bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY16-04: Contrasting effects of TGF-β signaling in the proangiogenic tumor stroma
Authors: Pietras Kristian 
Published: June 2012

Abstract
Cancer results from the concerted performance of tumor cells interacting with their microenvironment. The formation of a reactive stroma evidently contributes to tumor initiation, growth and progression by providing growth-regulatory factors, supporting tumor angiogenesis, and facilitating invasion. As a rich source of cancer-promoting factors, the tumor stroma is an underestimated target for the development of novel therapeutics.
Members of the transforming growth factor (TGF)-β family have been linked to vascular formation through mouse genetic studies. However, contradictory reports on the role of TGF-β signaling in physiological and pathological angiogenesis make the need for mechanistic studies apparent. Here, we describe functional studies on the role of the TGF-β receptor activin receptor-like kinase (ALK) 1 and its co-receptor endoglin in tumor angiogenesis. We demonstrate by genetic and pharmacological means that diminution of ALK1 gene dosage, or systemic treatment with an ALK1-Fc fusion protein, retarded tumor growth and progression by inhibition of angiogenesis. Moreover, we uncovered an unexpected synergy through which the combined action of different ALK1 ligands primed endothelial cells to respond to prototypical angiogenic stimuli both in vitro and in vivo. In parallel studies, genetic targeting of endoglin was revealed to give rise to an initial block in the angiogenic switch of tumors, which was overcome through acquired resistance characterized by an increased metastatic spread. The rise in metastatic dissemination was consequential to a loss of junctional patency in the endoglin-deficient vasculature due to ongoing endothelial-to-mesenchymal transition.
Taken together, our studies delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking TGF-β signaling in oncology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY16-04. doi:10.1158/1538-7445.AM2011-SY16-04
Abstract SY22-01: Interrogating gene expression programs from preclinical analyses of genetically engineered mouse models
Authors: Abate-Shen Cory , Meneses Alvaro Aytes , Kinkade Carolyn W. , Mitrofanova Antonina , Lefebvre Celine , Chua Chee Wai , Castillo-Martin Mireia , Gelmann Edward , Shen Michael M. , Califano Andrea 
Published: June 2012

Abstract
Our laboratories have been investigating novel mechanisms of cancer progression, as well as new therapeutic approaches for early intervention and treatment of advanced disease by integrating analyses of human clinical data with molecular and functional studies of genetically engineered mutant (GEM) mice. In our analyses of prostate cancer, we have generated GEM mice that recapitulate the entire spectrum of disease progression from preinvasive lesions, termed prostate intraepithelial neoplasia (PIN), to castration-resistant and metastatic disease, which are the lethal forms of the disease. These GEM models are based on perturbation of the Akt/mTOR and MAP kinase signaling pathways, which are often co-activated in human prostate cancer and which function synergistically to promote castration-resistant metastatic prostate cancer. We have found that combinatorial inhibition of these signaling pathways in GEM mice that display castration-resistant metastatic prostate cancer results in abrogation of primary tumors, improved survival and reduced metastasis. Using computational approaches for comparative analyses of large-scale gene expression profiling data for mouse and human prostate cancer, we have been assembling molecular networks, called interactomes, to elucidate conserved cancer pathways. We have been investigating the consequences of drugs perturbations on the transcriptional network with the ultimate goal of identifying new druggable targets. In summary, our comparative investigations of prostate cancer in humans and GEM mice have revealed promising new molecular targets and new therapuetic approaches for the treatment of human cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY22-01. doi:10.1158/1538-7445.AM2011-SY22-01
Abstract SY31-01: Combinatorial development of biomaterials for tissue engineering and drug delivery
Authors: Anderson Daniel G. 
Published: June 2012

Abstract
High throughput, combinatorial approaches have revolutionized small molecule drug discovery. Here we describe our work on high throughput methods for developing and characterizing biomaterials for drug delivery and tissue engineering. We have developed automated methods allowing for rapid nanoliter scale synthesis of 1000's of biomaterials, as well as the testing of their chemical, material, and biological properties. These methods have also been applied towards the development of new methods to control stem cell behavior, as well as vehicles for drug delivery. In particular, these combinatorial libraries of different biomaterials have enabled new methods for microparticulate drug delivery, non-viral gene therapy, siRNA delivery, and vaccines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY31-01. doi:10.1158/1538-7445.AM2011-SY31-01
Abstract A43: Inhibition studies of Siah2, a ubiquitin ligase, involved in hypoxia induced cancer
Authors: Gopalsamy Anupriya 
Published: June 2012

