tbuckley/cabot-search huggingface dataset:
Abstract LB-292: Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention
Authors: Kenneth K.W. To, Wing Wah Leung, Simon S.M. Ng
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. It develops in a complex multi-step process. The majority of studies to date have focused on genetic mutations and epigenetic changes that drive the CRC carcinogenesis process. Xenobiotic transporters play an important role in safeguarding our body from external toxic substances. These transporters lining the gastrointestinal tract may thus protect us from the dietary carcinogens. This study aims to investigate the downregulation of an efflux transporter ABCG2 in colorectal cancer versus normal colon mucosa, so as to shed some light on its relevance to CRC initiation and progression. We found that ABCG2 expression is at least 50-fold lower in adenomatous polyps and colon carcinoma specimens obtained from CRC patients than in their matched pair of adjacent normal colon mucosa. This may facilitate the accumulation of genotoxins to propel tumor initiation and progression. The underlying mechanism(s) for ABCG2 under-expression in CRC is currently not known. To this end, aberrant promoter methylation of ABCG2 has been reported to cause its repression in a few cancer types including renal carcinoma and multiple myeloma. On the other hand, ABCG2 promoter demethylation has been reported to upregulate the transporter to mediate multidrug resistance in lung cancer and acute lymphoblastic leukemia. In this study, miR-203 was found to be downregulated in all polyps and CRC specimens, relative to adjacent normal colon mucosa. We demonstrated that the de novo DNA methyltransferase DNMT3 is a direct target of miR-203. Importantly, by relieving the repression on DNMT3, the lower expression of miR-203 in CRC caused remarkable ABCG2 promoter methylation and lower ABCG2 expression in colon cancer cell lines and the patient CRC specimens. In spite of the complex sequential genetic mutations and epigenetic changes leading to CRC formation, we proposed that the restoration of the xenobiotic transporter ABCG2 function via modulating this new microRNA-DNA methylation mechanism in precancerous cells may represent an attractive strategy to stop or delay the carcinogenesis process. Citation Format: Kenneth K.W. To, Wing Wah Leung, Simon S.M. Ng. Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-292. doi:10.1158/1538-7445.AM2015-LB-292
PTH-216 Trace element measurement in hospitalised children on parenteral nutrition: Abstract PTH-216 Table 1
Authors: TIY Hassan, C Knox, S Hill
Journal: Gut (2015)

<h3>Introduction</h3> The aim of parenteral nutrition (PN) is to meet the body’s needs while avoiding complications of deficiency and toxicity.<sup>1</sup>Trace elements (Cu, Zn, Se) play an important role in many of the body’s functions including metabolism, immunity and enzymes.<sup>1</sup>ESPGHAN/ ESPEN guidelines recommended that levels of trace elements should be checked at the commencement and frequently after starting PN.<sup>1</sup>Our aim was to review the current practice in our tertiary paediatric hospital. <h3>Method</h3> In-patients receiving PN were identified from the pharmacy database. All records from patients receiving PN on two randomly allocated days in December and January were analysed for demographic data and diagnosis. From the laboratory database we looked for Zinc (Zn), Copper (Cu) and Selenium (Se) levels at the commencement and 4–8 weeks after starting PN. We excluded patients with no available data on the start of PN. <h3>Results</h3> 72 patients receiving PN were identified on the two days. Data were available for 63 patients and 9 others were excluded as data was not available on starting PN. The 63 patients with available results were aged 1–16 years, median age of 4.5 years. 36 were males. Overall; Trace Elements (TE) were checked in 26/63 (41.2%) (Table1). TE results were available before or within one week of starting PN in 18/63 (28.5%). Thirteen had TE follow up. Table 3 shows the levels of TE within one week of starting PN and the follow up results. 5 patients had low initial Zn, Cu and Se. These were patients with Tufting enteropathy, early onset inflammatory bowel disease (IBD), one patient with IPEX, one patient with Intestinal obstruction and one with missing records. The latter two in addition to another patient with HLH also had low levels on follow up. Out of the whole cohort of 63, 27 (43%) patients have an underlying gastrointestinal disorder, 20 (74%) of whom had levels checked initially and 9 (33%) had levels done on follow up. <h3>Conclusion</h3> Unfortunately determination of TE level is frequently missed in our institution. Although figures from the gastroenterology department were better than other departments, we recommended use of a proforma to be filled by the clinician before starting PN. We recommend TE to be checked at least once every 3 months for those with normal levels and once a month for those with low levels. A re-audit is planned later in the year. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Koletzko B, <i>et al</i>. J Pediatr Gastroenterol Nutr. 2005;41(Suppl 2)
Abstract 3241: Tumor-targeting Salmonella typhimurium A1-R inhibits peritoneal dissemination of ovarian cancer and prolongs survival of the tumor-bearing nude mice
Authors: Yasunori Matsumoto, Shinji Miwa, Ming Zhao, Yong Zhang, Shuya Yano, Fuminari Uehara, Mako Yamamoto, Yukihiko Hiroshima, Makoto Toneri, Michael Bouvet, Hisahiro Matsubara, Robert Hoffmann
Journal: Cancer Research (2015)

