bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A10: The impact of cancer-associated RAD51C mutations in homologous recombination
Authors: Sullivan Meghan R. , Prakash Rohit , Jasin Maria , Bernstein Kara A. 
Published: April 2017

Abstract
Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks (DSBs). Loss of function of key HR repair proteins have been linked to diseases characterized by genomic instability including cancers and Fanconi anemia. Regulation of RAD51 filaments is critical during HR repair and is mediated by several factors including the RAD51 paralogs, a group of proteins that share sequence homology with RAD51. The RAD51 paralog family consists of five proteins in humans, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. The RAD51 paralog, RAD51C, has recently become a key protein of interest as RAD51C mutations have been linked to familial breast and ovarian cancers. However, the specific functions of RAD51C have remained enigmatic as mouse and non-tumorigenic knockout models are inviable. Given these limitations, we have identified RAD51C point mutations from breast and ovarian cancer patients to study the phenotypes of these RAD51C mutants and how they impair homologous recombination. We have found that RAD51C mutations can disrupt interactions with RAD51 paralog binding partners, RAD51B and XRCC3, required for RAD51C stability. Through yeast-two/three-hybrid and co-immunoprecipitation experiments, we isolated RAD51C mutations that disrupt interactions within RAD51 paralog complexes. These complexes have important roles in the repair of classical DSBs induced by ionizing radiation or chemotherapeutic reagents as well as in replication fork protection such as after replication stress induced by hydroxyurea. Using RAD51C mutants to complement a conditional knockout model, we investigated how the roles of RAD51C were impacted by point mutations in response to these diverse substrates to ultimately understand how tumors with RAD51C mutations can be best targeted for treatment.
Citation Format: Meghan R. Sullivan, Rohit Prakash, Maria Jasin, Kara A. Bernstein. The impact of cancer-associated RAD51C mutations in homologous recombination [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A10.
Abstract A26: High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway
Authors: Hakkert Anne , Ebus Marli E. , Versteeg Rogier , Huib Caron N. , Koster Jan , Molenaar Jan J. 
Published: April 2017

Abstract
Background: Somatic mutations can be grouped into 96 tri-nucleotide patterns, termed mutational signatures. These signatures can provide insights into underlying processes that fuel the evolution of tumor cells, and may expose therapeutic intervention avenues. Here we investigated the mutational signature of 84 whole genome sequenced neuroblastoma cases.
Results: Mutational signature analysis revealed an extreme bias towards Cytosine to Adenine (CtoA) mutations in a majority of neuroblastoma tumors. This seems to be a unique feature of neuroblastoma. CtoA mutations are primarily found in high stage tumors and are therefore associated with a poor prognosis. Oxidative stress is known to be a source for such mutations, which can accumulate due to defects in the 8-Oxo-Guanine repair pathway genes OGG1, MUTYH and MTH1. We could show a strong correlation between CtoA mutations and chromosomal loss of MTH1, OGG1 and MUTYH. Besides copy number losses, sequencing also revealed a tumor with a homozygous mutation in OGG1 and this tumor showed a very strong bias towards CtoA mutations. Modified alkaline comet assays were performed for quantification of 8-Oxo-Guanine content present in the DNA of neuroblastoma cell lines. These comet assays showed that neuroblastoma cell lines with loss of either OGG1 or MUTYH, had higher 8-Oxo-Guanine content than cell lines without these losses. 8-Oxo-Guanine content is correlated with CtoA mutation frequency in short term cultured neuroblastoma organoids. Overexpression of OGG1 or MUTYH in neuroblastoma cell lines with losses of OGG1 or MUTYH respectively leads to rescue of the phenotype and a decrease in the amount of 8-Oxo-Guanine in the DNA. We are currently performing a compound screen to test the efficacy of 352 compounds functioning in the DNA damage repair in cell lines with and without MUTYH expression, and were testing compounds that further interfere in this specific branch of DNA damage repair including the newly developed MTH1 inhibitors.
Conclusion: We identified a subset of neuroblastoma tumors with a high CtoA mutation frequency, which correlates with losses of glycosylases involved in the repair of CtoA mutations. 8-Oxo-Guanine levels are elevated in cell lines with loss of OGG1 or MUTYH, which can be rescued by overexpression of OGG1 or MUTYH respectively.
Citation Format: Anne Hakkert, Marli E. Ebus, Rogier Versteeg, Caron N. Huib, Jan Koster, Jan J. Molenaar. High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A26.
Abstract A44: The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer
Authors: Timoteo Ana Rafaela de Souza , Souza Jorge Estefano Santana de , Lajus Tirzah Braz Petta 
Published: April 2017

