bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4607: G1/S transition-related gene mutations associated with survival of hepatocellular carcinoma patients
Authors: Zhang Bingyuan , Song Tianqiang , Yang Pingzhou , Yang Songzhu , Guo Chao , Li Lei , Ren Shuang , Yan Maolin , Hu Weiyu , Guo Honglin , Zhang Yongjian , Li Yanlin , Wang Weifeng , Wang Kai , Yao Ming 
Published: August 2018

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China and has limited therapeutic options. Genomic alterations in HCC had been widely explored and some prognostic genomic alterations were identified. Different etiologic characteristics were discovered in Chinese HCC patients compared with Western population; however, the genomic profiles of Chinese patients had not been thoroughly elucidated.
Methods: FFPE tumor samples of 94 Chinese HCC patients, including 79 males and 15 females with a median age of 56, were collected for next-generation sequencing (NGS)-based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and fusions were assessed. Gene Ontology (GO) analysis was conducted with the genes whose variation rates were higher than 5% (N = 22). The TCGA HCC dataset with 198 patients was used to assess the prognostic value of the significantly enriched GO terms.
Results: The top 10 highly mutant genes in the 94 Chinese HCC cohort were TP53 (64.9%), TERT (31.9%), CTNNB1 (23.4%), AXIN1 (16.0%), STK24 (12.8%), RB1 (11.7%), CCND1 (9.6%), ARID1A (9.6%), LRPIB (8.5%) and ARID2 (8.5%). The Gene Ontology analysis revealed these gene alterations were significantly associated with pivotal signal pathways and cell proliferation including phosphatidylinositol phosphorylation, protein kinase B signaling, cell cycle arrest, and G1/S transition of mitotic cell cycle. The G1/S transition-related genes included TP53, TERT, RB1, CCND1 and CDKN2A. Moreover, the TCGA HCC patients with mutations of G1/S phase transition and mitotic cell cycle-related genes had a poor survival (p = 0.029).
Conclusions: Our study showed that Chinese HCC patients had different genomic alteration profile compared with Western population. The most frequent mutant gene in Chinese HCC was TP53 in 65% of the HCC patients, compared to 31% in the TCGA dataset (PMID:28622513). Genomic alterations in G1/S transition of mitotic cell cycle-related genes in Chinese HCC patients might be a negative prognostic factor. Our preliminary result suggested that functional analysis of HCC genomic alteration profile could have prognostic utility.
Citation Format: Bingyuan Zhang, Tianqiang Song, Pingzhou Yang, Songzhu Yang, Chao Guo, Lei Li, Shuang Ren, Maolin Yan, Weiyu Hu, Honglin Guo, Yongjian Zhang, Yanlin Li, Weifeng Wang, Kai Wang, Ming Yao. G1/S transition-related gene mutations associated with survival of hepatocellular carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4607.
Abstract 461: An essential role of the iron-sulfur cluster assembly enzyme isu-1 in the aging and stress responses of C. elegans
Authors: Xiao Rui , Sheng Yi 
Published: August 2018

Abstract
Iron is essential for animal cellular homeostasis by acting in the biogenesis of two important redox-reactive prosthetic groups of enzymes: iron sulfur clusters (ISC) and heme. Previous studies have indicated that the misregulated iron metabolism is associated with multiple aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, how iron metabolism modulates the aging process remains largely elusive.In the current study, we aim to reveal the roles and mechanisms of iron metabolism in the aging process of C. elegans, a well-established genetic model organism for aging research. Through our preliminary studies, we have found that the iron-sulfur cluster assembly gene isu-1 plays an important role in the lifespan modulation and stress resistance of C. elegans. Specifically, RNAi knocking-down of isu-1 causes a significantly upregulated mitochondrial unfolded protein response (mitoUPR). Furthermore, the isu-1 RNAi-treated worms are significantly more resistant to heat shock and oxidative stress. Lastly, isu-1 RNAi significantly extends lifespan (~25.7%).Currently, we are examining the transcription factors downstream of isu-1 in regulating aging and stress responses. Surprisingly, the isu-1 RNAi-triggered lifespan extension is independent of insulin and IGF pathway, an evolutionarily conserved master regulator of animal growth and aging. Next, we will characterize the mechanisms underlying the effects of iron-sulfur cluster in animal aging and stress response using various genetic and biochemistry approaches.
Citation Format: Rui Xiao, Yi Sheng. An essential role of the iron-sulfur cluster assembly enzyme isu-1 in the aging and stress responses of C. elegans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 461.
Abstract 4616: Cancer-associated MUC1 epitope-recognizing antibody as a novel immunohistochemical marker for breast carcinoma
Authors: Shimizu Ai , Hatanaka Kanako , Hatanaka Yutaka , Naruchi Kentaro , Sato Masaharu , Kase Hiroshi , Mitsuhashi Tomoko , Yamashita Hiroko , Matsuno Yoshihiro 
Published: August 2018

