bluuebunny/crossref_metadata_2025 huggingface dataset:
Molten Carbonate Fuel Cells for Retrofitting Postcombustion CO2 Capture in Coal and Natural Gas Power Plants
Authors: Spinelli Maurizio , Campanari Stefano , Consonni Stefano , Romano Matteo C. , Kreutz Thomas , Ghezel-Ayagh Hossein , Jolly Stephen
Published: December 2017

The state-of-the-art conventional technology for postcombustion capture of CO2 from fossil-fueled power plants is based on chemical solvents, which requires substantial energy consumption for regeneration. A promising alternative, available in the near future, is the application of molten carbonate fuel cells (MCFC) for CO2 separation from postcombustion flue gases. Previous studies related to this technology showed both high efficiency and high carbon capture rates, especially when the fuel cell is thermally integrated in the flue gas path of a natural gas-fired combined cycle or an integrated gasification combined cycle plant. This work compares the application of MCFC-based CO2 separation process to pulverized coal fired steam cycles (PCC) and natural gas combined cycles (NGCC) as a “retrofit” to the original power plant. Mass and energy balances are calculated through detailed models for both power plants, with fuel cell behavior simulated using a 0D model calibrated against manufacturers' specifications and based on experimental measurements, specifically carried out to support this study. The resulting analysis includes a comparison of the energy efficiency and CO2 separation efficiency as well as an economic comparison of the cost of CO2 avoided (CCA) under several economic scenarios. The proposed configurations reveal promising performance, exhibiting very competitive efficiency and economic metrics in comparison with conventional CO2 capture technologies. Application as a MCFC retrofit yields a very limited (<3%) decrease in efficiency for both power plants (PCC and NGCC), a strong reduction (>80%) in CO2 emission and a competitive cost for CO2 avoided (25–40 €/ton).
Differences in Trabecular Microarchitecture and Simplified Boundary Conditions Limit the Accuracy of Quantitative Computed Tomography-Based Finite Element Models of Vertebral Failure
Authors: Hussein Amira I. , Louzeiro Daniel T. , Unnikrishnan Ginu U. , Morgan Elise F.
Published: December 2017

Vertebral fractures are common in the elderly, but efforts to reduce their incidence have been hampered by incomplete understanding of the failure processes that are involved. This study's goal was to elucidate failure processes in the lumbar vertebra and to assess the accuracy of quantitative computed tomography (QCT)-based finite element (FE) simulations of these processes. Following QCT scanning, spine segments (n = 27) consisting of L1 with adjacent intervertebral disks and neighboring endplates of T12 and L2 were compressed axially in a stepwise manner. A microcomputed tomography scan was performed at each loading step. The resulting time-lapse series of images was analyzed using digital volume correlation (DVC) to quantify deformations throughout the vertebral body. While some diversity among vertebrae was observed on how these deformations progressed, common features were large strains that developed progressively in the superior third and, concomitantly, in the midtransverse plane, in a manner that was associated with spatial variations in microstructural parameters such as connectivity density. Results of FE simulations corresponded qualitatively to the measured failure patterns when boundary conditions were derived from DVC displacements at the endplate. However, quantitative correspondence was often poor, particularly when boundary conditions were simplified to uniform compressive loading. These findings suggest that variations in trabecular microstructure are one cause of the differences in failure patterns among vertebrae and that both the lack of incorporation of these variations into QCT-based FE models and the oversimplification of boundary conditions limit the accuracy of these models in simulating vertebral failure.
Development of copper electroformed vacuum chambers with integrated non-evaporable getter thin film coatings
Authors: Lain Amador Lucia , Chiggiato Paolo , Ferreira Leonel M. A. , Nistor Valentin , Perez Fontenla Ana T. , Taborelli Mauro , Vollenberg Wilhelmus , Doche Marie-Laure , Hihn Jean-Yves
Published: December 2017

First results concerning a new approach of TiZrV non-evaporable getter (NEG) thin films coating on very small diameter vacuum chambers are presented. This new process is based on the electroforming of a vacuum chamber around a sacrificial mandrel, which is precoated with a NEG thin film. Aluminum was selected as the material of the mandrel and magnetron sputtering deposition for the coating. To improve the quality of the NEG coating, different coating layer sequences were applied and tested. The NEG activation was characterized by x-ray photoelectron spectroscopy (XPS). Data from flat samples prepared with the new technique were compared with those produced by the common magnetron sputtering method. Afterward, vacuum chambers equipped with flanges were produced. In addition to the XPS characterization, pumping speed measurements were performed. The results show CO pumping speeds comparable with the ones measured on a standard NEG coated vacuum chamber. However, H2 pumping speed exhibits ten times lower values than expected for standard NEG.
Everyone Bleeds Maroon: Colorblindness and the Desegregation of Mississippi State Football
Authors: Downs Benjamin J. , Love Adam
Published: December 2017

