tbuckley/cabot-search huggingface dataset:
Abstract LB-128: The N-terminus of the ASPP2 tumor suppressor binds Ras and enhances Ras/Raf/MEK activation to promote oncogene-induced cellular senescence
Authors: Zhiping Wang, Philip J. Stork, Charles D. Lopez
Journal: Cancer Research (2011)

Abstract The ASPP2 tumor suppressor is a pro-apoptotic member of a family of p53 binding proteins. It functions in part by selectively enhancing p53 transcriptional activation of pro-apoptotic target genes. Although the ASPP2 C-terminal domain binds the p53 core domain, little is known about the physical and functional interactions of other proteins to the highly structured ASPP2 N-terminus. Moreover, mounting evidence from our lab and others demonstrate that ASPP2 also mediates non-apoptotic p53-independent functions. However, the molecular mechanisms remain poorly understood. Previous reports have found that ASPP2 can localize to the cytoplasm and have identified a potential Ras-association domain in the ASPP2 N-terminus. Therefore, we wondered if novel ASPP2 functions could be mediated by ASPP2 N-terminal interaction with cytoplasmic Ras. Using co-immunoprecipitation and immunofluorescence microscopy, we identified ASPP2 in a complex with active Ras on the plasma membrane. Moreover, we also found that this interaction required the ASPP2 N-terminus since BBP, a naturally occurring alternatively spliced ASPP2 isoform lacking the N-terminus, showed markedly reduced ability to bind Ras. To determine if ASPP2 could modulate Ras function, we ectopically expressed ASPP2 in cells and found enhancement of Ras activation and subsequent stimulation of ERK phosphorylation. Conversely, ASPP2 knockdown by siRNA drastically reduced ERK phosphorylation and activation by EGF. Although it is oncogenic in tumor cells, constitutive Ras activation in normal cells leads to premature senescence in a Raf-MEK-ERK activation dependent manner. To explore if ASPP2 enhanced senescence, we knocked down ASPP2 expression with siRNA and found that senescence induced by RasV12 lentiviral infection in normal human fibroblasts was significantly attenuated. This was similar to the attenuation of senescence achieved by the MEK inhibitor PD98059. Together, our results demonstrate a novel function of the ASPP2 N-terminus in promoting cellular senescence via Ras-interaction and stimulation of Raf-MEK-ERK activity. These findings suggest a novel mechanism by which ASPP2-induced senescence may mediate its tumor suppression ability, and opens new avenues for investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-128. doi:10.1158/1538-7445.AM2011-LB-128
Final results of a multicentre phase II trial of high-dose methotrexate (HD-MTX), cytarabine, thiotepa, and idarubicin (MATILDE regimen) followed by whole-brain irradiation (WBRT) for primary CNS lymphomas (PCNSL)
Authors: A. J. Ferreri, S. Dell’oro, M. Foppoli, A. A. Brandes, M. Montanari, M. Balzarotti, M. Spina, F. Ilariucci, F. Zaja, M. Reni
Journal: Journal of Clinical Oncology (2005)