Abstract Peritoneal dissemination of cancer arising from an intra-abdominal organ has poor prognosis and is treatment resistant. A peritoneal dissemination nude mouse model of ovarian cancer was made with the human ovarian cancer cell line SKOV-3-GFP. Tumor-targeting Salmonella typhimurium A1-R (A1-R) was administrated i.v. or i.p. to the tumor-bearing nude mice. Survival of the tumor-bearing nude mice was prolonged by i.v. administration of A1-R (p = 0.025) as well as by i.p. administration of A1-R (p = 0.00003), compared with the untreated control. There was no significant difference in survival between i.v. and i.p. administration (p = 0.22). However, i.p. administration was less toxic. The present results suggest A1-R has clinical potential for what is currently a highly-treatment-resistant disease. Citation Format: Yasunori Matsumoto, Shinji Miwa, Ming Zhao, Yong Zhang, Shuya Yano, Fuminari Uehara, Mako Yamamoto, Yukihiko Hiroshima, Makoto Toneri, Michael Bouvet, Hisahiro Matsubara, Robert Hoffmann. Tumor-targeting Salmonella typhimurium A1-R inhibits peritoneal dissemination of ovarian cancer and prolongs survival of the tumor-bearing nude mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3241. doi:10.1158/1538-7445.AM2015-3241
Abstract 3718: Trends in tobacco use and prostate cancer mortality in four US states, 1999-2010
Authors: Miranda R. Jones, Corinne E. Joshu, Norma F. Kanarek, Ana Navas-Acien, Kelly A. Richardson, Elizabeth A. Platz
Journal: Cancer Research (2015)

Abstract Background: In the US, prostate cancer mortality rates have declined in past decades. Cigarette smoking, a risk factor for prostate cancer death, has also declined. It is unknown whether declines in smoking prevalence produced detectable declines in prostate cancer mortality in the population. Objective: To examine prostate cancer mortality rates in relation to changes in tobacco use in the population. Methods: We studied men ≥35 years of age from California, Kentucky, Maryland and Utah. State smoking prevalences were obtained from the Behavioral Risk Factor Surveillance System (BRFSS). Mortality rates for prostate cancer and external causes, as a control condition, were obtained from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) system. The average annual percent change for smoking and prostate cancer mortality for 1999 to 2010 was estimated using joinpoint analysis. Results: In 1999, the smoking prevalence among men ≥35 years of age was 31.7%, 20.9%, 19.9% and 14.8% in Kentucky, Maryland, California and Utah, respectively. Between 1999 and 2010, smoking in Kentucky declined by 3.0% per year (95% CI: -4.0%, -1.9%) and prostate cancer mortality declined by 3.5% per year (95% CI: -4.3%, -2.7%). In Maryland, smoking declined non-significantly by 3.0% per year (95% CI: -7.0%, 1.2%) and prostate cancer mortality declined by 3.5% per year (95% CI: -4.1%, -3.0%). In California, smoking declined by 3.5% per year (95% CI: -4.4%, -2.5%) and prostate cancer mortality declined by 2.5% per year (95% CI: -2.9%, -2.2%). In Utah, smoking declined by 3.5% per year (95% CI: -5.6%, -1.3%) and prostate cancer mortality declined by 2.1% per year (95% CI: -3.8%, -0.4%). No such patterns were observed for smoking and external causes of death in any of the states. Conclusion: Similar declines were observed in the prevalence of smoking and prostate cancer mortality. Although ecological, this study suggests that declines in prostate cancer mortality rates are consistent with a beneficial effect of reducing tobacco use at the population level. Citation Format: Miranda R. Jones, Corinne E. Joshu, Norma F. Kanarek, Ana Navas-Acien, Kelly A. Richardson, Elizabeth A. Platz. Trends in tobacco use and prostate cancer mortality in four US states, 1999-2010. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3718. doi:10.1158/1538-7445.AM2015-3718
PDCT-16. SURVIVAL BENEFIT WITH TRIPLE CHEMOTHERAPY AND TTFIELDS FOR GLIOBLASTOMA
Authors: Guangrong Lu, Mayank Rao, Lauren C. Delumpa, Zheyu Liu, Sigmund Hsu, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2016)

