bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2226: Loss of STAG2 in bladder cancer
Authors: Krishnan Nithya , Woloszynska-Read Anna , Wang Jianmin , Liu Song , Morrison Carl , Guru Khurshid , Smit Evelyn , Trump Donald , Johnson Candace 
Published: May 2015

Abstract
Bladder cancer (BC), 90% of which have transitional cell histology, is the fourth most common malignancy in the US. Transitional cell carcinoma (TCC), which occurs predominantly in men and whose incidence appears to be increasing, occurs most frequently as superficial disease which, while prone to recurrence, is not life threatening. However, TCC which invades the muscle layer of the bladder (stage T2-T4) is lethal in ∼50% of individuals. Stage T2-T4 TCC is present at initial diagnosis in ∼30% of patients and superficial TCC progresses to T2-T4 disease 20% of the time. We sequenced whole exomes of 28 muscle-invasive bladder tumors and performed an additional screen of over 200 genes in 119 additional TCCs. We found frequent alterations (10%) in STAG2, a gene encoding a subunit of the cohesin complex, which regulates the sister chromatids segregation process. Most mutations identified on STAG2 were nonsense, missense or frameshift. Genetic disruption of the sister chromatid segregation process leads to aneuploidy, which is one of the hallmarks of cancer. Based on recently published studies, however, it is uncertain whether a loss of STAG2 causes aneuploidy or not. In this study we sought to elucidate the role of STAG2 loss of expression in bladder tumorigenesis. We have analyzed the expression of STAG2 in 14 urothelial cell lines at both mRNA and protein levels by means of q-PCR and western blots, respectively. We found that STAG2 expression was lost in 2 of the 14 urothelial cell lines (HB-CLS-2 and UM-UC-3) analyzed. We chose SV-HUC (immortalized normal urothelium cells) along with two bladder cancer cell lines that had high expression of STAG2 (HB-CLS-1 and TCC-SUP) to study effects of STAG2 loss by transient knockdown. Knockdown of STAG2 in SV-HUC, TCC-SUP and HB-CLS-1 cells did not affect proliferation. Cell cycle analysis on TCC-SUP cells revealed that STAG2 knockdown resulted in a lower percentage of cells in the G0/G1 phase in comparison to the scrambled control. Taken together, these data suggest that STAG2 has a role in modifying DNA content but not proliferation. Our ongoing studies utilizing bladder cancer tissue microarray (TMAs) and copy number variation (CNV) array will help to clarify the consequences of STAG2 loss in bladder cancer.
Citation Format: Nithya Krishnan, Anna Woloszynska-Read, Jianmin Wang, Song Liu, Carl Morrison, Khurshid Guru, Evelyn Smit, Donald Trump, Candace Johnson. Loss of STAG2 in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2226. doi:10.1158/1538-7445.AM2014-2226
Abstract 2236: The Biospecimen Methodological Study (BMS): Identifying best practices for tissue preservation and maintenance of RNA integrity
Authors: Rao Abhi , Carithers Latarsha , Moore Helen 
Published: May 2015

Abstract
Researchers may use a number of traditional methods for human tissue preservation and stabilization such as liquid nitrogen (LN2) or dry ice, and yet the effectiveness of newer methods remains unclear. The National Cancer Institute's Biorepositories and Biospecimen Research Branch (BBRB; formerly known as OBBR) conducted a study to better understand such tissue preservation methods to inform BBRB's biospecimen collection efforts for the NIH Genotype-Tissue Expression (GTEx) program. The Biospecimen Methodological Study (BMS) was developed to provide an evidence-based structure to support future tissue collection and data analysis methods by comparing features of three different preservation methods: PAXgene Tissue (Qiagen); LN2; and dry ice. In preliminary studies, use of PAXgene Tissue has proven highly successful in preservation and maintenance of RNA quality. Another critical aspect of the BMS was to determine the degree to which the time between cardiac cessation and tissue preservation alters RNA integrity; such changes in molecular integrity could result in changes in molecular profiles upon gene expression analysis. The results of this study will provide valuable information about tissue processing parameters by identifying artifacts associated with different preservation methods and timing post cardiac cessation. Identifying and utilizing superior biospecimen preservation methods for RNA analysis will help identify patient-specific changes in gene expression and ultimately contribute to the development of targeted molecular medicine.
Citation Format: Abhi Rao, Latarsha Carithers, Helen Moore. The Biospecimen Methodological Study (BMS): Identifying best practices for tissue preservation and maintenance of RNA integrity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2236. doi:10.1158/1538-7445.AM2014-2236
Abstract 2238: Non-random genetic rearrangements driven highly malignant tumor-cell population dictates the development of high-risk neuroblastoma
Authors: Khan Faizan H. , Ramraj Satish K. , Pandian Vijayabaskar , Aravindan Sheeja , Herman Terence S. , Natarajan Mohan , Aravindan Natarajan 
Published: May 2015