1530 Background: A phase II trial was designed to assess MATILDE chemotherapy (CHT) regimen in untreated PCNSL pts. This combination includes drugs active in different phases of the cell cycle, with demonstrated efficacy against aggressive lymphomas and able to cross the blood-brain barrier. Methods: PCNSL pts (HIV-, ≤70 ys, PS<4) received 3 courses of MTX 3.5 g/m2 d1; idarubicin 13 mg/m2 d2; cytarabine 1.7 g/m2x2 d2; and thiotepa 20 mg/m2 d3; ev.3 wks, followed by WBRT (30–36 Gy in responders and 40 Gy in the others) plus a 9-Gy boost. Results: Pt Characteristics: 41 pts (median age 57 ys) were enrolled (5/00–1/04). All pts but one had brain lesions, with ocular and meningeal disease in 3/34 (9%) and 7 (17%) pts, respectively. According to the IELSG score [J Clin Oncol 2003;21(2):266], risk was low in 10 (24%) pts, intermediate in 23 (56%) and high in 8 (20%). Response and survival: At the end of CHT, 18 (44%) pts had CR, 13 (32%) PR (ORR=76%), 6 (15%) PD and 4 died of toxicity. Response rate after WBRT was 83% (n=34), with a CR rate of 56% (n=23). Five of the 7 pts with meningeal disease achieved CR, one had PR; 3 of them relapsed but without meningeal involvement; 3 pts with meningeal disease are alive at 14, 30 and 53 mos. 24 pts experienced failure, with a 3-yr FFS of 41±8%. 16 pts are alive, with a median f-up of 36 mos (13–56), and a 5-yr OS of 37±7%. According to the IELSG score, 3-yr OS was 70±12%, 37±10% and 0% (p=0.0002), respectively for pts with low, intermediate and high risk. Toxicity: G4 neutropenia, thrombocytopenia and sepsis were reported in 54%, 45% and 14% of the 97 delivered courses. Six pts did not complete CHT due to toxicity (lethal in 4). No pt required MTX dose reduction, while 15 pts needed a dose reduction of ≥1 of the other drugs. Complete data on MiniMental Status Examination were available in 13 survivors (median age 49), neurotoxicity was not observed at a median f-up of 26 mos. Conclusions: MATILDE regimen is active (ORR=76%). Pts >65 ys or with PS=3 require dose corrections. Meningeal disease can be controlled without intrathecal CHT. Neurotoxicity is rare in young pts. The prognostic value of the IELSG score is confirmed. No significant financial relationships to disclose.
Abstract 1054: Identification of progesterone receptor membrane component-1 as the putative sigma-2 receptor
Authors: Jinbin Xu, Chenbo Zeng, Wenhua Chu, Fenghui Pan, Robert H. Mach
Journal: Cancer Research (2010)

Abstract Sigma binding sites represent a unique class of receptors and are highly expressed in tumor cells. Two sigma binding site subtypes, known as sigma-1 and sigma-2 receptors, were distinguished based on differences in their pharmacological profiles and molecular weights. The sigma-1 receptor gene has been cloned and well characterized in the CNS and cancer biology. However, the sigma-2 receptor has not yet been cloned. The purpose of the current study is to identify and clone sigma-2 receptor. We have synthesized an irreversible sigma-2 receptor selective photoaffinity probe, WC-II-21, containing a fluorescein isothiocyanate (FITC) group. This ligand has high binding affinity for sigma-2 receptor (Ki = 13 nM) and relatively low binding affinity for sigma-1 receptor (Ki &amp;gt; 1,000 nM). This ligand irreversibly labeled sigma-2 receptors in the rat liver membrane fractions after UV irradiation. The ligand-labeled proteins were solubilized, enriched and then separated through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The position of a predominant band of the ligand-labeled protein in the gel was determined by western blot analysis using FITC antibody. MALDI-mass spectrometry analysis for the ligand-labeled proteins indentified the protein progesterone receptor membrane component-1 (PGRMC-1) with a convincingly high score of 81. Based on the similarities of the reported biological characteristics and functions between PGRMC1 and sigma-2 receptor, PGRMC1 was investigated in the current study. Immunocytochemistry revealed that PGRMC1 colocalized with molecular markers of endoplasmic reticulum and mitochondria in human melanoma cell line MDA-MB435. The subcellular localization of sigma-2 receptor also colocalized with fluorescent markers of endoplasmic reticulum and mitochondria as reported previously from our group (Cancer Res 2007; 67, 6708-6716). Thus, PGRMC1 and sigma-2 receptor appear to localize in the same subcellular organelles in the cell. PGRMC1 was knocked down with PGRMC1 siRNA in MDA-MB435 cells. Sigma-2 radioligand binding activity was significantly reduced in the PGRMC1 knocked down cells relative to the nontargeting siRNA transfected cells. These data suggest that PGRMC1 is the putative sigma-2 receptor. Further validation of PGRMC1 as the sigma-2 receptor is ongoing in our group. (Supported by CA 102869). 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 1054.
Allocating Scarce Medical Resources and the Availability of Organ Transplantation
Authors: H. Tristram Engelhardt
Journal: New England Journal of Medicine (1984)

