tbuckley/cabot-search huggingface dataset:
Abstract 681: Using a genome-editing approach for the stepwise establishment of zebrafish models of pediatric high-grade gliomas and MPNSTs
Authors: Felix Oppel, Shuning He, Ting Tao, Mark W. Zimmerman, Adam D. Durbin, Nina Weichert, Dong H. Ki, A Thomas Look
Journal: Cancer Research (2016)

Abstract By high-throughput sequencing of cancer patient's genomes, driver mutations have recently been described in high-grade pediatric glioma, an aggressive type of brain tumor in children. The most prominent recurrent mutations were found in four genes, namely NF1, TP53, ATRX and H3F3A. NF1 and TP53 are tumor suppressor genes and their loss of function is characteristic for various human malignancies. However, the mechanisms through which precise missense mutations in H3F3A and loss-of-function of ATRX influence tumor biology remain largely unknown. In our project, we employ the genome-editing technology CRISPR-Cas9 to develop a zebrafish model of pediatric high-grade glioma, in order to examine the impact of these mutations on tumor onset and progression. We previously created a zebrafish line that is deficient for tp53 (tp53-/-) and has a loss-of-function mutation in 3 of 4 alleles of nf1 (nf1a+/-, nf1b-/-), which is duplicated in zebrafish. These fish develop high-grade gliomas with low penetrance and malignant peripheral nerve sheath tumors (MPNSTs) with high penetrance. By CRISPR-Cas9 we further incorporated early frameshift mutations of atrx in the background of tp53-/-, nf1a+/-, nf1b-/-. All analyzed fish injected with Cas9-mRNA and CRISPR guide-RNAs (gRNAs) targeting atrx coding sequences showed germline transmission of mutant alleles, of which one third were frameshift mutations. Primary CRISPR-Cas9 atrx-gRNA injected tp53-/-, nf1a+/-, nf1b-/- fertilized eggs developed as mosaics and exhibited increased tumor penetrance and faster onset of MPNSTs and these tumors harbored atrx mutations in 8/10 analyzed samples. This indicates that atrx loss-of-function mutations cooperate with loss of tp53 and nf1 tumor suppressors. Gliomas were not observed in mosaic atrx mutated fish, and these will be reanalyzed in stable atrx mutant lines. Next, we will add previously described missense mutations of h3f3a. To unravel the synergy between oncogenic mutations in atrx and h3f3a in tumor progression, mutant stable lines for both genes will be investigated independently and in a combined manner. The zebrafish model of pediatric high-grade gliomas and MPNSTs that we are developing will be useful to dissect the mechanisms underlying cooperation among driver mutations and for small molecule screens to identify specific inhibitors of cell growth and survival in these malignancies. Citation Format: Felix Oppel, Shuning He, Ting Tao, Mark W. Zimmerman, Adam D. Durbin, Nina Weichert, Dong H. Ki, A Thomas Look. Using a genome-editing approach for the stepwise establishment of zebrafish models of pediatric high-grade gliomas and MPNSTs. [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 681.
Mechanical Versus Manual Chest Compression For Out-of-hospital Cardiac Arrest: A Cluster Randomized Trial
Authors: G D Perkins, R Lall, T Quinn, C D Deakin, M W Cooke, J Horton, S E Lamb, Slowther A-M., A Carson, M Smyth, R Whitfield, A Williams, H Pocock, J J Black, J Wright, K H Han, S Gates
Journal: Circulation (2014)