Abstract
Ascertaining the driving factors and molecular flow through that confiscate favorable to aggressive high-risk disease has momentous importance in neuroblastoma cure. Herein, we investigated the cytogenetic and tumorigenic/metastatic physiognomies of distinct population of highly malignant (NBP4) cells established from multi-site aggressive tumors after parental (SH-SY5Y) cell xenotransplantation. Karyotyping (G-banding) NBP4 revealed 47 (XX) with six novel non-random chromosomal rearrangements on 1q32, 8p23, 9q34, 15q24, 22q13 (additions), and 7q32 (deletion). Compared to the parental cells, high-resolution array CGH analysis of NBP4 cells and aggressive tumors revealed genetic alterations in chromosomes 1, 7, 8 and 22 corresponding to gain in coding regions of LOC100288142, CD1C, CFHR3, FOXP2, MDFIC, RALYL, CSMD3, SAMD12-AS1, MAL2 and loss in coding regions of ADAM5, LOC400927, APOBEC3B, RPL3, MGAT3, SLC25A17, EP300, L3MBTL2, SERHL, POLDIP3, A4GALT and TTLL1. Compared to SH-SY5Y cells, aggressive NBP4 cells exert stem-like phenotype and under stem-cell-growth conditions demonstrated a profound tumorosphere forming capabilities. Moreover, xenotransplantation of NBP4 cells exhibited high tumor forming capacity and metastatic potential in vivo. Together, these data demonstrate the clonal enrichment of select highly malignant cells drives neuroblastoma progression, and further implies that observed genetic alterations could mediate phenotypic transformation and functional response.
Citation Format: Faizan H. Khan, Satish K. Ramraj, Vijayabaskar Pandian, Sheeja Aravindan, Terence S. Herman, Mohan Natarajan, Natarajan Aravindan. Non-random genetic rearrangements driven highly malignant tumor-cell population dictates the development of high-risk neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2238. doi:10.1158/1538-7445.AM2014-2238
Abstract 2241: SHH pathway in uterine mesenchymal tumors
Authors: Garcia Natalia , Souza Faila C. , Bozzini Nilo , Baiocchi Glauco , Cunha Isabela W. , Soares Fernando A. , Baracat Edmund C. , Carvalho Kátia C. 
Published: May 2015

