bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL06-02: Inflammation, DNA mismatch repair, and colon cancer.
Authors: Carethers John M. 
Published: August 2014

Abstract
Colorectal neoplasia is driven by at least two pathogenic pathways for cancer development. Chromosomal instability, observed in ~80% of sporadic colorectal cancers, is named due to the rearrangement of chromosomes, resulting in aneuploid nuclei. The etiology for CIN is not known. A common finding is allelic mutation of a tumor suppressor gene, followed by loss of the remaining normal allele (termed loss of heterozygosity, LOH). Microsatellite instability (MSI), observed in up to 20% of sporadic colorectal cancers, is named for frameshifts (or instability) that occur at DNA microsatellite sequences. Cells remain diploid. The etiology for MSI is inactivation of DNA mismatch repair (MMR), an enzyme system functioning in the nucleus to repair interstrand nucleotide mispairs and loops of DNA that are formed on one strand at microsatellites. The specificity of mismatch recognition is directed by hMutSa and hMutSb; hMutSa (hMSH2-hMSH6 heterodimer) binds to single mispairs and single insertion-deletion loops, whereas hMutSb (hMSH2-hMSH3 heterodimer) binds larger insertion-deletion loops. MSI sporadic cancers are caused by hypermethylation of the MMR gene hMLH1's promoter, preventing its transcription and translation. With loss of hMLH1, MMR completely fails and mutations accumulate in the genome due to non-repair of DNA polymerase errors. Clinically, MSI tumors contain surrounding and intratumoral mononuclear inflammatory cells which are thought responsible in containing the tumor in place, leading to improved survival over same staged patients with non-MSI tumors. Although the types of inflammatory cells within MSI tumors have not been characterized, it is believed that neo-peptides from frameshifted proteins as a result of MMR failure are generated to attract mononuclear cells into the tumor, producing a protective immune response. Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature observed in 60% of sporadic colon cancers. Unlike MSI colorectal cancers in which hypermethylation of hMLH1 drives multiple target gene mutations, the cause of EMAST has been recently associated with reduced expression of hMSH3, which we have also observed in hamartomatous polyps and during the adenoma-to-carcinoma progression, and is hypothesized to be triggered as a consequence of inflammation with subsequent relaxation of MMR function. EMAST-positive human colorectal cancers are strongly associated with inflammation, particularly within tumor nests, but unlike MSI tumors, this inflammation is associated with advance staged colorectal cancer, implying reduced survival.
Citation Format: John M. Carethers. Inflammation, DNA mismatch repair, and colon cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PL06-02.
Abstract A27: Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer.
Authors: Ichinose Junji , Watanabe Kousuke , Sano Atsushi , Nagase Takahide , Nakajima Jun , Fukayama Masashi , Yatomi Yutaka , Ohishi Nobuya , Takai Daiya 
Published: August 2014

Abstract
Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important layer in gene regulation. APA is involved in cell proliferation, development, and cancer. APA may lead to disruption of microRNA-mediated gene regulation in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer.
We selected the top 10 genes specifically showing significant 3'UTR shortening in lung cancer, using the package of the Bioconductor for probe-level analyses of expression microarrays. We established and evaluated the APA score by qRT-PCR in 147 clinical specimens of non-small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA-related genes, including PABPN1, CPEB1, E2F1 and several proliferation markers (MKI67, TOP2A and MCM2).
High APA scores were correlated with an advanced tumor stage and poor prognosis (P &lt; 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both loss of PABPN1 and gain of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P &lt; 0.001).
Our results indicate that the loss of PABPN1, a recently identified suppressor of APA, promotes tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation.
Citation Format: Junji Ichinose, Kousuke Watanabe, Atsushi Sano, Takahide Nagase, Jun Nakajima, Masashi Fukayama, Yutaka Yatomi, Nobuya Ohishi, Daiya Takai. Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A27.
Abstract A32: RET fusion gene: Translation to personalized lung cancer therapy.
Authors: Kohno Takashi , Tsuta Koji , Tsuchihara Katsuya , Mizukami Tatsuji , Yoh Kiyotaka , Goto Koichi 
Published: August 2014

