bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 893: Mining the circulating immune cell transcriptome for ovarian cancer-specific biomarkers: A proof of concept study
Authors: Uppal Shitanshu , Kapur Arvinder , Felder Mildred , Medlin Erin , Shojaei Hadi , Gonzalez-Bosquet Jesus , Patankar Manish S. 
Published: May 2015

Abstract
The continuous interplay between cancer cells and immune system allows an opportunity to identify cancer-specific biomarkers in immune cells. Here, we compare the transcriptomes of peripheral blood mononuclear cells (PBMCs) obtained from advanced stage ovarian cancer patients and healthy donors in a proof-of-concept study to identify ovarian cancer-specific biomarkers. PBMCs were collected from patients undergoing surgery with the gynecologic oncology service. RNA was extracted from the PBMCs of five patients (training set) with confirmed diagnosis of epithelial ovarian cancer and 4 health donor blood samples. Microarray analysis using Illumina platform was conducted and analyzed using the R statistical package. After data normalization, differentially expressed genes in the two cohorts were identified controlling for false discovery rate at 5 and 10%. The top ten up- and downregulated genes were selected. Gene ontology and pathway analysis led to identification of a Candidate Biomarker Panel (CBP) comprising of five of the ten genes that were most likely to serve as biomarkers for ovarian cancer. Validation of the CBP was achieved using PBMCs isolated from a separate group of six patients and healthy donors (test set) was performed using qPCR and flow cytometry and in vitro culture experiments. Bioinformatics analysis identified 391 genes that were up-regulated and 599 that were down-regulated. A set of five genes with high biomarker potential and were included in the CBP. All of the CBP genes were differentially expressed by 3-5 fold (p&lt;0.03) in the cancer patient PBMCs as compared to healthy donors. Validation results for the CBP were similar between the training set and the test set. Co-culture experiments indicated differential expression of the CBP genes in healthy donor-derived PBMCs co-cultured with cancer cells. Continuous cross-talk between immune cells and abnormal tissues leads to changes in the immune cell transcriptome and proteome in response to a pathologic state. We demonstrate that the transcriptome and proteome of circulating immune cells is a repository for ovarian cancer-specific biomarkers. Our on-going studies are focused on validating the CBP in a larger cohort of samples obtained from healthy donors, ovarian cancer patients and subjects treated for benign gynecologic anomalies.
Citation Format: Shitanshu Uppal, Arvinder Kapur, Mildred Felder, Erin Medlin, Hadi Shojaei, Jesus Gonzalez-Bosquet, Manish S. Patankar. Mining the circulating immune cell transcriptome for ovarian cancer-specific biomarkers: A proof of concept study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 893. doi:10.1158/1538-7445.AM2014-893
Abstract 904: EGFR expression predicts recurrence in patients undergoing adjuvant chemotherapy for advanced bladder cancer
Authors: Mansour Ahmed , Abdulreheem Mona , Elsherbeeny Mamdouh , Sultan Mohammed , Shokeir Ahmed , Mosbah Ahmed , Abol-Enein Hassan , Park Taeeun , Kim Hyung , Kim Jayoung 
Published: May 2015

