bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2108: Prevalence of mutations in MSH6, PMS1 and PMS2 gene in Brazilian families with Lynch syndrome
Authors: Silva Felipe C. , Torrezan Giovana T. , Lisboa Bianca G. , Santos Erika M. , Gomy Israel , Rossi Benedito M. , Ferreira Fabio O. , Carraro Dirce M. 
Published: August 2012

Abstract
Background: Lynch syndrome (LS) is an autosomal dominant disorder predisposing to colorectal cancer and increased risk for cancers of the stomach, small intestine, hepatobiliary system, kidney, ureter, ovary, and sebaceous tumors. Germline mutations in the MMR genes MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), post- meiotic segregation increased 1 (PMS1) or post- meiotic segregation increased 2 (PMS2), are known to cause LS. While mutations in MLH1 and MSH2 gene, account for 70% - 80% of all Lynch syndrome colorectal cancers, the involvement of the MSH6, PMS2 and PMS1 gene is continually rising. Altogether, MSH6, PMS1 and PMS2 mutations account for 5-20% of kindreds in which MSH2 and MLH1 mutations are excluded. Objective: The aim of the study was evaluate the frequency of mutations in MSH6, PMS1 and PMS2 gene. Methods: Seventy one unrelated patients without MLH1/MSH2 mutations were eligible for this study. Genomic DNA was obtained from peripheral blood and primers were designed within introns of all exons of MSH6, PMS1 gene. In order to avoid the amplification of pseudogenes for the PMS2 gene, a set of four primer pairs were design. Results: Out of 71 patients, 20 fulfilled the Amsterdam criteria and other 51 fulfilled the Bethesda guideline. Four novel pathogenic mutations were detected, three in MSH6 and 1 in PMS2. In addition, 7 variants of uncertain significance were encountered, in which two of them were previously described as pathogenic. No mutations were found in PMS1 gene. Conclusion: Our data shows that 8.5% (6/71) of the individuals have mutations in MSH6 and PMS2 gene and these results strongly suggest that MSH6 and PMS2 should not be excluded from the MMR screening in Brazilian families suspected for Lynch syndrome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2108. doi:1538-7445.AM2012-2108
Abstract 211: Ubiquitin-proteolytic regulation of hematopoietic stem cell expansion
Authors: Lee Jennifer , Shieh Jae-Hung , Zhang Jianxuan , Liu Liren , Morrone Giovanni , Moore Malcolm A.S. , Zhou Pengbo 
Published: August 2012

Abstract
Direct transduction of the homeobox protein HOXB4 promotes the proliferation of hematopoietic stem cells (HSCs) without induction of leukemogenesis, but requires frequent administration to overcome its short protein half-life. We demonstrate here that the CUL4A ubiquitin ligase regulates the post-translational stability of multiple HOX proteins, including HOXB4, and we defined the degron of HOXB4 required for CUL4A-mediated degradation. Ectopic expression of degradation-resistant HOXB4 in myeloid progenitor cells confers a growth advantage over wild-type HOXB4-expressing cells. Finally, direct transduction of recombinant degradation-resistant HOXB4 protein to human adult HSCs significantly enhanced their maintenance in a more primitive state both in vitro and in vivo compared to transduction with wild-type HOXB4 protein. Our studies demonstrate the feasibility of engineering a stable HOXB4 variant to overcome a major technical hurdle in the ex vivo expansion of adult HSCs and early progenitors for human therapeutic use.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 211. doi:1538-7445.AM2012-211
Abstract 2111: Characterization of current and novel biomarkers of bladder cancer
Authors: Fowler Elizabeth , Woolworth Julie , Shao Yuan , Sobolesky Philip , Keane Thomas , Wolff Daynna , Watson Dennis , Moussa Omar 
Published: August 2012

