tbuckley/cabot-search huggingface dataset:
Abstract 3932: Dual role of p120ctn in cancer: epithelial vs mesenchymal
Authors: Pamali Fonseka, Suresh Mathivanan, Michael Liem, Ishara Atukorala
Journal: Cancer Research (2017)

Abstract Neuroblastoma, a paediatric cancer, accounts for 15% of childhood cancer mortality. Even though neuroblastoma is an aggressive cancer, the exact mechanisms by which the cells resist treatment is poorly understood. Here, we hypothesise that neuroblastoma cells have high expression of mesenchymal markers and hence could attribute to the aggressive phenotype. P120ctn is downregulated in epithelial cancers and is known to play a major role in EMT and aggressiveness. In this study, immunohistochemical staining of neuroblastoma patient tissues suggested that p120ctn is highly abundant. Hence, the role of p120ctn and N-Myc in neuroblastoma aggressiveness was investigated by using RNA interference. Amplification of N-Myc oncogene occurs in 20% of neuroblastoma patients and is considered high risk as it correlates with aggressiveness and poor prognosis. Interestingly, knockdown of p120ctn down regulated N-Myc both at mRNA and protein levels. Upon knockdown of p120ctn and N-Myc, the proliferation, invasion and migration of neuroblastoma cells were significantly reduced. Quantitative proteomic and qPCR analysis of the wild type and knockdown cells revealed that p120ctn knockdown cells underwent mesenchymal-to-epithelial transition. Confocal microscopy and Western blotting analysis of subcellular fractionation showed nuclear accumulation of β-catenin upon p120ctn knockdown. Once in the nucleus, β-catenin activated Wnt signalling pathway and up regulated Wnt target genes including C-Myc. Interestingly, down regulation of p120ctn sensitised the neuroblastoma cells to doxorubicin. Currently, there is no published study that explores the role of p120ctn in neuroblastoma. However, these findings are contradictory to scientific literature in the context of the functional role of p120ctn in epithelial cancer. Hence to validate our findings, we established knockdown of p120ctn in epithelial colorectal cancer cells. Consistent with the literature, knockdown of p120ctn induced EMT, proliferation and migration. These results suggest that the role of p120ctn is cell type dependent. Overall, the findings from this study suggest that p120ctn plays a pivotal role in progression of neuroblastoma. Citation Format: Pamali Fonseka, Suresh Mathivanan, Michael Liem, Ishara Atukorala. Dual role of p120ctn in cancer: epithelial vs mesenchymal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3932. doi:10.1158/1538-7445.AM2017-3932
RV pressure overload: from hypertrophy to failure
Authors: Cathelijne E.E. van der Bruggen, Ryan J. Tedford, Martin Louis Handoko, Jolanda van der Velden, Frances S. de Man
Journal: Cardiovascular Research (2017)

In pulmonary arterial hypertension (PAH), right ventricular (RV) adaptation is essential to overcome the chronic increases in RV pressure overload. Ultimately, RV compensatory mechanisms are not sufficient and patients succumb to RV failure. The processes underlying the transition of RV adaptation to RV failure are not well understood. In this review, we propose that important insights in RV adaptation processes can be obtained by comparing different etiologies of PAH, namely patients with PAH secondary to Eisenmenger syndrome, patients with PAH secondary to systemic sclerosis and patients where no cause is identified: idiopathic PAH. Although the amount of RV afterload does not differ between these patient groups, their prognosis is distinctly different. We will show that an adaptive RV phenotype, as is observed in Eisenmenger patients, coincides with RV hypertrophy, increased RV contractility, low RV fibrosis and low RV diastolic stiffness. Whereas a phenotype of RV failure, as is observed in patients with PAH-secondary to systemic sclerosis, is characterized by impaired contractile reserve, RV fibrosis and RV diastolic stiffness.
Abstract 686: onTARGET: a new computational strategy to predictin vivorelevant targets against neuroblastoma
Authors: Elin Almstedt, Ingrid Lönnstedt, Cecilia Krona, Sven Nelander
Journal: Cancer Research (2017)

