Li, Donglei Leng, Panqin Ma, Lijin Tong, Tianhong Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2014)

In order to evaluate the pharmacokinetic profile of paliperidone extended-release tablets in vivo, a simple and rapid ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) method was developed and validated for the determination of paliperidone in beagle dog plasma. Paliperidone and diazepam (internal standard) were extracted from plasma samples with diethyl ether, and then separated on a C18 column (2.1 × 50 mm, 2.6 μm) under gradient elution with methanol–0.1% formic acid at a flow rate of 0.3 ml/min. The compounds were detected using a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source. The validated method was linear over the concentration range of 1.00–1000.00 ng/ml and the lower limit of quantitation was 1.00 ng/ml. The intra-day and inter-day precision values were not more than 15% (relative standard deviation < 20% at low levels), while the accuracy was within ±10% of nominal values. The validated UHPLC–MS/MS method was successfully applied to an oral pharmacokinetic study of paliperidone extended-release tablets in a beagle dog.
Blocking Chemokine Responsive to γ–2/Interferon (IFN)-γ Inducible Protein and Monokine Induced by IFN-γ Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus–specific Cytotoxic T Lymphocytes
Authors: Kazuhiro Kakimi, Thomas E. Lane, Stefan Wieland, Valerie C. Asensio, Iain L. Campbell, Francis V. Chisari, Luca G. Guidotti
Journal: The Journal of Experimental Medicine (2001)

Using transgenic mice that replicate hepatitis B virus (HBV) at high levels in the liver as recipients of HBV-specific cytotoxic T lymphocytes (CTLs), we showed that the chemokines responsive to gamma-2/IFN-gamma inducible protein ([Crg2]IP-10) and monokine induced by interferon-gamma (Mig) are rapidly and strongly induced in the liver after CTL transfer. The transferred CTLs produce neither chemokine; rather, they activate (via the secretion of IFN-gamma) hepatocytes and nonparenchymal cells of the liver to produce (Crg2)IP-10 and Mig. Importantly, blocking these chemokines in vivo reduces the recruitment of host-derived lymphomononuclear cells into the liver and the severity of the liver disease without affecting the IFN-gamma-dependent antiviral potential of the CTLs. The finding that neutralization of these chemokines is associated with maintenance of antiviral effects but diminished tissue damage may be significant for the development of immunotherapeutic approaches for the treatment of chronic HBV infection.
Differential regulation of inotropy and lusitropy in overexpressed Gsα myocytes through cAMP and Ca2+ channel pathways
Authors: Song-Jung Kim, Atsuko Yatani, Dorothy E. Vatner, Satoshi Yamamoto, Yoshihiro Ishikawa, Thomas E. Wagner, Richard P. Shannon, Young-Kwon Kim, Gen Takagi, Kuniya Asai, Charles J. Homcy, Stephen F. Vatner
Journal: Journal of Clinical Investigation (1999)

We investigated the mechanisms responsible for altered contractile and relaxation function in overexpressed Gsalpha myocytes. Although baseline contractile function (percent contraction) in Gsalpha mice was similar to that of wild-type (WT) mice, left ventricular myocyte contraction, fura-2 Ca2+transients, and Ca2+ channel currents (ICa) were greater in Gsalpha mice in response to 10(-8) M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca2+ transients was accelerated at baseline in Gsalpha but did not increase further with ISO. In vivo measurements using echocardiography also demonstrated enhanced relaxation at baseline in Gsalpha mice. Forskolin and CaCl2 increased contraction similarly in WT and Gsalpha mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca2+ currents to ISO in WT and to forskolin in both WT and Gsalpha. It also blocked the accelerated relaxation in Gsalpha at baseline but not the contractile response to ISO in Gsalpha myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gsalpha compared with WT. These data indicate that overexpression of Gsalpha accelerates relaxation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca2+ channel activity; i.e the cellular mechanisms mediating these effects appear to involve a cAMP-independent as well as a cAMP-dependent pathway.
STUDIES WITH HUMAN INFLUENZA VIRUS CULTIVATED IN ARTIFICIAL MEDIUM
Authors: T. P. Magill, Thomas Francis
Journal: The Journal of Experimental Medicine (1936)

The in vitro cultivation of strains of human influenza virus has been successfully conducted through a prolonged series of successive transfers. The cultivated virus has retained the antigenic and immunological properties which characterized the animal passage virus from which it was derived. The culture virus is still virulent for mice and ferrets; it is capable of inducing an active state of immunity in animals vaccinated subcutaneously or intraperitoneally; it elicits specific neutralizing antibodies in the serum of infected or vaccinated animals. The virus has been successfully cultivated to date only in the presence of oxygen; when conditions of reduced oxygenation are imposed by the use of vaseline seal, with or without the addition of cystein, multiplication of the virus is not supported. On the other hand, it has been possible to cultivate the virus in the medium of Li and Rivers in ordinary test tubes. This affords a greatly simplified procedure, since the interval between transfers may be prolonged. The results of neutralization tests with various sera and the culture virus are presented and discussed.
Widened Mediastinum After a Penetrating Injury of the Chest
Authors: Jerrold M. Weiss
Journal: JAMA (1975)

<h3>History</h3> A 7-year-old boy was transferred to the hospital from a smaller community hospital three hours after walking through a plate glass window and sustaining a penetrating injury to the left anterior chest wall. A long glass fragment had been extracted, apparently intact, at the first hospital. The patient, on admission, showed evidence of diminished heart sounds and decreased breath sounds over the left hemithorax. The hemoglobin value was 8.3 gm/100 ml. A posteroanterior chest roentgenogram (Fig 1) was obtained on admission and an aortogram (Fig 2) done shortly thereafter. <h3>Diagnosis</h3> Laceration of the left internal mammary artery. <h3>Comment</h3> The admission chest roentgenogram (Fig 1) shows a widened mediastinum and left pleural effusion. The tentative diagnosis at that time was mediastinal hematoma and hemothorax on the left caused by penetrating injury of the aorta. However, as seen in Fig 2, the aorta is intact. The right internal mammary artery is