Abstract
Ubiquitin ligase siah2 has been shown to regulate the hypoxia response by regulating prolyl hydroxylase3 (PHD3) involved in a hypoxia inducible factor 1α (Hif-1α) dependent pathway which up regulates the genes like vascular endothelial growth factor (VEGF), resulting in tumor cell survival. Thus it has been suggested that siah2 may act as a target for developing inhibitors. In this study we have proved the interaction of siah2 and PHD3 using co-immunoprecipitation and GST pull down assay. Interaction studies indicate that C-terminal substrate binding domain (SBD) of Siah2 is involved in the binding to PHD3 irrespective of the N-terminal ring domain. The structure-based high throughput virtual screening (HTVS) method was used to identify potential small molecule inhibitors and we have identified five drug-like lead molecules specific for the Siah2 using 14400 drug-like subsets obtained from the Maybridge database, which might inhibit the interaction between Siah2 and PHD3. The lead molecules from screening were then tested in silico for their pharmacokinetic properties and percent human oral absorption using QikProp. Further, pharmacokinetic analysis based on Lipinski's rule of five which is based on ADMET (absorption, distribution, metabolism, excretion and toxicity) properties suggested potential utility of these compounds as drug leads. Docking studies were carried out to analyze the binding conformations of the identified lead molecules towards the Siah2 which reveals that Ser39 residue of SBD may be the key amino acid residue interacting with these ligands necessary for the induction of Siah2 activity. These results set the stage for the development of a workflow for selection of domain specific drug development. Five potential drug-like molecules specific to the SBD domain were eventually selected on the basis of binding characteristics, docking energy and ADMET properties. Further in-vivo and in-vitro experimental studies to investigate the inhibitory potential of these lead drug-like small molecules on this ligase and its binding are under progress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A43.
Abstract A54: Downregulation of hepatocyte growth factor activator inhibitor-2 is involved in the progression of prostate cancer cells
Authors: Lan Shao-Wei , Cheng Tai-Shan , Wu Shang-Ru , Shyu Hsin-Yi , Ko Chun-Jung , Hsiao Pei-Wen , Lee Ming-Shyue 
Published: June 2012

Abstract
Dysregulation of pericellular proteolysis has been strongly involved in tumorigenesis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 (HAI-2) in prostate cancer cell invasion and tumorigenicity within a human prostate cancer progression model (103E, N1, and N2 cells). This model was newly established by a serial of intraprostatic propagation of a human prostate cancer 103E cell line and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was gradually increased after the serial isolations (103E&lt;N1 &lt;N2). In this series of cells, the expression of HAI-2 was significantly decreased during the progression. Following the course of orthotopic tumor growth in mice, the expression level and activity of a HAI-2 target, matriptase, increased while the HAI-2 protein level decreased. Restoration of HAI-2 expression in N2 cells down-regulated the matriptase activity and cell proliferation, thus decreased the tumorigenicity. These results show that during the progression of human prostate cancer, matriptase was primarily controlled by HAI-2 expression. The imbalance in HAI-2 and matriptase expression led to matriptase activation, therefore increased cell invasion and tumorigenicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A54.
Abstract A66: Expression and immunotherapeutic targeting of the SSX family of cancer-testis antigens in prostate cancer
Authors: Smith Heath A. , Cronk Robert J. , Lang Joshua M. , McNeel Douglas G. 
Published: June 2012

Abstract
Members of the SSX family of proteins were among the first cancer-testis antigens (CTA) identified. Characterized by tissue-restricted expression to MHC class l-deficient germline cells and frequent ectopic expression in tumors of various histological origin, CTA are highly tumor-specific antigens. SSX proteins comprise a family of ten members with mRNA expression often found in advanced-stage disease and associated with worse patient prognosis. We have previously shown that humoral and cell-mediated immune responses to SSX2 can arise spontaneously in patients with prostate cancer, which combined with the expression of these proteins in MHC class l-negative tissue, makes SSX proteins potentially attractive targets for tumor immunotherapy. In the current study, we evaluated SSX family member expression in prostate cancer cell lines and tumor biopsies to identify therapeutic targets for vaccine therapy in prostate cancer. We found by RT-PCR and qRT-PCR that SSX1, SSX2, and SSX5 were frequently expressed in prostate cancer cell lines and could be induced by treatment with epigenetic modifying agents (EMA) such as 5-aza-2′-deoxycytidine. Furthermore, we observed differential SSX protein expression in paraffin-embedded prostate cancer biopsies on tissue microarray by immunohistochemical staining. Interestingly, SSX expression in patient samples was restricted to metastatic prostate cancer lesions (5/22; 23%), while expression in primary prostate tumors was not observed (0/73). Finally, we determined that it is possible to elicit cross-reactive immune responses to a dominant SSX epitope p103–111 shared by the different SSX family members by immunization of A2/DR1 transgenic mice with SSX peptides or a plasmid DNA vaccine encoding SSX2. Overall, these results suggest that multiple SSX family members are expressed in prostate cancer and can be simultaneously targeted using immunotherapeutic vaccines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A66.
Abstract B11: Development and validation of HPV-16 chimeric VLPs and peptide as vaccine candidates against cervical cancer
Authors: Singh Neeta 
Published: June 2012