Abstract One of the main bottlenecks of anticancer drug development is the assessment of the in vivo relevance of emerging therapies. Previously, drugs that suppress the in vivo progression of neuroblastoma have been hard to identify. To address this problem, we propose a new computational technique, onTARGET, that enables researchers to select, with good accuracy, compounds that are likely to induce changes in cellular pathways that are consistent with specific clinical outcomes and subgroups. onTARGET prediction is based on an integration of massive expression and other data resources, including the NIH LINCS dataset (with 1,300,000 expression profiles), the NIH TARGET and R2-AMC neuroblastoma cohorts, and our own in-house databases. In a first step, the datasets are preprocessed by factor analysis to remove systematic bias in these large data sets. In a second step, Bayesian statistics are applied to prioritize compounds whose cellular responses match clinically relevant differences between patient subsets, such as MYCN status, survival hazard ratio, or histopathological assessment. To evaluate the method, we used onTARGET prediction to identify compounds and gene targets relevant for clinical outcomes in the NIH-TARGET (n=249) and R2-AMC (n=98) neuroblastoma cohorts. The algorithm confirmed existing targets and made interesting predictions. Of 50 the top-ranking compounds associated with a survival outcome, agents targeting the mTOR/PI3K axis are highly prevalent. The algorithm correctly predicts targeting of the MYC pathway, and predicts possible modulators of MYC signaling, such as TRRAP, AURKA and BMP2. In addition to nominating agents with a favorable outcome, the algorithm can also flag compounds that might worsen prognosis, further facilitating the prioritization of targets for evaluation. In summary, onTARGET may guide target selection for neuroblastoma studies and can be adapted for other cancers as well. The many targets that were identified immediately suggest an opportunity for continued evaluation in cells and in vivo models. This work has been initiated in collaboration with researchers at Lund University. Citation Format: Elin Almstedt, Ingrid Lönnstedt, Cecilia Krona, Sven Nelander. onTARGET: a new computational strategy to predict in vivo relevant targets against neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 686. doi:10.1158/1538-7445.AM2017-686
Abstract 1398: Loss of PIWIL4 and piRNAs attenuate somatic methylome and genome stability
Authors: Syuan-Cih Lin, Chia-Chen Chiu, Shou-Tung Chen, Yao-Li Chen, Ping-Yi Lin, Shu-Huei Hsiao, Yu-Wei Leu
Journal: Cancer Research (2017)

Abstract Piwi-like RNA-mediated gene silencing 4 (PIWIL4) is expressed in somatic tissues and is proposed to silence the transposition of repetitive elements like long interspersed nuclear elements (LINEs) through DNA methylation and maintain the genome stability. Through the knockout of PIWIL4 gene by CRISPR/Cas9 system in mesenchymal stem cells (MSCs), MDA-MB-231 (breast cancer cell line), HT29 (colon cancer cell line) and AGS (gastric cancer cell line), the piRNA biogenesis was decreased and so was the methylation within LINE1 target loci and global methylation. The recruitment of SUV39H1, a histone H3 methyl-transferase, into nucleus was blocked, leading to the reduction of silencing tri-methylation of histone H3 at lysine 9. Concurrently, the active H3K4me3 mark increased after knockout. Also, global CTCF bindings were distorted after the knockout of PIWIL4 especially at the bindings franking the piRNA clusters. This distortion implied the disorganization of genomic conformation which was validated by karyotyping. Through chromosomal G-banding, aneuploidy was observed which indicated the loss of genomic stability. The knockout of PIWIL4 also results in disorganized cytoskeleton, therefore, changed cell stiffness as measured by atomic force microscopy. Neural and hepatic induction of MSCs were also blocked by the knockout of PIWIL4. In correlation, tissue arrays detected abnormal PIWIL4 expression in gastric (n=45), colon (n=30) and breast cancers (n=30). In conclusion, we found that PIWIL4-piRNA interaction helps to maintain somatic DNA methylome, genome stability and stiffness in somatic stem cells. The loss of PIWIL4 expression might then a candidate for cancer biomarker. (Supported by: MOST-105-2314-B-371 -008, MOST-105-2320-B-194 -004, MOST Taiwan) Citation Format: Syuan-Cih Lin, Chia-Chen Chiu, Shou-Tung Chen, Yao-Li Chen, Ping-Yi Lin, Shu-Huei Hsiao, Yu-Wei Leu. Loss of PIWIL4 and piRNAs attenuate somatic methylome and genome stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1398. doi:10.1158/1538-7445.AM2017-1398
Commentary on Leibovich et al.: What next?
Authors: Kelly S Mix, Nora S Newcombe, Susan C Levine
Journal: Behavioral and Brain Sciences (2017)

