bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 123: Hormonal and genetic risk factors of soft tissue sarcoma in Sweden.
Authors: Wagner Philippe , Magnusson Susanne , Olsson Håkan 
Published: August 2014

Abstract
BACKGROUND AND METHODS. The aetiology of soft tissue sarcoma (STS) is largely unknown. Merely a handful putative risk factors such as certain genetic syndromes, a positive family history of cancer/STS, specific chemical exposures and exposure to ionizing radiation have been identified. With respect to the genetic aetiology, most STS patients do not have a clear family history of cancer. Only in rare cases heritable or germline genetic abnormalities associated with cancer predisposition syndromes that manifest as STS have been identified. We study STS and cancer morbidity in first degree relatives (FDR) together with hormone related factors in the Swedish population in the years between the years 1988 and 2009 using a population-based case-control design. RESULTS. Our study is the largest on this topic to date, including 855 cases and 2024 controls. It identified protective effects of being shorter than your peers at age eleven with a relative risk (RR) of 0.5 (0.4 - 0.7). Having used oral contraceptives (OC), RR 0.6 (0.4 - 1.0), and high parity, RR 0.6 (0.3 - 0.9) comparing three or more children to none, also appeared to reduce the risk for STS. The reduction increased further comparing use for eleven years or more to use for three years or less, RR 0.2 (0.1 - 0.6). Those with an FDR with STS and with those with an FDR with cancer had increased risks, RR 5.16 (1.03 - 25.9) and 1.31 (1.05 - 1.65), respectively. The latter varied with sex and histological subtype. In men, the familial risk was significant for malignant fibrous histiocytoma/undifferentiated pleomorphic sarcomas (MFH), RR 2.21 (1.23 - 3.97) and was higher in younger men (P=0.015). In women, there was a significant overall familial risk when stratifying on OC use, RR 1.55 (1.06 - 2.26). This risk seemed to derive from a group of rare and unclassified tumours present mainly in retroperitoneum and visceral organs, RR 6.19 (0.54 - 71.2). CONCLUSIONS. STS are a heterogeneous group of tumours with possibly very different aetiologies. However, the genesis of sarcoma seems to be influenced by both sex and growth hormones as well as genetic factors. Studies are on the way of the molecular genetic background of these associations.
Citation Format: Philippe Wagner, Susanne Magnusson, Håkan Olsson. Hormonal and genetic risk factors of soft tissue sarcoma in Sweden. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 123. doi:10.1158/1538-7445.AM2013-123
Abstract 1235: Human antibodies specific for a novel isoform of the macrophage migration inhibitory factor are potential therapeutics for prostate cancer.
Authors: Thiele Michael , Freissmuth Michael , Hussain Filza , Douillard Patrice , Völkel Dirk , Ehrlich Hartmut , Scheiflinger Friedrich , Kerschbaumer Randolf 
Published: August 2014

Abstract
Macrophage migration inhibitory factor (MIF) was found to be upregulated in many cancers and to act in para- and autocrine loops within the tumor microenvironment. Thereby, MIF contributes to the modulation of cytokine patterns and triggers anti-apoptotic and pro-proliferative cell signaling events. MIF was also described as a pro-angiogenic factor promoting neoangiogenesis and vascularization. In prostate cancer, MIF mRNA and protein levels were shown to be increased and to contribute to tumor development. We have discovered a novel, previously unrecognized conformational isoform of MIF (designated ‘active MIF’) that is produced in diseases and cannot be detected in healthy subjects. A set of phage display derived human monoclonal anti-MIF antibodies neutralizing MIF biological activity in vitro and in vivo specifically recognize active MIF. In vitro, these antibodies elicited both, a growth inhibitory effect and a pro-apoptotic response on PC3 and DU145 prostate cancer cells by interfering with ERK1/2 and Akt/PKB signaling pathways and by promoting activation of caspase-3. Furthermore, the antibodies inhibited tumor cell invasion of PC3 cells in a transwell assay in a dose-dependent manner. In vivo, treatment with human antibodies specific for active MIF dose-dependently inhibited the growth of the human prostate cancer cell line PC3 xenografted into MF1 nude mice. New ELISA methods have been established to allow the detection of active MIF as well as non-active MIF in plasma samples. In the plasma of PC3 xenografted nude mice, we observed a reduction of active MIF upon antibody treatment. In addition we were able to prove the occurrence of active MIF in the plasma of prostate cancer patients (median 2445 pg/mL, p &lt; 0.002 versus controls), whereas active MIF was not detectable in plasma from healthy donors. These studies demonstrate that active MIF represents a new target in prostate cancer, as well as a promising marker for disease activity or disease progression. The data further suggest that our fully human anti-MIF antibodies have a good potential for clinical use in oncology.