Abstract
Background: MUC1 has been used in clinical practice as a serum tumor marker (CA15-3) for monitoring recurrence and response to the treatment of breast cancers. However, it is not so practical to use the conventional anti-MUC1 antibody (C-Ab) for the differential diagnoses among malignant and benign tumors, because of its limited specificity to cancer-associated sugar chain structures. Recently, a novel epitope-defined (ED) antibody, which specifically recognizes MUC1 with cancer-associated carbohydrate antigens including Tn and sialyl-T antigens, was developed by our collaborators. In the present work, we focused on this Tn antigen-recognizing ED antibody (Tn-ED Ab) for MUC1, and examined the potential utility of this novel antibody as an immunohistochemical diagnostic marker of the breast.Design: Tissue microarray (TMA) consisting of invasive lesions and their non-neoplastic counterparts were constructed from 169 lesions of 167 individuals with invasive breast carcinomas (including 2 bilateral cases) resected and diagnosed at Hokkaido University Hospital from 2000 to 2003. We compared MUC1 immunoreactivity of Tn-ED Ab (clone SN-102) to commercially available C-Ab (clone Ma552) using TMA to evaluate its diagnostic performance and to analyze the association with clinicopathologic factors. Results: In invasive cancer parts, the immunoreactive positivity of Tn-ED Ab was observed predominantly in the cytoplasm (146/169) rather than in the cell membrane (5/169). The positive reaction of C-Ab was found in the cytoplasm and the membrane as well (156/169 and 93/169). Tn-ED Ab showed a lower expression rate in non-neoplastic parts and a high specificity in invasive cancer parts. Sensitivity/specificity in invasive parts was 86%/92% for Tn-ED Ab and 92%/47% for C-Ab. Moreover, the invasive cancer group with Tn-ED-positivity was significantly correlated with their molecular subtypes, low Ki-67 indices, and high ages, compared to those with Tn-ED-negativity (p=0.008, p=0.010 and p=0.027, respectively). Conclusion: Compared to C-Ab, the newly-developed Tn-ED Ab for MUC 1 showed a higher specificity for invasive breast cancer with a low reactivity to non-neoplastic components. Future study plans are ongoing to show that this cancer-specific Tn-ED MUC1 Ab could be useful for differentiating malignant from benign intraductal breast lesions as well.
Citation Format: Ai Shimizu, Kanako Hatanaka, Yutaka Hatanaka, Kentaro Naruchi, Masaharu Sato, Hiroshi Kase, Tomoko Mitsuhashi, Hiroko Yamashita, Yoshihiro Matsuno. Cancer-associated MUC1 epitope-recognizing antibody as a novel immunohistochemical marker for breast carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4616.
Abstract 4617: High expression of snail is associated with EZH2 expression and lymph node metastasis in large neuroendocrine lung cancer
Authors: Fang Yueh-Fu , Lee Min-Chia 
Published: August 2018