Abstract
Background: Uterine leiomyoma (ULM) and leiomyosarcoma (ULMS) are smooth muscle tumors with distinct clinical behavior that can cause infertility and even lead to death. Little is known about the factors that influence these tumors biology. Identification of new molecular markers can help in the differential diagnosis between ULM from low grade ULMS. It was demonstrated that activation of the Sonic Hedgehog (SHH) signaling pathway is related to the development of several tumors, through its activity in the cell proliferation and differentiation. Here, we investigated the protein expression profile of SHH, PTCH1, SMO and GLI1 both ULM (including non-typical leiomyomas) and ULMS. Methods: We selected 57 samples of ULMS and 30 samples of ULM (10 samples non-typical - ULMA). All tissues were used in TMA construction. Immunohistochemistry reaction was performed using monoclonal antibody against SHH (1:50), PTCH (1:100), SMO (1:100) and GLI-1 (1:200) using sodium citrate pH 6,0 in pressure cooker. Results were evaluated by Aperio® automated method. Results: Our preliminary data showed similar protein profile between the leiomyosarcoma and non-typical leiomyoma. GLI 1 and PTCH showed higher expression compared to leiomyoma and myometrium (p&lt;0.05). SMO, and SHH showed higher expression only in leiomyossarcomas (p&lt;0.05). Conclusions: Ours preliminary results showed that expression of Sonic Hedgehog pathway members might play an important role in uterine smooth tumors, since ULMS showed higher levels of these proteins. However, the role of these proteins interactions must be clarified.
Citation Format: Natalia Garcia, Faila C. Souza, Nilo Bozzini, Glauco Baiocchi, Isabela W. Cunha, Fernando A. Soares, Edmund C. Baracat, Kátia C. Carvalho. SHH pathway in uterine mesenchymal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2241. doi:10.1158/1538-7445.AM2014-2241
Abstract 2251: nrf2-keap1 axis molecular profile in small cell lung cancer cell lines
Authors: Muscarella Lucia Anna , Torre Annamaria la , Sparaneo Angelo , Palumbo Orazio , Storlazzi Clelia Tiziana , Balsamo Teresa , Trombetta Domenico , Pellegrini Fabio , Barbano Raffaela , Pasculli Barbara , Graziano Paolo , Sanchez-cespedes Montse , Landi Maria Teresa , Parrella Paola , Fazio Vito Michele 
Published: May 2015

Abstract
The Keap1/Nrf2 pathway is a master regulator of antioxidants and cellular stress responses implicated in resistance of tumor cells against chemotherapeutic drugs. The link between molecular alterations of this pathway in Non Small Cell Lung Cancer (NSCLC) is well studied and appears to depend on several main factors including the existence of activating mutations in NFE2LE gene and/or loss of function mutations and methylation in the KEAP1 gene. At present, the data concerning the mechanism of alteration of Nrf2-Keap1 pathway in Small Cell Lung Cancer (SCLC) instead are almost incomplete and correlation analysis with therapeutic strategies targeting the molecular dysfunction of this pathway is ongoing.
Here we present a comprehensive molecular alteration profile of the main partners of the Nrf2/keap1 axis in 12 SCLC cell lines by integrating data from SNP-Array analysis, immunofluorescence, mutation screening by direct sequencing, methylation by QMSP and expression analyses by RT-qPCR and western blotting.
Our analyses confirm the global deregulation of Nrf2/Keap1 pathway in SCLC cell lines, showing an hypermethylation of the CpGs located into the P1 promoter region of the KEAP1 in 42% (5/12) of the cell lines, and a chromosomal amplification involving the NFE2LE gene locus (2q31.1) in two cell lines. Only one just described point mutation in the kelch-repeat 2 was observed in one of the cell line analysed.
Our gene-alteration profile of SCLC cell lines provides new insights into the mechanism of deregulation of Nrf2-Keap1 detoxification pathway in this group of high grade neuroendocrine lung cancers, suggesting the NFE2LE gene amplification and the KEAP1 promoter hypermethylation as alternative mechanisms of dysfunctional Nrf2/Keap1 in SCLCs.Analyses on tumor tissues are ongoing to confirm these observations. Moreover, the provided full molecular data from cell lines will be useful for in vitro functional studies aimed to establish new combined therapeutic strategies in targeted cancer treatments of this aggressive lung tumor histotype.
Citation Format: Lucia Anna Muscarella, Annamaria la Torre, Angelo Sparaneo, Orazio Palumbo, Clelia Tiziana Storlazzi, Teresa Balsamo, Domenico Trombetta, Fabio Pellegrini, Raffaela Barbano, Barbara Pasculli, Paolo Graziano, Montse Sanchez-cespedes, Maria Teresa Landi, Paola Parrella, Vito Michele Fazio. nrf2-keap1 axis molecular profile in small cell lung cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2014-2251
Abstract 2253: YAP nuclear accumulation involved in drug-induced cellular senescence in vitro
Authors: Ma Kai , Wang Shuren , Xu Qing , Liu Mei , Zhu Hongxia , Xu Ningzhi 
Published: May 2015