Background:
Mechanical chest compression devices have the potential to help maintain high-quality cardiopulmonary resuscitation (CPR), but despite their increasing use, little evidence exists for their effectiveness. We aimed to study whether the introduction of LUCAS-2 mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest.
Methods:
The pre-hospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial was a pragmatic, cluster-randomised open-label trial including adults with non-traumatic, out-of-hospital cardiac arrest from four UK Ambulance Services (West Midlands, North East England, Wales, South Central). 91 urban and semi-urban ambulance stations were selected for participation. Clusters were ambulance service vehicles, which were randomly assigned (1:2) to LUCAS-2 or manual CPR. Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene. The primary outcome was survival at 30 days following cardiac arrest and was analysed by intention to treat. Ambulance dispatch staff and those collecting the primary outcome were masked to treatment allocation. Masking of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. The study is registered with Current Controlled Trials, number ISRCTN08233942.
Findings:
We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 group, 2819 assigned to the control group) between April 15, 2010 and June 10, 2013. 985 (60%) patients in the LUCAS-2 group received mechanical chest compression, and 11 (<1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30 day survival was similar in the LUCAS-2 group (104 [6%] of 1652 patients) and in the manual CPR group (193 [7%] of 2819 patients; adjusted odds ratio [OR] 0·86, 95% CI 0·64–1·15). No serious adverse events were noted. Seven clinical adverse events were reported in the LUCAS-2 group (three patients with chest bruising, two with chest lacerations, and two with blood in mouth). 15 device incidents occurred during operational use. No adverse or serious adverse events were reported in the manual group.
Interpretation:
We noted no evidence of improvement in 30 day survival with LUCAS-2 compared with manual compressions. On the basis of ours and other recent randomised trials, widespread adoption of mechanical CPR devices for routine use does not improve survival.
Funding:
National Institute for Health Research HTA – 07/37/69.
Abstract 2914: Biphenylene and bipyridine connected benzofuran compounds as novel regulators of kRAS transcription
Authors: Harshul Batra, Mohammad K. Islam, David E. Thurston, Khondaker M. Rahman, Tracy A. Brooks
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is the fourth most deadly cancer with 5 year survival rate of ∼6%. One of the major attributes of pancreatic cancer is kRAS mutations. kRAS is a proto-oncogene with intrinsic GTPase activity, and is responsible for cell proliferation, division, and apoptosis. kRAS mutations are observed in &amp;gt;95% of pancreatic adenocarcinoma and in 30% all human tumors. When mutated it leads to continuous activity and uncontrolled proliferation which results in increased tumorigenicity and poor prognosis. Downregulating kRAS expression has shown to halt proliferation and leads to cellular death in pancreatic cancer models, but to date no small molecule capable of such transcriptional silencing has been described. A novel series of molecules with either biphenylene or bipyridine spacer connecting the terminal benzofuran ring was synthesized using solution phase chemistry. Tertiary amine side chains were incorporated to the C2-position of the benzofuran ring to improve the DNA binding affinity of these compounds. The synthesized compounds were purified using a “catch and release” method employing the sulfonic acid based resins. The eleven novel compounds were screened in parallel for their ability to stabilize G-quadruplex structures in the kRAS promoter, and to downregulate kRAS promoter activity. Two of the compounds increased the thermal profile of non-canonical DNA formations in the promoter region by &amp;gt;5 °C; however, on the whole these compounds did not seem to function as G-quadruplex-stabilizing agents. Eight compounds significantly decreased luciferase expression under the explicit control of the kRAS promoter by up to 75%, by compound BF 4.3, through an as-yet unknown mechanism of action. The compound series was examined for the inhibition of cellular viability in two mutant kRAS pancreatic cancer cell lines - Panc-1 and MIA PaCa-2; in both cell lines the compounds containing the bipyridine spacer had greater cytotoxic effects with IC50's of ∼30 μM, consistently. qPCR is being used to confirm the decrease in promoter activity in native cellular conditions. These agents are intriguing in both their novel scaffold and their unexpected activity decreasing kRAS expression in a mechanism unrelated to higher order DNA structures. Ultimately, down regulation of kRAS transcription will provide a novel therapeutic approach for pancreatic cancer and improve the prognosis of this highly lethal disease. Citation Format: Harshul Batra, Mohammad K. Islam, David E. Thurston, Khondaker M. Rahman, Tracy A. Brooks. Biphenylene and bipyridine connected benzofuran compounds as novel regulators of kRAS transcription. [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 2914.
Filaggrin gene loss‐of‐function variants modify the effect of breast‐feeding on eczema risk in early childhood
Authors: A. H. Ziyab, N. Mukherjee, S. Ewart, S. H. Arshad, W. Karmaus, F. Turati, P. Bertuccio, C. Galeone, C. Pelucchi, L. Naldi, J‐F. Bach, C. L. Vecchia, L. Chatenoud
Journal: Allergy (2016)
Abstract 3577: Pan-cancer analysis of mutagenesis by APOBEC cytidine deaminases
Authors: Dmitry A. Gordenin
Journal: Cancer Research (2016)

Abstract The elucidation of mutagenic processes that shape cancer genomes is a fundamental problem whose solution promises insights into new treatment, diagnostic, and prevention strategies. We and others previously identified mutation clusters and genome-wide mutagenesis bearing the single-strand DNA (ssDNA)-specific APOBEC cytidine deaminase signature at 5′-tC-3′ motifs across many cancer types. Because of high abundance of APOBEC mutagenesis in several cancer types, we have developed a statistical approach capable of identifying cancer samples with APOBEC mutagenesis pattern based on WGS as well as on WES mutation data. This analysis, called Pattern of Mutagenesis by APOBEC Cytidine Deaminases (P-MACD), has been recently integrated into the Broad Institute GDAC Firehose and is currently available for Firehose standard and AWG-customized runs. The results of analysis using the P-MACD package will be discussed, including correlations with molecular and clinical features of TCGA cancer samples as well as relative roles of different APOBEC enzymes in cancer mutagenesis. Citation Format: Dmitry A. Gordenin. Pan-cancer analysis of mutagenesis by APOBEC cytidine deaminases. [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 3577.
Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor (PI).
Authors: J. L. Wolf, R. Vij, S. Lonial, M. Wang, S. Jagannath, S. Singhal, M. H. Le, C. Kirk, S. Arastu-Kapur, D. S. Siegel
Journal: Journal of Clinical Oncology (2010)

