bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5173: Role of Gli2 in mediating the progression of prostate cancer to CRPC
Authors: Xia Lu , Qin Tai , Sun Luzhe 
Published: July 2016

Abstract
Background: Prostate cancer is a leading cause of cancer-related death in the US men, largely due to the development of castration resistant prostate cancer (CRPC) in the patients treated with androgen deprivation therapy. There is increasing evidence indicating that Hedgehog pathway is involved in the malignancy of prostate cancer, which includes the finding of two prostate tumors with loss-of-function mutations in the SuFu gene, correlation of tumor grade with high expression of Sonic hedgehog, Gli2 and/or hedgehog target genes including Ptch1 and HIP, and increased Gli2 expression in therapy-resistant tumor cells from patients. In addition, treatment of mice with hedgehog inhibitors significantly attenuated the growth of prostate tumor xenografts. Some recent studies also implicated a crosstalk between Hedgehog/Gli signaling and androgen signaling pathways in prostate cancer. However, the role of Gli2 in CRPC progression has not been investigated. Methods: A human Gli2 specific small hairpin RNA (shRNA) expression vector was constructed using Tet-PLKO-puro lentivector, which was delivered into the androgen-dependent human prostate cancer LNCaP cells. RT-PCR, Western Blot and Luciferase Reporter Assay were performed to confirm doxycycline-inducible Gli2 knockdown. The effect of Gli2 knockdown on anchorage-dependent or -independent growth was assessed with MTT and Soft Agar Assays respectively. Cells were cultured in androgen depleted medium or treated with the anti-androgen, Casodex, to mimic androgen deprivation condition. Mouse xenograft models were used to assess the role of Gli2 in the development of CRPC in vivo. Results: Androgen deprivation promoted the expression of Hedgehog signaling components including Gli2 in the LNCaP cells. Gli2 knockdown inhibited anchorage-dependent and -independent growth of LNCaP cells. Casodex complemented the inhibition of Gli2 knockdown on the growth of LNCaP cells. Gli2 knockdown prevented the outgrowth of androgen-independent cells from LNCaP cells cultured in androgen depleted medium. Induced-knockdown of Gli2 by doxycycline inhibited the growth of castration-resistant tumors in vivo in mice. Conclusions: Our study demonstrated the important role of Gli2 in the development of CRPC. Therefore, it may have the potential to serve as a novel therapeutic target for the prevention of CRPC.
Citation Format: Lu Xia, Tai Qin, Luzhe Sun. Role of Gli2 in mediating the progression of prostate cancer to CRPC. [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 5173.
Abstract 5184: MiXeno Humanized Mouse Model as an Efficient Tool to Evaluate in Vivo Activity of Anti-Cancer Immunotherapeutics
Authors: Zhang Juan , Qiao Meng , Ding Jian , Wang Zhensheng , Li zhongliang , Shi Qian 
Published: July 2016

Abstract
Background: Fighting cancer by taking advantage of a patient's own immune system is showing considerable success in oncology research. Targeting therapeutic antibodies against tumor-associated antigens or the host immune system has been shown to prolong survival of patients in various tumor types. However, the lack of experimental immunotherapy models is a major obstacle toward better evaluating new immunotherapeutics and testing their exploratory combination strategies. To address this need, we set out to validate a new platform MiXenoTM by implanting human PBMC to immune-deficient mice. The MiXenoTM mice were partially reconstituted with human immune components. In vivo efficacy of several immunotherapeutics were evaluated.
Results: We have reported before that several MiXenoTM models could be used to evaluate anti-human PD-1 or PD-L1 antibodies, where human T cells were well reconstituted in the mouse system. Here one of our MiXenoTM collection: HCC827 model was further optimized and identified as a PD-1/PD-L1 inhibitor highly sensitive model. Involvement of T cells in the tumor microenvironment was observed in HCC827 tumors. Furthermore, the dynamics of NK cell population in blood, tumor and other organs (e.g. spleen and lymph nodes) was established in MiXenoTM models. NK cell function was evaluated as well.
Conclusion: The MiXenoTM model provides an alternative to the full stem cell reconstitution approach, and may allow various types of immunotherapies being evaluated in these partially humanized xenograft models.
Citation Format: Juan Zhang, Meng Qiao, Jian Ding, Zhensheng Wang, zhongliang Li, Qian Shi. MiXeno Humanized Mouse Model as an Efficient Tool to Evaluate in Vivo Activity of Anti-Cancer Immunotherapeutics. [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 5184.
Abstract 5189: Caloric restriction augments the chemotherapeutic response in a murine triple negative breast cancer model
Authors: Simone Brittany , Dan Tu , Palagani Ajay , LaRose Meredith , Savage Jason E. , Simone Nicole 
Published: July 2016