This study investigated the desegregation of Mississippi State University varsity football, focusing on newspaper coverage of the first Black players at the university, Robert Bell and Frank Dowsing. Two hundred and three articles about Bell and Dowsing from three newspapers (Starkville Daily News, Mississippi State Reflector, and Jackson Clarion-Ledger) were examined using a three-tiered qualitative analysis. Data analysis resulted in 426 frame instances and 686 theme instances, or a total of 1,112 codes. The resulting data were interpreted using Critical Race Theory (CRT) as an analytical lens to generate understanding of the desegregation of the football program. The CRT-guided interpretation challenges popular narratives about the amicable nature of desegregation at the university, indicating that the football team and the careers of Bell and Dowsing were covered in a way that promoted colorblindness and supported the Whitecentric interests of the university’s and community’s dominant power structure.
Full-Length Genome Sequence of Japanese Encephalitis Virus Strain FC792, Isolated from Guangxi, China
Authors: Lu Bingxia , Qin Yibin , Li Bin , He Ying , Duan Qunpeng , Liang Jiaxing , Chen Zhongwei , Su Qianlian , Bi Bingfen , Zhao Wu
Published: December 2017

We report here the complete genomic sequence of Japanese encephalitis virus (JEV) strain FC792, isolated from aborted fetuses of sows which were unimmunized with JEV vaccines in Guangxi Province, southern China. The complete JEV genome of strain FC792 had the highest nucleotide homology (99.7%) and amino acid identity (99.4%) with the sequence of JEV strain SA14-14-2 (GenBank accession number AF315119). Phylogenetic analysis showed that strain FC792 had the closest phylogenetic relationship to the sequence of strain YUNNAN0901 (GenBank accession number JQ086762). This study will help us understand the molecular pathogenesis and genetic diversity of genotype III Japanese encephalitis virus in pigs.
Complete Genome Sequence of Bacillus velezensis L-1, Which Has Antagonistic Activity against Pear Diseases
Authors: Sun Pingping , Cui Jianchao , Jia Xiaohui , Wang Wenhui
Published: December 2017

Bacillus velezensis
L-1 is an effective biocontrol agent against pear diseases. Here, we report the complete genome sequence of
B. velezensis
L-1 in which clusters related to the biosynthesis of secondary metabolites were predicted. This genome provides insights into the possible biocontrol mechanisms and furthers application of this specific bacterium.
Draft Genome Sequence of Alcaligenes faecalis BDB4, a Polyaromatic Hydrocarbon-Degrading Bacterium Isolated from Crude Oil-Contaminated Soil
Authors: Singha L. Paikhomba , Kotoky Rhitu , Pandey Piyush
Published: December 2017

Alcaligenes fecalis
BDB4 was isolated from crude oil-contaminated soil in India. The genome sequence of
A. faecalis
BDB4 revealed the presence of important genes required for polyaromatic hydrocarbon (PAH) metabolism and other associated functions, such as chemotaxis, membrane transport, and biofilm formation, giving insight into the complete PAH mineralization potential of this bacterium.
Complete Genome Sequence of Bacillus velezensis YJ11-1-4, a Strain with Broad-Spectrum Antimicrobial Activity, Isolated from Traditional Korean Fermented Soybean Paste
Authors: Lee Hyo Jung , Chun Byung-Hee , Jeon Hye Hee , Kim Yeon Bee , Lee Se Hee
Published: December 2017

Bacillus velezensis
YJ11-1-4 is a strain that exhibits broad-spectrum antimicrobial activity against various pathogens. It was isolated from doenjang, a traditional Korean fermented soybean paste. The genome comprises a single circular chromosome of 4,006,637 bp with 46.42% G+C content without plasmids.
Draft Genome Sequence of Vibrio splendidus DSM 19640
Authors: Chibani Cynthia Maria , Poehlein Anja , Roth Olivia , Liesegang Heiko , Wendling Carolin Charlotte
Published: December 2017

Here, we present the draft genome sequence of
Vibrio splendidus
type strain DSM 19640.
V. splendidus
is an abundant species among coastal vibrioplankton. The assembly resulted in a 5,729,362-bp draft genome with 5,032 protein-coding sequences, 6 rRNAs, and 117 tRNAs.
Vonoprazan prevents low-dose aspirin-associated ulcer recurrence: randomised phase 3 study
Authors: Kawai Takashi , Oda Kazunori , Funao Nobuo , Nishimura Akira , Matsumoto Yasushi , Mizokami Yuji , Ashida Kiyoshi , Sugano Kentaro
Published: December 2017

Objective

Compare efficacy and safety of vonoprazan and lansoprazole for secondary prevention of low-dose aspirin (LDA)-associated peptic ulcers in a 24-week study and long-term extension therapy in separate study.

