tbuckley/cabot-search huggingface dataset:
Abstract 3523: C7, C9-dimethylifosfamide analogs evaluation for antitumor activity and toxicity: Detoxification pathways might explain nephrotoxicity
Authors: Bérénice GIRAUD, Guillaume HEBERT, Alain DEROUSSENT, Estelle DAUDIGEOS, Sonia MARTELLI, Gilles VASSAL, Angelo PACI
Journal: Cancer Research (2010)

Abstract Ifosfamide (IFO) is an anticancer drug, widely used against various types of human solid tumors. This prodrug produced active alkylating isophosphoramide mustard. But its side-chain oxidative metabolism is associated with toxicities in high-dose chemotherapy. As acrolein urotoxicity is limited by coadministration of mesna, chloroacetaldehyde (CAA) is responsible for neurotoxicity and nephrotoxicity. C7, C9 dimethyl-ifosfamide analogs have been synthesized to prevent these side effects. In vitro metabolism and anticancer activity investigations demonstrated that the generated dimethylated mustards were faster alkylating agents (28 fold faster) than isophosphoramide mustard and IC50 values on 9L glioblastoma cells showed higher cytotoxicity of analogs, especially the 7S,9S enantiomer (1). This later was selected for in vivo investigations. As these analogs were still metabolized through the same N-deschloroalkylation pathway, monoochloroacetone (MCA) is produced instead of CAA. In a first step, in vitro/ex vivo experiments were conducted to investigate its toxicity. The toxicity of both metabolites was compared by evaluation of cell viability using canine kidney cell lines (MDCK) and rabbit renal proximal tubules (RRPT). Cell viability experiments showed that similar IC50 values were obtained for CAA and MCA (21 and 23 µM) on MDCK. To determine detoxification pathways, several experiments were conducted on RRPT. Whereas these compounds could react directly with glutathione (GSH), identification of GSH and its conjugates (GSR) was performed by LC/MS after incubation of MDCK and RRPT with 200 µM CAA and MCA. Both enzymatic reduction and GSH conjugation pathways occurred. Conjugates were then quantified by LC-MS/MS over 1-650 µM for GSH and over 1-200 µM for GSR from 20 to 120 min. The results demonstrated a rapid depletion of GSH and few differences in detoxification's kinetics for CAA and MCA. As MCA in vivo generated levels are still unknown, 7S,9S dimethyl-IFO analog is currently under investigation on human tumor cells xenografted in mice in order to confirm its antitumor activity and to evaluate its toxicity. (1) Storme T, Deroussent A, Mercier L, Prost E, Re M, Munier F, Martens T, Bourget P, Vassal G, Royer J and Paci A. J Pharmacol Exp Ther. 2009, 328(2):598-609. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3523.
An open-label phase II study of the safety and efficacy of etanercept for the therapy of hidradenitis suppurativa
Authors: E.J. Giamarellos-Bourboulis, E. Pelekanou, A. Antonopoulou, H. Petropoulou, F. Baziaka, V. Karagianni, N. Stavrianeas, H. Giamarellou
Journal: British Journal of Dermatology (2007)

Journal Article An open‐label phase II study of the safety and efficacy of etanercept for the therapy of hidradenitis suppurativa Get access E.J. Giamarellos‐Bourboulis, E.J. Giamarellos‐Bourboulis 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Correspondence: Evangelos J. Giamarellos‐Bourboulis. E‐mail: giamarel@ath.forthnet.gr Search for other works by this author on: Oxford Academic Google Scholar E. Pelekanou, E. Pelekanou 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar A. Antonopoulou, A. Antonopoulou 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar H. Petropoulou, H. Petropoulou 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar F. Baziaka, F. Baziaka 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar V. Karagianni, V. Karagianni 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar N. Stavrianeas, N. Stavrianeas 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar H. Giamarellou H. Giamarellou 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ‘ATTIKON’, 1 Rimini Str, 124 64 Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 158, Issue 3, 1 March 2008, Pages 567–572, https://doi.org/10.1111/j.1365-2133.2007.08372.x Published: 01 March 2008
Perforation of the Trachea and Bronchus by the Bronchoscope
Authors: W. Gordon
Journal: Thorax (1950)