Abstract
Background Large neuroendocrine lung cancer was less than adenocarcinoma or squamous cell carcinoma of lung. EZH2 expression was high in small cell lung cancer with component of neuroendocrine. There was no study of EZH2 in large neuroendocrine lung cancer. We planned to identify the expression of EZH2 and EMT markers and the clinical outcome in large neuroendocrine lung cancer. Methods and Patient There were 25 resectable large neuroendocrine lung cancer patients in our hospital before 2014. Twenty-two patients' tissue was done for EZH2 and EMT markers. The EZH2-GSK3 and EMT signaling were performed in H1299 and H460 cancer cell lines. EZH2 inhibitor, Akt inhibitor and protease inhibitor was used to validate the cell signaling from EZH2 to EMT markers. Results There were 10 patients had high EZH2 and snail and 10 patients had low EZH2 and snail. The correlation between EZH2 and snail was very high. Snail expression showed high prevalence of lymph node metastasis but no EZH2. The overall survival and progression free survival showed no definite in EZH2 and other insomnia. The recurrence was also not significant difference. The cellular study showed the same result. Conclusion Over expression of snail showed high correlation with EZH2 and was a predictable marker.
Citation Format: Yueh-Fu Fang, Min-Chia Lee. High expression of snail is associated with EZH2 expression and lymph node metastasis in large neuroendocrine lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4617.
Abstract 463: Glucose-regulated protein 94 modulates the response of osteosarcoma to chemotherapy
Authors: Chien-Yu Huang , Wei Po-Li , Chang Yu-Jia 
Published: August 2018

Abstract
Background: Osteosarcoma (OS) is the most common and most aggressive primary solid malignant bone tumor in children and young adults and has high rates of recurrence and metastasis. The endoplasmic reticulum (ER) stress pathway is important in regulating chemo-responsiveness in cancer. However, the role of glucose-regulated protein 94 (GRP94) in regulating the chemotherapy response of OS has never been explored.
Method: In this study, GRP94-knockdown (GRP94-KD) MG63 OS cells were generated using short hairpin RNAs, and the response to chemotherapy was assessed by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.
Results: GRP94-KD cells were shown to be more resistant to chemotherapy than scrambled control cells, and the scrambled control cells had higher levels of apoptosis after chemotherapy than GRP94-KD cells.
Conclusion: Therefore, silencing GRP94 may increase resistance to chemotherapy treatment in OS cells by inhibiting the activation of apoptosis. Thus, GRP94 may be a key biomarker for the chemotherapeutic response of OS.
Citation Format: Huang Chien-Yu, Po-Li Wei, Yu-Jia Chang. Glucose-regulated protein 94 modulates the response of osteosarcoma to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 463.
Abstract 4644: Patient-derived 3D tumor cultures for clinical diagnostics and pre-clinical drug development
Authors: Dijkmans Thomas , Basten Sander , Herpers Bram , Yan Kuan , Giesemann Torsten , Schueler Julia , Vader Willemijn , Price Leo 
Published: August 2018

Abstract
Ex vivo cultures of patient-derived tumor enable functional testing of treatment options and optimization of pre-clinical drug development. Patient biopsies or tumor from patient-derived xenografts (PDX) mouse models are a valuable source of human tumor material that can be cultured in 3D for screening of drug efficacy, drug resistance and cellular processes such as proliferation, survival and invasion. A high throughput approach using 384 well plates enables evaluation of multiple drug treatments and dose ranges in parallel. After compound exposure, cultures are fixed and stained with cellular markers. 3D image stack acquisition is followed by ultra-high content multiparametric analysis using the OMiner platform to profile drug responses and quantify tumor spheroid volume, apoptosis and tumor invasion.
Dissected PDX material and tumor biopsy material, were used to establish 3D tumor cultures derived from various indications, including breast, ovarian, cervix, endometrium, stomach, pancreatic, colon, bladder and lung cancer. These were exposed to standard-of-care chemotherapeutics (e.g. 5-FU, taxanes, platinum compounds, anthracyclines, alkylating agents), small molecules (e.g. erlotinib, lapatinib, trametinib), targeted therapies (PARPi; niraparib, olaparib, rucaparib), antibodies (e.g. cetuximab, trastuzumab) and antibody-drug-conjugate (ADC, T-DM1) dose ranges. The tumor culture response was measured, generating dose-dependent profiles for relevant features.
Patient-derived 3D tumor cultures were tested with standard-of-care and novel therapeutic agents and high content analysis was used to evaluate drug sensitivity. This method enables both the in vitro selection of drug candidates in a pre-clinical setting as well as efficient selection of PDX models for in vivo follow-up in the same tumor. This highly translational in vitro-in vivo PDX pipeline is expected to reduce attrition and increase efficiency in early drug-discovery. Correlation of drug sensitivity in 3D cultures from fresh patient tumor biopsies, on the other hand, can be used for development of predictive diagnostics and also provides a unique source of patient material for drug discovery and development.
Citation Format: Thomas Dijkmans, Sander Basten, Bram Herpers, Kuan Yan, Torsten Giesemann, Julia Schueler, Willemijn Vader, Leo Price. Patient-derived 3D tumor cultures for clinical diagnostics and pre-clinical drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4644.
Abstract 4647: Identifying drug targets in sarcoma using machine learning and cell phenotype-based compound screening
Authors: Lachacz Eric J. , Wu Zhi Fen , Bixby John L. , Lemmon Vance P. , Merajver Sofia D. , Al-Ali Hassan , Soellner Matthew B. 
Published: August 2018