Abstract
Hereditary breast cancer corresponds to 10-15% of all diagnosed cases of breast cancer in the world. The majority germline mutations are identified in BRCA1/2 genes, however the application of multigene panels has increased the number of pathogenic variations detected in DNA repair genes. According to the current version of NCCN Guideline, mutations in BRCA1/2, TP53 and PTEN confers high risk to develop breast cancer, and mutations in CDH1, CHEK2, PALB2, ATM and BRIP can increases over than 20% this risk. We analyzed 157 individuals from Northeastern region of Brazil with personal and/or familial breast cancer history. Genomic DNA was isolated from peripheral blood through saline-based extraction and samples were analyzed using next-generation sequencing (NGS). We identified 15 pathogenic variants and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17%), in which three are asymptomatic. Six novel variants in 4 genes were identified: BRCA1_c.3409A&gt;G; BRCA2_c.5800C&gt;T; BRCA2_c.5228G&gt;A; BRCA2_c.5305delG; ATM_c.634delT and ATR_c.3043C&gt;T. Sixty-eight percent (13/19; 68%) of variants was detected in BRCA1/2 genes, while 32% (6/19) were identified in moderate risk genes ATM (2/19); ATR (1/19); CDH1 (1/19); MLH1 (1/19) and MSH6 (1/19). The individuals were separated in two groups for comparative analysis: high-risk genes and moderate risk genes. Among three asymptomatic individuals, two present variants in moderate risk genes ATM and MLH1. Among breast cancer individuals, eighteen patients (18/24; 75%) presents mutations in high-risk genes, while six (6/24; 25%) harbors mutations in moderate risk genes. Both groups had a high incidence of early-onset breast cancer, 83%. The group of individuals harboring variants in high-risk genes presented a greater occurrence of high-grade tumors (83% vs. 67%, P= 0.0090). In the group of individuals harboring mutation in moderate risk genes, tumors presented a more aggressive phenotype with bilateral cancer (33% vs. 11%, P= 0.0002), occurrence of metastasis (33% vs. 5.6%, P&lt;0.0001) and incidence of deaths (33% vs. 5.6%, P&lt;0.0001). Altogether, 1/3 of variants were identified in moderate risk genes in patients presenting a more aggressive phenotype. These results reinforce the importance of applying multigene analysis in individuals at-risk for breast cancer, especially in a heterogeneous population as Brazilian.
Citation Format: Ana Rafaela de Souza Timoteo, Jorge Estefano Santana de Souza, Tirzah Braz Petta Lajus. The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A44.
Abstract B24: Genomic prediction of response to PARP inhibition in breast cancer
Authors: Hassan Saima , Esch Amanda , Heiser Laura M. , Gray Joe W. 
Published: April 2017

Abstract
Efficacy of PARP inhibition has been demonstrated in several cancer types including prostate, ovarian, and breast. Most recently, anti-PARP therapy was shown to be effective in combination with carboplatin in triple-negative breast cancer patients in the neoadjuvant setting. However, it is not yet well known which subset of triple-negative breast cancers will benefit from single-agent anti-PARP therapy. We determined the therapeutic efficacy of three PARP inhibitors: veliparib, olaparib, and BMN 673, in a panel of eight triple-negative breast cancer cell lines. We used a 10-day in-vitro assay, after which we fixed the cells and determined 53BP1 expression using immunofluorescence and high-content imaging. We used cell counts to derive IC50 values and enumerated 53BP1 foci per cell to determine EC50 values. We used pre-treatment whole-transcriptome data to identify genes associated with 53BP1 response using gene set enrichment and pathway enrichment analysis. We determined the prevalence of these genes in a dataset of triple-negative breast cancer patients, and performed survival analysis. We found PARP inhibition to be effective in both BRCA-mutant and BRCA wild-type breast cancer cell lines. BMN 673 was the most potent PARP inhibitor, with the lowest concentrations required for DNA damage (measured by 53BP1 expression) and cell kill (measured by cell count), followed by olaparib, and then veliparib. We found a strong correlation between the IC50 values for cell count and the EC50 values for 53BP1 response. We identified a gene set associated with 53BP1 response, which was involved with three major pathways: DNA repair, cell cycle, and programmed cell death. These genes were found to be downregulated in triple-negative breast cancer patients. Patients with aberrations in these genes demonstrated poorer overall survival (P = 0.03). In conclusion, we identified a gene set involved with DNA repair, cell-cycle, and programmed cell death, which was associated with poor outcomes in triple-negative breast cancer patients that could potentially benefit from anti-PARP therapy.
Citation Format: Saima Hassan, Amanda Esch, Laura M. Heiser, Joe W. Gray. Genomic prediction of response to PARP inhibition in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B24.
Abstract IA11: Signatures of mutational processes in human cancer
Authors: Alexandrov Ludmil B. 
Published: April 2017