Abstract
Cellular senescence is accompanied by some striking morphological changes, such as becoming large, flat and multinucleated. However, how these changes are established is poorly understood. The Hippo pathway plays an important role in the control of organ size. Previous study reported that YAP, one major downstream effector of Hippo pathway, could be regulated by mechanical signals through F-actin bundles. However, whether YAP participates in the control of cell size through cytoskeleton remains unexplained. In our current study, we found that the senescent cells induced with adriamycin or camptothecin became large and flat, and the stress fibers of the senescent cells seemed to maintain or increase, observed by F-actin staining, though in a way of inappropriate actin clumping. Moreover increased nuclear level and activity of YAP were identified in drug-induced senescent cells. Hence, our data indicated that the increased F-actin bundles and mechanical signals could be acquired in senescent cells induced by adriamycin or camptothecin. In summary, based on our findings here, we proposed that YAP might play some roles during drug-induced cellular senescence in vitro.
Citation Format: Kai Ma, Shuren Wang, Qing Xu, Mei Liu, Hongxia Zhu, Ningzhi Xu. YAP nuclear accumulation involved in drug-induced cellular senescence in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2253. doi:10.1158/1538-7445.AM2014-2253
Abstract 2255: DHA may enhance proteasome activity in human cervical cancer cells: Indirect modulation of proteasome by DHA
Authors: Lim Kyu , Jing Kaipeng , Shin Soyeon , Jeong Soyeon , Kim Soyeon , Kweon Gi-Ryang , Park Seung-Kiel , Wu Tong , Park Jong-Il 
Published: May 2015

Abstract
The omega-3 fatty acid, docosahexaenoic acid (DHA), has been shown to induce the proteasomal degradation of various cancer-associated molecules such as beta-catenin and estrogen receptor, implying its regulatory effect on proteasome. To verify this possible link between DHA and proteasome function, we explored the impacts of DHA on human papillomavirus-positive HeLa cervical cancer cells that constitutively express two known endogenous proteasome substrates E6 and E7 viral proteins. Exposure HeLa cells to DHA resulted in elevated proteasome activities along with decreased levels of E6/E7 viral proteins, and these effects of DHA were remarkably reversed in the presence of proteasome inhibitors, suggesting that DHA improves proteasome function in the cells and thereby accelerates the degradation of proteasome substrates. The DHA-induced increase in cellular proteasome activity was preceded by reactive oxygen species (ROS) overproduction and could be blocked by preincubation of the cells with ROS scavengers. Likewise, HeLa cells treated with exogenous ROS, H2O2, also exhibited significantly improved proteasome function. Unexpectedly, when the purified proteasome and whole-cell lysates isolated from HeLa cells were directly exposed to DHA or H2O2, such marked increases in proteasome activity were not seen. Taken together, these findings indicate that DHA may induce proteasome activation in cervical cancer cells mainly by indirect regulation of the proteasome.
Citation Format: Kyu Lim, Kaipeng Jing, Soyeon Shin, Soyeon Jeong, Soyeon Kim, Gi-Ryang Kweon, Seung-Kiel Park, Tong Wu, Jong-Il Park. DHA may enhance proteasome activity in human cervical cancer cells: Indirect modulation of proteasome by DHA. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2255. doi:10.1158/1538-7445.AM2014-2255
Abstract 2259: Oxidative DNA damage causes premature senescence in mouse embryonic fibroblasts deficient for krüppel-like factor 4
Authors: Liu Changchang , Rosa Stephen La , Hagos Engda 
Published: May 2015