Abstract
Bladder cancer is one of the most common cancers in industrialized countries. It is reported that 3.51 billion dollars are spent each year on bladder cancer treatment making it the most expensive cancer to treat on a per patient basis. Approximately 80% of bladder cancer patients have at least one reported recurrence thereby prompting meticulous lifetime screening and surveillance by health care professionals. Therefore, careful evaluation of our institution's current fluorescent in situ hybridization surveillance tools in addition to investigation of novel biomarkers is imperative. Our investigation of novel biomarkers focused on apoptosis regulating genes which are often unbalanced in cancerous tissues. Our institution recently adopted BioView, an automated FISH capture/analysis system, to replace the manual protocol. Validation and assessment of the automated system for fluorescent in situ hybridization (FISH) interpretation to detect urothelial cancer was determined using patient cases to evaluate concordance, overall positivity, interpretative time spent, sensitivity, and specificity. To evaluate novel biomarkers, mRNA from patient samples was reversed transcribed to cDNA then utilized for biomarker quantification by RT-PCR. In addition, immunohistochemistry was performed on the most promising gene to further confirm its clinical usefulness. The automated BioView capture/ detection system does prove to be more time efficient and accurate when addressing all parameters described. In evaluation of novel biomarkers, API5, BIRC3, BIRC4, SURVIVIN, and BFAR provided the most promising data with sensitivity and specificity percentages all ranging from 83% to 97%. From this study of bladder cancer markers, we focused on API5 and its role in bladder cancer initiation and progression. API5 is strongly expressed early in tumorigenesis. Our data confirm that the automated FISH capture/detection system improves laboratory efficiency and accuracy. Furthermore, our data indicate that apoptotic regulators are promising biomarkers for clinical use. In addition, API5 is expressed early in tumorigenesis, which makes it an ideal early diagnostic marker. We have noticed increase in the level of API5 protein associated with tumor grade and stage which also suggest that API5 might be a potential prognostic marker for bladder cancer. In conclusion, detection of apoptosis regulating genes is a promising diagnostic and prognostic approach to aid our screening and surveillance tools.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2111. doi:1538-7445.AM2012-2111
Abstract 2111A: Molecular genetics of non-alcoholic fatty liver disease
Authors: Shi Ivy , Sakaguchi Takuya 
Published: August 2012

Abstract
Non-alcoholic fatty liver disease (NAFLD) is a widespread condition of growing concern. It affects up to 25% of people in the United States, and is caused by the buildup of lipids in the liver. NAFLD may lead to hepatocellular carcinoma, the 5th most common cancer in the world, and the 3rd most common cause of death from cancer. Steatosis is the earliest stage in the progression of NAFLD. It is characterized by the deposition of triglycerides as lipid droplets in the cytoplasm of hepatocytes. Although not usually lethal alone, it may develop into nonalcoholic steatohepatitis, and develop further into cirrhosis and ultimately hepatocellular carcinoma. A mutation in zebrafish is created that completely obstructs the guanine monophosphate synthase. The mutants show a phenotype of steatosis. We hypothesize that genes involved in de novo lipogenesis, lipid oxidation, or lipid transportation are altered in the mutants. To test our hypothesis, we conducted gene expression analysis using qPCR. The data indicates that the genes involved in de novo lipogenesis had no significant change. However, the genes involved in lipid oxidation were all significantly downregulated. This downregulation indicates that inadequate lipid metabolism is responsible for the buildup of lipids and steatosis. The genes involved in lipid transportation showed a downregulation trend. It might be a result of steatosis as the liver takes in less fat. Overall, the data suggests that the mutant cell is unable to metabolize enough lipids through oxidation, causing lipid buildup in the liver.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2111A. doi:1538-7445.AM2012-2111A
Abstract 2113: Elucidating mechanisms of regulation of homologous recombination utilizing a PALB2 fusion protein that contains the BRCT repeats of BRCA1
Authors: Zhang Fan , Bick Gregory , Andreassen Paul R. 
Published: August 2012

Abstract
The products of the breast cancer susceptibility genes, BRCA1 and PALB2, directly interact through coiled-coil domains present in each protein. How PALB2 is recruited to sites of DNA damage and how the BRCA1-PALB2 interaction regulates the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have remained unclear, however. Here, the BRCT repeats of BRCA1, which are required for its localization, were fused to a PALB2 mutant incapable of binding BRCA1. We introduced this fusion protein into HCC1937 breast cancer cells that contain a truncated BRCA1 or into cells in which full-length BRCA1 was depleted using a siRNA. The fusion protein corrected the deficiency for PALB2 foci in both systems, either with or without exposure to ionizing radiation. Importantly, expression of the fusion protein also corrected a defect in PALB2-dependent assembly of foci by the RAD51 recombinase. Further, we also introduced the fusion protein into PALB2/FANCN-deficient cells from a Fanconi anemia patient. The fusion protein restored both PALB2 and RAD51 foci in these cells without binding to BRCA1. Strikingly, the fusion protein also conferred resistance to mitomycin C (MMC) and corrected a defect in DSB-initiated HR in PALB2-deficient cells. Our data convincingly demonstrate that BRCA1 localizes PALB2 to sites of DNA damage, and that this is necessary for recruitment of RAD51 and for HR. Contrary to a published report, since the fusion protein is incapable of binding to PALB2, our results suggest that PALB2 functions, such as HR, are mediated by the BRCA1-PALB2 interaction rather than the PALB2-PALB2 dimer. Given that BRCA1 and PALB2 participate in a pathway of DNA repair by HR, our results suggest that mutations which disrupt the BRCA1-PALB2 interaction may lead to the genetic instability that underlies the development of cancer. Additionally, the BRCA1-PALB2 interaction may be a potential therapeutic target for sensitization of cancer cells to DNA damaging agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2113. doi:1538-7445.AM2012-2113
Abstract 2114: Trypanosoma brucei: A model to evaluate joint contribution of BRCA2 and PARP in DNA damage repair
Authors: Cooper Rachel , Misra Smita , Chaudhuri Minu , Chaudhuri Gautam 
Published: August 2012