8135 Background: Treatment-induced peripheral neuropathy (TIPN) is a common, frequently debilitating, therapy-limiting complication in multiple myeloma (MM). Chemotherapies associated with TIPN in MM include thalidomide and bortezomib (BTZ). CFZ, a novel, highly selective PI, is structurally and mechanistically distinct from BTZ. In Ph I-II trials single-agent CFZ is active without dose-limiting PN in pts with relapsed and/or refractory (R/R) MM. Here we compare CFZ and BTZ in a neurotoxicity model and report clinical experience with CFZ in R/R MM. Methods: An in vitro neurotoxicity model established with differentiated SH-SY5Y neuroblastoma cells was used to investigate PI effects on neurite degeneration. A possible mechanism was pursued by bioinformatic and biochemical methods. Data were pooled from 2, ongoing Ph II trials of single-agent CFZ in pts with R/R MM, including neuropathy history, baseline neuropathic symptoms and neurological exam findings, prospective neurological exams, and FACT-GOG/NTx pt survey scores. PN adverse event data were also included. Results: Following 24 hrs of exposure to 10 nM BTZ, SH-SY5Y cells showed 40% reduction in neurite length/cell compared to CFZ- or vehicle-treated cells. Both agents induced equivalent proteasomal inhibition suggesting off-target effects induce neurodegeneration. HtrA2/Omi, a mitochondrial serine protease with a role in neuron survival was identified in databases and confirmed as a target of BTZ (IC50 = 3 nM), but not of CFZ (>10 μ M). At screening, 72% of 135 pts had active Grade (G) 1/2 PN; 81% had a history of TIPN. Pts received a mean of 30.4 CFZ doses (range 2–72) and 17% received >10 mo of therapy. New onset PN or PN worsening from baseline was reported in 16% of pts. There were no reports of G4 PN, missed doses, or treatment discontinuations. Only 1 pt was dose-reduced due to PN. Conclusions: In contrast to BTZ TIPN, CFZ-related PN is uncommon and not dose-limiting. In vitro, BTZ induces neurotoxicity in a proteasome-independent manner and potently inhibits a neuronal cell survival factor, HtrA2. These in vitro and clinical data suggest that severe PN is not a PI class effect. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Bristol-Myers Squibb, Celgene, Facet, Millennium, Novartis, Onyx Onyx Celgene, Johnson & Johnson, Merck, Millennium, Onyx, Ortho, Takeda Bristol-Myers Squibb, Celgene, Facet, Gloucester Pharmaceuticals, Millennium, Novartis, Onyx
Definitions for Sepsis and Septic Shock—Reply
Authors: Clifford S. Deutschman, Mervyn Singer
Journal: JAMA (2016)

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Abstract 2983: Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1
Authors: Edward J. Morris, Eiko Kawamura, Jordan Gillespie, Paul McDonald, William Muller, Shoukat Dedhar
Journal: Cancer Research (2016)

Abstract Centrosome amplification and supernumerary centrosomal content are common features of cancer cells. Such cells must cluster their centrosomes to form a bipolar spindle and achieve productive mitosis. Targeting the mechanisms that allow cells to cluster extra centrosomes is considered a promising cancer therapeutic strategy. We have now identified Stat3, a protein that is frequently activated in many types of cancers and also regulates stem cell function, as a regulator of centrosome clustering in cancer cells. A high content chemical screen for the identification of inhibitors of centrosome clustering identified Stattic, a Stat3 inhibitor, as a centrosome clustering inhibitor. Stat3 depletion in cell lines as well as in tumors in vivo resulted in significant inhibition of centrosome clustering and in decreased tumor viability and growth. Interestingly, we identify a novel, transcription-independent mechanism for Stat3-mediated centrosome clustering that requires activities of Stathmin, a Stat3 interactor involved in microtubule depolymerisation, and polo-like kinase1 (PLK1). Furthermore, stem cell function in PLK4-driven centrosome amplified breast tumor cells is highly sensitive to Stat3 inhibitors, reflected in higher inhibitor sensitivity of tumors derived from these cells in vivo. We have therefore identified a novel role of Stat3 in the regulation of centrosome clustering, and this role of Stat3 may be critical in identifying tumor types that are sensitive to Stat3 inhibitors. Citation Format: Edward J. Morris, Eiko Kawamura, Jordan Gillespie, Paul McDonald, William Muller, Shoukat Dedhar. Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1. [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 2983.
Abstract 3445: C-reactive protein and lung cancer risk: a Mendelian randomization analysis
Authors: Orestis A. Panagiotou, Neil E. Caporaso, Maria T. Landi, Nilanjan Chatterjee
Journal: Cancer Research (2016)

