tbuckley/cabot-search huggingface dataset:
Abstract 3061: AS-10: a new small molecule with promising activity against pancreatic cancer
Authors: Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Shantu Amin, Arun K. Sharma
Journal: Cancer Research (2016)

Abstract Patients with pancreatic cancer (PC) have a median survival of only 6 months and a five-year survival of less than 5%, hence making PC one of the deadliest cancer. Severity of PC is due to its identification at late stages, rapid local invasion, early metastases, and meager response to current chemotherapeutic agents. Current therapies result in minimal survival advantage and are linked with multiple adverse events and drug resistance. Hence, there is an urgent need for novel agents which are less toxic and offer greater benefits over conventional therapy. There is ample evidences in literature demonstrating that inflammation plays a critical role in PC growth and promotion. Nuclear factor κB (NF-κB) pathway, one of the major inflammatory pathway, is well known for its inflammatory response, cell proliferation, and resistance to apoptosis. It has been demonstrated that activation of NF-κB in PC is also responsible for resistance towards first line chemotherapeutic agent, gemcitabine, in PC. Through extensive structure-activity relationship studies, we have recently identified a novel small molecule, AS-10, which was lethal to PC cells. We sought to evaluate the mechanism of action of AS-10 responsible for inhibiting the growth of PC cells. In vitro, AS-10 reduced PC cell growth with an EC50, in the range of 2.5 to 5 μM. Growth arrest was confirmed by cell cycle studies, which showed that AS-10 induced G1 and G2 cell cycle arrest. The cell cycle arrest was associated with an increase of cell cycle inhibitory markers like p21 and p27. Effect of AS-10 on cell cycle was translated into activation of apoptosis, confirmed by caspase 3/7 activity, PARP cleavage and Annexin V staining. Due to its structural characteristics, we evaluated the effect of AS-10 on inflammatory NF-κB pathway. Our studies, in Panc-1 cells, showed that AS-10 inhibited NF-κB DNA binding activity as well as NF-κB translocation to the nuclei in the presence of inflammatory stimuli (tumor necrosis factor (TNFα)). Since, up regulation of NF-κB activity has been known to be responsible for gemcitabine resistance in PC, we evaluated the activity of our NF-κB inhibitor AS-10 in combination with gemcitabine, and showed that AS-10 synergistically potentiated gemcitabine activity in PC cells. Taken together, these results suggest that AS-10, may represent a potentially promising therapeutic agent for PC. Detailed investigations regarding the efficacy and mechanism of action of these compounds will be presented. Citation Format: Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Shantu Amin, Arun K. Sharma. AS-10: a new small molecule with promising activity against pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3061.
AT-05 * PHASE II STUDY OF IFOSFAMIDE, CARBOPLATIN, AND ETOPOSIDE INPATIENTS WITH A FIRST RECURRENCE OF GLIOBLASTOMA MULTIFORME
Authors: T. Aoki, T. Ueba, S.-I. Miyatake, K. Nozaki, Y. Arakawa, S. Miyamoto, T. Tsukahara, M. Matsutani
Journal: Neuro-Oncology (2014)

OBJECTIVE: The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. METHODS: This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks. RESULTS: Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22-50%). The median duration of PFS was 17 weeks (95% CI 10-24 weeks). The response rate was 25% (95% CI 9-34%). Adverse events were generally mild and consisted mainly of alopecia. CONCLUSIONS: This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM. (DOI: 10.3171/2009.5.JNS081738)
Composition of the Sepsis Definitions Task Force
Authors: Ellen L. Burnham, Jesse Roman
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract LB-154: Epigenetic silencing of triple-negative breast cancer hallmarks by Withaferin A
Authors: Wim Vanden Berghe, Katarzyna Szarc vel Szic, Ken Declerck, René A.J. Crans, Jolien Diddens, Clarissa Gerhäuser
Journal: Cancer Research (2016)