Design

Double-blind, randomised, non-inferiority study; single-blind extension study at 104 Japanese sites, including 621 patients (439 in extension) with a history of peptic ulcers who required long-term LDA therapy. Randomised (1:1:1, computer generated) patients received lansoprazole 15 mg (n=217), vonoprazan 10 mg (n=202) or vonoprazan 20 mg (n=202) once daily for 24 weeks (double blind) and ≤2 years (extension). The following measurements were made: 24-week (primary outcome; double blind) and 12-week peptic ulcer recurrence rate, 24-week GI bleeding rate, cumulative incidences of peptic ulcer recurrence and GI bleeding, treatment-emergent adverse events, laboratory results, serum gastrin and pepsinogen I/II concentrations.

Results

The 24-week peptic ulcer recurrence rate was 2.8%, 0.5% and 1.5% in the lansoprazole 15 mg, vonoprazan 10 mg and vonoprazan 20 mg groups, respectively. Vonoprazan was non-inferior (Farrington and Manning test: margin 8.7%, significance level 2.5%) to lansoprazole. In the post hoc analyses of the extension study, peptic ulcer recurrence rates were significantly lower with vonoprazan 10 mg (log-rank test, P=0.039), but not vonoprazan 20 mg (P=0.260), compared with lansoprazole 15 mg. GI bleeding rates were higher with lansoprazole compared with two doses of vonoprazan in both 24-week study and extension study.

Conclusion

Vonoprazan (10 and 20 mg) was as effective as lansoprazole (15 mg) in preventing peptic ulcer recurrence during LDA therapy, had a similar long-term safety profile and was well tolerated.

Trial registration numbers

NCT01452763; NCT01456247.
Characterization of free radicals in clathrate hydrates of pyrrole, thiophene, and isoxazole by muon spin spectroscopy
Authors: Mozafari Mina , Chandrasena Lalangi , McKenzie Iain , Samedov Kerim , Percival Paul W.
Published: December 2017

Gas hydrates have long been of interest to the petrochemical industry, but there has been growing interest in potential applications for carbon dioxide sequestration and hydrogen storage. This has prompted many fundamental studies of structure and host–guest interactions, but there has been relatively little investigation of chemical reactions of the guest molecules. In previous work, we have shown that it is possible to use muon spin spectroscopy to characterize H atom like muonium and muoniated free radicals formed in clathrate hydrates. Muonium (Mu) forms in clathrate hydrates of cyclopentane and tetrahydrofuran, whereas furan and its dihydro derivatives form radicals. The current work extends studies to clathrates hydrates of other five-membered heterocycles: thiophene, pyrrole, and isoxazole. All form structure II hydrates. In addition to the clathrates, pure liquid samples of the heterocycles were studied to aid in the assignment of radical signals and for comparison with the enclathrated radicals. Similar to furan, two distinct radicals are formed when Mu reacts with thiophene and pyrrole. However, only one muoniated radical was detected from isoxazole. Muon, proton, and nitrogen hyperfine constants were determined and compared with values predicted by DFT calculations to aid the structure assignments. The results show that Mu adds preferentially to the carbon adjacent to the heteroatom in thiophene and pyrrole and to the carbon adjacent to oxygen in isoxazole. The same radicals are formed in clathrates, but the spectra have broader signals, suggesting slower tumbling. Furthermore, additional signals in the avoided level-crossing spectra indicate anisotropy consistent with restricted motion of the radicals in the clathrate cages.
Study on Performance of EDM Electrodes Produced Through Rapid Tooling Route
Authors: Mohanty Saumya Darsan , Mohanty Ramesh Chandra , Mahapatra Siba Sankar
Published: December 2017

The present study highlights a multi-objective optimization problem by applying utility concept coupled with Taguchi method through a case study in electric discharge machining of D2 steel by using electrode produced by direct metal laser sintering (LS). The study aimed at evaluating the best process environment which could simultaneously satisfy multiple requirements such as tool wear rate, material removal rate, and surface roughness. As traditional Taguchi method cannot solve a multi-objective optimization problem, to overcome this limitation, utility theory has been coupled with Taguchi method. Depending on Taguchi’s lower-the-better and higher-the-better criteria, individual response characteristics have been transformed into corresponding utility values. Individual utility values have been added finally to compute overall utility degree which serves as representative objective function for optimization using Taguchi method. The present study combined utility theory and Taguchi method for predicting optimal settings. Optimal result was verified through confirmatory test. This indicates application feasibility of the aforesaid methodology proposed for multi-response optimization and off-line control of multiple quality characteristics in electric discharge machining using electrode produced by direct metal LS.
Computational Study of N-Job M-Machine Flow Shop Scheduling Problems: SPT, EDD, NEH, NEH-EDD, and Modified-NEH Algorithms
Authors: Kurniawati Dwi Agustina , Nugroho Yoga Isnaini
Published: December 2017