Glioblastoma multiforme (GBM) is the most aggressive and common glial tumor. Historical data shows that median overall survival (OS) is 14.6 months with maximum safe resection followed by radiation and chemotherapies. We have been treating recurrent GBM patients with triple chemotherapies [Temozolomide (TMZ), bevacizumab (BV) and Irinotecan (CPT-11)] since 2010. We also offer patients tumor treating fields (TTFs) for recurrent GBM following FDA approval and participated in the EF-14 clinical trial for newly diagnosed GBM from 2011. Here we report OS data of our institute’s patients on TTFs treatment, with or without the triple chemotherapy, from February 2011 to June 2016. Data review was approved by the Committee for the Protection of Human Subjects at UT Health. Kaplan-Meier survival curve and log rank test were used for statistical analysis. Primary objectives were OS and adverse events. Fifty-two GBM patients (21-76 years old, average age=54 ± 11.6) received TTFs treatment, 32 of which expired, 17 patients are alive and the survival status of 3 patients remains unknown. For patient received triple chemotherapies (TMZ cycles=17.9 ± 11.2; BV infusion times= 23.5 ± 10.8; CPT-11 infusion times=13.7 ± 6.8) plus TTFs (446 ± 396 days), median OS is 34.5 months (n=29, 95% CI: 27.8-49.7). Median OS is 14.0 months (n=23, 95% CI: 11.5-17.90) for patients receiving BV/CPT-11 (TMZ cycles=4.9 ± 7.2; BV infusion times=6.6 ± 6.2) plus TTFs (164 ± 198 days), log rank test p<0.05. For patients who started TTFs within 125 days from their initial diagnosis, OS is 39.4 months (n=15, 95% CI: 11.8-53.1). Major adverse events are chemotherapy related thrombocytopenia (grade III in 2 cases), neutropenia, anemia, GI toxicities (nausea, vomiting and diarrhea) and TTFs related scalp lesions. Molecular profile will be provided at the time of presentation. Treating recurrent GBM with triple chemotherapies (BV, TMZ, and CPT-11) is reasonably well-tolerated with manageable side effects. Triple chemotherapies plus TTFields demonstrates superior OS benefit compared to historical data.
Abstract 3837: Super-enhancers define breast cancer subclasses and identify novel tumor cell vulnerabilities
Authors: Cindy Collins, Mei Wei Chen, Matthew Eaton, David Orlando, Michael McKeown, Christian Fritz, Eric Olson, Matthew Guenther
Journal: Cancer Research (2015)