Abstract Background: Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. We found that the steroidal lactone Withaferin A (WA), isolated from the plant Withania somnifera, triggers active chromatin remodeling and elicits promising chemosensitizing effects in triple negative breast cancer (BC) cells. Here, we have further characterized potential involvement of epigenetic reprogramming by Withaferin A in TNBC treatment. Materials and methods: By Infinium HumanMethylation450 arrays, Epityper Mass array and CpG pyrosequencing, we determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines treated with a pharmacologically relevant concentration of 700 nM WA. In parallel, we performed ChIP analysis of histone mark H3K4Me3 to evaluate histone demethylation by JARID1B/KDM5B. Furthermore, epigenetic changes in response to WA were crosscompared with genomewide methylation changes and clinical breast cancer patient characteristics in The Cancer Genome Atlas database. Results: In contrast to the DNA hypomethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of TNBC cells silences an epigenetic cancer network through gene-specific hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Remarkably, DNA hypermethylation of corresponding CpG sites in these genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ER)/progesterone receptor (PR) positive status in primary BC tumors. Increased expression levels of JARID1B, promoter-specific loss of active H3K4me3 chromatin marks and gain of DNA methylation suggest that WA-specific gene silencing involves epigenetic reprogramming of HER2/ER/PR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks with an improved therapeutic sensitivity. Conclusions: WA may represent a novel and attractive phytopharmaceutical to overcome therapy resistance in TNBC. Citation Format: Wim Vanden Berghe, Katarzyna Szarc vel Szic, Ken Declerck, René A.J. Crans, Jolien Diddens, Clarissa Gerhäuser. Epigenetic silencing of triple-negative breast cancer hallmarks by Withaferin A. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-154.
A safety and tolerability study of vadimezan in combination with docetaxel in Japanese patients with advanced or recurrent solid tumors.
Authors: T. Hida, K. Takeda, H. Daga, S. Ishikawa, J. Shimizu, S. Tokunaga, Y. Horio, K. Ito, K. Kobayashi
Journal: Journal of Clinical Oncology (2010)

e13106 Background: Vadimezan (ASA404; 5,6-dimethylxanthenone-4-acetic acid), is a novel tumor vascular disrupting agent. It induces apoptosis of tumor vascular endothelial cells and production of cytokines and nitric oxide, leading to irreversible tumor vascular collapse and hemorrhagic tumor necrosis. A global phase III study in NSCLC patients is ongoing with vadimezan in combination with docetaxel 75 mg/m2 every 3 weeks (ATTRACT-2). This docetaxel dose is not approved in Japan for NSCLC. The objectives of this study were to confirm the safety and tolerability of vadimezan in combination with docetaxel (75 mg/m2 q3w) in Japanese patients in order to allow Japanese patients to participate in the ATTRACT-2 study. Methods: Patients with advanced or recurrent solid tumors, who had previously received > 1 chemotherapy or hormone therapy regimen (excluding docetaxel), had a performance status of 0–1 and adequate organ function were eligible. Vadimezan was administered intravenously following docetaxel on day 1 of a 21-day cycle. Dose escalation proceeded using “3+3” design: dose levels (DL) 1 and 2 corresponded to docetaxel 60 and 75 mg/m2, respectively, plus vadimezan 1800 mg/m2. PK samples were collected to measure total and free plasma concentration of vadimezan. Results: Nine patients (3 at DL 1 and 6 at DL 2) were treated for a median of 4 cycles. One dose limiting toxicity (grade 3 febrile neutropenia) occurred in 1 patient during cycle 1 at DL 2. Grade 3/4 neutropenia occurred in all patients, and was managed using G-CSF. Other grade 3/4 toxicities were leukopenia, constipation, hyperuricemia, urinary retention, and allergic reaction. One patient experienced grade 2 interstitial lung disease and improved after study discontinuation. One patient at DL 1 had a partial response, and 5 patients (1 at DL 1, 4 at DL 2) had stable disease. PK parameters for total and free vadimezan were similar between the DL 1 and DL 2. Conclusions: Docetaxel 75 mg/m2 q3w plus vadimezan 1,800 mg/m2 was tolerable in Japanese patients, supporting enrollment of Japanese patients in the ATTRACT-2; a global phase III study of vadimezan in combination with docetaxel in advanced NSCLC. No significant financial relationships to disclose.
WT1 Mutations Are Secondary Events In AML and Show Varying Frequencies Within Genetic Subgroups and Different Impact On Prognosis
Authors: Susanne Schnittger, Christiane Eder, Tamara Alpermann, Frank Dicker, Madlen Ulke, Alexander Kohlmann, Sabrina Kuznia, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach
Journal: Blood (2013)
O-004 Effects of nal-IRI (MM-398) ± 5-fluorouracil on quality of life (QoL) in NAPOLI-1: a phase 3 study in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine
Authors: R. Hubner, A. Cubillo, J.-F. Blanc, D. Melisi, D. Von Hoff, A. Wang-Gillam, L.-T. Chen, C. Becker, K. Mamlouk, B. Belanger, Y. Yang, F. de Jong, J. Siveke
Journal: Annals of Oncology (2016)
Abstract 3657: ZBTB7A is a tumor suppressor and novel therapeutic target in triple-negative breast cancer
Authors: Mary Ellen Molloy, Monika Lewinska, Xue-Song Liu, Angela A. Wang, Zhi-Min Yuan
Journal: Cancer Research (2016)