Abstract
Purpose:
Triple negative breast cancers (TNBC) are a highly aggressive subtype of breast cancer, linked with a poor prognosis. TNBC tumors have a higher propensity for metastasis and unfortunately have fewer treatment options due to their lack of estrogen, progesterone or Her-2/neu receptors. We sought to determine if caloric restriction (CR) could augment the response of chemotherapy including docetaxel and cisplatin in a TNBC model and improve survival.
Methods:
An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, cisplatin alone, docetaxel alone or a combination of CR and chemotherapy. Three times a week, primary tumors were measured with calipers and in vivo imaging was performed to evaluate the metastatic burden of disease. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for increased sensitivity to chemotherapy.
Results:
Combining either docetaxel or cisplatin with CR, significantly decreased the rate of primary tumor growth (p&lt;0.001). Average time to metastases (19 days in ad lib group) was increased by an average of 10.5 +/- 3 days with the addition of either docetaxel or cisplatin, and increased by an additional 6 days in the CR+cisplatin (35 days until metastases, p&lt;0.01). The addition of CR to chemotherapy decreased the overall number and volume of lung metastases, and increased overall survival as compared with those groups receiving chemotherapy alone. Molecularly, CR was noted to augment the effect of chemotherapy by decreasing inflammation that results from IL-1β mediated acute RT toxicity and molecular effectors in the insulin (insulin, IGF-1, IGF-BP3 and IGF-1R) and adipokine signaling pathways (decreased leptin and increased adiponectin).
Conclusions:
CR augments the effect of systemic chemotherapy in an aggressive TNBC mouse model, in part by decreasing the inflammatory response. The novel use of CR in combination with systemic chemotherapy has the potential to enhance clinical outcomes for patients with triple negative breast cancer and should be tested in the clinical setting.
Citation Format: Brittany Simone, Tu Dan, Ajay Palagani, Meredith LaRose, Jason E. Savage, Nicole Simone. Caloric restriction augments the chemotherapeutic response in a murine triple negative breast cancer model. [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 5189.
Abstract 5190: Correspondence between clinical patient outcome and in vivo carboplatine response of high grade ovarian cancer PDX
Authors: du Manoir Stan P. , Delpech Helene , Orsetti Beatrice , Tessier Jeremy , Colombo Pierre-Emmanuel , Theillet Charles G. 
Published: July 2016