Citation Format: Michael Thiele, Michael Freissmuth, Filza Hussain, Patrice Douillard, Dirk Völkel, Hartmut Ehrlich, Friedrich Scheiflinger, Randolf Kerschbaumer. Human antibodies specific for a novel isoform of the macrophage migration inhibitory factor are potential therapeutics for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1235. doi:10.1158/1538-7445.AM2013-1235
Abstract 126: BRCA-positivity: Multicultural scenes from the rear view mirror .
Authors: Miller-Samuel Susan , Simone Nicole , Rosenberg Anne L. 
Published: August 2014

Abstract
Background: To date, BRCA1 and BRCA2 mutations have been associated with specific breast cancer subtypes and patient demographics. BRCA testing has predominantly been performed in the Caucasian population. Certain breast cancer subtypes such as Triple Negative Breast Cancer (TNBC), have previously been associated with African American (AA) women and BRCA1 positivity. Novel targeted agents such as PARP inhibitors may be beneficial for TNBC and BRCA-positive cancers. Appropriate genetic referral and testing could influence patient treatment options. We sought to determine the patterns of patient referral and outcome for BRCA testing at Thomas Jefferson University Hospital (TJUH).
Methods: After obtaining IRB approval, a retrospective case review was performed to identify women who proceeded with genetic counseling from January 2008 through May 2012. Patients with positive genetic tests were assessed. Pathology reports of mutation-positive women were reviewed. Patient characteristics such as ethnicity were confirmed from genetic counseling records.
Findings: 461 new patients were seen for genetic counseling from January 2008 through May 2012. 309 (67%) proceeded with BRCA genetic testing and 26 (9%) were found to carry a deleterious BRCA1 or BRCA2 mutation. Hormone receptor profiles, age at diagnosis, and ethnic background varied among mutation carriers. The predominant ethnic background represented in TJUH mutation carriers is now AA. In 2008-2009 (24 months), only one AA woman was diagnosed with a BRCA mutation; however, from 2010-May 2012 (29 months), 9 AA women and 2 Hispanic women were diagnosed as BRCA-mutation carriers.
Conclusions: BRCA-positive patients have diverse demographic and hormone receptor profiles. Although we found that TNBC remains associated with BRCA1 carriers and estrogen positivity with BRCA2 carriers, it is not absolute. A recent shift has noted substantially more AA women being diagnosed with BRCA mutations. While this may indicate that more diverse populations are being referred for genetic counseling, more importantly, it suggests that diverse populations are becoming more receptive to participating in genetic counseling and when appropriate, receiving genetic testing.
Citation Format: Susan Miller-Samuel, Nicole Simone, Anne L. Rosenberg. BRCA-positivity: Multicultural scenes from the rear view mirror . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 126. doi:10.1158/1538-7445.AM2013-126
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1264: Mutated CD80 may facilitate T-cell activation by inhibiting PDL1-PD1 suppression and by costimulating.