Abstract
Oncogenic RET fusion gene, occurring in 1–2% of LADCs, was recently identified by us and others as a new targetable driver gene in lung adenocarcinoma. Existing FDA-approved inhibitors of RET tyrosine kinase, such as vandetanib, show promising therapeutic effects both in vitro and in vivo, as well as in a few patients. A phase II clinical trial, investigating the therapeutic effects of vandetanib, has been started in Japan (UMIN00001009) in Q1 of 2013. The RET fusion screening is being conducted in &gt; 120 hospitals throughout Japan by a consortium designated “LC-SCRUM (Lung Cancer Genomic Screening Project for Individualized Medicine in Japan)”. Approximately 4% of &gt;300 EGFR-mutation negative NSCLC patients screened have been diagnosed as being positive for RET fusion, and the therapy of several patients has started. Positive responses to vandetanib have been observed as expected. In addition, the structure of breakpoints of RET fusion in lung adenocarcinoma indicates that the different molecular processes generate oncogenic RET fusions between lung adenocarcinoma and papillary thyroid carcinoma. Etiology and therapeutic significance of RET fusion in lung adenocarcinoma will be discussed.
Citation Format: Takashi Kohno, Koji Tsuta, Katsuya Tsuchihara, Tatsuji Mizukami, Kiyotaka Yoh, Koichi Goto. RET fusion gene: Translation to personalized lung cancer therapy. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A32.
Abstract A37: Ectopic claudin 6 and 18.2 expression as potential treatment target in non-small cell lung cancer.
Authors: Mattsson Johanna SM , Micke Patrick , Edlund Karolina , Lohr Miriam , Jirström Karin , Berglund Anders , Botling Johan , Rahnenfuehrer Jörg , Marincevic Millaray , Pontén Fredrik , Ekman Simon , Hengstler Jan G. , Wöll Stefan , Sahin Ugur , Türeci Özlem 
Published: August 2014

Abstract
Claudins are central components of tight junctions that regulate epithelial cell barrier function and polarity. Altered claudin expression patterns have been demonstrated in numerous cancer types and lineage-specific claudins have been proposed as therapy targets. The objective of this study was to assess claudin 6 (CLDN6) and claudin 18 isoform 2 (CLDN18.2) expression in human non-small cell lung cancer (NSCLC).
Transcript levels were evaluated based on gene expression microarray data from a fresh-frozen NSCLC tissue cohort (n=196). Protein expression levels of CLDN6 and CLDN18.2 were examined by immunohistochemistry on a tissue microarray (n=355), and analyzed with regard to frequency distribution and association with clinical parameters.
High mRNA levels of CLDN6 and total CLDN18 were observed in subsets of non-squamous lung carcinomas. Correspondingly, distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) was displayed by virtually non-overlapping subgroups of adenocarcinomas and large cell carcinomas, while pneumocytes and bronchial epithelial cells were consistently negative. CLDN18.2 positive tumors were enriched among slowly proliferating, TTF1-negative adenocarcinomas, suggesting that isoform-specific claudin expression may delineate a specific subtype. Noteworthy, high CLDN6 mRNA as well as protein expression was associated with worse prognosis in lung adenocarcinoma.
In conclusion, distinct CLDN6 and CLDN18.2 positivity was observed in minor subsets of non-squamous NSCLC, indicating that tumor-specific claudin expression may define molecular subtypes associated with clinical parameters. These findings encourage further clinical exploration of targeting ectopic claudin expression as a valuable treatment concept in NSCLC.
Citation Format: Johanna SM Mattsson, Patrick Micke, Karolina Edlund, Miriam Lohr, Karin Jirström, Anders Berglund, Johan Botling, Jörg Rahnenfuehrer, Millaray Marincevic, Fredrik Pontén, Simon Ekman, Jan G. Hengstler, Stefan Wöll, Ugur Sahin, Özlem Türeci. Ectopic claudin 6 and 18.2 expression as potential treatment target in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A37.
Abstract B28: Histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of non-small cell lung cancer.
Authors: Watanabe Kousuke , Sunohara Mitsuhiro , Amano Yosuke , Ishikawa Rie , Ichinose Junji , Nakajima Jun , Fukayama Masashi , Yatomi Yutaka , Nagase Takahide , Ohishi Nobuya , Takai Daiya 
Published: August 2014

Abstract
MicroRNA expression is frequently altered in human cancers, and some microRNAs act as oncogenes or tumor suppressors. Mir-139 has recently been reported to function as a tumor suppressor in hepatocellular carcinoma and gastric cancer, but its function in non-small cell lung cancer (NSCLC) and the mechanism of its suppression have not been studied in detail. Mir-139 was suppressed frequently in lung cancer cell lines and primary NSCLCs. Mir-139 was silenced with its host gene PDE2A by histone methylation, which was independent of DNA methylation. In primary NSCLCs, decreased expression of mir-139 was significantly associated with distant lymph node metastasis and histological invasiveness (lymphatic invasion and vascular invasion) on both univariate and multivariate analyses. Overexpression of mir-139 suppressed the proliferation of lung cancer cells. Collectively, these results suggest that histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of lung cancer.
Citation Format: Kousuke Watanabe, Mitsuhiro Sunohara, Yosuke Amano, Rie Ishikawa, Junji Ichinose, Jun Nakajima, Masashi Fukayama, Yutaka Yatomi, Takahide Nagase, Nobuya Ohishi, Daiya Takai. Histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B28.
Abstract B36: Synthesizing new proteins from 3-dimensional spheroids, compare to 2-dimensional cell line culture.
Authors: KIM KI-UP , Koo So-My 
Published: August 2014

