bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3556: Sam68 is required for the growth and survival of non-melanoma skin cancer
Authors: Fu Kai , Wan Fengyi 
Published: August 2018

Abstract
Skin cancer is the most commonly diagnosed malignancy in the United States, and the incidence of skin cancer has increased dramatically over the last few decades. Non-melanoma skin cancer (NMSC), which includes squamous cell carcinomas (SCC) and basal cell carcinomas (BCC), is the most common type of skin cancer with substantial associated morbidity and mortality. Whereas targeting DNA repair signaling pathways has emerged as a promising therapeutic for skin cancer, the relevance of DNA damage responses (DDR) in the development and survival of non-melanoma skin cancer (NMSC) remains obscure. Here we report that Src-associated substrate during mitosis of 68 kDa (Sam68), an early signaling molecule in DDR, is elevated in skin tumor tissues derived from NMSC patients and skin lesions from Gli2-transgenic mice. Downregulation of Sam68 impacts the growth and survival of human tumor keratinocytes and genetic ablation of Sam68 delays the onset of basal cell carcinomas (BCC) in Gli2-transgenic mice. Moreover, Sam68 plays a critical role in DNA damage-induced DNA repair and nuclear factor kappa B (NF-κB) signaling pathways in keratinocytes, hence conferring keratinocyte sensitivity to DNA damaging agents. Together our data reveal a novel function of Sam68 in regulating DDR in keratinocytes that is crucial for the growth and survival of NMSC.
Citation Format: Kai Fu, Fengyi Wan. Sam68 is required for the growth and survival of non-melanoma skin 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 3556.
Abstract 3557: Beta-hydroxybutyrate inhibits oncogenic signaling and cellular motility in pancreatic cancer cells
Authors: Shukla Surendra K. , Chaika Nina V. , Singh Pankaj K. 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma is a devastating malignancy with a five-year survival rate less than 7%. It is characterized by a plethora of metabolic and signaling pathways, which plays a critical role in the pathogenesis of the disease. Caloric restriction and ketogenic diets have been shown to be beneficial in the management of several kinds of malignancies including pancreatic cancer. During caloric restriction or ketogenic diet supplementation, blood level of ketone bodies (beta-hydroxy butyrate or BHB, acetoacetate, acetone) gets elevated in the body. Among, these ketone bodies, BHB, the most abundant ketone body in mammals has been shown to act as the modulator of several signaling and inflammatory pathways. We have evaluated the effect of BHB on oncogenic signaling pathways and motility of pancreatic cancer cells. We observed reduced activation of key oncogenic signaling pathways, including mTOR. We also observed inhibition of cellular motility in a dose-dependent manner. Furthermore, we observed reduced expression of c-Myc, a key oncogene and a downstream effector molecule of mTOR. Correspondingly, we also observed reduced expression of several c-Myc target genes. We have also evaluated the effect of BHB on epithelial-mesenchymal transition (EMT) markers and observed altered expression of EMT markers like N-cadherin and E-cadherin. We also evaluated the effect of BHB on the expression of inflammatory cytokines in the pancreatic cancer cells and observed that BHB treatment leads to the reduction of expression of several inflammatory cytokines including IL6 and IL1-beta. Overall, our findings suggest that BHB inhibits inflammatory signaling in pancreatic cancer cells and reduces the cellular motility by modulating the expression of EMT regulators.
Citation Format: Surendra K. Shukla, Nina V. Chaika, Pankaj K. Singh. Beta-hydroxybutyrate inhibits oncogenic signaling and cellular motility in pancreatic cancer cells [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 3557.