Authors: Dalal Sonia P. , Haile Samuel , Somasundaram Preethi , Ostrand-Rosenberg Suzanne 
Published: August 2014

Abstract
CD80 functions as a costimulatory signal to activate T cells when it binds to CD28 or as an apoptotic signal when it binds to CTLA4. We recently identified another function for CD80 and showed that co-expression of CD80 by Program Death Ligand-1+ (PDL1+) human tumor cells prevents PDL1 binding to its receptor PD1 on activated T cells, and enhances activation of tumor-reactive T cells. To distinguish if CD80 is facilitating T cell activation by preventing PDL1-PD1 interactions and/or by functioning as a costimulatory molecule, we have generated a recombinant CD80 molecule that does not bind to CD28. Since we hypothesize that CD80 may be a therapeutic for inhibiting tumor-mediated immune suppression via PDL1-PD1 interactions, the recombinant CD80 is also designed to not interact with CTLA4. Using site directed mutagenesis we generated CD80 with the following mutations: H96A, L97A, and E99A (CD8096,97,99). CD28 and CTLA4 bind to 35.3% and 37.4%, respectively, of tumor cells expressing wild type CD80. In contrast, only 1.2% and 1.4% of tumor cells expressing CD8096,97,99 bind CD28 and CTLA4, respectively, demonstrating that the mutant CD80 does not bind to CD28 or CTLA4. Previous studies demonstrated that CD80 prevents PDL1-PD1 interactions by binding to PDL1 and obscuring its detection. Only 7.05% of CD8096,97,99 mutants have detectable PDL1 (vs. 98% of untransfected parental human tumor cells), demonstrating that the CD8096,97,99 mutant does not bind CD28 or CTLA4, but retains the ability to inhibit PDL1-PD1 interactions. We are also generating a soluble form of CD8096,97,99 (sCD8096,97,99) that could be administered to cancer patients to prevent tumor cell-mediated PDL1 immune suppression. The construct for the soluble form was generated by ligating the two extracellular domains of CD80 containing the 96,97,99 mutations to the Fc region of human IgG1, followed by incorporation into the Pet21a+ plasmid containing the T7 promoter. Recombinant protein will be isolated from transformed E. coli using a protein G affinity column, and tested in functional experiments with PDL1+ tumor cells to determine if CD80 increases T-cell activation by inhibiting PDL1-PD-1 immune suppression and/or by facilitating costimulation.
This work was funded, in part, by grants from the HHMI Precollege and Undergraduate Science Education Program (52006949), CBI (T32 GM066706), and NIH (R01CA84232 and RO1CA115880).
Citation Format: Sonia P. Dalal, Samuel Haile, Preethi Somasundaram, Suzanne Ostrand-Rosenberg. Mutated CD80 may facilitate T-cell activation by inhibiting PDL1-PD1 suppression and by costimulating. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1264. doi:10.1158/1538-7445.AM2013-1264
Abstract 1267: Identification of HPV-derived CD4+ T-helper epitopes for improving therapeutic anti-HPV vaccine potency.
Authors: Grabowska Agnieszka K. , Hoppe Stephanie , Blatnik Renata , Riemer Angelika B. 
Published: August 2014

Abstract
Persistent infection with high-risk types of human papillomavirus (HPV) can lead to malignant transformation and the development of various human malignancies, such as cervical cancer, anal cancer or a subset of oropharyngeal carcinomas. Fortunately, most HPV infections are successfully eradicated by the immune system. Accumulating evidence suggests that both CD8+ and CD4+ T cell responses play a pivotal role in the clearance and control of HPV infection. Up to now, therapeutic anti-HPV vaccines have mostly been developed to elicit CD8+T cell responses. The exclusive targeting of HLA class I-restricted HPV epitopes might be insufficient, as HLA class I surface expression may be reduced as a result of HPV immune evasion strategies. In contrast, HLA class II molecules are expressed in high-grade cervical lesions and cervical cancer. Therefore in this study, we aim to identify novel E2-, E5-, E6- and E7-derived CD4+ T cell epitopes that bind to multiple HLA class II alleles, are naturally processed and presented, and immunogenic.
