bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1441: Systems-level interrogation of resistance mechanisms to immunotherapy through pooled shRNA screens
Authors: Wang Zhe , Malu Shruti , Peng Weiyi , McKenzie Jodi , Mbofung Rina , Williams Leila , Seth Sahil , Heffernan Tim , Hwu Patrick 
Published: July 2016

Abstract
Despite the impressive clinical efficacy of immunotherapy in some patients, many still do not respond or progress following an initial response. The molecular mechanisms underlying the tumor resistance in those non-responders remain largely undefined. To address this issue, we set out to perform high-throughput unbiased pooled shRNA screens to identify critical genes that confer immune resistance. Patient-derived melanoma cells were transduced with barcoded pooled lentiviral shRNA libraries that targeted the human kinome, followed by exposure to cytotoxicity mediated by autologous tumor infiltrating lymphocytes. Tumor cells were then subject to genomic deep sequencing and integrated analysis to identify depleted barcodes and corresponding genes. One identified candidate of particular interest is Aurora Kinase A (AURKA), a cell cycle regulator that has previously been shown to contribute to tumorigenesis and correlate with poor prognosis for cancer patients. Importantly, our independent screening with a bioactive compound library also implicated Aurora Kinase as an immune resistance candidate against T cell immunotherapy. Further studies showed that suppression of Aurora kinase activity with a pan inhibitor - AMG900, exhibited a synergistic cytotoxic effect with tumor infiltrating lymphocyte-mediated killing on autologous tumor cells from patients. Furthermore, our Nanostring analysis of tumor biopsies from patients that received adoptive T cell therapy revealed significantly increased expression of AURKA in tumors from non-responding patient when compared with responder counterparts. These results have substantiated the validity of our pooled shRNA screening platform. Further investigations are ongoing to elucidate the underpinnings of Aurora kinase-mediated tumor resistance to immunotherapy and to functionally and physiologically validate other putative targets we have identified.
Citation Format: Zhe Wang, Shruti Malu, Weiyi Peng, Jodi McKenzie, Rina Mbofung, Leila Williams, Sahil Seth, Tim Heffernan, Patrick Hwu. Systems-level interrogation of resistance mechanisms to immunotherapy through pooled shRNA screens. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1441.
Abstract 1455: IL-4 derived from T follicular helper cells in tumor draining lymph nodes regulate myeloid cell properties and anti-tumor immunity
Authors: Shirota Hidekazu , Klinman Dennis M. , Ito Shuku-ei A. , Ishioka Chikashi 
Published: July 2016

Abstract
Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4 in particular is up-regulated. Current results demonstrate that T follicular helper (Tfh) cells arise in tumor draining lymph nodes where they produce an abundance of IL-4. Deletion of IL-4 expressing Tfh cells improves anti-tumor immunity, delays tumor growth and reduces the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) and M2 macrophages. These findings suggest that IL-4 from Tfh cells impact anti-tumor immunity and constitute an attractive therapeutic target to reduce immune suppression in the tumor microenvironment and thus enhance the efficacy of cancer immunotherapy.
Citation Format: Hidekazu Shirota, Dennis M. Klinman, Shuku-ei A. Ito, Chikashi Ishioka. IL-4 derived from T follicular helper cells in tumor draining lymph nodes regulate myeloid cell properties and anti-tumor immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1455.
Abstract 1462: Non-inflammatory role of ASC-dependent inflammasomes in promoting gastric tumourigenesis via IL-18
Authors: Jenkins Brendan , Deswaerte Virginie , West Alison , Nguyen Paul , Putoczki Tracy 
Published: July 2016