This paper discusses about the flow shop scheduling problems using shortest processing time, earliest due date (EDD), Nawaz, Enscore, and Ham (NEH), NEH-EDD, and modified-NEH methods. The objective of this research is to determine the performance of these methods in minimizing makespan and total tardiness. Processing times and due dates were randomly generated, and computational studies were performed in Microsoft Visual Basic 6.0. The experiments are performed for small and medium data sets. Efficiency index, relative error, and run time measure the performance of each method. Experimental results showed that NEH has the best performance in minimizing the makespan in both data sets; these are 53.35 time unit for small data sets and 83.803 time unit for medium data sets. NEH-EDD has the best performance in minimizing total tardiness with 9.37 time unit for small data sets and 231.02 time unit for medium data sets. Modified-NEH, as the proposed method for minimizing makespan and total tardiness at the same time, has good enough result. For minimizing the makespan, modified-NEH results in 57.15 time unit for small data sets and 88.107 time unit for medium data sets. For minimizing total tardiness, the modified-NEH results in 14.21 time unit for small data sets and 246.57 time unit for medium sets.
No Association of Waist Circumference and Prostate Cancer in the Cancer Prevention Study II Nutrition Cohort
Authors: Stevens Victoria L. , Jacobs Eric J. , Maliniak Maret L. , Patel Alpa V. , Gapstur Susan M.
Published: December 2017

Background: The relationship between excess body weight and prostate cancer risk is unclear. However, some evidence suggests that waist circumference, which provides a measure of central adiposity, may be positively associated with more advanced stages or grades of prostate cancer.

Methods: The association between waist circumference and prostate cancer was investigated among 46,094 men enrolled in the Cancer Prevention Study II Nutrition Cohort, of whom 5,711 were diagnosed with this cancer between 1997 and 2013. Using Cox proportional hazards regression, we examined associations of weight circumference with total and high-grade prostate cancer incidence and with prostate cancer mortality.

Results: In both categorical and continuous analyses, waist circumference was not associated with total or high-grade (Gleason score ≥ 8) prostate cancer incidence or with prostate cancer mortality regardless of whether body mass index was adjusted for in the statistical model. Waist circumference was inversely associated with low-grade (Gleason score < 8) prostate cancer, but the association was not statistically significant after adjustment for body mass index.

Conclusions: Our results suggest that central adiposity, as measured by waist circumference, is not significantly associated with prostate cancer incidence or mortality.

Impact: Compared with men in other studies with significant results, men in our study were considerably older, suggesting that age may influence the association between waist circumference and prostate cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1812–4. ©2017 AACR.
Abstract A20: Genomic study of KRAS/NRAS mutations of metastatic colorectal cancer in eastern Algeria
Authors: Mazouzi Khaoula
Published: December 2017

Background: Biological advances made a big lap in the treatment of metastatic patients where several therapeutic options are now available for patients based on research of gene. For colorectal cancer, it is essential to test KRAS-BRAF-NRAS mutations before starting any treatment and it is known in the literature that these mutations are found in approximately 45% of patients, that what made us thinking about analyzing the results of our patients' mutational tests.

Methods: It is a Prospective study that aims to analyze the KRAS/NRAS mutational profile of metastatic colorectal cancer patients treated at CHU Constantine-Anti Cancer Center during the period of January 2014 - August 2016. The molecular study includes: codon 12 and 13 of exon 2, codons 59 and 61 of exon 3 and codons 117 and 146 of exon 4 of K-Ras gene. The exons 2, 3 and 4 for the N-Ras gene have also been tested and no molecular testing has been done for B-RAF mutation. The search for mutations was performed by the Allele Specific PCR technique and a second confirmation by sequencing was done.

Results: 490 patients with colorectal cancer were registered; 34.69% were presented with metastases, of which 61, 17% are men and 38, 82% women. The extremes of age is 27 to 77 years, the average age is 52.6 years. 67.64% of these tumors have colic origin, 28.82% of rectal origin 3.52% from the recto sigmoidal junction. The histological presentation is: 95.29% adenocarcinoma [57.40% well differentiated, 37.03% moderately differentiated, 2.46% poorly differentiated and 3.08% are undifferentiated], 2.35% are adenocarcinomas with colloid component and 2.35% are independent cell carcinomas. 42.94% were wild type, 51.17% are mutated and 5.88% remained without status given the small quantity of DNA available for testing (not sufficient DNA) and the impossibility of re-biopsy.

The mutational profile for K-Ras gene was: 94.5% mutated in exons 2 with 76.82% in codon 12 and 23.17% in codon 13. 3.44% had mutations exons 3 without any detail of codons mentioned and 2.29% had rare mutations in the N-Ras gene without any extensive information.

Conclusion: The analysis of data find that the mutational profile of our patients is different than the profile presented in the literature, therefore, extensive molecular and genetic studies should be conducted in our area in search of explanations and in the hope of future therapeutic implications.