We started with in silico epitope predictions using several web-based prediction algorithms. 15-mer candidate epitopes from the HPV16 E2, E5, E6 and E7 proteins were determined for seven HLA class II alleles - DRB1*0101 (DR1), DRB1*0301 (DR3), DRB1*0401 (DR4), DRB1*0701 (DR7), DRB1*1101 (DR11), DRB1*1501 (DR2b), and DRB1*0901 (DR9); together providing &gt;90% population coverage. To identify promiscuous epitopes, the average binding score to multiple HLA-DR alleles was calculated and peptides ranked accordingly. To assess immunogenicity of HPV-derived candidate peptides, IFN-γ-ELISPOT assays were conducted with lymphocytes isolated from healthy donors. T cells isolated from the majority of healthy donors responded to at least one HPV-derived peptide. The most reactive HPV-derived peptides were further investigated in long-term T cell cultures. Significant production of IFN-γ as well as T cell proliferation was observed in nearly 100% of tested individuals against this panel of epitopes.
As the above immunoreactivities most likely represent memory responses that led to viral clearance in healthy donors, we conclude that the identified CD4+ T-helper epitopes are candidates for the development of comprehensive epitope-specific HPV immunotherapy approaches.
Citation Format: Agnieszka K. Grabowska, Stephanie Hoppe, Renata Blatnik, Angelika B. Riemer. Identification of HPV-derived CD4+ T-helper epitopes for improving therapeutic anti-HPV vaccine potency. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2013-1267
Abstract 1273: Adaptive immunity in a zebrafish model of melanoma.
Authors: Painter Corrie A. , Ceol Craig 
Published: August 2014

Abstract
The recent success of the anti-CLTA-4 antibody, ipilimumab, for late stage metastatic melanoma, provides proof of principle that stimulating the immune system can have profound effects on patient outcome. However, a detailed understanding of the role of immune-modulating cells within the tumor microenvironment has been confounded by the lack of a suitable model system that would allow for direct visualization of cells within the intact tumor microenvironment. Previous work has demonstrated that the zebrafish, Danio Rerio, can be genetically manipulated to produce melanomas that recapitulate BRAFV600E;P53-/- human tumors. Due to its translucency, ease of genetic manipulation and high fecundity, the zebrafish is an attractive model system that allows for in vivo characterization of cells within intact tissue. Using this model system, we have begun investigating the adaptive immune response to melanoma in zebrafish. We have focused our initial investigations on determining whether transcript expression of key adaptive immune-modulatory proteins are present in the zebrafish and to what extent they are expressed intratumorally . Our studies have found that orthologs of CLTA-4, FOXP3, and CD8 are all expressed in wild-type zebrafish, but not in rag-/- zebrafish. Furthermore, transcript levels of CTLA-4 were greatest in the melanoma tumor relative to other regions of the zebrafish, which is consistent with the constitutive expression of CTLA-4 in human melanomas. Additionally, we have cloned the promoters for zebrafish FOXP3 and CD8 and are developing fluorescent reporter lines that will enable us to visualize and ablate subpopulations of T cells within the tumor. These lines, along with previously described reporter lines for MHC II and lck, will enable us to determine the role of adaptive immune cells during melanoma onset and progression in the zebrafish. Our research supports the notion that there is conservation between the human and zebrafish adaptive immune systems, and that similar immune evasion mechanisms may be contributing to melanoma growth in zebrafish. These data position the zebrafsh as a powerful model system for immunological investigations that focus on the adaptive immune response to melanoma.
Citation Format: Corrie A. Painter, Craig Ceol. Adaptive immunity in a zebrafish model of melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1273. doi:10.1158/1538-7445.AM2013-1273
Abstract 1283: Role of ERCC1 in metformin enhancing paclitaxel-induced cytotoxicity.