Abstract
High-throughput phenotypic screens that incorporate compound biochemical activity annotations are positioned for novel target discovery in cancer. We used machine learning approaches to correlate kinome-wide profiling data of a collection of kinase inhibitors with phenotypic cell proliferation data for the same compounds. We assembled a library of profiled kinase inhibitors with diverse chemotypes and kinome-wide selectivities and determined their anti-proliferative activities in a panel of sarcoma cell lines. Using a previously published machine learning algorithm, we related the compound inhibition profiles across 237 kinases to their abilities to inhibit cell proliferation. This identified Protein Kinase D (PRKD) as a putative novel target kinase selectively in synovial sarcoma cell lines, such that its inhibition leads to a decrease in proliferation in these cells. Next, we reasoned that our approach could be leveraged to identify targets that, when co-inhibited, induce a synergistic phenotype. This would enable rational design of drug combinations for further testing as opposed to the labor-intensive, random, pairwise testing commonly performed. To identify targets synergistic with PRKD, we performed a screen of a synovial sarcoma cell line in the presence of a selective PRKD inhibitor. Several kinases became prioritized as new targets in this “synergy screen.” Combining selective inhibitors for each synergistic target, as defined by Chou-Talalay, (here, CDK and AKT) with PRKD inhibitors synergistically reduced synovial sarcoma cell proliferation. Conversely, combining PRKD inhibitors with a selective inhibitor of a kinase that was deprioritized in the synergy screen (p38 MAPK) resulted in non-synergistic or even antagonistic effects. Overall, our approach provides a promising framework to identify new targets of cancer subtypes and a novel methodology to identify new combinational strategies for treatment.
Citation Format: Eric J. Lachacz, Zhi Fen Wu, John L. Bixby, Vance P. Lemmon, Sofia D. Merajver, Hassan Al-Ali, Matthew B. Soellner. Identifying drug targets in sarcoma using machine learning and cell phenotype-based compound screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4647.
Abstract 4653: Intracellular Delivery of SOCS3 Suppresses Pancreatic Cancer Progression
Authors: Lee Kuysook , Shin Seulmee , Hwang Yunseo , Choi Youngsil , Jo Daewoong 
Published: August 2018