Abstract 3564: A combination of chimeric switch-receptor T cells targeting both PD1 and CTLA4 suppresses tumor growth
Authors: Li Peng , Qin Le , Wei Xinru , Zhao Ruocong , Lai Yunxin 
Published: August 2018

Abstract
Chimeric antigen receptor (CAR) T cells have been successfully used to treat B cell malignancies, but faces many obstacles in solid tumors. A major challenge is the immune-suppressive effects induced by PD-L1 expression in tumors and CD80/86 that ligate with CTLA-4 and are expressed in myeloid-derived immune suppressive cells. Dual blockade of PD-1 and CTLA-4 with monoclonal antibodies has achieved promising anti-tumor effects in clinics. Here, we designed two switch receptor constructs. One contains the truncated extracellular domain of human PD1, costimulatory domains of 4-1BB and TLR2, and the CD3z signaling domain (cPD-1). cPD-1 T cells specifically lysed PD-L1+ tumor cell lines and augmented cytokine secretion in vitro. In addition, cPD-1 T cells were able to suppress the growth of lung cancer, gastric cancer, and osteosarcoma in xenografts. The other construct, similarly, is composed of the truncated extracellular domain of murine Ctla4, human CD28, TLR2, and CD3z signaling domains (cmCtla-4). Because CD80/CD86 are expressed in murine myeloid cells rather than human tumor cells in PDX models, cmCtla4 T cells targeted mouse myeloid cells that were abundant in tumors but not human tumor cells. We found that cmCtla4 T cells hindered tumor growth in gastric cancer PDX. In combination, cPD-1 and cmCtla4 T cells synergistically induced superior anti-tumor effects in lung cancer PDX. Taken together, our findings demonstrated the anti-tumor function of switched immune checkpoint receptors and revealed a strategy of combining T cells targeting both tumor cells and tumor microenvironment, promoting clinical investigation of these chimeric switch-receptor T cells for cancer treatment.
Citation Format: Peng Li, Le Qin, Xinru Wei, Ruocong Zhao, Yunxin Lai. A combination of chimeric switch-receptor T cells targeting both PD1 and CTLA4 suppresses tumor growth [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 3564.
Abstract 357: Phosphorylated histone H3 mediates epigenetic regulation of Brf1 and Pol III genes in alcohol-associated breast cancer
Authors: Lu Lei , Fang Zeng , Li Wen , He Zhimin , Zhong Shuping 
Published: August 2018

Abstract
Approximately 3.6% human cancers worldwide derive from chronic alcohol drinking, including cancers of breast and multiple other organs. Alcohol intake is consistently associated with an increased risk of BC (breast cancer). Alcohol consumption is more pronounced in ER+ BC cases than in ER- cases. However, the molecular mechanism remains to be determined. RNA polymerase (Pol) III genes, such as 5S rRNA and tRNAs, are elevated in both transformed and tumor cells. Brf1 (TFIIIB-related factor 1), a subunit of TFIIIB complex, specifically regulates Pol III gene transcription. Our studies have demonstrated that Brf1 expression and Pol III gene transcription are increased in alcohol-induced mice liver tumor. Alcohol-induced deregulation of Pol III gene transcription may be fundamental to the development of BC. We have found that alcohol-increased Pol III gene transcription in ER+ BC cells is significantly higher than in ER- normal breast cells and BC cells. The induction is ER dependent. The cellular levels of Brf1 protein and mRNA are increased in ethanol-treated MCF-7 cells. Ethanol markedly stimulates phosphorylation of MSK1 (MSK1ph) and histone H3 (H3ph). Our previous studies demonstrated that MSK1 mediates H3ph. MSK1 mediates ERα expression. Inhibition of MSK1 signal reduces alcohol-induced ERα expression to decrease cellular level of Brf1 and Pol III genes. Repression of Brf1 expression decreases alcohol-induced anchorage-independent cell growth and tumor formation. Furthermore, our analysis indicates that ethanol treatment increases occupancy of ERα to Brf1 promoter. The results by using Co-IP and ChIP assays indicate that MSK1, ERα and Brf1 form a complex to mediate Pol III gene transcription. Studies of human biopsies of BC patients indicate that Brf1 expression is increased in human cases of BC. High expression of Brf1 displays longer overall survival period after Tamoxifen treatment. Co-localization analysis indicate that MSK1ph and H3S10ph localizes in nuclear with Brf1. These results support the idea that alcohol activates MSK1 and induces epigenetic modification of H3ph to enhance ERα and Brf1 expression and Pol III gene transcription, resulting greater phenotypic changes. Together, our studies indicate that ethanol-induced epigenetic modification of H3ph may play a critical role in alcohol-induced cell transformation and alcohol-associated ER+ BC. The project is supported by NIH grants: AA017288, AA021114, AA02324 and AA024169
Citation Format: Lei Lu, Zeng Fang, Wen Li, Zhimin He, Shuping Zhong. Phosphorylated histone H3 mediates epigenetic regulation of Brf1 and Pol III genes in alcohol-associated breast 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 357.