Abstract
Epidermal growth factor receptor (EGFR) overexpression has been associated with bladder cancer progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based protocols in other tumor types. This has not been studied in the clinical adjuvant setting in bladder cancer. In this study, we aimed to investigate the prognostic significance of EGFR expression in patients receiving adjuvant chemotherapy following radical cystectomy for advanced bladder cancer. Mansoura Urology and Nephrology Center database was reviewed. Patients treated with radical cystectomy and thereafter completed adjuvant chemotherapy for adverse pathological features or node positive diseases were identified. Patients who underwent palliative cystectomy, those with histological diagnosis other than pure transitional cell carcinoma and patients who received adjuvant radiotherapy were excluded. Immunohistochemical analysis for EGFR expression was performed on archived bladder specimens. The relationship of EGFR expression and clinical outcomes was assessed. In vitro studies were performed to determine whether EGFR expression associates with resistance to chemotherapeutic reagents. The study included 58 patients. Mean age was 57 years. All patients had pathologic stage T2 or greater. Majority of patients had node positive disease (n=53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan Meyer analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p=0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p=0.04). In vitro functional analysis demonstrated that EGFR expression level altered response to cisplatin-induced apoptosis, and that inhibition of EGFR enhanced sensitization of bladder cancer cells to cisplatin-induced apoptosis. In summary, our findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced bladder cancer. EGFR status may help predict prognosis and select patients for adjuvant chemotherapy.
Citation Format: Ahmed Mansour, Mona Abdulreheem, Mamdouh Elsherbeeny, Mohammed Sultan, Ahmed Shokeir, Ahmed Mosbah, Hassan Abol-Enein, Taeeun Park, Hyung Kim, Jayoung Kim. EGFR expression predicts recurrence in patients undergoing adjuvant chemotherapy for advanced bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 904. doi:10.1158/1538-7445.AM2014-904
Abstract 916: A multidimensional analysis of predictive biomarkers in colorectal cancer
Authors: Mariani Marisa , He Shiquan , McHugh Mark , Andreoli Mirko , Pandya Deep , Sieber Steven , Wu Zheyang , Fiedler Paul , Shahabi Shohreh , Ferlini Cristiano 
Published: May 2015

Abstract
Background: CRC cancer is one of the deadliest diseases in Western countries. In order to develop predictive biomarkers for CRC (colorectal cancer) aggressiveness, we analyzed retrospectively 267 CRC patients via a novel, multidimensional biomarker platform.
Methods: Using nanofluidic technology for qPCR analysis and quantitative fluorescent immunohistochemistry for protein analysis, we assessed 33 microRNAs, 124 mRNAs and 9 protein antigens. Analysis was conducted in each single dimension (microRNA, gene or protein) using both the multivariate Cox model and Kaplan-Meier method. Thereafter, we simplified the censored survival data into binary response data (aggressive vs. non aggressive cancer). Subsequently, we combined the data into multidimensional scores using inverse sliced regression for sufficient dimension reduction. Accuracy was assessed using the Area under the Curve (AUC) and the receiver operating characteristic (ROC) method.
Results: Single dimension analysis led to the discovery of individual factors that were significant predictors of outcome. These included seven specific microRNAs, four genes, and one protein. When these factors were quantified individually as predictors of aggressive disease, the highest demonstrable area under the curve (AUC) was 0.68. By contrast, when all results from single dimensions were combined into multidimensional biomarkers, AUCs were dramatically increased with values approaching and even exceeding 0.9. Conclusions: Single dimension analysis generates statistically significant predictors, but their predictive strengths are suboptimal for clinical utility. A novel, multidimensional approach overcomes these deficiencies. Newly derived multidimensional biomarkers have the potential to meaningfully guide the selection of therapeutic agents for individual patients while elucidating molecular mechanisms driving disease progression.
Citation Format: Marisa Mariani, Shiquan He, Mark McHugh, Mirko Andreoli, Deep Pandya, Steven Sieber, Zheyang Wu, Paul Fiedler, Shohreh Shahabi, Cristiano Ferlini. A multidimensional analysis of predictive biomarkers in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2014-916
Abstract 92: Generating new syngeneic models for oral squamous cell carcinoma metastasis study
Authors: Shi Zonggao , Johnson Jeff , Liu Yueying , Stack Sharon 
Published: May 2015