Abstract
Background: JAK/STAT signaling, regulated by SOCS family proteins, plays a role in the progression of the inflammation, growth and metastasis of pancreatic adenocarcinoma. SOCS3 suppresses JAK kinase activity and degrades the activated cytokine receptor complex, and its loss contributes to pancreatic cancer development. We have developed advanced macromolecule transduction domains (aMTDs) to deliver recombinant proteins into to cells and tissues. In principle, aMTD enabled SOCS3 could provide an effective treatment for pancreatic tumors that depends on JAK/STAT signaling for growth or survival.
Objective: The present study utilized aMTD sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutic against pancreatic cancer.
Methods: Improved cell-permeable SOCS3 proteins, with and without a 12-amino acid aMTD sequence, were expressed at high yields in E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers.
Results: The iCP-SOCS3 exhibited high solubility, cell-/tissue-permeability and biological activity in pancreatic cancer cell lines (BxPC3, HPAC and PANC-1) with decreased endogenous SOCS3 levels, hyperactived JAK/STAT signaling and hypermethylated SOCS3 promoter region. The iCP-SOCS3 suppressed cancer-associated phenotypes (i.e., up to 90% inhibition of cell viability, 52% induction of apoptosis, 14.8% inhibition of cell cycle progression, 54% inhibition of migration and 61.5% inhibition of invasion) in pancreatic cancer cells dependent on elevated JAK/STAT signaling, whereas, these effects were not observed in non-cancer cells (H6c7, pancreatic duct epithelial cell) or with proteins lacking the aMTD sequence. In contrast, gemcitabine, a conventional pancreatic cancer therapeutic, showed undesirable cytotoxic effects including decreased cell viability and induced apoptosis in non-cancer cells. Furthermore, iCP-SOCS3 (30 mg/kg) induced tumor regression (-168% at day 18) in PANC-1 CDX model. In BxPC-3 orthotopic CDX model, iCP-SOCS3 suppressed tumor growth by 98% which was significantly higher compared to the suppressed tumor growth induced by gemcitabine (77%). Correlating to the tumor suppression, iCP-SOCS3 significantly decreased the secretion of TNF-α and the expression of p-STAT1, p-STAT3 and VEGF in tumor tissues.
Conclusion: These results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of SOCS3 with iCP-SOCS3 may provide a novel protein therapy against pancreatic cancer.
Citation Format: Kuysook Lee, Seulmee Shin, Yunseo Hwang, Youngsil Choi, Daewoong Jo. Intracellular Delivery of SOCS3 Suppresses Pancreatic Cancer Progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4653.
Abstract 4662: Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide
Authors: Chowdhury Nayela N. , Das Nandita G. , Das Sudip K. 
Published: August 2018

Abstract
Clinical efficacy of paclitaxel, a potent chemotherapeutic agent, is limited by its nonspecificity that leads to toxic side effects. Polymeric micellar formulations of paclitaxel were designed with the long term goals of decreasing toxicity by tumor targeting, increasing circulation time, and enhancing permeability and retention in solid tumors. Biodegradable amphiphilic block copolymers that self assemble into micelles were used to entrap hydrophobic paclitaxel in the core. Traditional 2D cell culture models are standard for cytotoxicity assays. However, they lack the diffusion gradient and cell to cell interactions present in solid tumors which 3D multicellular tumor spheroids are capable of providing. We evaluated the in vitro cytotoxicity of polymeric micelles entrapping paclitaxel in 3D multicellular tumor spheroids of triple negative breast cancer cells and compared it with the standard 2D model. We added the cell penetrating iRGD peptide with the expectation that the iRGD peptide will increase the cellular uptake of the paclitaxel micelles. Particle uptake is enhanced due to the interaction of the iRGD peptide with the highly expressed integrin receptor on the cell surface, followed by neuropilin receptor binding which mediates an active transport system for deep tumor permeation. Paclitaxel loaded micelles were prepared and the drug content was analyzed. The cytotoxicity of the micellar paclitaxel nanocarrier system was studied in both the 2D and 3D cell culture models. Micellar paclitaxel induced cytotoxicity was significantly higher than free paclitaxel for the same concentrations of paclitaxel. Furthermore, a synergistic growth inhibitory response was observed upon coadministration of iRGD compared to treatment with the paclitaxel loaded nanocarriers on their own. Significantly higher concentration of the drug was needed in the 3D cultures to achieve comparable levels of cytotoxicity to the 2D cell culture models. This suggested that multicellular tumor spheroids exhibit higher resistance to anticancer drugs, supporting the fact that 3D culture is the better model to study in vitro cytotoxicity and likely to produce biorelevant data.
Citation Format: Nayela N. Chowdhury, Nandita G. Das, Sudip K. Das. Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4662.