Abstract 3573: Novel DNA vectors encoding a chimeric antigen receptor mediate long term expression without genomic integration
Authors: Schmidt Patrick , Bozza Matthias , Berger Aileen , Luckner-Minden Claudia , Tuch Alexandra , Zörnig Inka , Jäger Dirk , Harbottle Richard 
Published: August 2018

Abstract
Adoptive immunotherapy is one of the most encouraging therapeutic strategies for the treatment of a range of cancers. One particularly promising avenue of research is the functional introduction of Chimeric Antigen Receptors (CARs) into naive Human T-Cells for autologous-immunotherapy. Currently, the genetic engineering of these cells is achieved through the use of proprietary integrating vector systems such as lentiviruses or the sleeping beauty transposon system which present a risk of genotoxicity associated with their random genomic integration.
We have invented a novel DNA Vector platform for the safe and efficient generation of genetically engineered T-Cells for Human Immunotherapy. This DNA vector system contains no viral components and comprises only clinically approved sequences, it does not integrate into the target cell's genome but it can replicate autonomously and extrachromosomally in the nucleus of dividing human primary cells. These DNA Vectors offer several advantages over currently used vector systems; they are not subject to commercial licences, they are cheaper and easier to produce, and they can more quickly genetically modify human cells without the inherent risk of integrative mutagenesis.
In preclinical experiments we have successfully generated genetically engineered human T-Cells expressing the CAR receptor against several epitopes and have demonstrated their viability and capability in targeting and killing human cancer cells which express these epitopes. The long term anti-tumor activity of our DNA-CAR-T cells has been confirmed in vivo using xenotransplanted cell lines in immunodeficient mice.
We believe that this novel DNA Vector system provides a unique and innovative approach to this exciting therapeutic strategy for cancer therapy. We estimate that this novel methodology will provide a simpler method of CAR T-cell manufacturing, resulting in a 10-fold reduction in the cost of the CART-product.
Citation Format: Patrick Schmidt, Matthias Bozza, Aileen Berger, Claudia Luckner-Minden, Alexandra Tuch, Inka Zörnig, Dirk Jäger, Richard Harbottle. Novel DNA vectors encoding a chimeric antigen receptor mediate long term expression without genomic integration [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 3573.
Abstract 3579: RegCAR-TTM: Enabling next-generation CAR-T therapy
Authors: Zhang Xu , Tang Ke , Song Qingxuan , Chen Si , Kasbek christopher , Wang Tianjiao , Huang Jun 
Published: August 2018

Abstract
Chimeric Antigen Receptor (CAR) T-Cell Therapy has been emerging as a means of powerful cancer immunotherapy with its exceptional therapeutic efficacy, however, the full potential of CAR-T therapy is hampered by its severe side effects. Thus, CAR-T therapy that is controllable for optimal efficacy and safety is in need developing. To enable controllable CAR-T therapy, we have established a technology platform, RegCAR-TTM. In RegCAR-TTM, aptazymes are generated by in vitro selection/evolution of combinatory nucleic acid libraries and are used as molecular switches for controlling CAR expression. Aptazymes are RNA molecules consisting of an aptamer module and a ribozyme module, in which ribozyme self-cleavage can be allosterically regulated by the aptamer-ligand (e.g. a small molecule drug) interaction. With an aptazyme switch incorporated into the untranslated region (UTR) of a CAR gene, CAR expression can be temporally and dose-dependently controlled at mRNA level by a ligand, which may result in controllability of CAR-T efficacy and safety. Using RegCAR-TTM technology, we have generated aptazyme switches responsive to FDA-approved small molecules drugs with IC50 at micromolar level. Thus, next generation CAR-T therapies with aptazyme switches would be controllable by safe oral small molecules drugs. In conclusion, we have developed a technology platform (RegCAR-TTM) to generate aptazyme switches for enabling controllable CAR-T therapy.