A case of perforation of the trachea by the bronchoscope prompted a study of the records of this clinic, and it was found that in approximately 15,000 bronchoscopies performed during the last 13 years only one similar case, a perforation of the bronchus, had occurred.These two cases are now recorded.In the literature of the past 20 years there appears to be no record of perforation of the intrathoracic portion of the trachea or the bronchi by the bronchoscope nor any reference to such an accident having occurred previously.Possibly, unrecorded cases have occurred.Describing a patient with mediastinal emphysema following bronchoscopy, Jones (1945) assumed damage at some point in the tracheo-bronchial tree, but the site and nature of the lesion were not visualized.In the following cases there was bronchoscopic and radiographic or clinical evidence of a perforated trachea in one patient and a perforated bronchus in the other.
DNA Cross-linking and Cytotoxicity of the Alkylating Cyanomorpholino Derivative of Doxorubicin in Multidrug-Resistant Cells2
Authors: S. A. Scudder, J. M. Brown, B. I. Sikic
Journal: JNCI Journal of the National Cancer Institute (1988)

The cyanomorpholino derivative of doxorubicin (MRA-CN) is an anthracycline that is extremely potent and non-cross-resistant with doxorubicin (DOX) in multidrug-resistant cells. MRA-CN binds to and cross-links DNA and thus has been proposed to act as a targeted alkylating agent. In our study, the number of DNA interstrand and DNA-protein Cross-links produced by MRA-CN was identical in multidrug-resistant Dx5 and parental MES-SA Cells, as shown by alkaline elution analysis. The amount of cross-linking was directly proportional to drug concentration at concentrations from 10−11 to 10−7M MRA-CN. Extensive DNA cross-linking was evident within 30 minutes of drug exposure. After 1 hour of drug exposure, the number of DNA cros-links increased for 90 minutes, reached a plateau, and then began to decrease after 120 minutes. Loss of cell viability was also observed as early as 3 hours after exposure to MRA-CN. The finding of the same number of DNA cross-links in MES-SA and Dx5 cells indicates that similar amounts of MRA-CN are likely to enter the nuclei of multidrug-resistant and sensitive cells. Other anthracyclines have major differences in nuclear dis-tribution in sensitive and resistant cells. Several factors may contribute to the non-cross-resistance of MRA-CN in multidrug-resistant cells, (a) The lipophilicity of MRA-CN facilities cell entry. (b) The substitution and loss of basicity at the amino nitrogen may reduce the affinity of the drug for the P-glycoprotein efflux pump, compared with that of DOX. (c) The detoxification function of P-glycoprotein may be less effective for drugs that produce rapid and irreversible cell damage, such as the DNA-targeted alkylation caused by MRA-CN.
Metabolic response to human growth hormone during prolonged starvation
Authors: Philip Felig, Errol B. Marliss, George F. Cahill
Journal: Journal of Clinical Investigation (1971)