Abstract
Survival rate for high grade ovarian cancer (HGOC) remains low and has not significantly evolved for several years. This poor outcome is due to several mechanisms of resistance (initial or acquired) in different context (Homologous recombination deficience, CCNE1 amplification). We developed a collection of High-grade ovarian cancer Patient Derived Xenografts (PDX) with extensive characterization (CGH, transcriptome and exome sequencing, Colombo et al, Oncotarget. 2015 Sep 29;6(29):28327-40). Our objective is to create a panel of HGOC PDX which encompasses main types of platinium sensitivity/resistance in HGOC. We selected 10 PDX models (9 serous histiotypes and one carcinosarcomas) among our collection of 39 HGOC PDXs from two patient extreme platinium response categories (resistant with a progression-free inferior to 6 months and sensible with a progression-free higher than 18 months, some of the sensitives with BRCA1 mutations). These PDXs included PDXs were grafted sub-cutaneously on nude mice and submitted to carboplatin treatment (50mg/kg twice a week, for 4 weeks) and impact on tumor growth was evaluated as well as histological characterization. For the carcinosarcomas, no selection of the epithelial or sarcomatous component upon treatment was observed. Outgrowth of the tumors after end of treatment is currently under assessment.
Remarkably, tumor PDXs response was in accordance with clinical status with complete and partial response for the sensitive PDXs; slowed growth under treatment or stabilization for resistant PDXs. Outgrowth of the tumor after the end of treatment is currently under assessment.
For each PDXs model, the large majority of the 7-9 treated tumor reacted in identical fashion if classified according to RECIST criteria with occasionally divergent responses reflecting tumor heterogeneity. Genetic and histological characterization of these outliers is ongoing.
This collection is a valuable resource to model carboplatine resistance in a well-defined context and will be the cornerstone of our future studies to conduct preclinical drugs tests, in particular for combination selected in vitro and to evaluate clonal evolution under treatment.
Citation Format: Stan P. du Manoir, Helene Delpech, Beatrice Orsetti, Jeremy Tessier, Pierre-Emmanuel Colombo, Charles G. Theillet. Correspondence between clinical patient outcome and in vivo carboplatine response of high grade ovarian cancer PDX. [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 5190.
Abstract 5216: Broadening tumor spectrum in Lynch syndrome: increased incidence for 15 distinct cancer types
Authors: Therkildsen Christina , Ladelund Steen , Lindberg Lars Joachim , Smith-Hansen Lars , Nilbert Mef 
Published: July 2016

Abstract
Introduction: Lynch syndrome is a multi-tumor syndrome predominantly associated with an increased risk of colorectal cancer, but is indeed linked to a yet uncertain number of extra-colonic tumor types.
Methods: In order to determine the risk for extra-colonic tumors in Lynch syndrome, we determined the incidence rates for 21 distinct malignancies in the national Danish Lynch syndrome cohort compared to an age-and sex matched control cohort from the Danish population.
Results: Based on data from 1494 Lynch syndrome mutation carriers, significantly increased risks were demonstrated for 15 cancer types. These included Lynch syndrome-related malignancies, such as cancer of the endometrium, the ovary, the small bowel, the urinary tract and brain tumors as well as tumor types with an undefined role in Lynch syndrome, such as breast cancer, gastric cancer, pancreatic cancer, skin cancer, prostate cancer, lung cancer, kidney cancer, and testicular cancer. Distinctive peak ages were defined with the highest incidence rate ratio at age 30-49 years for ovarian cancer and 50-69 years for endometrial cancer, breast cancer, and brain tumors to continuously increasing incidence rate ratios with increasing age for e.g. urothelial cancer, gastric cancer, pancreatic cancer and skin cancer.
Conclusion: The broad tumor spectrum in Lynch syndrome is of relevance to consider during genetic counseling, whereas the variable peak incidence ages provide a basis for precision surveillance programs that consider the different risks throughout life.
Citation Format: Christina Therkildsen, Steen Ladelund, Lars Joachim Lindberg, Lars Smith-Hansen, Mef Nilbert. Broadening tumor spectrum in Lynch syndrome: increased incidence for 15 distinct cancer types. [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 5216.
Abstract 5220: Evaluation of ACMG guideline classified variants in 180 cancer and incidental non-cancer genes in families with breast/ovarian cancer
Authors: Maxwell Kara N. , Hart Steven N. , Vijai Joseph , Schrader Kasmintan A. , Thomas Tinu , Wubbenhorst Bradley , Ravichandran Vignesh , Moore Raymond M. , Hu Chunling , Guidugli Lucia , Wenz Brandon , Slavin Thomas P. , Domchek Susan M. , Robson Mark E. , Szabo Csilla , Neuhausen Susan L. , Weitzel Jeffrey N. , Offit Kenneth , Couch Fergus J. , Nathanson Katherine L. 
Published: July 2016