Abstract Breast cancer cell state is driven by genomic mutational events, aberrant signaling cascades and transcriptional misregulation. The profound clinical impact of ER-modulatory drugs underscores the importance of understanding and targeting the transcriptional dependencies of breast cancer cells in an effort to create new therapeutics. Recently, large clusters of cis-acting enhancers, termed Super-enhancers, have emerged as dominant transcriptional regulators of oncogenes and other key tumor drivers in cancer cells, indicating that these elements control and maintain breast tumor cell state. Mapping these elements and the genes they control in patient tumors can provide insight into breast cancer classification and identify therapeutic targets. We have discovered Super-enhancers in breast cancer patient tissue and have characterized their roles in enforcing tumor cell state. We find that Super-enhancers define known clinical subgroups in invasive ductal carcinoma and pinpoint the putative transcriptional drivers of each subgroup. Super-enhancer-associated genes encode both known and novel therapeutic targets including kinases, phosphatases, chromatin regulators and transmembrane proteins, including key drivers such as ERRB2 in HER2+ patient samples, ESR1 in estrogen receptor positive samples, and CCND1 in samples of luminal subtype. shRNA knockdown confirms that Super-enhancer regulated genes are indeed essential for tumor cell survival and that Super-enhancer analysis in primary patient samples can be used to define new subtype specific cancer vulnerabilities. In sum, we describe the biological and disease relevance of Super-enhancer-associated genes in the context of tumor cell state, genome mutational landscape and drug target discovery. Citation Format: Cindy Collins, Mei Wei Chen, Matthew Eaton, David Orlando, Michael McKeown, Christian Fritz, Eric Olson, Matthew Guenther. Super-enhancers define breast cancer subclasses and identify novel tumor cell vulnerabilities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3837. doi:10.1158/1538-7445.AM2015-3837
Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways
Authors: Adeeb Derakhshan, Zhong Chen, Carter Van Waes
Journal: Clinical Cancer Research (2016)

Abstract The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell survival, and NF-κB signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred in vitro, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα in vivo. In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients. Clin Cancer Res; 23(6); 1379–87. ©2016 AACR.
Akap-mediated signalling: the importance of being in the right place at the right time
Authors: Cinzia Perrino, Bruno Trimarco
Journal: Cardiovascular Research (2016)

This editorial refers to ‘Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve’ by Li et al. , pp. 147–159. 

Seven transmembrane receptors (7TMR) are crucial regulators of cardiac function and remodelling in disease; they are the target of the vast majority of small molecule therapy and prescriptions for cardiovascular diseases, i.e. inhibitors of signalling through adrenergic receptors and angiotensin.1,2 ‘Traditional’ G protein-dependent signalling of 7TMR activates effector kinases such as cAMP-dependent Protein Kinase A (PKA) or Protein Kinase C (PKC) and phosphorylation of intracellular substrates. Within the cells, signals generated at the plasma membrane are spatially and temporally amplified by a large class of A kinase Anchor Proteins (AKAPs), assembling complexes of signal transmission and propagation at specific intracellular locations.3 Multi-protein complexes nucleated by AKAPs create intracellular sites wherein signalling pathways converge and are locally and temporally attenuated or amplified, thereby optimizing the biological response to extracellular stimuli.4 While β-adrenergic receptors (β-ARs) levels and responsiveness are consistently blunted in response to pathological stimuli and in human heart failure, phosphorylation levels of cardiac substrates are variably affected indicating the importance of the local signalling cascade.5,6 Given their spatial-temporal modulation of localized phosphorylation/dephosphorylation events, AKAPs represent novel interesting and promising therapeutic targets in cardiovascular diseases.3

Several AKAPs have been described in the heart and vasculature, targeting PKA and other proteins at specific cellular locations such as, for example, the sarcolemma, sarcoplasmic reticulum, nuclei, and mitochondria.3,4,7 AKAP150, the murine ortholog of human AKAP79 and one of the most extensively characterized AKAPs in the cardiovascular system, interacts …
Safety of Defibrotide (DF) In Stem Cell Transplant (SCT) Patients (Pts).
Authors: Selim Corbacioglu, Enric Carreras, Dietger W Niederwieser, Marco Sardella, Margaret Hoyle, Robin Hume, Joseph Massaro, Alison L. Hannah, Massimo Iacobelli, Paul G Richardson
Journal: Blood (2010)
Immunosuppressant Sinomenine Promotes Differentiation of Bone Marrow Progenitors to IL-10-Producing Ialow Regulatory Dendritic Cells Leading to the Prolongation of Allograft Survival.
Authors: Quanxing Wang, Jianchun Wu, Jianli Wang, Yushan Liu, Guoyou Chen, Xuetao Cao
Journal: Blood (2007)
560. Therapeutic Editing of the HBB Locus Using the Endogenous HBD Locus as a Donor Template
Authors: Cecilia Cotta-Ramusino, Tanushree Phadke, Morgan Maeder, David Bumcrot
Journal: Molecular Therapy (2015)