The metabolic response to human growth hormone (HGH) was studied in five obese subjects in the fed state and during prolonged (5-6 wk) starvation. In the fed state (three subjects), HGH induced an elevation in basal serum insulin concentration, a minimal increase in blood and urine ketone levels, and a marked reduction in urinary nitrogen and potassium excretion resulting in positive nitrogen and potassium balance. In prolonged fasting (four subjects), HGH administration resulted in a 2- to 3-fold increase in serum insulin which preceded a 50% elevation in blood glucose. Persistence of the lipolytic effects of HGH was indicated by a rise in free fatty acids and glycerol. The response differed markedly from the fed state in that blood beta-hydroxybutyrate and acetoacetate levels rose by 20-40%, resulting in total blood ketone acid concentrations of 10-12 mmoles/liter, ketonuria of 150-320 mmoles/day, and increased urinary potassium loss. The subjects complained of nausea, vomiting, weakness, and myalgias. Despite a 50% reduction in urea excretion during HGH administration, total nitrogen loss remained unchanged as urinary ammonia excretion rose by 50% and correlated directly with the degree of ketonuria. It is concluded that in prolonged starvation (a) HGH may have a direct insulinotropic effect on the beta cell independent of alterations in blood glucose concentration, (b) persistence of the lipolytic action of HGH results in severe exaggeration of starvation ketosis and interferes with its anticatabolic action by necessitating increased urinary ammonia loss, and (c) failure of HGH to reduce net protein catabolism in starvation suggests that this hormone does not have a prime regulatory role in conserving body protein stores during prolonged fasting.
Nkx2-8 Downregulation Promotes Angiogenesis and Activates NF-κB in Esophageal Cancer
Authors: Chuyong Lin, Libing Song, Hui Gong, Aibin Liu, Xi Lin, Jueheng Wu, Mengfeng Li, Jun Li
Journal: Cancer Research (2013)

Abstract Angiogenesis is a major clinical feature of esophageal squamous cell carcinoma (ESCC), an aggressive disease of increasing incidence in developed countries. In ESCCs, the proangiogenic factor VEGF-C is an independent prognostic factor for ESCC, where understanding the mechanisms of VEGF-C upregulation may cue possible therapeutic insights. Here, we report that expression of the transcription factor Nkx2-8 is downregulated in ESCCs where it inversely correlates with progression and VEGF-C upregulation. Patients with ESCCs with lower Nkx2-8 expression exhibited reduced overall survival. Modulating expression of Nkx2-8 up or down inhibited or enhanced, respectively, proangiogenic activity in vitro and in vivo. Mechanistic investigations showed that Nkx2-8 repressed NF-κB activity by restraining nuclear localization of NF-κB p65 via downregulation of AKIP1, a NF-κB p65 binding partner, and also by directly targeting the AKIP1 promoter. We confirmed evidence for the importance of the Nkx2-8/AKIP1/NF-κB axis identified in ESCC cell models through an immunohistochemical analysis of a large cohort of human ESCC specimens. Taken together, our results showed that Nkx2-8 functions as a tumor suppressor in ESCCs, the downregulation of which contributes to NF-κB activation and ESCC angiogenesis. Cancer Res; 73(12); 3638–48. ©2013 AACR.
Impact of multimedia information on bronchoscopy procedure
Authors: Ersin Günay, Sevinc Sarinc Ulasli, Serdar Kokulu, Gurhan Oz, Olcay Akar, Erman Bagcioglu, Elif Dogan Baki, Mehmet Unlu
Journal: European Respiratory Journal (2014)

AIM: During medical procedures, anxiety is a common problem that may lead to decrease in tolerance and increase in stress of patients. It was known that there is an association between information of patients about the intervention and decreased level of anxiety. Here, we aimed to investigate the effect of written informed consent and comprehensive multimedia information on the anxiety level of patients, consumption of sedatives, difficulties during bronchoscopy, complications and duration of procedure.

METHODS: 150 patients undergoing bronchoscopy was included. They were randomized in to two groups (Multimedia information group (MIG) (N=75) and written-informed consent group (WICG) (N=75)). Signed written informed consent was obtained from all patients. Comprehensive multimedia presentation was watched only to MIG. State anxiety scores were evaluated with State-Trait anxiety inventory (STAI-S).

RESULTS: STAI-S score of MIG group (40.31±8.08) was lower than WICG (44.29±9.62) (P=0.007). Satisfaction level was higher in MIG (P=0.001). Higher difficulties during “passage through vocal cords” and “interventions during bronchoscopy” were present in WICG group (P=0.013 and P=0.043, respectively). Midazolam consumption during bronchoscopy, and duration of bronchoscopy was statistically lower in MIG group (P<0.001 and P=0.045, respectively). Difficulties during “waiting period”, “passage through nasal/oral route”, “applications of local anesthesia” and “complication frequency” were similar in both groups.