Abstract
Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG designated reportable cancer and non-cancer genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole exome sequencing in 404 individuals in 257 families and classified 1640 variants from these genes. Potentially clinically actionable (likely-pathogenic/pathogenic, LP/P) versus nonactionable (VUS/likely-benign/benign) calls were 92% and 88% concordant with locus specific databases and Clinvar, respectively. LP/P mutations were identified in 11 of 25 breast cancer susceptibility genes in 27 BRCA1/2 negative families (11%). Evaluation of 84 additional autosomal dominant cancer susceptibility genes identified LP/P mutations in only four additional families (1.7%), suggesting they do not influence risk in this cohort. However, individuals from nine of 257 families (3.5%) had incidental LP/P mutations in 32 non-cancer disease genes, and 7% of individuals were monoallelic carriers of an LP/P mutation in 39 autosomal recessive cancer syndrome genes. Furthermore, 90% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant classification guidelines. In addition, evaluation of extended panels of cancer genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.
Citation Format: Kara N. Maxwell, Steven N. Hart, Joseph Vijai, Kasmintan A. Schrader, Tinu Thomas, Bradley Wubbenhorst, Vignesh Ravichandran, Raymond M. Moore, Chunling Hu, Lucia Guidugli, Brandon Wenz, Thomas P. Slavin, Susan M. Domchek, Mark E. Robson, Csilla Szabo, Susan L. Neuhausen, Jeffrey N. Weitzel, Kenneth Offit, Fergus J. Couch, Katherine L. Nathanson. Evaluation of ACMG guideline classified variants in 180 cancer and incidental non-cancer genes in families with breast/ovarian cancer. [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 5220.
Abstract 523: Activating mutations in EGFR abrogate hypoxia-associated radiation resistance in non-small cell lung cancer
Authors: Saki Mohammad , Makino Haruhiko , Tomimatsu Nozomi , Ding Lianghao , Story Michael D. , Burma Sandeep , Nirodi Chaitanya 
Published: July 2016

Abstract
Hypoxic tumors tend to be 3-5 times more resistant to ionizing radiation relative to well-oxygenated tumors in part because oxygen is required to stabilize radiation-induced DNA damage. Tumor-adaptive responses also contribute to hypoxia-associated radioresistance but the precise mechanisms are not fully understood. Here we test our evidence-based hypothesis that the epidermal growth factor receptor (EGFR), which is frequently over-expressed in non-small cell lung carcinomas (NSCLCs), has critical roles in a tumor adaptive DNA damage response (DDR) pathway in hypoxic tumors. We find that, despite elevated EGFR activity and pro-survival signaling, hypoxia-associated radioresistance is dramatically reduced in a biologically distinct class of NSCLCs harboring activating mutations, L858R and ΔE746-E750 in EGFR. Hypoxic NSCLCs with EGFR mutations exhibit a unique spectrum of basal and hypoxia-induced DSBs not found in hypoxic wild type EGFR-expressing NSCLCs. These lesions dominate the S-phase of the cell cycle and are linked to collapsed replication forks in hypoxic cells. Replication fork-associated DSBs are repaired in wild type, but not in mutant, EGFR expressing NSCLCs. Microarray gene expression analysis revealed that mutant, but not wild type, EGFR expression results in an altered DDR characterized by dramatic down-regulation of several key components of the HR pathway within 24 hours of exposure to 0.1% oxygen. Our model predicts that NHEJ, not HR, dominates an altered DDR in hypoxic tumors. Elevated EGFR signaling may contribute to this altered DDR state where the EGFR-NHEJ axis becomes critical for hypoxia associated radioresistance and could be a potential target for hypoxic tumor radiosensitization.
Citation Format: Mohammad Saki, Haruhiko Makino, Nozomi Tomimatsu, Lianghao Ding, Michael D. Story, Sandeep Burma, Chaitanya Nirodi. Activating mutations in EGFR abrogate hypoxia-associated radiation resistance in non-small cell lung cancer. [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 523.
Abstract 5240: Lacking hepatic retinoid storage in mice suppresses NASH-related hepatocarcinogenesis
Authors: Ideta Takayasu , Shirakami Yohei , Miyazaki Tsuneyuki , Sakai Hiroyasu , Tanaka Takuji , Blaner William S. , Shimizu Masahito 
Published: July 2016