The ProblemSome: controversies have a staying power because they spring from unavoidable moral and conceptual puzzles. The debates concerning transplantation are a good example. To begin with, they are not a single controversy. Rather, they are examples of the scientific debates with heavy political and ethical overlays that characterize a large area of public-policy discussions.1 The determination of whether or not heart or liver transplantation is an experimental or nonexperimental procedure for which it is reasonable and necessary to provide reimbursement is not simply a determination on the basis of facts regarding survival rates or the frequency with which . . .
Abstract 682: Design and discovery of novel small molecule modulators of reactive oxygen species-mediated cell signaling
Authors: Divya Pathania, Mario Sechi, Michele Palomba, Alessia Cosseddu, Vanna Sanna, Francesco Berrettini, Angela Sias, Laleh Taheri, Nouri Neamati
Journal: Cancer Research (2011)

Abstract Oxidative stress is an important hallmark of cancer. Elevated levels of intrinsic reactive oxygen species (ROS) make tumor cells more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death. Increasing ROS production or decreasing ROS scavengers shows potential for selectively targeting tumor cells that are under persistent oxidative stress. Recently, we have discovered novel class of quinazolinediones that exert their anticancer effects by modulating ROS-mediated cell signaling.The sub-micromolar anti-proliferative properties of these compounds were demonstrated by MTT and colony formation assays in a panel of cancer cell lines of different origins. Treatment with these agents induced cell cycle arrest, and increased superoxide production in cancer cells. Furthermore, proteomics analysis of 600 target antibody array revealed that these molecules significantly affected several cell signaling pathways implicated in carcinogenesis, cancer progression, redox signaling, and cell death.In conclusion, quinazolinediones are promising lead compounds that selectively enhance ROS production and induce ROS-mediated cell death in cancer cells, and warrant further preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 682. doi:10.1158/1538-7445.AM2011-682
P274 MICROPARTICLES FROM HYPERTROPHIED ADIPOCYTES OR OBESE MICE ACTIVATE MONOCYTES AND MACROPHAGES CONTRIBUTING TO LIVER INFLAMMATION
Authors: A. Eguchi, M. Lazic, A. Mulya, M.P. Berk, A. Gornicka, S.A. Phillips, D.D. Sears, A.E. Feldstein
Journal: Journal of Hepatology (2014)
Traitement endoscopique des sténoses biliaires bénignes par mise en place provisoire d'une prothèse métallique entièrement couverte. Résultats intermédiaires d'une étude française prospective multicentrique
Authors: U Chaput, S Leblanc, P Bichard, P Bauret, B Napoléon, D Coumaros, H Lamouliatte, T Ponchon, JC Duchmann, R Laugier, B Vedrenne, M Gaudric, S Chaussade, F Prat
Journal: Endoscopy (2011)

Introduction: Le traitement endoscopique classique des sténoses biliaires bénignes consiste à mettre en place une ou plusieurs prothèses biliaires plastiques après sphinctérotomie endoscopique. Ce traitement est inconstamment efficace et s'accompagne d'une morbidité et d'un inconfort liés aux fréquents gestes endoscopiques nécessaires. L'objectif de ce travail était d'évaluer prospectivement la faisabilité de la mise en place et de l'extraction endoscopique de prothèses métalliques expansives entièrement couvertes (PMEC) dans cette indication. Etude réalisée sous l'égide de la Société Française d'Endoscopie Digestive (SFED).
Abstract 1541: Role of GSH in mediating stromal-leukemia interaction and promoting cell survival and drug resistance in chronic lymphocytic leukemia
Authors: Wan Zhang, Dunyaporn Trachootham, Jinyun Liu, Michael J. Keating, Peng Huang
Journal: Cancer Research (2010)