Sickle Cell Anemia is a recessive disorder caused by a single point mutation in the human beta globin (HBB) gene. Affecting nearly 1 million people worldwide, this disease is severely lacking in long-term treatment options and is a prime candidate for a gene editing therapeutic approach. Here we report the use of the CRISPR/Cas system to target the human HBB gene in the region of the sickle cell anemia-causing mutation. Utilizing two different Cas9 nickases as well as the wild type nuclease, we are able to introduce blunt double-strand breaks, single strand nicks, and dual-nicks in which the nicks are placed on opposite strands and leave either 3' or 5' overhangs of varying lengths. Using either single strand oligonucleotide (ssODN) or plasmid DNA donors, we characterize several different DNA repair outcomes including indel mutations resulting from non-homologous end-joining, homology-dependent repair (HDR) using the donor as a template, and finally HDR using the closely related HBD gene as an endogenous template. Repair using homologous sequences from the HBD gene results in partial gene-conversion yielding a chimeric HBB-HBD gene. The region of gene conversion includes the sequence most commonly mutated in sickle cell anemia. The frequency of this event depends on the nature of the break. The data support a therapeutic approach in which correction of the sickle-cell mutation is efficiently mediated through HDR using a donor template or by gene-conversion using the endogenous HBD gene.
PREDICT phase II: A trial to prospectively validate a gene signature associated with clinical benefit from MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) in patients with unresected metastatic cutaneous melanoma.
Authors: P. Saiag, J. S. Weber, B. Dreno, A. Hauschild, C. Jamoul, O. Peeters, P. Therasse
Journal: Journal of Clinical Oncology (2011)

TPS231 Background: Active immunization towards the tumor-specific antigen MAGE-A3 is a potential new option under investigation to treat cancer. Clinical activity of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) has been observed in a Phase II trial (NCT00086866) in patients with unresected metastatic cutaneous melanoma. Current data showed that combination of MAGE-A3 recombinant protein with the AS15 immunostimulant induced a robust and long-lasting antibody and CD4 T-cell immune response as well as clinical responses. Retrospective gene expression profiling of the tumor taken prior immunization led to the characterization of a gene signature (GS) associated with clinical benefit (Louahed et al., EORTC-NCI-AACR 2009). Methods: The aim of this open-labeled, single-arm trial (PREDICT, NCT00942162) is to prospectively validate the GS as a predictive biomarker of the clinical outcome of the MAGE-A3 ASCI. Main eligibility criteria are patients with histologically proven measurable MAGE-A3+ metastatic cutaneous melanoma, (unresectable stage III or stage IV M1a melanoma - AJCC 2002), an ECOG performance status of 0-1. Patients will receive a maximum of 24 doses of MAGE-A3 ASCI (recMAGE-A3 + AS15) by i.m. injections over 48 months. The primary endpoint is 1-Year overall survival rate (OSR) in the GS+ population. Main secondary endpoints include 1-Year OSR in global and GS- populations but also the clinical response rate and other clinical activity indicators (PFS, median OS) in these 3 populations. The GS will be determined on the tumor collected for the MAGE-A3 screening. This trial is also an opportunity to validate the technology transfer to support large scale identification of the GS: from micro-array on fresh tissue (NCT00086866) to qRT-PCR on FFPE tumor samples (PREDICT). Data of Jan 10, 2011 showed that 280 patients were screened. Out of the 236 tumor samples valid for MAGE-A3 expression testing, 111 were found MAGE-A3+ with a MAGE-A3 expression rate of 47% and 82 patients were finally enrolled. The identification of the GS status is ongoing for the enrolled population.
Umbilical Cord Blood Derived CD133+ Hematopoietic Stem Cells Are Defective Antigen Presenting Cells (APC), Lack Expression of Co-Stimulatory Receptors, and Generate TH2 T-Lymphocyte Responses In Vitro.
Authors: L.R. Fanning, M.R. Finney, V.J. Pompili, N.J. Greco, H.M. Lazarus, M. Kozik, H. Meyerson, R. Nair, J. Maciejewski, M. Tary-Lehmann, M. Ratajczak, Mary J. Laughlin
Journal: Blood (2006)