Abstract
Introduction
Gastric cancer is the third most lethal cancer worldwide and represents a growing number of cancers linked with inflammation. However, the identity of innate immune regulators with oncogenic potential in the host gastric mucosal epithelium remains obscure. We aim to identify the molecular basis by which specific pattern recognition receptors belonging to the inflammasome family promotes gastric tumorigenesis.
Experimental procedures
We have employed the gp130F/F gastric cancer mouse model coupled with mice lacking specific inflammasome-related genes. In addition, human gastric cancer tumor (and matched non-tumor) biopsies and cell lines were used. Immunohistochemistry on gastric tissue sections was used to assess the extent of cellular proliferation, apoptosis, inflammation and angiogenesis, and quantitative real-time PCR was used to measure the expression of genes of interest. Immunoblotting and ELISA were used to measure the activation and expression levels of inflammasome-related proteins.
Results
A causal role for ASC-dependent inflammasomes in gastric tumorigenesis was confirmed upon the genetic ablation of ASC in gp130F/F:Asc-/- mice, which resulted in a ∼50% reduction in tumor burden compared to parental gp130F/F mice. The suppressed gastric tumorigenesis in gp130F/F:Asc-/- mice was associated with increased gastric epithelial (tumor) cell apoptosis, as determined by elevated numbers of TUNEL and caspase-8 positive cells. Surprisingly however, no changes in the number and activation status of inflammatory cells were observed. The suppressed gastric tumorigenesis in gp130F/F:Asc-/- mice was also characterized by a gene signature comprising apoptotic-related genes. In gastric tumor tissue, IL-18, but not IL-1β, protein levels were augmented compared to matched non-tumour tissue, and genetic ablation of IL-18 in gp130F/F:IL-18-/- mice suppressed gastric tumorigenesis comparable to that observed upon ASC deficiency. The treatment of human gastric cancer cells with IL-18 also potentiated their growth compared to IL-1β.
Conclusions
Collectively, these data reveal that ASC-dependent inflammasomes and their downstream mediator IL-18 represent a novel oncogenic mechanism in gastric cancer.
Citation Format: Brendan Jenkins, Virginie Deswaerte, Alison West, Paul Nguyen, Tracy Putoczki. Non-inflammatory role of ASC-dependent inflammasomes in promoting gastric tumourigenesis via IL-18. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1462.
Abstract 147: Exome sequencing identifies frequent histone methyltransferase mutations in metastatic SCC
Authors: Toland Amanda Ewart , Allain Dawn , Gillespie Jessica , Nagarajan Priyaharsini , Peters Sara , Ozer Hatice Gulcin , Olencki Thomas , Yilmaz Ayse Selen , Teknos Theodoros 
Published: July 2016

Abstract
Although only a small proportion of cutaneous squamous cell carinomas (cSCC) metastasize, approximately 3900-8800 individuals in the United States die of metastatic cSCC each year. Little is known about the molecular events that lead approximately 2-6% of cSCCs to metastasize. Treatment efforts are hampered by a lack of ability to predict which lesions are more likely to recur or metastasize as these known correlates do not have high specificity for prediction. Furthermore, there is no FDA approved therapy that is specifically indicated for metastatic cSCC. Deep-sequencing efforts have identified targetable mutations and pathways for several cancers. Exome and targeted sequencing of primary cSCCs led to the discovery that inactivating mutations in NOTCH pathway genes occur in over 75% of tumors; however NOTCH mutations are not indicative of metastasis. Published studies identified frequent mutations in KMT2C and KMT2D in cSCCs with aggressive features. To identify mutations that are unique to or enriched in metastatic samples which may help to identify novel therapeutics for treating aggressive cSCCs, we performed exome sequencing of 37 samples consisting of matched normal DNAs, primary tumors and metastatic cSCCs. Many of the mutations found in the metastatic samples were also observed in the matched primary tumors. We found an enrichment of mutations in chromatin remodeling genes. Epigenetic regulatory genes mutated in the metastatic samples included KMT2D (64%), KMT2C (44%), SETD2 (45%), KAT6A (36%), EP300 (18%), and KDM6A/UTX (9%). We performed additional targeted deep-sequencing to evaluate whether candidate genes were frequently mutated in non-aggressive cSCCs. Initial analyses of targeted-sequencing of 10
non-aggressive primary cSCCs and 7 additional metastatic cSCCs as well as data from published exome studies on non-aggressive cSCCs suggest that chromatin remodeling genes are mutated at a much higher rate in metastatic cSCCs. These data provide potential pathways for therapeutic intervention for this deadly cancer.
Citation Format: Amanda Ewart Toland, Dawn Allain, Jessica Gillespie, Priyaharsini Nagarajan, Sara Peters, Hatice Gulcin Ozer, Thomas Olencki, Ayse Selen Yilmaz, Theodoros Teknos. Exome sequencing identifies frequent histone methyltransferase mutations in metastatic SCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 147.
Abstract 1492: Development of a CD123xCD3 bispecific antibody to treat acute myeloid leukemia (AML)
Authors: Gaudet Francois , Nemeth Jennifer F. , McDaid Ronan , Li Yingzhe , Harman Benjamin , Millar Hillary , Teplyakov Alexey , Wheeler John , Luo Jinquan , Tam Susan , Wu Sheng-Jiun , Chen Emily , Babich Alexander , Elsayed Yusri , Attar Ricardo 
Published: July 2016