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries. The interaction between CLL cells and the bone marrow stromal environment is thought to play a major role in promoting the leukemia cell survival and drug resistance. Here we show a novel biochemical mechanism by which the bone marrow stromal cells exert a profound influence on the redox status of primary CLL cells and enhance their ability to sustain oxidative stress and drug treatment. Fresh leukemia cells isolated from the peripheral blood of CLL patients exhibited two major redox alterations when they were cultured alone: a significant decrease in cellular glutathione (GSH) and an increase in basal ROS levels. However, when cultured in the presence of bone marrow stromal cells, CLL cells restored their redox balance with an increased synthesis of GSH, a decrease in spontaneous apoptosis, and an improved cell survival. Further study showed that CLL cells were under intrinsic ROS stress and highly dependent on GSH for survival, and that the bone marrow stromal cells promoted GSH synthesis in CLL cells through a novel biochemical mechanism. Cysteine is a limiting substrate for GSH synthesis and is chemically unstable. Cells normally obtain cysteine by uptaking the more stable and abundant precursor cystine from the tissue environment and convert it to cysteine intracellularly. We showed that CLL cells had limited ability to take up extracellular cystine for GSH synthesis due to their low expression of the transporter Xc-, but had normal ability to uptake cysteine. In the co-culture system, the bone marrow stromal cells effectively took up cystine and reduced it to cysteine for secretion into the tissue microenvironment to be taken up by CLL cells for GSH synthesis. The elevated GSH in CLL cells in the presence of bone marrow stromal cells significantly protected the leukemia cells from stress-induced apoptosis, and rendered them resistant to standard therapeutic agents such as fludarabine and oxaliplatin. Importantly, disabling of this protective mechanism by depletion of cellular GSH using a pharmacological approach potently sensitized CLL cells to drug treatment, and effectively enhanced the cytotoxic action of fludarabine and oxaliplatin against CLL in the presence of stromal cells. This study reveals a key biochemical mechanism of leukemia-stromal cells interaction, and identifies a new therapeutic strategy to overcome drug resistance in vivo. 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 1541.
Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis
Authors: Mark Lebwohl, Bruce Strober, Alan Menter, Kenneth Gordon, Jolanta Weglowska, Lluis Puig, Kim Papp, Lynda Spelman, Darryl Toth, Francisco Kerdel, April W. Armstrong, Georg Stingl, Alexa B. Kimball, Herve Bachelez, Jashin J. Wu, Jeffrey Crowley, Richard G. Langley, Tomasz Blicharski, Carle Paul, Jean-Philippe Lacour, Stephen Tyring, Leon Kircik, Sergio Chimenti, Kristina Callis Duffin, Jerry Bagel, John Koo, Gary Aras, Joanne Li, Wenjie Song, Cassandra E. Milmont, Yifei Shi, Ngozi Erondu, Paul Klekotka, Brian Kotzin, Ajay Nirula
Journal: New England Journal of Medicine (2015)

Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis.In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100).At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab.Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).
Snowstorm-Related Mortality — Erie County, New York, November 2014
Authors: Gale R Burstein, Janinne Blank, Tracy Fricano Chalmers, Tara Mahar, Martin C. Mahoney
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