Abstract
Krüppel-like factor 4 (KLF4) is a zinc-finger-containing transcription factor with tumor suppressor activity in various cancer types. Cells that sustain double strand breaks (DSBs) in their DNA due to high levels of reactive oxygen species (ROS) can develop genomic instability, which can result in cancer formation. One protective response to increased levels of ROS is the induction of cellular senescence. Recently, we found that mouse embryonic fibroblasts (MEFs) null for Klf4 are genetically unstable, as evidenced by the presence of DNA DSBs. However, it is yet unknown whether KLF4 is involved in regulating oxidative stress-induced DNA damage. Therefore, we sought to determine the mechanisms by which ROS induce genomic instability in Klf4-deficient MEFs. With SA-β-Gal staining, we show that Klf4-/- MEFs enter senescence earlier than Klf4+/+ MEFs, and western blot shows accumulation of p21 and p53 with increasing passages. In addition, immunostaining against γ-H2AX indicates that the increased level of DNA damage in Klf4-/- MEFs positively correlates with ROS accumulation. Consistent with ROS as a source of DSB in Klf4-/- MEFs, treatment with NAC, reduced the accumulation of DNA damage. Our RT-PCR result demonstrates that Klf4-/- MEFs have decreased expression of the antioxidant gene, Gstα4. The downregulation of the Gstα4 correlates with significant levels of ROS accumulation, as shown by DCFDA and FACS analysis, and thus the oxidative stress-induced premature senescence. Together these findings suggest a mechanism by which KLF4 protects against DNA damage and oxidative stress at least in part through the regulation of Gsta4 and likely related genes.
Note: This abstract was not presented at the meeting.
Citation Format: Changchang Liu, Stephen La Rosa, Engda Hagos. Oxidative DNA damage causes premature senescence in mouse embryonic fibroblasts deficient for krüppel-like factor 4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2259. doi:10.1158/1538-7445.AM2014-2259
Abstract 2261: Natural redistribution of end-protection proteins in aging cells as telomeres shorten
Authors: Baribault Michelle E. , Swanson Mark J. , Bae Nancy S. 
Published: May 2015

Abstract
Telomeres are the nucleoprotein structures at the ends of linear chromosomes. In mammalian cells, a six-member protein complex, called shelterin, protects telomeres from being recognized as DNA double-strand breaks and from nucleolytic degradation. It has been speculated that as telomeres become progressively shorter with each round of replication, the number of binding sites for the components of shelterin would decrease as well. In an attempt to determine whether there is a relationship between the length of telomeres and shelterin binding, primary human dermal fibroblasts from neonatal foreskin (HDFn) were grown in culture, and the levels of a number of shelterin components were measured over time. Unlike other previous studies where artificially constructed telomeres were used to address this question, we are following the natural progression of aging of a population of cultured cells. Comparisons were made between young cells at a population doubling (PDL) between 3 and 6 and aged cells at a PDL of 28 to 38. Southern blotting using a telomeric probe showed that the aged cells possessed significantly shorter telomeres than their younger counterparts, supporting the notion that there will be fewer shelterin binding sites. Using immunoblotting to compare the levels of several shelterin subunits (TRF2, hRAP1, and POT1), we found that TRF2, the DNA binding subunit that targets hRAP1 to the telomeres, and POT1 decrease in level as would be expected when fewer binding sites are present for the complex. Interestingly, the levels of hRAP1 did not decrease proportionally and remained relatively high compared to other subunits. These data suggest that as telomeres decrease in length and shelterin binding sites become less numerous, most shelterin subunits are degraded, but hRAP1 most likely plays an additional role. We have stressed young HDFn cells with hydrogen peroxide to age them prematurely. Upon treatment, the young cells (PDL of 8) became similar in appearance to the untreated, aged cells at PDL greater than 25. In the treated, young cells, hRAP1 levels in the nucleus decreased in a manner that was unaffected by inhibition of the proteasome, suggesting that during the oxidative stress, hRAP1 translocates from the nucleus to the cytoplasm. Taken together, our data suggest that RAP1 plays a role in stress signaling or response to cellular aging.
Citation Format: Michelle E. Baribault, Mark J. Swanson, Nancy S. Bae. Natural redistribution of end-protection proteins in aging cells as telomeres shorten. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2261. doi:10.1158/1538-7445.AM2014-2261