Abstract Due to lack of targeted therapies triple-negative breast cancers (TNBC) are the deadliest form of breast cancer, raising a pressing need to develop new therapeutic strategies. Recent advances in tumor metabolism have created exciting therapeutic opportunities by unveiling many previously unrecognized therapeutic targets. Like other tumor types, TNBCs also feature elevated glucose and glutamine metabolism (Shen, L., et al. 2015; McCleland, M., et al. 2012). A better understanding of the underlying mechanisms may uncover novel therapeutic targets for TNBC. Our lab has recently discovered that ZBTB7A suppresses glycolysis by transcriptionally repressing key genes within the glycolytic pathway in various cancer types (Liu, X.S., et al. 2014). Currently, ZBTB7A is proposed as an oncogene in breast cancer (Zu, X., et al. 2011), however our data suggest that ZBTB7A acts as a tumor suppressor specifically in TNBC. The purpose of this study was to determine the potential therapeutic value of targeting ZBTB7A in TNBC. Using publicly available databases, we find that low ZBTB7A expression is associated with poor prognosis in patients with hormone receptor-negative breast cancers. Our studies corroborate with patient derived data by demonstrating that reduced expression of ZBTB7A in TNBC cell lines leads to increased proliferation and resistance to radiation and chemotherapy. Differential gene expression analysis across human breast cancer samples in TCGA database revealed an inverse correlation between ZBTB7A and glycolytic genes. Overexpression of ZBTB7A in TNBC cells leads to decreased MCT1, LDHB and GLUT3 expression at the transcript level, consistent with our published data. Modulation of ZBTB7A expression also leads to changes in lactate production and glucose consumption in TNBC cells. Results from this study support ZBTB7A as a novel tumor suppressor and perspective therapeutic target in TNBC. Citation Format: Mary Ellen Molloy, Monika Lewinska, Xue-Song Liu, Angela A. Wang, Zhi-Min Yuan. ZBTB7A is a tumor suppressor and novel therapeutic target in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3657.
Abstract 1598: LncRNA AK001796 as a therapeutic target in aggressive breast cancers
Authors: Maneesh Kumar, Rebecca Sinnott DeVaux, Julia J. Shen, Steven P. Davis, Marcel E. Dinger, John S. Mattick, Charles M. Perou, Jeffrey M. Rosen, Sendurai A. Mani, Jason I. Herschkowitz
Journal: Cancer Research (2016)

Abstract Breast cancer is a heterogeneous disease that can be classified into several distinct molecular subtypes based on gene expression. Like mRNAs and miRNAs, long noncoding RNAs (lncRNAs) differ dramatically in expression across subtypes and can be used for classification. While there has been considerable emphasis on miRNAs, our knowledge is still lacking about the role of lncRNAs that comprise the majority of the mammalian transcriptome. Recently, the importance of lncRNAs in cancer has been highlighted by several studies. We have examined the expression profiles of &amp;gt;17,000 lncRNAs in a large set of breast tumors and have identified a lncRNA, AK001796, that is overexpressed in aggressive breast cancers. In particular, AK001796 is enriched in the aggressive claudin-low, HER-enriched, and luminal B subtypes. Furthermore, in four different models, we find that AK001796 is significantly upregulated in cell lines induced to undergo EMT and in putative mesenchymal-like cancer stem cells within cell lines suggesting this lncRNA as an inducer/facilitator of EMT. Similar results were obtained when a lung cancer cell line was induced to EMT through TGF beta treatment. Using cell fractionation, we have discovered that AK001796 is maintained predominantly in the nucleus. By RACE we have identified two isoforms of AK001796 in breast cancer cells that differ by the presence or absence of a 94 nucleotide intron. The short form (with intron spliced out) appears to be the variant enriched following EMT and may serve as a marker of aggressiveness. Interestingly, knockdown of AK001796 using antisense oligonucleotides lead to significantly increased apoptosis in EMT positive cell lines whereas in EMT negative cells knockdown had little effect. Preliminary studies for finding out the protein interacting partners identified some mesenchymal phenotype-associated proteins in pull-down studies using biotinylated oligos. To further investigate the molecular mechanisms regulated by AK001796 and its utility as a therapeutic target, we will determine the pathways induced by AK001796 by mapping its protein interaction network and downstream signaling pathways. These results nominate AK001796 as a promising therapeutic target in aggressive breast cancers. Citation Format: Maneesh Kumar, Rebecca Sinnott DeVaux, Julia J. Shen, Steven P. Davis, Marcel E. Dinger, John S. Mattick, Charles M. Perou, Jeffrey M. Rosen, Sendurai A. Mani, Jason I. Herschkowitz. LncRNA AK001796 as a therapeutic target in aggressive breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1598.
Abstract 1500: How K-Ras4B attaches to the membrane and forms a dimer: A new paradigm
Authors: Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2016)