Abstract
The DNA repair protein BRCA2, initially discovered as a tumor suppressor for familial breast cancer cases, is now found to play critical role in the biology of many eukaryotes. The extracellular protozoan parasite Trypanosoma brucei significantly relies on its BRCA2 protein for stress management as well as surviving from host humoral immunity during its mammalian stage of its complex digenetic life cycle. An interesting aspect of BRCA2 deficiency in cancer cells is that these cells are ultra-sensitive to the inhibitors of the chromatin modifying enzyme poly(ADP-ribose) polymerase (PARP). In the absence of PARP, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Thus, PARP activity is essential in homologous recombination-deficient BRCA2-mutant cancer cells. BRCA2 and PARP are not only expressed in the mammalian cells but also present in high levels in many other eukaryotic cells including the parasitic protozoan T. brucei. To evaluate the universality of the importance of these two proteins in the management of DNA damage, we determined the effect of PARP inhibitors such as 3-AB, Veliparib, PF-01367338, Olaparib and Iniparib in BRCA2 knocked down T. brucei cells treated with the DNA damaging agent cisplatin. Our in vitro data strongly suggest that a combination of a BRCA2 inhibitor (e.g. BRCA2 BRC peptide), a PARP inhibitor and a DNA damaging agent (e.g. cisplatin) will be a chemical regimen for the management of trypanosomiasis and similar protozoan infections. Supported by NIH grants 2SC1GM081146-05 to MC, 1U54RR026140-01 to SM and NIH grants R01AI042327, R21AI076757 to GC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2114. doi:1538-7445.AM2012-2114
Abstract 2120: Hepatitis B virus X protein interacts with PARP1 that inhibits DNA repair
Authors: Na Tae Young , Lee Mi Ock 
Published: August 2012

Abstract
Hepatitis B virus (HBV) is strongly associated with the development of hepatocellular carcinoma (HCC). Among the HBV viral proteins, X protein (HBx) is regarded as a major risk factor of HCC. HBx contributes to HCC development through regulating expression of many host or viral genes and interacting with other cellular proteins. In this study, proteins that interact with HBx were analyzed by immunoprecipitation and subsequent LC/MS/MS. We identified 60 HBx interacting proteins that function in a wide spectrum of biology. Among these proteins, we were interested in PARP1, Poly (ADP-ribose) polymerase, a crucial factor in base excision repair (BER) pathway, since HBx was known to inhibit DNA repair capacity in cancer cells. Therefore, we characterized the cross-talk between HBx and PARP-1. HBx and PARP-1 colocalized in the nucleus and they are physically associated. Coimmunoprecipitation experiments revealed that the catalytic domain of PARP-1 bound to HBx. Chromatin immunoprecipitation showed that HBx inhibited the recruitment of DNA damage induced by paraquat treatment. HBx overexpression significantly inhibited the protein expression of the DNA damage response factors that respond to the paraquat-induced oxidative stress. Finally, HBx further enhanced the level of 8-OHdG, the marker of DNA damage, under oxidative stress. Together, these data suggest that the interaction between HBx and PARP1 inhibits DNA repair, which could result in onset of hepatocarcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2120. doi:1538-7445.AM2012-2120
Abstract 2129: Regulation of DNA repair by Kruppel-like factor 8
Authors: Lu Heng , Hu Liu , Li Tianshu , Mukherjee Debarati , Lahiri Satadru , Wason Melissa , Yu Lin , Zhao and Jihe 
Published: August 2012