Abstract
Cancer metastasis is a complex problem that presents clinical challenges and is the cause of most cancer-related deaths. Mechanistic studies on metastasis hold promise for finding better approaches to control cancer mortality. Oral cavity cancer brings over 200,000 deaths annually and is one of the top eight most frequently diagnosed cancers worldwide. However there is a lack of appropriate experimental models to address oral cancer metastasis. An ideal experimental system should recapitulate the complete process of cancer metastasis in vivo while maintaining molecular-level manipulability. Our current efforts are directed at development of a series of murine oral squamous cell carcinoma (OSCC) cell lines that will be amenable for syngeneic transplantation studies in immuno-competent mice. The cell lines were created from C57BL/6J mice, a strain frequently used in targeted gene manipulation. This strategy ensures that the cells also have utility in orthotopic xenograft cancer models using currently available knockout mice made with a syngeneic background. As abundant knockout mice are available on the C57BL/6J background, our new syngeneic cancer cell lines will greatly facilitate studies on the interrelationship between host and tumor during the process of metastasis. Cell lines were generated from primary murine tongue epithelial cells by hTERT induced immortalization and oncogene induced transformation. They were screened for tumorigenicity and metastasis in both immunocompetent and immunocompromised mice. Properties of in vitro and vivo growth, morphology and cytogenetics were characterized. As proof of concept, one type of gene knockout mouse was used to test transplantation of such new cellular models in vivo to observe the impact of gene loss in the host on the growth and metastasis of tumors. The completion of this project will establish solid and currently unavailable tools for the oral cancer metastasis research community.
Citation Format: Zonggao Shi, Jeff Johnson, Yueying Liu, Sharon Stack. Generating new syngeneic models for oral squamous cell carcinoma metastasis study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 92. doi:10.1158/1538-7445.AM2014-92
Abstract 93: Antagonizing pathways leading to differential dynamics in colonic carcinogenesis in azoxymethane (AOM)-treated Sgo1 (Shugoshin1)-haploinsufficient chromosome instability (CIN) model mice
Authors: Rao Chinthalapally V. , Sanghera Saira , Zhang Yuting , Biddick Laura , Lightfoot Stan , Dai Wei , Yamada Hiroshi Y. 
Published: May 2015

Abstract
(a) Colon cancer is the second most lethal cancer and is predicted to claim 50,830 lives in 2013. Chromosome Instability (CIN) is observed in 80-90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. For drug development, animal models that reflect cancer-specific etiology is necessary. However, animal models focusing on CIN have not been validated for colon cancer development and for drug testing. In this study, we set out to validate a mitotic error-induced CIN model mice, Shugoshin1 (Sgo1) haploinsufficient mice, as a colon cancer study model.
(b) We treated control and Sgo1-/+ mice with colonic carcinogen Azoxymethane (AOM), and tracked colon cancer development over 12, 24 and 36 weeks after AOM treatments. The three endpoints provided information regarding the time course for colon cancer development.
(c) Although we predicted an increase in colon tumors in Sgo1-/+ mice at a later (24 or 36 weeks) endpoint, precancerous lesions the Aberrant Crypt Foci (ACF) did not develop to larger tumors straightforwardly. Unexpectedly, the numbers of gross colon tumors showed no difference (P&gt;0.05). Immunohistological analyses indicated IL6, Bcl2 and p16INK4A were differentially expressed in Sgo1-/+ mice.
(d) We propose that formation of ACF in Sgo1-/+ mice are facilitated by IL6-STAT3-SOCS3 oncogenic pathway and Bcl2-anti-apoptotic pathway, yet further development of the ACF to tumors are inhibited by p16INK4A tumor suppressor pathway. Manipulating these pathways would be beneficial for inhibiting development of colon cancer with CIN. The CIN mice may be useful for investigating carcinogenesis in earlier stage and tumor regression in later stage.
Citation Format: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Stan Lightfoot, Wei Dai, Hiroshi Y. Yamada. Antagonizing pathways leading to differential dynamics in colonic carcinogenesis in azoxymethane (AOM)-treated Sgo1 (Shugoshin1)-haploinsufficient chromosome instability (CIN) model mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 93. doi:10.1158/1538-7445.AM2014-93
Abstract 931: Role of IKKα in K-ras-driven lung carcinogenesis
Authors: Song Na-Young , Willette-Brown Jami , Dalta Mahesh , Hu Yinling 
Published: May 2015