During November 18-21, 2014, a narrow band of central and southern Erie County in New York received unprecedented amounts of snowfall. The duration of the storm and amount of snowfall rapidly exceeded weather service forecasts, with some areas receiving 60-84 inches (1.5-2.1 meters) of snow. The rapid accumulation resulted in stranded drivers, travel bans, and logistical challenges associated with snow removal. Sporadic power outages affected a limited number of households. Eleven deaths were linked to the snowstorm, including one that was directly related, nine that were indirectly related, and one that was classified as possibly storm-related.
IMMEDIATE ECHOCARDIOGRAPHIC AND HEMODYNAMIC RESULTS OF PERCUTANEOUS TRANSVENOUS MITRAL COMMISSUROTOMY IN PATIENTS WITH SYMPTOMATIC MITRAL RESTENOSIS AFTER CLOSED SURGICAL COMMISSUROTOMY
Authors: Md.Toufiqur Rahman, Farazi Bakhtiar Ahmed, MD. Shahidul Islam, Abdullah Majumder, Syed Haque
Journal: Journal of the American College of Cardiology (2015)
Abstract 3992: Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features
Authors: Osada Hirotaka, Eri Nishikawa, Chinatsu Arima, Yasumasa Okazaki, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi
Journal: Cancer Research (2011)

Abstract Lung cancers with neuroendocrine (NE) features are often very aggressive, though the underlying molecular mechanisms have not been clearly elucidated. We previously reported that the basic helix-loop-helix protein, achaete-scute homologue 1 (ASH1/ASCL1), a master regulator of pulmonary neuroendocrine cell development, is crucially involved in the pathogenesis of lung cancers with neuroendocrine features (NE-lung cancers). In the present study, we searched for miRNAs regulated by ASH1 in order to gain insight into the involvement of miRNAs downstream of ASH1 in NE-lung cancer pathogenesis. We consequently found that introduction of ASH1 into A549 cells markedly induced miR-375 and down-regulated miR-200b. Interestingly, these two miRNAs inversely affected cell-cell interaction and cell motility, and they together conferred looser cell attachment and a more motile feature. miR-375 was found to be directly transactivated by ASH1. Global gene expression analysis using miR-375-introduced A549 cells and the subsequent pathway analysis using the Ingenuity IPA software revealed altered gene expressions in several cancer-related pathways (e.g., cellular movement and morphology). Interestingly, we also found that miR-375 alone can induce NE differentiation markers in A549 cells and that miR-375 is required to elicit ASH1-indued NE features. In accordance with these findings in vitro, clear induction of NE features as well as enhanced tumor growth was observed in xenografts of A549 cells stably expressing miR-375. We further found that a transcriptional co-activator YAP1 is most significantly repressed by miR-375 through recognition of its two miR-375 binding sites. A positive correlation between ASH1 and miR-375 as well as a negative correlation between miR-375 and YAP1 were observed in lung cancers, indicating the ASH1-miR-375-YAP1 regulatory pathway is indeed functionally implemented in lung cancer cells. In addition, we found that growth-regulatory functions of YAP1 is cell-lineage dependent in lung cancer cell lines. In conclusion, the present study identified the ASH1-miR-375 axis, providing clues for a better understanding of the molecular and cellular biological roles of ASH1-centered microRNA regulatory networks in the pathogenesis of NE-lung cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3992. doi:10.1158/1538-7445.AM2011-3992
A Randomized, Double-Blind, Placebo-Controlled PIII Study of Fentanyl Buccal Tablet (FBT) for Breakthrough Cancer Pain
Authors: K. Shinozaki, S. Tanda, Y. Shima, K. Yomiya, M. Matoba, I. Adachi, T. Yoshimoto, K. Eguchi, F. Goto
Journal: Annals of Oncology (2013)
Endoluminal vacuum therapy for anastomotic insufficiency after gastrectomy
Authors: I. Wallstabe, R. Plato, A. Weimann
Journal: Endoscopy (2010)

The reported incidence of anastomotic leaks is between 5 % and 25 %. Depending on the position and dimensions of the leaks, they are associated with a mortality of up to 60 % [1]. So far endoluminal vacuum therapy has mainly been used for treatment of anastomotic insufficiencies of the rectum [2]. Its use in the esophagus was first reported in 2007 and in only three more cases since then [3] [4] [5].