Citation Format: Xu Zhang, Ke Tang, Qingxuan Song, Si Chen, christopher Kasbek, Tianjiao Wang, Jun Huang. RegCAR-TTM: Enabling next-generation CAR-T therapy [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 3579.
Abstract 358: miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing of locus genes and associates with bortezomib-induced apoptosis of leukemia
Authors: Wang Ju-Ming , Chu Yu-Yi , Ko Chiung-Yuan , Wang Shao-Ming , Lin Pin-I , Wang Han-Ying , Lin Wen-Chi , Wu Dong-Yu 
Published: August 2018

Abstract
miRNAs are a class of non-coding RNAs, which bind to the 3'-untranslated regions of their target mRNAs to repress translation. However, the details of miRNA-mediated epigenetic regulation targeting genomic DNA remained largely unknown. Here, we demonstrated that transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, is a highly selective reversible inhibitor for leukemia treatment, and resulting in caspase activation and apoptosis. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 feedback to suppress the transcription of CEBPD itself and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Additionally, we previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for mediating epigenetic silencing of the CEBPD gene; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. Moreover, we revealed that miRNA binding plays a key role for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. Altogether, we provided new insights for miRNA-mediated epigenetic regulation in the case of bortezomib-induced cell death in leukemia.
Citation Format: Ju-Ming Wang, Yu-Yi Chu, Chiung-Yuan Ko, Shao-Ming Wang, Pin-I Lin, Han-Ying Wang, Wen-Chi Lin, Dong-Yu Wu. miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing of locus genes and associates with bortezomib-induced apoptosis of leukemia [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 358.
Abstract 3581: Convergence of the specificity and cross-reactivity of multiple T cell receptors isolated against a single cancer peptide/HLA complex
Authors: Sharma Preeti , Harris Daniel T. , Hager Marlies V. , Kranz David M. 
Published: August 2018

Abstract
Adoptive T cell therapy using T cell receptors (TCRs) or chimeric antigen receptors (CARs) requires careful selection of the receptor so as to target only the specific cancer antigen, without cross-reactivity toward structurally similar antigens. In this study, we used two TCRs (T1 and RD1) that bind to the HLA-A2 restricted melanoma antigen MART-1 (ELAGIGILTV). TCR-T1 was initially isolated from a melanoma-reactive T cell line specific for MART-1 whereas TCR-RD1 was derived completely by in vitro engineering, switching the specificity of the well-studied A6 TCR from its cognate viral peptide (Tax) to MART-1 by directed evolution. Despite their distinct origins, engineered high-affinity forms of both TCRs had remarkably similar fine-specificities as determined using a panel of MART-1 variant peptides. This binding signature allowed us to conduct a bioinformatic scan of the human and mouse proteomes for peptides that were homologous to MART-1. Our analysis resulted in identification of a self-peptide (TM74B: IIAGLGILTV) that also bound to both T1 and RD1 TCRs. T1-transduced T cells (CD4+) from HLA-A2/Db transgenic (AAD) mice were potently activated by MART-1, and cross-reacted (at 1000-fold higher doses) with the TM74B peptide. CD8+ T cells transduced with the T1 TCR were activated by AAD+ antigen presenting cells, indicating recognition of an endogenous peptide, possibly TM74B. To extend these studies, we have shown that T1-transduced AAD T cells (CD4+) are also stimulated by murine MART-1 (EAAGIGILIV) and that transfer of T1-transduced T cells into AAD mice did not result in overt toxicity. Thus, the AAD mouse could be used to study efficacy and toxicity of T1 TCR in syngeneic models. We are currently developing a B16/AAD tumor model to compare recognition of B16 melanoma by MART-1 directed TCRs and CARs. In summary, the convergence of specificity of T1 and RD1 suggests that TCRs against a cancer peptide antigen are focused on the same exposed features of the peptide. Furthermore, the results with RD1 suggest that it is possible to engineer TCRs completely in vitro, and that these TCRs can recapitulate the fine-specificities of conventional TCRs isolated from T cell clones.