Abstract The conclusions reached by Leibovich et al. urge the field to regroup and consider new ways of conceptualizing quantitative development. We suggest three potential directions for new research that follow from the authors' extensive review, as well as building on the common ground we can take from decades of research in this area.
Howard B. Andervont: An Appreciation and bibliography
Authors: Michael B. Shimkin, M.D.
Journal: JNCI Journal of the National Cancer Institute (1968)

Howard B. Andervont: An Appreciation and bibliography Get access Michael B. Shimkin, M.D. Michael B. Shimkin, M.D. Temple University, Health Sciences Center, Philadelphia, Pennsylvania 19140 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 40, Issue 6, June 1968, Pages XIII–XXV, https://doi.org/10.1093/jnci/40.6.XIII Published: 01 June 1968
Tumor Purity as an Underlying Key Factor in Glioma
Authors: Chuanbao Zhang, Wen Cheng, Xiufang Ren, Zheng Wang, Xing Liu, Guanzhang Li, Sheng Han, Tao Jiang, Anhua Wu
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Glioma tissues consist of not only glioma cells but also glioma-associated nontumor cells, such as stromal cells and immune cells. These nontumor cells dilute the purity of glioma cells and play important roles in glioma biology. Currently, the implications of variation in glioma purity are not sufficiently clarified. Experimental Design: Here, tumor purity was inferred for 2,249 gliomas and 29 normal brain tissues from 5 cohorts. Based on the transcriptomic profiling method, we classified CGGA and TCGA-RNAseq cohorts as the RNAseq set for discovery. Cases from TCGA-microarray, REMBRANDT, and GSE16011 cohorts were grouped as a microarray set for validation. Tissues from the CGGA cohort were reviewed for histopathologic validation. Results: We found that glioma purity was highly associated with major clinical and molecular features. Low purity cases were more likely to be diagnosed as malignant entities and independently correlated with reduced survival time. Integrating glioma purity into prognostic nomogram significantly improved the predictive validity. Moreover, most recognized prognostic indicators were no longer significantly effective under different purity conditions. These results highlighted the clinical importance of glioma purity. Further analyses found distinct genomic patterns associated with glioma purity. Low purity cases were distinguished by enhanced immune phenotypes. Macrophages, microglia, and neutrophils were mutually associated and enriched in low purity gliomas, whereas only macrophages and neutrophils served as robust indicators for poor prognosis. Conclusions: Glioma purity and relevant nontumor cells within microenvironment confer important clinical, genomic, and biological implications, which should be fully valued for precise classification and clinical prediction. Clin Cancer Res; 23(20); 6279–91. ©2017 AACR.
Abstract 2552: MDM2 induces cell fusion in breast cancer and osteosarcoma
Authors: David J. Olivos, Mikhail Chtcherbinine, Eric R. Wolf, Ciarán McAtarsney, Lindsey D. Mayo
Journal: Cancer Research (2017)