Abstract
AML is a heterogeneous disease characterized by uncontrolled clonal expansion of leukemic stem cells (LSCs). Current therapies for AML are not curative, in part due to their inability to eradicate LSCs from the bone marrow. T cell redirection has been shown to be effective in heme malignancies and represents a promising approach to treat AML by targeting markers differentially expressed on the cell surface of cancer cells. One marker, CD123 (α-chain of the interleukin-3 receptor) is often present on AML LSCs and blasts. We developed a human bispecific antibody (CD123xCD3; Ab-178) capable of binding to the extracellular domain of CD123 and the ϵ chain of CD3 on T cells to induce T cell–mediated tumor cell killing. This bispecific IgG4 antibody can recruit T cells to CD123+ AML cells (MOLM-13, KG-1 and OCI-AML5) and induce T cell activation as evidenced by CD69 and CD25 up-regulation on T cells. Ab-178 potently killed these CD123+ AML cell lines in vitro (EC50 = 0.51-0.91 nM) but not a CD123− cell line (JIM3). Ab-178 was also able to induce tumor inhibition (MOLM-13 cells) and regression (KG-1 cells) in murine xenograft CD123+ AML models in the presence of human PBMCs. Furthermore, this antibody was able to kill AML blasts in primary AML blood samples ex vivo in the absence of exogenous T cells (autologous setting; EC50 = 0.83 nM). Related bispecific antibodies directed against a viral epitope (nullxCD3 or CD123xnull) did not activate T cells or cause tumor cell killing in the various assays tested. Ab-178 had no impact on T cell activation when incubated with T cells alone. These results indicate that Ab-178 can potently and specifically activate T cells in the presence of CD123+ AML cells and induce their killing. Furthermore, because of the antibody format, this molecule is expected to have a longer half-life compared to smaller bispecific biologic scaffolds. Ab-178 is currently being evaluated pre-clinically for its potential to treat patients with AML.
Citation Format: Francois Gaudet, Jennifer F. Nemeth, Ronan McDaid, Yingzhe Li, Benjamin Harman, Hillary Millar, Alexey Teplyakov, John Wheeler, Jinquan Luo, Susan Tam, Sheng-Jiun Wu, Emily Chen, Alexander Babich, Yusri Elsayed, Ricardo Attar. Development of a CD123xCD3 bispecific antibody to treat acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1492.
Abstract 1518: Lung adenocarcinoma differential expression analysis using the Maverix RNA-Seq pipeline
Authors: Fitzsimons Michael S. , Lee Mei-Chong Wendy , Lee Byung-In , Subramanian Lenin 
Published: July 2016