Authors: Lin Yun-Wei , Tseng Sheng-Chieh , Huang Yu-Ching , Chiu Hsien-Chun , Chen Huang-Jen , Weng Shao-Hsing , Huang Yi-Jhen , Wo Ting-Yu 
Published: August 2014

Abstract
Metformin, an extensively used and well-tolerated drug for treating individuals with type 2 diabetes, has recently gained significant attention as an anticancer drug. On the other hand, paclitaxel (taxol) is a new antineoplastic drug that has shown promise in the treatment of non-small cell lung cancer (NSCLC). High expression levels of excision repair cross-complementary 1 (ERCC1) in cancers have been positively associated with the DNA repair capacity and a poor prognosis in NSCLC patients treated with platinum-containing chemotherapy. In this current study, paclitaxel was found to increase phosphorylation of mitogen-activated protein kinase (MAPK) kinase 3/6 (MKK3/6)-p38 MAPK as well as protein and mRNA levels of ERCC1 in H1650 and H1703 cells. Moreover, paclitaxel-induced ERCC1 protein and mRNA levels significantly decreased via the downregulation of p38 activity by either a p38 MAPK inhibitor SB202190 or p38 knockdown with specific small interfering RNA (siRNA). Specific inhibition of ERCC1 with siRNA was found to enhance the paclitaxel-induced cytotoxic effect and growth inhibition. Furthermore, metformin was able to not only decrease the paclitaxel-induced p38 MAPK-mediated ERCC1 expression, but also augment the cytotoxic effect induced by paclitaxel. Finally, expression of constitutive activate MKK6 or HA-p38 MAPK vectors in lung cancer cells was able to abrogate ERCC1 downregulation by metformin and paclitaxel as well as cell viability and DNA repair capacity. Overall, our results suggest that inhibition of the p38 MAPK signaling by metformin coupled with paclitaxel therapy in human NSCLC cells may be a clinically useful combination, which however will require further validation.
Citation Format: Yun-Wei Lin, Sheng-Chieh Tseng, Yu-Ching Huang, Hsien-Chun Chiu, Huang-Jen Chen, Shao-Hsing Weng, Yi-Jhen Huang, Ting-Yu Wo. Role of ERCC1 in metformin enhancing paclitaxel-induced cytotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1283. doi:10.1158/1538-7445.AM2013-1283
Abstract 1284: Combined genetic and nutritional risk models of triple negative breast cancer.
Authors: Hu Jennifer J. , Lee Eunkyung M. , Allen Glenn O. , Levine Edward A. 
Published: August 2014

Abstract
Purpose: Triple negative breast cancer (TNBC), which lacks treatment targets for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), has been associated with African-American race, BRCA1/2 mutations, TP53 mutations, and poor prognosis. However, the etiology of TNBC remained unknown, which represents a critical barrier in reducing breast cancer mortality. Therefore, we designed a case-only study to test combined genetic and nutritional risk models of TNBC.
Methods: In 354 breast cancer patients diagnosed between 1998 and 2004, we evaluated 18 DNA-repair non-synonymous single nucleotide polymorphisms (nsSNPs) using the Sequenom MassARRAY system. The 110-item Block 1998 food frequency questionnaire was used to evaluate dietary/nutritional intakes. The Multivariate Adaptive Regression Splines (MARS)-logit models were used to define nutritional intakes cut-offs for their associations with TNBC.
Results: TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or 3 micronutrients (zinc, folate, and β-carotene). Combined DNA-repair risk genotypes and lower micronutrient intakes had a significant dosage-dependent association with TNBC (p&lt;0.001): ORs=2.77 (95%CI=1.01-7.64), 9.57 (95%CI=2.87-31.84), and 20.78 (95%CI=2.46-175.71) for 2, 3, and at least 4 risk factors, respectively.
Conclusion: To the best of our knowledge, this is the first study to demonstrate multiple DNA repair SNPs and nutritional factors are associated with TNBC. Our results suggest that dietary modulation and micronutrient supplementation may have implication in preventing or reversing TNBC, particularly in genetically susceptible women.
Citation Format: Jennifer J. Hu, Eunkyung M. Lee, Glenn O. Allen, Edward A. Levine. Combined genetic and nutritional risk models of triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1284. doi:10.1158/1538-7445.AM2013-1284