Abstract
Background: High-risk HPVs such as HPV-16 have been implicated in the pathogenesis of cervical cancer and its premalignant lesions. Prophylactic vaccines derived from the noninfectious protein coat of HPV 16 and 18 are available commercially. However, therapeutic vaccines capable of eliminating HPV-infected cells and clearing HPV-associated tumors are not available. CTLs specific for E6 and E7 act as desirable immune effectors in recognizing and destroying HPV-infected cells and therefore HPV 16, E6, and E7 proteins pose as logical targets for immunotherapy against cervical cancer.
Objective: To develop vaccine strategies which would have both prophylactic and therapeutic potential against HPV16.
Methods: Software predicted synthetic CTL epitope dominant peptide from HPV-16, L1, L2, E6, and E7 region was synthesized (48mer) and its therapeutic vaccine potential evaluated using different adjuvants.
For chimeric VLPs, DNA was isolated from HPV-16-positive cervical cancer, cloning of L1 and E7 was done in appropriate vector, recombinant protein expressed and purified. In vitro assembly of chimeric virus-like particles (CVLPs) done. Immune response to peptide and CVLPs was measured by T cell proliferation assay, cytokine ELISA, cytotoxicity measured using LDH assay, and in vivo tumor induction (using TC-1 cells) and regression analysis done in C57BL/6J mice.
Results: Subcutaneous injection with peptide along with different adjuvants (mycobacterium Mw, alum, PLGA microspheres) enchanced serum IgG levels, showed lymphocyte proliferation, generated peptide-specific CTL-mediated cytotoxic secretion of different cytokines. Regression of tumors on in vivo challenge to TC-1 cells in C57BL6 mice was observed. Among adjuvants, peptide encapsulated in PLGA microspheres showed the best response.
CVLPs showed lymphoproliferative response and CTL generation in vitro against E7 protein and essentially showed Th-1 response. Antitumor efficacy to TC-1 cells induced tumors in C57BL/6 mice was also seen. Seroreactivity of young women with persistent HPV16 infection showed that CVLPs detected neutralizing antibodies against L1 capsid protein. Antibodies against L1 capsid protein were able to inhibit hemaglutination.
Conclusion: The above study has provided a basis for rational design of peptide-based vaccine and protein-based chimeric vaccine for controlling HPV-16 infection and its associated tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B11.
Abstract A112: Postoperative prognostic predictors of pancreatic ductal adenocarcinoma: Clinical analysis and immunoprofile on tissue microarrays
Authors: Park Joo Kyung , Lee Se Hoon , Ryu Ji Kon , Kim Yong-Tae , Yoon Yong Bum , Kim Min A 
Published: June 2012

Abstract
Background: The most of pancreatic ductal adenocarcinomas metastasize even after curative resection. Our goals were to investigate the important factors affecting metastasis and overall survival. Patients and methods: We studied 88 PDACs with R0 resection and evaluated immunohistochemical markers on tissue microarrays to assess the expression levels of the following: EGFR, amphiregulin, VEGF, p-c-met, MMP2, MMP7, MMP9, CXCR3 and CXCR4.
Results: The median OS in patients who had positive vs. negative expression of AREG and MMP9 were 25 vs. 16mo and 24 vs. 13mo respectively (p=0.03, p=0.006). However, the median OS in patients with positive vs. negative expression of MMP2 was 22 vs. 37mo (p=0.04). Adjuvant treatment, postoperative decrement of CA 19–9, angiolymphatic invasion, AREG and MMP2 were independent prognostic factors affecting OS in multivariate analysis. Immunoprofiles revealed that patients with positive expression of p-c-met or VEGF had significantly shorter distant metastasis free survival.
Conclusions: Immunoprofiles revealed the groups with unfavorable tumor biology: negative expression of AREG and positive expression of MMP2. Also, high immunoreactivity of p-c-met or VEGF can be considered as indicators of early distant organ metastasis. These results may give us useful insights in choosing adjuvant treatment modalities and understanding the patterns of PDAC dissemination.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A112.
Abstract A29: The TMPRSS2:ERG gene fusion, ERG expression and prostate cancer outcomes: A cohort study and meta-analysis
Authors: Graff Rebecca E. , Ligon Azra H. , Suppan Catherine , Flavin Richard , Sesso Howard D. , Rider Jennifer R. , Sweeney Christopher , Stampfer Meir , Fiorentino Michelangelo , Kantoff Philip W. , Sanda Martin , Pettersson Andreas , Giovannucci Edward , Ding Eric L. , Loda Massimo , Mucci Lorelei A. , Bauer Scott R. , Pitt Michael , Lis Rosina T. , Stack Edward C. , Martin Neil E. , Kunz Lauren , Penney Kathryn 
Published: June 2012