Abstract
Background
RNA-Seq is a powerful means of identifying changes in gene expression in cancerous tissue. Widespread adoption of RNA-Seq is hampered by lack of familiarity with the appropriate analysis tools and excessive turn around time. Maverix Biomics, Inc offers a scalable, reliable, validated, and easily accessible differential expression pipeline for translational and clinical researchers to analyze and explore RNA-Seq data. Here we describe the pipeline, demonstrate the available tools and visualizations, and provide benchmarks for completion time from lung adenocarcinoma.
Results
Lung adenocarcinoma samples appear very different compared to their normal counterparts in terms of overall gene expression and exhibit many differentially expressed genes. For analysis completion time, parallelization is far superior than the theoretical curve without parallelization. It took 7.9 hours to analyze two samples, but took only 13.1 hours to analyze 25 samples. We found 2246 significant genes common to three different differential expression tools: DESeq, edgeR, and cuffdiff.
Conclusions
The Maverix RNA-Seq pipeline is demonstrated here to be highly scalable, easy to use, and includes a range of tools and visualizations for understanding differential expressions results. This pipeline is a great analytic option to accelerate translational and clinical research in the field of oncology.
Citation Format: Michael S. Fitzsimons, Mei-Chong Wendy Lee, Byung-In Lee, Lenin Subramanian. Lung adenocarcinoma differential expression analysis using the Maverix RNA-Seq pipeline. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1518.
Abstract 1521: Transcriptional networks of the normal human kidney
Authors: Lindgren David , Hansson Jennifer , Nilsson Helen , Krawczyk Krzysztof , Johansson Martin , Axelson Håkan 
Published: July 2016

Abstract
The kidney is a complex but highly structured organ composed of more than 20 different cell types. Disturbances among these cell types leads to a plethora of diseases of acute or chronic type, some of which are life threatening. In addition, kidney cancer represents about 3 percent of all malignancies. Considerable efforts have been made to profile the different cell types of the kidney. However, these are mainly based on studies in rodents. In the current study we present a method, called composition based cellular stratification that define gene signatures specific to different cell types and regions of the kidney. The method uses correlation-based analyses of gene expression microarrays of needle core biopsies obtained from histologically normal kidney tissues. For example, a HNF-driven gene expression signatures of proximal tubuli cells could be defined. This signature was validated in publically available data at the gene expression as well as at the protein level. We employ these gene expression signatures as a framework to study expressional changes observed in renal cell carcinoma, thus increasing the possibility to pin-point cell specific alterations associated with the transformation of renal epithelial cells.
Citation Format: David Lindgren, Jennifer Hansson, Helen Nilsson, Krzysztof Krawczyk, Martin Johansson, Håkan Axelson. Transcriptional networks of the normal human kidney. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1521.
Abstract 1523: Cross-disciplinary methods for personalizing screening modalities for early gastric cancer intervention
Authors: Walker Rachel , Mejia Jaime , Enderling Heiko , Pimiento Jose M. , Coppola Domenico 
Published: July 2016

Abstract
Background.
Up to 80% of patients in the early stages of gastric cancer are asymptomatic, making early diagnosis and hence effective treatment challenging. The poor prognosis of patients with late diagnoses clearly necessitates the identification of markers for early detection and the development of streamlined screening protocols. This is particularly crucial in high-risk populations, for example regions in which Helicobacter Pylori infection and associated chronic inflammation, responsible for over 70% of gastric cancers worldwide, is prevalent. At present, an efficient and personalized program for early detection does not exist.
Methods.
Specific biomarkers for the progression of gastric cancer have been identified in preliminary studies, including CD44, Lgr5 and CD133. In retrospective tissue samples incremental increases in expression of these markers was observed during the progression from normal gastric tissue to precancerous histologic lesions such as intestinal metaplasia and ultimately dysplasia and carcinoma. We developed a mechanistic mathematical model capable of simulating these marker-positive population dynamics, calibrated using the existing clinical data. The predictive capability of the model is validated by comparison of simulated to actual marker expression patterns in an independent test cohort of endoscopic gastric biopsies taken at sequential points during individual patients’ disease progression.
Results.
Based on clinically obtainable, patient-specific tissue conditions, the computational model can simulate the dynamics of marker-positive cells and, when calibrated and validated with clinical data from specific patient populations, may forecast disease progression and suggest optimal screening schedules for individual patients.
Conclusions.
The tools of mathematical oncology have the potential to directly inform clinical screening protocols. Verified prognostic factors for disease progression can be incorporated into mathematical models to improve diagnostic accuracy and allow clinically-actionable screening optimization. This can guide personalized screening schedules according to current marker expression on a case-by-case basis to achieve more efficient prognosis and reduced healthcare costs.
Citation Format: Rachel Walker, Jaime Mejia, Heiko Enderling, Jose M. Pimiento, Domenico Coppola. Cross-disciplinary methods for personalizing screening modalities for early gastric cancer intervention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1523.
Abstract 153: Patterns of genetic progression in high grade prostatic intraepithelial neoplasia
Authors: Jung Seung-Hyun , Shin Sun , Lee Sug Hyung , Chung Yeun-Jun 
Published: July 2016