Abstract Ras is a small GTPase, controlling signal transduction pathways and promoting cell proliferation and survival. KRAS is frequently mutated in cancer. Ras consists of highly homologous catalytic domains (G-domains) and flexible C-terminal hypervariable regions (HVRs) that differ significantly across Ras isoforms. Recent nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations discovered that the HVR of K-Ras4B in the GDP-bound state extensively interacts with the catalytic domain. However, it weakly interacts with the catalytic domain in the GTP-bound state. Here, using MD simulations we modeled K-Ras4B membrane interaction and dimerization. Membrane binding of K-Ras4B through the anchoring of the positively charged HVR is thought to be critical to its function as an oncogene and initiates signaling events. At the membrane, the catalytic domain takes on multiple orientations, including perpendicular and parallel alignments of the allosteric helices with respect to the membrane normal. In the autoinhibited state, the HVR is sandwiched between the effector lobe and the membrane; in the active state, with the farnesyl anchored into the membrane and the HVR unrestrained, the catalytic domain fluctuates reinlessly, exposing its effector binding site. Notably, we also observe HVR-autoinhibited K-Ras4B-GTP states that display GDP-bound-like orientations of the helices. We thus propose that GDP/GTP nucleotide exchange may not be sufficient for K-Ras4B activation; composite mechanisms including HVR sequestration, farnesyl insertion, and orientation/localization of the catalytic domain on the membrane can determine the functional state of K-Ras4B. Remarkably, K-Ras4B-GTP, but not GDP-bound, is able to form stable homodimers with different dimer interfaces, suggesting that the nucleotide-dependent dimerization with various dimer interfaces can resolve nanoclustering and cluster reorganization accomplishment with Raf's activation. Ras was believed to function as a monomer; however, since Raf dimerizes, it has been suspected that Ras can also dimerize. Dimerization and clustering could rein the fluctuations producing more productive pre-organized conformations. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Hyunbum Jang, Ruth Nussinov. How K-Ras4B attaches to the membrane and forms a dimer: A new paradigm. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1500.
Abstract 4172: A role for RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus
Authors: Rachel Lieberman, Donghai Xiong, Ming You
Journal: Cancer Research (2016)

Abstract Although 80-90% of lung cancer patients smoke, only about 10% of heavy smokers develop lung cancer. This suggests that although tobacco smoke undoubtedly increases one's risk for lung cancer, genetic risk factors most likely predispose certain individuals. Recent genome-wide association studies identified variation in the recombination repair gene, RAD52, associated with increased lung cancer risk, and particularly with squamous cell lung carcinoma (SCC). SCC development is strongly associated with smoking and individuals who smoke have increased DNA repair, presumably to address ongoing DNA damage from exposure to tobacco smoke. Hence, it fits that the genomic region of 12p13.33 containing RAD52 shows both copy number amplification and an increase in gene expression in SCC tumors compared to normal. Functionally, we have previously demonstrated that overexpression of Rad52 in mouse bronchial epithelial and lung tumor cells leads to an increase in growth rate and that depletion leads to decreased cell growth, senescence, and an accumulation of cells in G2/M. Our current study focuses on genetic instability within lung tumor progression and how the DNA repair gene RAD52 allows primary tumor cells to become genetically stable enough to be able to invade and avoid apoptosis. C57BL6 wildtype or Rad52−/− mice at 8 weeks of age were randomized into two groups and treated topically with 0.04 M NTCU in 100-microliter drop, twice a week for 40 weeks. Unlike mouse lung adenocarcinomas, mouse SCC does not form visible solid nodules on the surface of the lung. Lungs were fixed and stained with H&amp;E and examined histologically under a light microscope to establish tumor multiplicity and the types of lesions (invasive SCC, SCC in situ, or bronchial hyperplasia/metaplasia). Lung tissue was also stained for TUNEL analysis as well as markers of SCC and proliferation. Our novel findings demonstrate that depletion of Rad52 in vitro generates increased DNA damage and sensitivity to cell death, while knockout of the Rad52 gene in an in vivo mouse model of carcinogenesis decreases murine lung hyperplasia, in situ carcinoma and lung SCC. In addition, knockout appears to increase apoptosis. Thus, our functional studies continue to support genetic findings by revealing that loss of RAD52 can enhance cell death and DNA damage in lung tumor cells. This complementary evidence further strengthens the notion of RAD52 as a potential oncogene and implicates a major role for the process of recombinational repair in determining risk for SCC. Citation Format: Rachel Lieberman, Donghai Xiong, Ming You. A role for RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4172.
PLASMA-LIPOPROTEIN COMPOSITION AND GLOMERULAR APOLIPOPROTEIN AND LIPID DISTRIBUTION IN RATS WITH CHRONIC NEPHROTIC SYNDROME INDUCED BY A SINGLE LOW-DOSE OF ADRIAMYCIN
Authors: Ja Joles, H Vangoor, Aj Rabelink, Ha Koomans, Ehjm Jansen, A Vantol
Journal: Kidney International (1992)