Abstract Background: Elevated levels of C-reactive protein (CRP) are associated with increased risk of lung cancer in observational studies. We investigated the causal relation between CRP and lung cancer using previously discovered single-nucleotide polymorphisms (SNPs) associated with CRP levels as genetic instruments. Methods: We analyzed four lung cancer case-control studies (EAGE, PLCO, ATBC, CPSII) with available GWAS data (total 5,713 cases and 5,736 controls). We identified 21 SNPs associated with CRP levels at P&amp;lt;10-7 in genome-wide association studies (GWAS) and constructed a weighted polygenic score (PGS) multiplying the number of CRP-increasing alleles in each locus by the GWAS-reported effect of the respective allele on CRP levels; this is the largest number of CRP SNPs used in a Mendelian randomization for lung cancer to date. We first examined whether the PGS is associated with smoking phenotypes (smoking status, cigarettes per day, pack-years, smoking duration). Subsequently, we used this PGS as an instrumental variable and estimated the odds ratio (OR) and 95% confidence interval (CI) of lung cancer per standard deviation change in the PGS using logistic regression and adjusting for age, gender, and smoking. We conducted subgroup analyses for different types of lung cancer histologies. Analyses were performed separately for each study and study-specific results were combined through random-effect meta-analysis. Results: The PGS was not significantly associated with the number of cigarettes smoked per day (P = 0.621), pack-years (P = 0.829), smoking status (0.739), or smoking duration (P = 0.743). Overall, there was no association between PGS and lung cancer risk in EAGLE (OR = 1.02, 95% CI 0.77-1.36; P = 0.876), PLCO (OR = 0.94, 95% CI 0.68-1.31; P = 0.722), ATBC (OR = 0.80, 95% CI 0.59-1.07; P = 0.132), or CPSII (OR = 0.61, 95% CI 0.37-1.02; P = 0.059) as well as after meta-analysis (OR = 0.88, 95% CI 0.73-1.05; P = 0.149; I2 = 17.3%]. Meta-analysis results were similar for adenocarcinoma (OR = 0.94, 95% CI 0.74-1.20; P = 0.630; I2 = 9.3%), squamous cell carcinoma (OR = 1.03, 95% CI 0.79-1.34; P = .844; I2 = 0%), small-cell lung cancer (OR = 0.97, 95% CI 0.62-1.50; P = 0.882; I2 = 34.9%), and other non-small cell lung cancer (OR = 0.93 (0.53-1.65), P = 0.815, I2 = 59.2%). Conclusions: Genetically elevated CRP levels are not associated with the risk lung cancer. Hence, our results provide no evidence of causality between CRP and lung cancer. Citation Format: Orestis A. Panagiotou, Neil E. Caporaso, Maria T. Landi, Nilanjan Chatterjee, NCI Lung Cancer GWAS Group. C-reactive protein and lung cancer risk: a Mendelian randomization analysis. [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 3445.
Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis
Authors: Manjula Kurella Tamura, Glenn M. Chertow, Thomas A. Depner, Allen R. Nissenson, Brigitte Schiller, Ravindra L. Mehta, Sai Liu, Tammy L. Sirich
Journal: Journal of the American Society of Nephrology (2016)

Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance dialysis. We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients participating in a trial of frequent hemodialysis. We assessed executive function with the Trail Making Test Part B and the Digit Symbol Substitution test. Impaired executive function was defined as a score ≥2 SDs below normative values. Four metabolites-4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline-were associated with impaired executive function at the false-detection rate significance threshold. After adjustment for demographic and clinical characteristics, the associations remained statistically significant: relative risk 1.16 (95% confidence interval [95% CI], 1.03 to 1.32), 1.39 (95% CI, 1.13 to 1.71), 1.24 (95% CI, 1.03 to 1.50), and 1.20 (95% CI, 1.05 to 1.38) for each SD increase in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetate and impaired executive function was replicated in the second cohort (relative risk 1.12; 95% CI, 1.02 to 1.23), whereas the associations for phenylacetylglutamine, hippurate, and prolyl-hydroxyproline did not reach statistical significance in this cohort. In summary, four metabolites related to phenylalanine, benzoate, and glutamate metabolism may be markers of cognitive impairment in patients receiving maintenance dialysis.