Abstract
High grade prostatic intraepithelial neoplasia (HGPIN) is considered a neoplastic lesion that precedes prostate cancer (PCA). Genetically, HGPIN is known to have some driver mutations such as TMPRSS2-ERG fusion and 8p loss. However, we still do not know how the whole picture of somatic mutations in HGPIN is and what are added during the progression to PCA. To identify the genomic differences between HGPIN and PCA, we analyzed 20 regions of paired HGPIN and PCA from 6 patients by whole-exome sequencing and array-comparative genomic hybridization. As expected, the number of total mutations and CNAs of HGPINs were significantly fewer than those of PCAs. Mutations in FOXA1 and CNAs (1q and 8q gains) were detected in both HGPIN and PCA (common), suggesting their roles in early PCA development. Mutations in SPOP, KDM6A, and KMT2D were PCA-specific, suggesting their roles in HGPIN progression to PCA. The 8p loss was either common or PCA-specific. HRAS and FOXA1 mutations were PIN-specific. Our data show that PCAs are direct descendants of HGPINs in most cases that require more genomic alterations to progress to PCA. The nature of heterogeneous HGPIN population that might attenuate genomic signals should further be studied. Our results provide a clue to explain the long latency from HGPIN to PCA and provide useful information for clinical decision making in the genetic diagnosis of HGPIN and PCA.
Citation Format: Seung-Hyun Jung, Sun Shin, Sug Hyung Lee, Yeun-Jun Chung. Patterns of genetic progression in high grade prostatic intraepithelial neoplasia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 153.
Abstract 1538: Vimentin expression as a potential immunomarker of predicting aggressive disease in clear cell renal cell carcinoma
Authors: Mohamed Mahmoud , Hu Lulin , Liu Haiyan , Lin Fan , Williams Heinric 
Published: July 2016

Abstract
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. Overexpression of vimentin has been detected in prostate cancer, lung cancer, gastrointestinal cancer, and melanoma. Although vimentin has been used for diagnosing and classifying renal neoplasms, little is known regarding its prognostic value. This study examines the prognostic significance of vimentin expression in clear cell renal cell carcinoma (ccRCC), chromophobe renal cell carcinoma (chRCC) and oncocytoma. Our patient group (n = 88) consisted of 63 men and 25 women with a mean age of 59 years at the time of diagnosis. Paraffin embedded specimens from these patients’ renal tumors were selected for this study which included ccRCC (n = 66), chRCC (n = 11) and oncocytoma (n = 11). Vimentin expression was determined by a tissue microarray technique (TMA) performed by a single pathologist (HL). Tumor staining results were classified as negative (&lt;5%), weak positive (5-25%), intermediate positive (25-50%), moderate positive (50-75%), or strong positive (&gt;75%). Clinicopathologic data was also included tumor histology, tumor size, T stage, grade, presence of sarcomatoid differentiation, presence of metastasis, and survival outcome following diagnosis were determined for each patient. Chi square statistical test analysis was performed in order to test the association of clinical parameters with vimentin immunoreactivity. Our results show that positive (&gt;5%) vimentin expression was present in 100% of ccRCC cases, 9% of oncocytoma, and 0% of chRCC cases. In addition, vimentin expression in ccRCC was associated with metastasis (p&lt;0.047) but was not significantly associated with pathologic T stage (P&lt;0.185), Fuhrman grade (P&lt;0.636), or the presence of sarcomatoid differentiation (P&lt;0.855). With a median follow up of 7.2 years, there were 26 deaths in the ccRCC and none in the chRCC or oncocytoma groups. Positive vimentin staining was not associated with overall survival in the ccRCC group. Our results suggest that vimentin may be valuable predictor of metastatic disease in ccRCC patients.
Citation Format: Mahmoud Mohamed, Lulin Hu, Haiyan Liu, Fan Lin, Heinric Williams. Vimentin expression as a potential immunomarker of predicting aggressive disease in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1538.