Abstract Cell fusion is a physiological process utilized by a variety of biological systems during fertilization, embryogenesis, and cellular differentiation and morphogenesis. During the malignant transformation of breast and bone tissues, normal and malignant cells become fused to form hybrid structures. These enhanced phenotypes acquire genetic characteristics which support initiation, progression, and oncogenesis. In breast cancer and osteosarcoma cell lines, cell fusion generates chromosomal instability, aneuploidy, and DNA damage while maintaining the characteristics of enhanced migration, invasion, and chemoresistance. We have found that mouse double minute 2 (Mdm2) significantly induces cell fusion and the generation of large multinucleated cells in MDA468, MDA231, MDA157, T47D breast cancer and MG63 osteosarcoma cell lines under normoxia when compared to silenced Mdm2 controls (P&amp;lt;0.0005). Interestingly, silencing mutant p53 in the MDA468 cell line resulted in significantly higher fusion events (P&amp;lt;0.0004) suggesting mutant p53 may play a regulatory role in reducing Mdm2-associated cell fusion. Silenced Mdm2 MDA231 cells showed a three-fold increase under hypoxia whereas MG63 cells showed similar levels of cell fusion events as in normoxic conditions suggesting cell specific dependency to environmental stimulus. The variation in proportions of cell fusion among each cell type suggests this phenomenon is dependent on Mdm2 expression and cell type. CD133+ MDA468 cells have increased fractions of polyploidal cell events suggesting stemness may influence the polyploidal giant cancer cell (PGCC) dynamics. The mechanism by which cell fusion occurs in breast and osteosarcoma is poorly understood. Collectively these data suggest the interplay of Mdm2, p53, and stemness in supporting the formation of fused polypoidal cells and may serve as relevant targets for cancer therapy. Citation Format: David J. Olivos, Mikhail Chtcherbinine, Eric R. Wolf, Ciarán McAtarsney, Lindsey D. Mayo. MDM2 induces cell fusion in breast cancer and osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2552. doi:10.1158/1538-7445.AM2017-2552
A novel mechanical simulator for hands-on bariatric endoscopy training in intragastric balloon placement
Authors: Marco D’Assunçao, Fernando Mota, Lucas Nova da Costa, Willian Ferreira Igi, Dejan Radenkovic, Alvaro Martinez-Alcalá, Paul Kröner
Journal: Endoscopy (2017)

Bariatric endoscopy is a novel and expanding field in gastrointestinal (GI) endoscopy [1]. The most common bariatric endoscopy procedure is intragastric balloon (IGB) placement [2]. Currently most training occurs with a proctor and a patient. Of course, this approach has potential ethical disadvantages [3], and obtaining the skills for IGB placement using an ex vivo hands-on model would be an ideal solution [4].
Abstract 1653: Modeling tumor immuno-dynamics to predict patient survival and immunotherapy efficacy
Authors: Nicholas K. Akers, Eric E. Schadt, Bojan Losic
Journal: Cancer Research (2017)

Abstract State of the art models of cancer survival are increasingly utilizing molecular data that feature the number of non-synonymous mutations, or a network based stratification of mutations, as significant predictors. It is widely hypothesized that this association between mutations and survival is a result of neo-epitopes that induce a robust anti-tumor immune response. Naively this implies that patient neo-epitope burden should better predict survival than that of mutations alone, however this has generally been difficult to prove. Indeed, mutations and predicted neo-epitopes explain roughly the same survival variance, likely due to the intertwined difficulties of neo-epitope prioritization and the often immuno-suppressive tumor microenvironment. Reasoning that integrating leading order immune response with novel neo-epitope prioritization will lead to superior performance, we built a statistical model to quantify the influence of tumor immune-dynamics on patient survival. Neoepitopes (MHC-I/II) were predicted from mutations and filtered on a self-ligandome. The clonal structure of these mutations and the distribution of resulting epitopes were assessed as predictive features. Additionally, the existing response to epitopes was assayed by incorporating TCR and BCR sequence counts and entropy as a proxy for clonal tumor infiltrating lymphocyte expansion. Leveraging the cancer genome atlas (TCGA) for 9 major cancer types including bladder (BLCA), breast (BRCA), colorectal (COAD/READ), glioblastoma (GBM), liver (LIHC), lung (NSCLC), melanoma (SKCM), pancreatic (PAAD), and uterine (UCEC) cancer, we obtained omics data for a total of 2,866 patients. Random forest based recursive feature elimination was used to determine which features were most likely to be predictive while overfitting was controlled with k-fold cross validation. A cox proportional hazard model of survival as a function of mutation burden and functions of neoepitope and immune response predictors was constructed using the selected features. Our results confirm that neoepitope and immune response based predictors for survival often significantly outperform mutation burden alone and simultaneously suggest a quantitative classification of immunotherapy efficacy across cancer subtypes. Citation Format: Nicholas K. Akers, Eric E. Schadt, Bojan Losic. Modeling tumor immuno-dynamics to predict patient survival and immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1653. doi:10.1158/1538-7445.AM2017-1653
Abstract 5622: Acquired resistance to EGFR-TKI upregulates the expression of PD-L1 and promotes immune escape in lung cancer
Authors: Shunli Peng, Qi Li, Wei Wang
Journal: Cancer Research (2017)