Abstract
Introduction: Researches are basically in vitro. However, their results apply to in vivo were disappointed. That may be caused by 3-dimensional structure, not pure cell components, and cell to cell/matrix interactions. If artificial organisms, multicellular tumor spheroids (MCTS), have similar cell components, it may be closer to tumor and more advanced model. The represented protein from 2- and 3-dimensional culture may be different because their milieu is changed.
Objective: We tried a multicellular tumor spheroids (MCTS) from cancer cell line, fibroblasts from human, and PBMC by combination or singly as a model to cancer research. And we tested the differences from represented proteins at 2- and 3-dimensional condition from A549 cancer cell line.
Method: Cell from 3 conditions were cultured to agarose coated plate singly or combined at DME media. Their formation of spheroids were observed daily by inverted microscope and got samples serially for 4 weeks. Cell components from combined spheroids were stained immunohistochemically by their specific antibody. Proteins, which were cultured from 2-dimension and 3-dimension at 3 day from A549 cancer cell line, were loaded by 2-dimensional gel electrophoresis and were analyzed by MALDI-TOF.
Result: Cells were conglomated and made clusters except PBMC within a few days and formed spheroids between 4 to 7 days. The mixed cluster with A549, fibroblast and PBMC were formed round shape. Cell components from spheroids had been confirmed by immunohistochemical stain. Compare to 2-dimensional culture, 23 proteins by 2-dimensional gel electrophoresis were newly detected from spheroids. The most prominent protein was heat shock protein 90.
Conclusion: MCTS is a new model for tumor research, and heat shock protein 90 is an important role for 3-dimensional structure.
Citation Format: KI-UP KIM, So-My Koo. Synthesizing new proteins from 3-dimensional spheroids, compare to 2-dimensional cell line culture. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B36.
Abstract A12: Regulation of ovarian cancer OVCAR-3 cell proliferation and viability by calcium/calmodulin-dependent protein kinase kinase 2
Authors: Gocher Angela M. , Azabdaftari Gissou , Edelman Arthur M. 
Published: August 2014

Abstract
Protein kinases play crucial roles in cancer progression and are considered potential targets for novel anti-cancer therapeutics. Oncogenic kinases mediate a variety of events characteristic of the malignant phenotype including transcriptional activation, accelerated cell proliferation and enhanced cellular survival. Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) has been implicated as a signaling mechanism in prostate and breast cancers, but has not been studied in ovarian cancer (OvCa). We report here the following. CaMKK2 expression is greatly increased in high grade serous papillary cystadenocarcinoma compared to benign tissue. Knockdown of CaMKK2 expression by RNA interference in OvCa OVCAR-3 cells resulted in slowing of cell growth and decreased number of cells entering S phase. At the molecular level, CaMKK2 knockdown led to significant decreases in cyclin D1 expression at both mRNA and protein levels and to a drop in phosphorylation of the retinoblastoma tumor suppressor (Rb) at Ser 807/811. These results indicate that CaMKK2 expression in OVCAR-3 OvCa cells is required for optimal G1/S phase cell cycle progression and proliferation. CaMKK2 knockdown also resulted in a significant decrease in OVCAR-3 cell survival and an increase in both Poly ADP Ribose Polymerase (PARP) cleavage (inactivation) and in the activity of executioner Caspases-3/7 indicating that CaMKK2 knockdown in OVCAR-3 cells results in apoptosis. Preliminary data showed a decrease in phosphorylation of the activation site of Akt (Thr 308) in CaMKK2 depleted cells suggesting that the G1/S phase cell cycle arrest and apoptosis in CaMKK2 silenced cells may occur either directly or indirectly through an Akt-dependent pathway. Altogether these data show that CaMKK2 is required for optimal growth and viability of OVCAR-3 cells and furthermore imply that CaMKK2 may be a promising and novel therapeutic target for OvCa.
Citation Format: Angela M. Gocher, Gissou Azabdaftari, Arthur M. Edelman. Regulation of ovarian cancer OVCAR-3 cell proliferation and viability by calcium/calmodulin-dependent protein kinase kinase 2. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A12.
Abstract A38: DDB2 suppresses tumorigenicity of ovarian cancer cells through reducing the subpopulation of cancer stem cells
Authors: Han Chunhua , Zhao Ran , Kroger John , Liu Xingluo , Wang Qi-En 
Published: August 2014