Abstract
All cancers are caused by somatic mutations. These mutations may be the consequence of the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA, or defective DNA repair. In some cancer types, a substantial proportion of somatic mutations are known to be generated by exogenous arcinogens, for example, tobacco smoking in lung cancers and ultraviolet light in skin cancers, or by abnormalities of DNA maintenance, for example, defective DNA mismatch repair in some colorectal cancers.
Each biological process causing mutations leaves a characteristic imprint on the genome of a cancer cell, termed, mutational signature. In this talk, I will present mutational signatures analyses encompassing 12,023 cancer genomes across 40 distinct types of human cancer revealing more than 30 different signatures of mutational processes. Some signatures are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer etiology, prevention and therapy.
Citation Format: Ludmil B. Alexandrov. Signatures of mutational processes in human cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA11.
Abstract IA14: Mechanisms of the ATR-dependent replication stress response
Authors: Cortez David 
Published: April 2017

Abstract
Replication stress can be caused by DNA damage, difficult to replicate DNA sequences, collisions between replication and transcriptional machineries, and aberrations in the replication timing or other regulatory mechanisms. Cancer cells often have elevated levels of replication stress driven by oncogenes. Replication stress response pathways are important in these contexts to allow cells to complete replication, maintain genome stability, and remain viable. Drugs that increase the replication stress burden or inactivate components of the replication stress response pathway can be useful as cancer therapeutics. For example, inhibitors of the replication checkpoint kinase ATR are currently being tested in clinical trials. To better understand how replication stress response pathways operate, we have taken both genetic and proteomic approaches. These approaches include purifying active and stressed replication fork proteomes using isolation of proteins on nascent DNA (iPOND). iPOND can monitor changes in the replication fork proteome and when combined with mass spectrometry provides an unbiased analysis. These approaches have allowed us characterize the consequences of replication stress and functions of ATR. For example, we found that ATR does not regulate the stability of the replisome itself in response to stress, but it does direct the action of a number of fork remodeling enzymes including SMARCAL1 that act to protect and repair damaged forks. In addition, iPOND identified new replication stress response proteins including ETAA1—a new regulator of the ATR checkpoint kinase. I will present our latest data on the replication stress response emphasizing the results from iPOND proteomic analyses.
Citation Format: David Cortez. Mechanisms of the ATR-dependent replication stress response [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA14.
Abstract IA23: Using PARP inhibitors to target ATM-deficient cancers
Authors: Lees-Miller Susan P. 
Published: April 2017

Abstract
The Ataxia-Telangiectasia Mutated (ATM) serine/threonine protein kinase plays an important role in orchestrating the cellular response to DNA double strand breaks (DSBs). Germline loss of ATM function results in Ataxia-Telangiectasia (A-T), a devastating childhood syndrome characterized by progressive loss of neuromuscular control, immune deficiency and cancer predisposition. ATM is also deleted in a large proportion of human mantle cell lymphoma (MCL) and other lymphomas and recent studies have revealed that ATM is altered in many sporadic cancers including lung, colorectal, breast and prostate cancer. We previously showed that MCL and gastric cancer cell lines with deletion or mutation of ATM are sensitive to the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib and that loss of TP53 enhances olaparib sensitivity (Williamson et al Molecular Cancer Therapeutics, 2010, 9:347-57; Williamson et al, EMBO Molecular Medicine, 2012, 4, 515-527; Kubota et al, Cell Cycle 2014, 13: 2129-37). Here we show that lung and colorectal cancers with mutation or loss of ATM are similarly sensitive to olaparib. The potential for use of PARP and ATM inhibitors in the treatment of ATM deficient malignancies will be explored.
Citation Format: Susan P. Lees-Miller. Using PARP inhibitors to target ATM-deficient cancers [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA23.
Night and the Japanese Fairy Tale
Authors: Petkova Gergana 
Published: April 2017