Abstract
IKKα, one of subunits of the IKK complex, is required for the epidermal homeostasis. We previously demonstrated that keratin 5-specific deletion of IKKα induces spontaneous skin squamous cell carcinomas (SCCs) in mice. Interestingly, IKKα kinase dead knockin (IKKαK44A/K44A, KA) mice spontaneously develop lung SCCs which is associated with increased inflammation and IKKα reduction. Thus, IKKα downregulation is crucial for the SCC formation in skin and lung. Here, we attempted to verify whether IKKα inactivation plays a role in the development of lung adenocarcinomas (ADCs) as well. We have crossed between KA mice and K-rasG12D oncogenic mutant (Kras) mice. Then, these IKKαK44A/K44A;K-rasG12D (KA;Kras) mice were intratracheally treated with adenovirus carrying the cre recombinase gene to activate K-ras oncogene. At 4.5 months after intratracheal injection, the lung weight was significantly increased in KA;Kras compared to Kras mice. Moreover, the lungs of KA;Kras mice showed increased bronchial epithelial cells and Ki67-positive cells in the bronchial regions. At 7 months after treatment, lung tumors in KA;Kras mice were larger compared to tumors in Kras mice. Finally, KA;Kras mice had shorter life span due to breathing problems. KA;Kras mice started to die at around 20 weeks after injection, while KR mice started to die from around 30 weeks. To confirm whether IKKα reduction promotes K-ras-driven lung carcinogenesis, we generated IKKαf/f (FF) mice crossed with Kras (FF;Kras) mice. Similar to KA;Kras, FF;Kras mice showed significant increase of lung weight, hyperproliferative bronchial abnormalities, Ki-67-positive cells in the bronchial regions and the number of large tumors at 4 months following treatment compared with Kras only group. Taken together, these data suggest that IKKα downregulation promotes K-ras-driven lung tumorigenesis and plays an important role in lung ADCs as well as in SCCs. The underlying molecular mechanism needs to be further investigated.
Citation Format: Na-Young Song, Jami Willette-Brown, Mahesh Dalta, Yinling Hu. Role of IKKα in K-ras-driven lung carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 931. doi:10.1158/1538-7445.AM2014-931
Abstract 96: A novel in vivo preclinical model for the study of human tumor angiogenesis with human vessels
Authors: Holden Kirsty A. , Batey Michael A. , Bottomley Martyn , Booth Catherine 
Published: May 2015

Abstract
The preclinical assessment of anti-angiogenic drug efficacy is hampered by the lack of availability of suitable model systems to study anti-human therapies. Good in vitro assays exist for testing anti-human-specific therapies but these are let down by the lack of robust translatable in vivo models. Currently available preclinical models such as the matrigel plug assay and the window chamber assay focus on the angiogenesis of mouse vessels which may not be truly reflective of the influence of test items on human vasculature, and in vivo models to study the angiogenesis of human tumors by human vessels are unfortunately lacking. We have developed a sophisticated model to address this using adult human skin engrafted onto immunocompromised CB17-SCID mice. Angiogenesis of the skin follows, with human and host vessels anastomosing, resulting in a viable skin graft containing functioning human CD31-labelled vessels. This skin graft can be intradermally injected with a cell line of interest, such as the human melanoma cell line A375, and the ensuing tumors contain human vessels as evidenced by immunohistochemistry with a human-specific anti-CD31 antibody. Using the Aperio® Scanscope and FDA-approved microvessel analysis algorithm, 5-10 human vessels per mm2 of human tumor are observed. Furthermore, the model has the potential to be used in combination with non-invasive in vivo imaging techniques to assess tumor growth inhibition in response to therapies in a longitudinal fashion. This novel technique could potentially enable the rapid preclinical testing of anti-angiogenic anti-human therapies to help provide a go/no-go decision prior to costly clinical trials.
Citation Format: Kirsty A. Holden, Michael A. Batey, Martyn Bottomley, Catherine Booth. A novel in vivo preclinical model for the study of human tumor angiogenesis with human vessels. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 96. doi:10.1158/1538-7445.AM2014-96
Abstract 963: IDH2(R140Q) knock-in mouse recapitulating human type II D-2-hydroxyglutaric aciduria
Authors: Wang Fang , Travins Jeremy , Lin Zhizhong , Silverman Lee , Chen Yue , Lu Yuxuan , Yang Hua , Su Michael , Cang Yong , Ellwood-Yen Kate , Jin Shengfang 
Published: May 2015