Abstract
Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, has become one of the most common causes of chronic liver disease in developed countries. Some patients with NAFLD develop a more serious form of the disease, non-alcoholic steatohepatitis (NASH), and NASH can develop cirrhosis or even hepatocellular carcinoma (HCC). Although hepatic retinoid (vitamin A) stores are progressively lost during the development of liver diseases, how this affects NAFLD/NASH and NASH-related hepatocarcinogenesis is unknown. In order to investigate this, we used streptozotocin (STZ) and high-fat diet (HFD) to induce NASH and related hepatic tumorigenesis in matched wild-type and lecithin:retinol acyltransferase (LRAT) knockout (KO) mice, which lack stored retinoid in the liver. LRAT is the sole enzyme responsible for hepatic retinyl ester synthesis since LRAT KO mice completely lack lipid droplets in hepatic stellate cells. Mice were injected with STZ within 48 hours after birth and then fed HFD from 4 to 16 weeks of age. At the termination of the experiment, liver tumors were observed macroscopically and microscopically in both groups. In LRAT KO mice, the development of hepatic adenoma and HCC was significantly suppressed compared to control group. LRAT KO mice showed decreased expression levels of cyclin D1 and TGF-beta mRNA in the liver. The serum levels of d-ROMs and BAP were measured and the d-ROM/BAP ratio, which indicates oxidative stress, markedly decreased in LRAT KO mice. The fibrosis in the liver of the LRAT KO mice was decreased. In addition, liver fibrosis in LRAT KO mice was suppressed. These findings indicate that LRAT KO mice are less susceptible to STZ and HFD-induced liver tumorigenesis due to regulation of cell cycle and attenuation of oxidative stress.
The amount of hepatic retinoid may affect the progression of NASH and the development of NASH-related HCC.
Citation Format: Takayasu Ideta, Yohei Shirakami, Tsuneyuki Miyazaki, Hiroyasu Sakai, Takuji Tanaka, William S. Blaner, Masahito Shimizu. Lacking hepatic retinoid storage in mice suppresses NASH-related hepatocarcinogenesis. [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 5240.
Abstract 5264: The National Cancer Institute's biospecimen research database: A community resource for improving specimen quality
Authors: Engel Kelly B. , Greytak Sarah R. , Guan Ping , Moore Helen 
Published: July 2016

Abstract
Tissue and blood biospecimens used in cancer research are collected, processed and stored using standard operating procedures (SOPs) that can vary tremendously across institutions. This lack of standardization in biospecimen collection and processing practices across sample sets and institutions can be a contributing source of research variability and can compromise analytical results. In an effort to minimize preanalytical variability and improve the quality of biospecimens used for cancer research, the National Cancer Institute's Biorepositories and Biospecimen Research Branch (BBRB) developed the Biospecimen Research Database (BRD; http://biospecimens.cancer.gov/brd). The BRD is a free and publically accessible online database that aims to (i) improve access to peer-reviewed articles that investigate the impacts that biospecimen collection and handling practices can have on clinical, molecular, and proteomic endpoints, (ii) facilitate transparency between institutions and researchers by promoting SOP sharing and distribution, and (iii) improve the quality of biospecimens through the development of evidence-based procedural guidelines. To date, the BRD houses more than 2,300 articles and 200 SOPs from 30 different participating biobanking institutions. Articles are meticulously categorized and annotated by a team of Ph.D.-level scientists according to the type of biospecimen and technology platform used and the preanalytical factors investigated. Literature contained within the BRD serves as the foundation for internally developed reviewed papers as well as evidence-based procedural guidelines, termed Biospecimen Evidence-Based Practices, which focus on biospecimen collection, preservation, and processing. In addition, more than 90% of the BRD's SOP library was contributed by other government offices, non-profit, private, and international biobanks and institutions. BBRB has invested a substantial and continued level of effort in the establishment of this scientifically accurate and robust database. Ongoing participation by the scientific community in the form of public commenting, article suggestions and SOP submissions is encouraged and will increase both the diversity and value of the BRD.
Citation Format: Kelly B. Engel, Sarah R. Greytak, Ping Guan, Helen Moore. The National Cancer Institute's biospecimen research database: A community resource for improving specimen quality. [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 5264.