Time, and particularly night, in folktales can be approached from various perspectives. In the present study, we shall see time in its structural function and will analyze the protagonist’s experience of time, as well as the “anthropic” nature of time and night as structural elements in fairy tales. We shall accomplish this by examining the theme of time, and particularly nighttime with its functions and characteristics, within the framework of the Japanese tale. We shall attempt to rethink the position of night and time in fairy tales as a motif, a background, a facilitator, and an opportunity that exists because of the human factor in the process of storytelling.
The present study is based on the subgenre of ordinary folktales (also known as true folktales, or Zaubermärchen). The source material (59 tales out of the total 189 defined as “true”) can be found in volumes ii-vii of Seki Keigo’s Index of Japanese Folktales. All of the 59 tales that form the basis of this study are examined in regard to time, and conclusions are illustrated by a few selected examples. The time-motifs are discussed as originating from the storytelling process; as being part of the binomial world of the folktale; as illustrating the physical and psychological experience of time quantities and qualities; and as forming a framework that facilitates the relationships between the dramatis personae.
Girls Playing Persephone (in Marriage and Death)
Authors: Mackin Ellie 
Published: April 2017

AbstractArguably, the most famous myth told about Persephone is her abduction and marriage to Hades. The story clearly articulates the strong connection between marriage and death, and this episode became significant in both literature and religious practice in the wider classical Greek world. Reference to the story of Persephone’s abduction came to be used as a shorthand for evoking this connection, particularly in myth. This paper discusses two particular ways in which Persephone’s narrative was used in marriage and death. I examine the pre-marriage offerings to Persephone at Lokroi Epizephyrioi, in southern Italy, and the tradition of Athenian girls who died unmarried being buried as brides. These cultic instances frame a discussion of Brides of Hades, particularly in tragedy. Overall, I conclude that these girls do not attempt to replace Persephone, but rather to imitate her: they ‘play the role’ of Persephone at various stages of her own abduction and marriage story.
Is Synaesthesia More Prevalent in Autism Spectrum Conditions? Only Where There Is Prodigious Talent
Authors: Hughes James E. A. , Simner Julia , Baron-Cohen Simon , Treffert Darold A. , Ward Jamie 
Published: April 2017

Savant syndrome is a condition where prodigious talent co-occurs with developmental difficulties such as autism spectrum conditions (ASC). To better understand savant skills, we previously proposed a link with synaesthesia: that savant syndrome may arise in ASC individuals who also happen to have synaesthesia. A second, unrelated claim is that people with autism may have higher rates of synaesthesia. Here we ask whether synaesthesia is indeed found more often in autism per se, or only in cases where autism co-occurs with savant skills. People with autism in previous studies when tested for synaesthesia were not differentiated into those with and without savant abilities. Here we tested three groups: people with autism who also have savant skills (), people with autism without savant skills (), and controls without autism (). We used a validated test to diagnose grapheme–colour synaesthesia. Results show a significantly higher prevalence of synaesthesia in people with ASC, but only those who also have savant skills. This suggests that synaesthesia in autism is linked to those with savant abilities rather than autism per se. We discuss the role of synaesthesia in the development of prodigious talent.
An Improved Small-Angle Approximation for Forward Scattering and Its Use in a Fast Two-Component Radiative Transfer Method
Authors: Sun Bingqiang , Kattawar George W. , Yang Ping , Mlawer Eli 
Published: April 2017

Abstract
The vector radiative transfer equation is decomposed into two components: a forward component and a diffuse component. The forward component is analytically solved with a small-angle approximation. The solution of the forward component becomes the source for the diffuse component. In the present study, the diffuse component is solved using the successive order of scattering method. The strong anisotropy of the scattering of radiation by a medium is confined to the forward component for which a semianalytical solution is given; consequently, the diffuse component slowly varies as a function of scattering angle once the forward-scattering peak is removed. Moreover, the effect on the diffuse component induced by the forward component can be interpreted by including the low orders of the generalized spherical function expansion of the forward component or even replaced by the Dirac delta function. As a result, the computational effort can be significantly reduced. The present two-component method is validated using the benchmarks related to predefined aerosol and cloud layers with a totally absorbing underlying surface. As a canonical application, the optical properties of water clouds and ice clouds used for the Moderate Resolution Imaging Spectroradiometer (MODIS) Collection 6 cloud-property retrieval products are used for radiative transfer simulations under cloudy conditions.