Abstract
Ovarian cancer is an extremely aggressive disease associated with a high percentage of recurrence and chemotherapy resistance. Damaged DNA binding protein 2 (DDB2) is a 48-kDa protein originally identified as a component of the damage-specific DNA-binding heterodimeric complex DDB. Besides the known ability of DDB2 protein to bind ultraviolet (UV)-damaged DNA and serving as the initial damage recognition factor during nucleotide excision repair (NER). DDB2 was also reported to be involved in the promotion of apoptosis to reduce cisplatin resistance of ovarian cancer cells, control of cell migration, invasiveness and breast tumor progression, as well as suppression of metastasis of colon cancer through a transcriptional regulatory mechanism. Here we show that DDB2 overexpression in human ovarian cancer cell line CP70 suppressed its capability to recapitulate tumors in athymic nude mice, as well as the growth of these cells cultured in semisolid media. Flow cytometry analyses indicate that DDB2 overexpression in CP70 cells reduced the abundance of CD117+ cells and ALDH+ cells, which are believed to be markers of cancer stem cells (CSCs) in ovarian cancer. In contrast, downregulation of DDB2 in ovarian cancer cell line A2780 increased the percentage of ALDH+ cells. In addition, we analyzed the expression level of DDB2 in the putative CSCs isolated from various ovarian cancer cell lines, and demonstrated that DDB2 expression is decreased in the CSCs in comparison with their parental bulk tumor cells. Overexpression of DDB2 in the ovarian CSCs reduced the expression of CSC markers, e.g., Sox2 and Nanog. In addition, overexpression of DDB2 in CSCs isolated from ovarian cancer cell line SKOV-3 also decreased the tumorigenicity of these cells in NOD/SCID mice. In summary, our data suggest that DDB2 suppresses tumorigenicity of ovarian cancer cells through reducing the CSCs pool in cancer cells. Thus, increasing the expression of DDB2 may provide a molecular strategy to inhibit the recurrence of ovarian cancer. (Supported by NIH R01 grant CA151248 to QEW)
Citation Format: Chunhua Han, Ran Zhao, John Kroger, Xingluo Liu, Qi-En Wang. DDB2 suppresses tumorigenicity of ovarian cancer cells through reducing the subpopulation of cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A38.
Abstract A54: Evaluation of effect of metformin and its various combinations on epithelial ovarian cancer
Authors: Patel Seema , Singh Neeta 
Published: August 2014

Abstract
Background & objectives: Ovarian cancer is the third most common cause of cancer in Indian women, the most common being epithelial type. Most patients relapse within 1-2 years of treatment and develop resistance to chemotherapy. The identification of new drugs with ability to resensitise ovarian cancer cells to existing chemotherapy has become a major challenge. In this study we have attempted to evaluate the effect of metformin (an antidiabetic drug) in ovarian cancer as it has shown promising effects in other solid tumours.
Methods: Primary culture of ovarian cancer cells was established from ascitic fluid of untreated ovarian cancer patients. The cells were treated with carboplatin, paclitaxel and metformin alone and their various combinations and their ability to induce apoptosis seen. In vitro drug dosage was established using the MTT assay. The control and treated cells were then analysed by flowcytometry.
Results: The mean percentage apoptosis in untreated control cells was 4.9 %( range from4-8%), with metformin for 48 hrs was 12.7 %( 9-16.8%), carboplatin 14.2% (9.9-20%), paclitaxel 16.06% (10-20.5%) , metformin and carboplatin 20.2% (12-28.4%), metformin and paclitaxel 26% (18.2-29%), carboplatin and paclitaxel 22.2% (16-27.3%), metformin carboplatin, paclitaxel combination 49% (46-55%)i.e. maximum.
Interpretation & conclusions: Metformin treatment significantly inhibited the proliferation of primary ovarian cancer cells culture. At the cellular level, metformin interferes with cell cycle leading to G0/G1 or S phase arrest. Besides its anti-neoplastic activity as a single agent, metformin treatment with carboplatin and paclitaxel demonstrated increase apoptosis as compared to single agents alone offering its potential as a therapeutic agent with carboplatin and paclitaxel for epithelial ovarian cancer.
Citation Format: Seema Patel, Neeta Singh. Evaluation of effect of metformin and its various combinations on epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A54.