Abstract
A single amino acid substitution, R140Q, in isocitrate dehydrogenase 2 (IDH2) confers a novel enzymatic activity that converts α-ketoglutarate (αKG) to D-2-hydroxyglutarate (D-2-HG). This gain-of-function mutation has been identified in patients with type II D-2-hydroxyglutaric aciduria (D-2-HGA), a rare and severe neurometabolic disorder that presents with a range of clinical findings, including seizures, hypotonia, developmental delay, cardiomyopathy, dysmorphic features and early death. There are no effective therapies for this inherited autosomal dominant disease. Here, we report the generation and characterization of a mouse genetic model that recapitulates key features of type II D-2-HGA. A single amino acid replacement, R140Q, was introduced via homologous recombination into the endogenous mouse IDH2 gene locus, to create heterozygous IDH2(R140Q) knock-in (KI) mice. These KI mice produce significantly elevated levels of D-2-HG in all tissues tested, and exhibit multiple defects consistent with symptoms from D-2-HGA patients, including early mortality, brain lesions, and cardiac hypertrophy. Echocardiogram reveals impaired systolic function with a diffusely hypokinetic left ventricle and low ejection fraction.
The IDH2(R140Q) knock-in mouse model provides a valuable tool to elucidate the underlying disease mechanism of D-2-HGA and to evaluate ways to mitigate the disease.
Citation Format: Fang Wang, Jeremy Travins, Zhizhong Lin, Lee Silverman, Yue Chen, Yuxuan Lu, Hua Yang, Michael Su, Yong Cang, Kate Ellwood-Yen, Shengfang Jin. IDH2(R140Q) knock-in mouse recapitulating human type II D-2-hydroxyglutaric aciduria. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 963. doi:10.1158/1538-7445.AM2014-963
Abstract 967: A novel regulator of Wnt-signaling in colorectal cancer
Authors: Betge Johannes , Voloshanenko Oksana , Erdmann Gerrit , Demir Kubilay , Ebert Matthias P. , Boutros Michael 
Published: May 2015

Abstract
Background: Active Wnt signaling is a hallmark of colorectal cancer (CRC). Alterations in Wnt pathway components activate the pathway and thereby initiate and drive carcinogenesis. Recent efforts have aimed at a comprehensive structural characterization of the genomes of a variety of cancer types including colorectal cancer. The function of many altered genes, however, is still elusive.
Methods: We used an integrative genomics approach, combining functional genomic data from a genome-wide RNAi screen for Wnt-regulators in colon cancer cells and structural genomic data to identify novel oncogenes in CRC that regulate Wnt/β-catenin signaling. Candidates were validated and characterized in vitro with molecular biologic- and biochemical assays and in silico with bioinformatic analyses.
Results: Synovial sarcoma translocation gene on chromosome 18-like 1 (SS18L1) is a homolog of the synovial sarcoma driving translocation gene SS18. It was one of the top hits in the genome-wide RNAi screen and it showed significant gene amplifications (8%) and mRNA upregulation (35%) in the TCGA CRC cohort. Silencing of SS18L1 in CRC cells led to decreased TCF4/Wnt-reporter luciferase activity and decreased levels of canonical target gene AXIN2 in qPCR and Western analyses. GFP-tagged SS18L1 was localized nuclear, suggesting involvement in transcriptional regulation by β-catenin. Indeed, we found interaction of SS18L1 with β-catenin and TCF4, as well as with known interacting proteins CBP and p300 by co-immunoprecipitation. Furthermore, interaction of SS18L1 with β-catenin deletion mutants indicated binding of SS18L1 to β-catenin. Copy number of the SS18L1 gene in the CRC cohort of TCGA was positively correlated with RNA expression levels of the gene. Analysis of differentially expressed genes in SS18L1 overexpressing tumors showed enrichment of Wnt-pathway related genes.
Conclusions: Our data suggests that SS18L1 regulates Wnt-signaling by interacting with the complex of β-catenin, TCF4 and CBP/p300. Gene copy number gains and increased mRNA expression levels are detected in CRC. SS18L1 may act as an oncogene in CRC enhancing cell proliferation.
Citation Format: Johannes Betge, Oksana Voloshanenko, Gerrit Erdmann, Kubilay Demir, Matthias P. Ebert, Michael Boutros. A novel regulator of Wnt-signaling in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 967. doi:10.1158/1538-7445.AM2014-967