Citation Format: Khaoula Mazouzi. Genomic study of KRAS/NRAS mutations of metastatic colorectal cancer in eastern Algeria [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A20.
Abstract B25: Sometimes it's spiritual: A mixed-methods study of cervical cancer stigma among women in Ghana, West Africa
Authors: Williams Michelle Sharonda , Kenu Ernest
Published: December 2017

Cervical cancer is the leading cause of cancer death among women in Ghana, West Africa. Previous studies have found that many Ghanaian women hold stigmatizing beliefs about cervical cancer, which may lead them to minimize their perceived susceptibility to the disease and reduce their perceived need for preventive cervical cancer screenings. The purpose of this study was to assess cervical cancer stigma among Ghanaian women and determine if there is a difference in the level of cervical cancer stigma among nurses and non-healthcare providers. The PEN-3 model provided the framework for this study. A convergent parallel mixed methods study design was used to conduct this study; therefore the study was divided into two strands, the quantitative strand and the qualitative strand. For the quantitative strand, 298 women who were recruited from public venues in Accra, completed a questionnaire containing items from the global cancer stigma index scale. For the qualitative strand, in-depth interviews were conducted with 21 nurses who worked in a large public hospital in Accra and 21 nurses who worked in a small private hospital in Battor. A semi-structured interview guide was used to assess cervical cancer stigma among the nurses. Univariate and bivariate analyses were preformed to explore the quantitative data. The qualitative data were analyzed using open coding and focused coding. The results of the quantitative and qualitative data analyses indicated that stigmatizing beliefs about cervical cancer were reported by nurses and women in the general population who were not healthcare providers. However, stigmatizing beliefs such as Women with cervical cancer are responsible for causing their own cancer, Women with cervical cancer are sexually easy, and Only promiscuous women need to have a regular cervical cancer screening were reported more frequently by women who were not healthcare providers. The results of this study can be used to inform the development of culturally-relevant cervical cancer stigma reduction interventions. Reducing cervical cancer stigma may lead to an increase in the number of Ghanaian women who seek regular, preventive cervical cancer screenings.

Citation Format: Michelle Sharonda Williams, Ernest Kenu. Sometimes it's spiritual: A mixed-methods study of cervical cancer stigma among women in Ghana, West Africa [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B25.
Abstract A08: in vivo CRISPR screening enables precision medicine by identifying novel drug combinations and modeling anticancer drug sensitivity
Authors: ADLI Mazhar
Published: December 2017

Identifying novel targets to synergistically improve the efficacy of existing chemotherapy is a major goal in cancer research. Here, we report in vivo CRISPR knockout (KO) screening in a patient derived xenograft (PDX) model of pancreatic cancer to identify genes that mediate the resistance to trametinib, an inhibitor of the MEK signaling pathway, which is aberrantly active in pancreatic cancers due to oncogenic KRAS mutations. The screening and subsequent genetic as well as in vitro and in vivo pharmacological validations identified a set of kinetochore function genes whose depletion is synthetic lethal with MEK inhibition. by triggering mitotic slippage and polyploidy. Notably, using the unbiased knowledge of gene-specific survival scores from the in vivo KO screening under the pressure of a chemotherapeutic agent, we devised a novel Drug Response Evaluation approach Based on in vivo CRISPR screening (DREBIC). The DREBIC is a major detour from conventional machine learning and statistical prediction models as it integrates functional screening based gene viability scores and basal expression levels to project cancer type- and mutation-specific drug sensitivity profiles. Using large-scale experimentally identified drug-response data from the Cancer Genome Project (CGP) and Cancer Cell Line Encyclopedia (CCLE) as a gold standard, DREBIC models trametinib response with high sensitivity and specificity across thousands of cancer cell lines. DREBIC identifies intrinsic fitness properties of various genotypes, enabling identification of therapeutic vulnerabilities of cancer-causing mutations with great precision. DREBIC will improve precision medicine by enabling patient-centered clinical decision-making for effective choice of chemotherapy.

Note: This abstract was not presented at the conference.

Citation Format: Mazhar ADLI. in vivo CRISPR screening enables precision medicine by identifying novel drug combinations and modeling anticancer drug sensitivity [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A08.
Abstract A09: Decomposing Oncogenic Transcriptional Signatures to Generate Maps of RAS/MAPK Cellular States
Authors: Kim Jongwook William , Hahn William C. , Mesirov Jill , Tamayo Pablo
Published: December 2017

The systematic sequencing of the cancer genome has provided a powerful framework for identifying genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework, and associated experimental and computational methodology, to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. Using this approach, we generated series of RAS/MAPK sub-signatures that reflect known and novel downstream pathways. These sub-signatures were then used to classify KRAS and BRAF mutant cancers into sub groups or cell states, as represented in the novel visual paradigm OncoGPS map. The approach not only accurately classified three groups of BRAF mutant cancers that aligned with sensitivity to BRAF inhibitors, but also identified resistance mechanisms associated with each state. OncoGPS also identified four major cell states associated with KRAS mutant cancers. Further characterization of the four cell states showed that multiple molecular features representing epithelial-EMT states and activation of NF-κB pathway delineated two major axes of KRAS mutant cancers. In addition to the pathways and cell states defined in each group, the OncoGPS approach is able to identify effective drug combinations which was experimentally tested and confirmed. These results show that the Onco-GPS is an effective analytic framework to explore the complex landscape of oncogenic cellular states across cancers, and a powerful framework to summarize knowledge, establish relationships, and generate more effective disease models for research or as part of individualized precision medicine paradigms.