Abstract Background and purpose: Acquired resistance is a severe problem of EGFR inhibitors (EGFR-TKIs) therapy in lung cancer patients. Immune checkpoint therapy is a new revolution in cancer treatment with dramatic outcomes in a subset of patients. In this study, we explored the possibility of immune checkpoint therapy in lung cancers with three well-known resistant mechanisms to EGFR-TKIs, T790M, MET amplification and hepatocyte growth factor (HGF), and investigated internal regulation mechanisms. Experimental Design: PD-L1 expression and immune escape ability were evaluated in EGFR-TKIs resistant lung cancer cells by MET amplification, HGF, and T790M, as well as T790M transfected-human renal derived cells (293FT). MAPK and PI3K pathways were investigated simultaneously. PD-L1 gene deleted resistant cells were used in NOD-SCID xenograft models to evaluate immune escape in vivo. Results: All of three resistant mechanisms increased PD-L1 expression. Both MAPK and PI3K pathways are involved in MET amplification or HGF induced PD-L1 overexpression, whereas only MAPK pathway mediated it in T790M-transfected cells. The decreased cytotoxicity of lymphocytes can be restored by anti-PD-L1 antibodies. Moreover, xenograft tumors by EGFR-TKIs sensitive cells but not resistant cells responded to treatment of human lymphocytes. However, deletion of PD-L1 successfully restored cytotoxicity of lymphocytes in EGFR-TKIs resistant tumors. Conclusion: Acquired Resistance to EGFR-TKIs augments the expression of PD-L1 and promotes immune escape in EGFR mutant lung cancer. Immune checkpoint therapy might be a promising alternative therapeutic strategy for NSCLC that acquired resistant to EGFR-TKIs. Note: This abstract was not presented at the meeting. Citation Format: Shunli Peng, Qi Li, Wei Wang. Acquired resistance to EGFR-TKI upregulates the expression of PD-L1 and promotes immune escape in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5622. doi:10.1158/1538-7445.AM2017-5622
Abstract 5799: Targeting CX3CR1 impairs the reseeding of cancer cells recirculating from metastatic tumors
Authors: Chen Qian, Asurayya Worrede-Mahdi, Ramanpreet Kaur, Fei Shen, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis
Journal: Cancer Research (2017)

Abstract Cancer cells re-enter systemic blood from established metastatic tumors. Recent evidence indicates that these recirculating cancer cells further seed and colonize skeleton and soft tissues to expand metastatic dissemination, thus precipitating the clinical progression to terminal disease. We have previously shown that the chemokine receptor CX3CR1 is implicated in the metastatic seeding of breast cancer cells and that novel small-molecule antagonists for this receptor effectively contains the number and size of secondary tumors in animal models. Using the same models, we now report that targeting CX3CR1 also restrains the re-seeding of skeleton and soft-tissue by circulating cancer cells (CTCs) departing from existing metastatic lesions. Notably, we also found that CTCs unable to re-seed are forced to remain in the blood circulation longer, eventually succumbing to apoptotic death. It has been proposed that when either spontaneously or forcibly (re)circulating in the blood, cancer cells from solid tumors are more vulnerable to the effects of both cytotoxic and targeted therapeutics. Given the role of CX3CR1 antagonists in prolonging the time spent by CTCs in the blood, we sought to assess whether these compounds could synergize with docetaxel by extending bioavailability and its cytotoxic effects. Thus, we tested this paradigm on CTCs departing from skeletal and soft-tissue lesions generated by breast and prostate cancer cells in mice. Based on the results obtained from these experiments, it can be concluded that implementing the development of CX3CR1 antagonists and promoting their clinical use will provide novel and effective tools to contain the progression of metastatic disease in cancer patients. Citation Format: Chen Qian, Asurayya Worrede-Mahdi, Ramanpreet Kaur, Fei Shen, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. Targeting CX3CR1 impairs the reseeding of cancer cells recirculating from metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5799. doi:10.1158/1538-7445.AM2017-5799