CONCLUSION: Besides reducing the state anxiety in patients undergoing bronchoscopy, multimedia information can reduce the amount of sedation used, shorten the processing duration and reduce the difficulties during bronchoscopy.
Expression ratio of CCND1 to CDKN2A mRNA predicts RB1 status of cultured cancer cell lines and clinical tumor samples
Authors: Shinji Mizuarai, Takumitsu Machida, Tsutomu Kobayashi, Hideya Komatani, Hiraku Itadani, Hidehito Kotani
Journal: Molecular Cancer (2011)

The retinoblastoma product (RB1) is frequently deregulated in various types of tumors by mutation, deletion, or inactivation through association with viral oncoproteins. The functional loss of RB1 is recognized to be one of the hallmarks that differentiate cancer cells from normal cells. Many researchers are attempting to develop anti-tumor agents that are preferentially effective against RB1-negative tumors. However, to identify patients with RB1-negative cancers, it is imperative to develop predictive biomarkers to classify RB1-positive and -negative tumors.Expression profiling of 30 cancer cell lines composed of 16 RB1-positive and 14 RB1-negative cancers was performed to find genes that are differentially expressed between the two groups, resulting in the identification of an RB1 signature with 194 genes. Among them, critical RB1 pathway components CDKN2A and CCND1 were included. We found that microarray data of the expression ratio of CCND1 and CDKN2A clearly distinguished the RB1 status of 30 cells lines. Measurement of the CCND1/CDKN2A mRNA expression ratio in additional cell lines by RT-PCR accurately predicted RB1 status (12/12 cells lines). The expression of CCND1/CDKN2A also correlated with RB1 status in xenograft tumors in vivo. Lastly, a CCND1/CDKN2A assay with clinical samples showed that uterine cervical and small cell lung cancers known to have a high prevalence of RB1-decifiency were predicted to be 100% RB1-negative, while uterine endometrial or gastric cancers were predicted to be 5-22% negative. All clinically normal tissues were 100% RB1-positive.We report here that the CCND1/CDKN2A mRNA expression ratio predicts the RB1 status of cell lines in vitro and xenograft tumors and clinical tumor samples in vivo. Given the high predictive accuracy and quantitative nature of the CCND1/CDKN2A expression assay, the assay could be utilized to stratify patients for anti-tumor agents with preferential effects on either RB1-positive or -negative tumors.
Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature
Authors: Sheng Zhong Duan, Michael G. Usher, Richard M. Mortensen
Journal: Circulation Research (2008)

Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear receptor and transcription factor in the steroid superfamily. PPAR-γ agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-γ also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-γ activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-γ activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-γ activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor κB. This system is likely to be even more prominent in modulating disease in vascular cells. The effects of PPAR-γ in the vascular cells translate into the beneficial function of this transcription factor in vascular disorders, including hypertension and atherosclerosis. Both human genetic studies and animal studies using transgenic mice have demonstrated the importance of PPAR-γ in these disorders. However, recent clinical studies have raised significant concerns about the cardiovascular side effects of thiazolidinediones, particularly rosiglitazone. Weighing the potential benefit and harm of PPAR-γ activation and exploring the functional mechanisms may provide a balanced view on the clinical use of these compounds and new approaches to the future therapeutics of vascular disorders associated with diabetes.
Preclinical Characterization of Mitochondria-Targeted Small Molecule Hsp90 Inhibitors, Gamitrinibs, in Advanced Prostate Cancer
Authors: Byoung Heon Kang, Markus D. Siegelin, Janet Plescia, Christopher M. Raskett, David S. Garlick, Takehiko Dohi, Jane B. Lian, Gary S. Stein, Lucia R. Languino, Dario C. Altieri
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This study aimed to characterize the preclinical activity of the first class of combinatorial, mitochondria-targeted, small molecule heat shock protein-90 (Hsp90) inhibitors, gamitrinibs, in models of hormone-refractory, drug-resistant, localized, and bone metastatic prostate cancer in vivo. Experimental Design: Mitochondrial permeability transition, apoptosis, and changes in metabolic activity were examined by time-lapse videomicroscopy, multiparametric flow cytometry, MTT, and analysis of isolated mitochondria. Drug-resistant prostate cancer cells were generated by chronic exposure of hormone-refractory PC3 cells to the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG). The effect of gamitrinibs on s.c. or intratibial prostate cancer growth was studied in xenograft models. Bone metastatic tumor growth and bone parameters were quantified by micro–computed tomography imaging. Results: In the NCI 60-cell line screening, gamitrinibs were active against all tumor cell types tested, and efficiently killed metastatic, hormone-refractory, and multidrug-resistant prostate cancer cells characterized by overexpression of the ATP binding cassette transporter P-glycoprotein. Mechanistically, gamitrinibs, but not 17-AAG, induced acute mitochondrial dysfunction in prostate cancer cells with loss of organelle membrane potential, release of cytochrome c, and caspase activity, independently of proapoptotic Bcl-2 proteins Bax and Bak. Systemic administration of gamitrinibs to mice was well tolerated, and inhibited s.c. or bone metastatic prostate cancer growth in vivo. Conclusions: Gamitrinibs have preclinical activity and favorable safety in models of drug-resistant and bone metastatic prostate cancer in vivo. Clin Cancer Res; 16(19); 4779–88. ©2010 AACR.
Controlled Mechanical Ventilation Leads to Remodeling of the Rat Diaphragm
Authors: Liying Yang, Jun Luo, Johanne Bourdon, Meng-Chi Lin, Stewart B. Gottfried, Basil J. Petrof
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Little is known about the structural response of the diaphragm to controlled mechanical ventilation. We examined effects of this intervention on muscle mass, myosin heavy chain isoforms, and contractile function in the rat diaphragm. Animals were mechanically ventilated for up to 4 days, and comparisons were made with normal control rats as well as spontaneously breathing animals anesthetized for the same duration as the mechanical ventilation group. The diaphragm-to-body weight ratio was significantly reduced in the mechanical ventilation group only. After mechanical ventilation, an increase in hybrid fibers coexpressing both type I (slow) and type II (fast) myosin isoforms was found within the diaphragm, which occurred at the expense of the pure type I fiber population. In contrast, the percentages of type I, type II, and hybrid fibers in the limb muscles (soleus and extensor digitorum longus) did not differ between experimental groups. The optimal length for force production, as well as maximal force-generating capacity of the diaphragm, was also significantly decreased in mechanically ventilated animals. We conclude that even short-term controlled mechanical ventilation produces significant remodeling and functional alterations of the diaphragm, which could impede efforts at discontinuing ventilatory support.
Pulmonary resection undertaken with a provisional but unsubstantiated diagnosis of bronchial carcinoma
Authors: B. T. le Roux
Journal: Thorax (1972)

Over a 15-year period when frozen-section examination was not regularly available, 918 patients with peripheral pulmonary lesions (the routine preliminary investigation of which did not provide a diagnosis) were managed aggressively by a diagnostic pulmonary resection which, before 1954, was in some patients of the magnitude of pneumonectomy, but after that date was never more extensive than lobectomy and often no more than segmental resection. In 756 patients (82%) the lesion was shown to be a primary or metastatic pulmonary tumour and in 162 patients (18%) the lesion was a chronic inflammation or a pulmonary infarct. The commonest pulmonary lesion judged so closely to mimic pulmonary carcinoma that management by exploratory thoracotomy and diagnostic pulmonary resection was mandatory was pulmonary tuberculosis (82 patients); other lesions encountered were cavitated (8 patients) and non-cavitated (16 patients) pneumonias; pulmonary gummata (2 patients); progressive massive fibrosis (4 patients); and a pulmonary infarct (5 patients). It is estimated that in perhaps 60 patients (6·5% of the total) with nontumorous lesions the pulmonary resection undertaken was needless, or of unnecessary magnitude, and some of these resections might have been avoided if skilled interpretation of frozen sections had constantly been available.