Citation Format: Jongwook William Kim, William C. Hahn, Jill Mesirov, Pablo Tamayo. Decomposing Oncogenic Transcriptional Signatures to Generate Maps of RAS/MAPK Cellular States [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A09.
Abstract A22: Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency
Authors: Han Mingqi , Napier Christine E. , Frölich Sonja , Everett Roger D. , Cesare Anthony J. , Reddel Roger R.
Published: December 2017

In human somatic cells, telomeres shorten every cell division due to the end replication problem. Once reaching a critically short length, the cells will undergo permanent cell cycle arrest and become senescent. Cancer cells acquire unlimited proliferation ability by activation of a telomere maintenance mechanism, either the enzyme telomerase or the homologous recombination-based mechanism Alternative Lengthening of Telomeres (ALT). Cancers that utilize the ALT mechanism commonly are deficient for ATRX protein expression, are difficult to treat, and have a poor prognosis. We discovered that ICP0-null herpes simplex virus type 1 (HSV-1) was ten to one thousand-fold more effective in killing cancer cell lines that are ATRX-deficient. Sensitivity to mutant HSV-1 infection resulted from ATRX-dependent regulation of PML expression at both the transcriptional and post-transcriptional levels. Reduction of PML protein resulted in a concomitant reduction in PML nuclear bodies, which weakened the innate cellular immunity to viral infection. Infection of co-cultured primary and ATRX-null cancer cells revealed that mutant ICP0-null HSV-1 treatment preferentially killed ATRX-null cells. Our results suggest that mutant ICP0-null HSV-1 may have therapeutic benefit against ATRX-null cells. Moreover, these data provide an applicable approach for predicting, based on tumor ATRX or PML protein status, which tumors will respond to an oncolytic herpes virus.

Citation Format: Mingqi Han, Christine E. Napier, Sonja Frölich, Roger D. Everett, Anthony J. Cesare, Roger R. Reddel. Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A22.
Abstract A26: Prediction of synergistic anticancer drug combinations by integrating chemical and genetic screens
Authors: Jaiswal Alok , Gautam Prson , Tang Jing , Wennerberg Krister , Aittokallio Tero
Published: December 2017

Identification of effective drug combinations inhibiting multiple target genes that are essential for cancer cell survival is seen as an effective strategy to overcome drug resistance. Cellular pathways are often redundant, and network rewiring in the face of an assault promotes the emergence of resistant cells that contribute to clinical relapse. However, the number of possible drug-target combinations to investigate by conducting experiments is exponentially large and impractical, therefore warranting the need for systematic approaches to prioritize the most effective drug combinations. Here, we aimed to integrate large-scale drug screening, drug-target affinity knowledge and public RNAi screening datasets on a huge compendium of cancer cell lines to predict synergistic drug combinations. In a case study in an individual breast cancer cell line, MDA-MB-231, we identified drugs selectively active in this cell line compared to the background distribution. We find that target genes of active drugs and other genes involved in related cellular processes were also differentially essential in RNAi screening data. Further, we observe that the drug combinations of these selectively active drugs were synergistic. We propose a systematic approach for integrating chemical screening, drug target and cellular processes knowledge, and functional genetic screens to optimize drug combination testing efforts.

Citation Format: Alok Jaiswal, Prson Gautam, Jing Tang, Krister Wennerberg, Tero Aittokallio. Prediction of synergistic anticancer drug combinations by integrating chemical and genetic screens [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A26.
Abstract A32: Screening for synthetic lethal interactions using customized epigenetic CRISPR-Cas9 libraries
Authors: Zhou Wenrong , Long Min , Li Xi , Peng Zhengang , Ji Qunsheng , Cang Yong
Published: December 2017

Identification of synthetic lethal (SNL) interactions provides a framework for exploring novel treatment options to cancer based on biomarker analysis. Recent research in this field has been powered up by the latest CRISPR-Cas9 gene editing technology, which allows for single gene manipulation or genome-scale knockout/activation screens. Typically, any non-essential gene can be inactivated in a cell line to generate an isogenic mutant cell line, and single-guide RNA (sgRNA) sequences against any list of genes of interest can be constructed to lentiviral Cas9 vectors to interrogate the isogenic cell lines for SNL interactions. Here we demonstrated two alternative types of SNL screens using customized epigenetic CRISPR-Cas9 libraries. In one screen, we built two sgRNA libraries targeting the N terminus or functional domains of 710 human epigenetic regulators. The libraries were infected to a pomalidomide-resistant multiple myeloma (MM) cell line, which was then followed by pomalidomide treatment. Deep sequencing of the sgRNAs from these cells identified potential targets which when inactivated would re-sensitize the cells to pomalidomide. In the other screen, we built a sgRNA library targeting the functional domains of 116 mouse methyltransferases and demethylases, which was infected to a mouse melanoma cell line Cloudman S91. Syngeneic mouse tumor model derived from the infected cells was treated with anti-mPD-1 monoclonal antibody. Deep sequencing of the tumors would identify potential druggable targets to sensitize or antagonize the tumors to anti-PD-1 immunotherapy. In summary, SNL screens combining CRISPR-Cas9 library with targeted therapeutics or with single gene editing in isogenic cell lines can enable discovery of novel targets for precision cancer treatment.