Abstract
Krüppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. Recently we have identified poly(ADP-ribose) polymerase-1(PARP-1) as a novel KLF8-interacting and regulating protein. However, whether KLF8 is involved in PARP-1 relulated DNA repair is unknown. Here, we report that KLF8 plays a role in the PARP-1-dependent DNA repair. Western blotting and immunofluorescence staining indicated that overexpression of KLF8 attenuated the αH2A.X levels in doxorubicin-treated PARP-1+/+ MEF cells but not in the PARP-1−/− MEF cells, whereas the PARP-1-interaction-defective KLF8 mutant did not affect the αH2A.X levels. Clonogenic assay and tetrazolium salt (WST-1) assay showed that KLF8 promoted cell survival in human breast cancer cells. Comet assay revealed that KLF8 expression could decrease DNA damage levels. Interestingly, we found that in response to DNA damage KLF8 was phosphorylated by DNA-PKcs and subsequently sumoylated, which depended on the interaction between KLF8 and PARP-1. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2129. doi:1538-7445.AM2012-2129
Abstract 2133: MCPH1 interacts with the anaphase-promoting complex subunit Cdc27
Authors: Wiltshire Timothy D. , Singh Namit , Mer Georges , Couch Fergus 
Published: August 2012

Abstract
Microcephalin (MCPH1), the first gene identified as causative for primary recessive autosomal microcephaly, is aberrantly expressed in autism-like disorders and human malignancy of breast and ovarian origin. MCPH1, the encoded protein product, has been implicated in various cellular processes including the DNA damage checkpoint, DNA repair and transcription. While our understanding of the cellular context in which MCPH1 operates continues to develop, a structural understanding of the C-terminal tandem BRCT domains of MCPH1 remains unexplored. Here, we identify Cdc27, a component of the anaphase-promoting complex (APC/C), as a novel interacting partner of MCPH1. We provide in vitro and in vivo evidence that the C-terminal tandem BRCT domains of MCPH1 (C-BRCTs) bind Cdc27 in a phosphorylation-dependent manner. To further characterize this interaction, we determined the structure of MCPH1 C-BRCTs in complex with a phosphorylated Cdc27 peptide (pCdc27) using X-ray crystallography. Based on this structure, we identified single amino acid mutations targeted at the binding interface that disrupted the MCPH1-pCdc27 interaction. Collectively, our data defines the biochemical, structural and cellular determinants of the novel interaction between MCPH1 and Cdc27 and suggests that this interaction may occur within the larger context of MCPH1-APC/C.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2133. doi:1538-7445.AM2012-2133
Abstract 2136: Nuclear trafficking of Tie2 is associated with radioresistance of gliomas
Authors: Hossain Mohammad B. , Gururaj Anupama , Cortes-Santiago Nahir , Gabrusiewicz Konrad , Fueyo Juan , Gomez-Manzano Candelaria 
Published: August 2012

Abstract
Resistance and relapse are still primary causes that result in poor effectiveness of chemo- and radiotherapy in glioblastoma multiforme (GBMs), the most frequent subtype of primary brain tumors in adults. Patients suffering from this disease exhibit a median survival that ranges from 9 to 15 month, and the disease invariably recur after therapy due to the presence of cells exhibiting a multidrug-resistance phenotype. Aberrant DNA repair pathways can enable tumor cells to survive DNA damage that is induced after chemotherapy and radiotherapy. Therefore, development of new therapeutic strategies requires the identification of key molecular pathways regulating the resistant phenotype of these tumors. Previous work from our laboratory showed that Tie2, a previously considered specific vascular tyrosine kinase receptor, was expressed in glioma tumors and in brain tumor stem cells. The degree of expression of Tie2 was related to the malignancy of these tumors, and played an essential role in the multidrug resistance phenotype of gliomas. Our current research is focused on deciphering the mechanisms underlying this critical function. We found that density of Tie2 receptors in the membrane decreased upon exposure to both ligand (angiopoietin 1, Ang1) and ionizing irradiation (IR). Immunoflurorescence studies using confocal microscope and subcellular fractionation followed by Western blot showed that Tie2 traffics from the cellular membrane to the nucleus upon both stimuli. Western blot analysis using antibodies against N- and C-terminus, and against phosphorylated-Tie2, indicated that the nuclear Tie2 is a full-length protein, and importantly that is phosphorylated at Tyr992. Of biological importance, to find the role of Tie2 in the nucleus, we irradiated the glioma cells, U251.Tie2, and found that ionizing radiation also helps Tie2 to move to the nucleus and importantly it binds with γH2AX one of the key DNA repair protein complex. By using confocal microscopy we found that Tie2 makes foci with γH2AX after DNA damage. We also found that after genotoxic stress like ionizing radiation or DNA-damaging drugs, Tie2-expressing cells were more resistant to DNA damaging effect, as assessed by cell viability assay and comet assay. Collectively, the nuclear Tie2 plays important role in the DNA repair which will result in the design of Tie2-targeting combinational therapies for patients with glioblastomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2136. doi:1538-7445.AM2012-2136