Citation Format: Preeti Sharma, Daniel T. Harris, Marlies V. Hager, David M. Kranz. Convergence of the specificity and cross-reactivity of multiple T cell receptors isolated against a single cancer peptide/HLA complex [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 3581.
Abstract 359: IWS1 is essential for mouse development
Authors: Orlacchio Arturo , Foray Claudia , Sheetz Tyler , Reese Erika , Amari Foued , Stark Aaron E. , Perle Krista La , Sanidas Ioannis , Tsichlis Philip N. , Palmieri Dario , Coppola Vincenzo 
Published: August 2018

Abstract
Iws1 (Interacts with Spt6) was originally identified in Saccharomyces Cerevisiae as a binding partner of Spt6, a histone H3/H4 chaperone.As a transcription factor, Iws1 plays a key role in defining the composition of the RNA polymerase II (RNAPII) elongation complex and in modulating the production of mature mRNA transcripts.Iws1 is phosphorylated, following stimulation with growth factors, by Akt3 and Akt1 at Ser720/Thr721 in human cells (Ser667/Thr668 in the mouse).Preliminary evidence supports a critical protumorigenic role of Iws1 and its phosphorylation in several types of malignancies such as lung cancer (NSCLC), mammary adenocarcinomas and melanomas.For example, it has been shown that, while IWS1 expression in normal human lung is very low, dramatically increases in many NSCLCs. Interestingly the level of IWS1 phosphorylation is variable between tumors and correlates with Akt3 expression.Moreover data from the TCGA database show that Iws1 is expressed at higher levels in tumors than in normal mammary gland specimens and also that basal and HER-2-enriched tumors express the highest levels. The genetic depletion of Iws1 in human mammary adenocarcinoma cell lines inhibits anchorage-independent growth in soft agar and mammosphere formation and growth. Similar experiment revealed that human melanoma cells were extraordinarily sensitive to the knockdown of Iws1. These experiments identify mammary adenocarcinomas and melanomas as tumors potentially addicted to Iws1. However, Iws1 biological functions are poorly characterized and there is no reported in vivo investigation about this RNA-processing factor.To begin to shed some light on the function of this protein at organismal level, we performed a thorough analysis of the expression of Iws1 and generated Iws1-deficient mice.The systematic analysis of expression in mouse tissues shows that Iws1 is ubiquitously expressed. We also report that ablation of Iws1 causes lethality at very early stages of mouse development. In fact, Iws1-deficient mouse embryos die at pre-implantation stage. Overall, these results show that Iws1 is an essential gene for mouse development and suggest a critical function in mammary adenocarcinomas as well as in melanoma.
Citation Format: Arturo Orlacchio, Claudia Foray, Tyler Sheetz, Erika Reese, Foued Amari, Aaron E. Stark, Krista La Perle, Ioannis Sanidas, Philip N. Tsichlis, Dario Palmieri, Vincenzo Coppola. IWS1 is essential for mouse 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 359.