Citation Format: Wenrong Zhou, Min Long, Xi Li, Zhengang Peng, Qunsheng Ji, Yong Cang. Screening for synthetic lethal interactions using customized epigenetic CRISPR-Cas9 libraries [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A32.
Abstract B03: Functional Stratification of Cancer Variants via Network Perturbations
Authors: Sahni Nidhi , Yi Song
Published: December 2017

In the past decade, genome and exome sequencing projects have identified thousands of genetic variants in patients across a large number of cancer types. However, the explosion of genomic information has left many fundamental questions regarding genotype-phenotype relationships unresolved. One critical challenge is to distinguish causal disease mutations from non-pathogenic polymorphisms. Even when causal mutations are identified, the functional consequence of such mutations is often elusive. Classical one gene, one function, one disease models can not reconcile with the complexity that different mutations of the same gene often lead to different phenotypes. The extent to which network perturbations are involved in disease malfunction and how distinct interaction perturbation patterns can distinguish cancer mutations are largely unknown. Here we report a systematic approach to investigate genetic variant-specific effects on molecular interactions at large scale across diverse human cancers. Remarkably, in comparison to non-disease polymorphisms, disease mutations are more likely to associate with interaction perturbations. A large fraction of missense disease mutations are found to cause protein interaction alterations. While half result in loss of all their interactions, the other half exhibit selective elimination of specific interactions (edgetic). Different mutations of the same gene give rise to different interaction profiles, accounting for distinct disease outcomes. Edgetic mutations perturb interactions through disrupting specific interaction interfaces, and the perturbed partners are more likely expressed in relevant disease tissue. Together, our approach is insightful in prioritizing disease-causing variants, and uncovering patient mutation-specific disease mechanisms at a base-pair resolution, a critical step towards personalized precision medicine. Furthermore, our results suggest distinct interaction perturbations as a widespread mechanism underlying genetic heterogeneity, providing a fundamental link between genotype and phenotype in cancer.

Citation Format: Nidhi Sahni, Song Yi. Functional Stratification of Cancer Variants via Network Perturbations [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B03.
Abstract B05: Discovery, validation and targeting of novel synthetic lethal interactions in academic drug discovery
Authors: March H. Nikki , Chapman Phil , Blaikley Elizabeth , Eberlein Catherine A. , Cockerill Mark , Hitchin Samantha , Waddell Ian D. , Ogilvie Donald
Published: December 2017

The identification of novel oncology targets for small molecule drug discovery is becoming increasingly challenging despite 10-15% of the human genome estimated to be druggable. The literature is an important source of novel targets; however, several recent reports by pharma and academia have indicated that approximately 11-55% of published studies are irreproducible. Moreover, oncology drug attrition rates are extremely poor, with 66% of candidates in Phase III clinical trials not achieving approval. This is reflected by increasing failure rates of drug development projects in Phase II, from 72% in 2006-2007 to 82% in 2008-2009. These failures have been attributed to lack of efficacy, thus highlighting the critical requirement for new novel drug targets that demonstrate clear promise of clinical efficacy through predictive in vitro and in vivo models. Furthermore, it is important to prioritize and pursue targets that are most likely to bind a small molecule inhibitor with high infinity. We sought to utilize the wealth of unvalidated genomic data now available in the public domain by developing a bioinformatic pipeline founded on the collateral vulnerability hypothesis, which is based on the concept of synthetic lethality and exploits the co-occurrence of deletions of genes flanking tumor suppressors that are lost during the course of tumor evolution. We can then target the paralogs of these genes if together they belong to gene families with essential predicted function, thereby exploiting a vulnerability of the cancer cells with these losses. Here, we describe our industry-standard approaches to the target validation of the output generated from lung adenocarcinoma data, and present the validation and de-validation of several novel targets predicted by the collateral vulnerability pipeline, including SMARCA2, KMT2C, and SETD1B.

Citation Format: H. Nikki March, Phil Chapman, Elizabeth Blaikley, Catherine A. Eberlein, Mark Cockerill, Samantha Hitchin, Ian D. Waddell, Donald Ogilvie. Discovery, validation and targeting of novel synthetic lethal interactions in academic drug discovery [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B05.
Abstract B06: HTSvis: An user-friendly application for analysis of arrayed high-throughput experiments by interactive data representations
Authors: Scheeder Christian , Heigwer Florian , Boutros Michael
Published: December 2017

The presented application HTSvis provides an user-interface tool for interactive analysis of arrayed high-throughput screening experiments. Arrayed formats are broadly used for cell-based screens which help to reveal mechanisms of complex diseases such as cancer. Technological advances allow to screen tens of thousands experimental conditions in a single experiments resulting in large datasets with complicated annotation files. Software packages for standardized analysis with a minimized programming effort have been developed accordingly. Even though such pipelines provide comprehensive analysis options, interpretation of the results remains a challenge as the user has to manually compare files and possibly re-run the analysis to prosecute certain hypotheses. Here we present HTSvis, a web application that visualizes data from arrayed screens. The data can be read-in as result files of the established R package CellHTS2 or as any spreadsheet table. This enables the user to feed in data which has been statistically analyzed whilst preserving flexibility to analyze data independent of the CellHTS2 package. The application provides several informative data representations like heatmaps, scatter plots and tables. Within the application, the data can be browsed in an ad hoc manner via the implemented user interface. This allows the user to assess data quality, compare experiments, identify measurements of interest and to verify generated hypotheses in an exploratory manner. The direct allocation of data points to experimental conditions is preserved in all representations facilitating an intuitive interpretation. HTSvis is easy to install, data input is straight forward and no programming skills are required for the usage. The application is compatible with common web browsers and can be set up on local computers as well as on server clusters which allows parallel access for multiple users. Summarized, HTSvis provides a helpful tool for interactive data analysis and interpretation for both, users with and without programming skills. Thereby, the application also promotes the cooperation and exchange of ideas between bioinformaticians and experimental biologists or between collaborators.

Citation Format: Christian Scheeder, Florian Heigwer, Michael Boutros. HTSvis: An user-friendly application for analysis of arrayed high-throughput experiments by interactive data representations [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B06.
Abstract B16: Epistatic mapping of signaling and chromatin regulators
Authors: Henkel Luisa , Heigwer Florian , Winter Jan , Rauscher Benedikt , Boutros Michael
Published: December 2017

Phenotypes are often not only based on the effect of a single gene, but are rather influenced by multiple genetic (also termed epistatic) interactions. Prominent examples are synthetic lethal interactions, where the individual loss-of-function of two genes does not lead to phenotypic alterations, whereas their simultaneous perturbation results in reduced fitness or even cell death. Previously, we have established large-scale genetic interaction mapping experiments in Drosophila cells that discovered a high-number of functional interactions of conserved factors. Here, we aim to create a platform to investigate epistatic interactions of genes encoding chromatin remodeling and signaling factors in human cells.

As part of the transcriptional regulatory machinery, chromatin remodeling enzymes buffer various genetic perturbations via adaptations within the transcriptional program, e.g. via repression of mutant or activation of functional alleles. Furthermore, chromatin remodeling factors link epigenetic modifications to corresponding signaling pathway outputs. While some of these enzymes have been extensively studied, many remain largely uncharacterized. As epigenetic dysregulation constitutes a characteristic feature of many cancers, chromatin remodeling proteins are promising targets in anticancer therapies.

To map interaction networks of chromatin and signaling factors, we use pooled genome-scale CRISPR/Cas9 genetic interaction screens. To this end, CRISPR/Cas9 mapping will be performed in a human cell line to reveal unknown functions and interactions of chromatin remodeling enzymes. We will present our screening platform, including custom library design and analysis tools to identify screening hits that emerge to be promising for synthetic lethality targeting in anticancer therapy.

Citation Format: Luisa Henkel, Florian Heigwer, Jan Winter, Benedikt Rauscher, Michael Boutros. Epistatic mapping of signaling and chromatin regulators [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B16.
Abstract B18: Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins
Authors: Couturier Anthony M. , Buisson Rémi , Pauty Joris , Rodrigue Amélie , Caron Marie-Christine , Coulombe Yan , Joshi Niraj , Zou Lee , Masson Jean-Yves
Published: December 2017

One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination. Therefore, the regulation of PALB2 during the DNA damage response and the effect of cancer-causing mutation is of high interest. Two mechanisms of regulation of PALB2 will be presented. The first mechanism regulates PALB2 localization to DNA damage sites in S-phase. To date, predicting the functional consequences of PALB2 mutations has been challenging as they lead to different aggressive phenotypes. Here, we performed a structure-function analysis of PALB2 using PALB2 truncated mutants (R170fs, L531fs, Q775X and W1038X), and uncovered a second PALB2 regulation mechanism by which cancer cells could drive genomic instability. We will present these regulatory mechanisms and synthetic lethal strategies to kill PALB2 deficient cells harbouring such mutations using PARP inhibitors. These strategies also apply to APRIN, A BRCA2 interactor, which also promote double-strand break repair by homologous recombination.

Citation Format: Anthony M. Couturier, Rémi Buisson, Joris Pauty, Amélie Rodrigue, Marie-Christine Caron, Yan Coulombe, Niraj Joshi, Lee Zou, Jean-Yves Masson. Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B18.