Abstract
Background: The TMPRSS2:ERG gene fusion is a common genomic abnormality in prostate cancer that has been studied as a possible biomarker of prognosis.
Methods: We undertook a prospective cohort study and meta-analysis to evaluate whether TMPRSS2:ERG is associated with more aggressive prostate cancers. The cohort consisted of 1,052 men with prostate cancer treated by radical prostatectomy between 1982 and 2005 nested within the Physicians' Health Study and Health Professionals Follow-Up Study. We identified presence of the fusion by immunohistochemical assessment of ERG protein expression. We used Cox proportional hazards models for associations of the fusion with biochemical recurrence and lethal prostate cancer. The meta-analysis included 6,448 subjects with prostate cancer from 43 studies (including our cohort) published since 2005. Studies characterized presence of the fusion by fluorescence in situ hybridization, polymerase chain reaction, or immunohistochemistry.
Results: During a median follow-up of 12.5 years, 245 men in the cohort experienced biochemical recurrence, and 95 developed lethal disease (distant metastases or cancer-specific mortality). Men whose tumors harbored the fusion were more likely to be diagnosed at a higher stage (p=0.02). There was no association, however, between the fusion and Gleason score (Gleason 8–10 vs. 2–6; p=0.45), biochemical recurrence (HR: 0.93; 95% CI: 0.72–1.20), and lethal disease (HR: 0.81; 95% CI: 0.54–1.22). For men treated with radical prostatectomy, the meta-analysis yielded similar results. Fusion status was associated with higher stage at diagnosis (RR: 1.19; 95% CI: 1.11–1.28), but not with Gleason score (RR: 0.91; 95% CI: 0.76–1.10), biochemical recurrence (RR: 1.01; 95% CI: 0.84–1.22) or lethal disease (RR: 0.93; 95% CI: 0.44–1.99).
Conclusions: The results suggest that TMPRSS2:ERG fusion status and ERG expression are associated with higher stage at diagnosis but are not strong predictors of Gleason score, biochemical recurrence or cancer-specific death among men with prostate cancer treated with radical prostatectomy.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A29.
Abstract A3: Premenopausal serum androgens and breast cancer risk: A nested case-control study
Authors: Zeleniuch-Jacquotte Anne , Koenig Karen L. , Afanasyeva Yelena , Kaaks Rudolf , Rinaldi Sabina , Scarmo Stephanie , Liu Mengling , Arslan Alan A. , Toniolo Paolo , Shore Roy E. 
Published: June 2012

Abstract
Introduction: Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited.
Methods: A case-control study nested within a prospective cohort, the NYU Women's Health Study, was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls (1:2 matching) were included. Matching variables included age and date of blood donation, as well as phase and day of menstrual cycle. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were measured using direct radioimmunoassays. Free testosterone was calculated. Samples from a second blood donation at a median of 2 years after the first blood donation were also analyzed for 138 cases and 268 controls.
Results: Premenopausal serum testosterone and free testosterone concentrations were positively associated with subsequent breast cancer risk. In models adjusted for known risk factors of breast cancer (BMI, age at menarche, family history of breast cancer, parity/age at first birth, and history of breast biopsy), the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9–2.3), 1.2 (95% CI, 0.7–1.9), 1.4 (95% CI, 0.9–2.3) and 1.8 (95% CI, 1.1–2.9) with the P value for trend of 0.04, and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7–1.8), 1.5 (95% CI, 0.9–2.3), 1.5 (95% CI, 0.9–2.3), and 1.8 (95% CI, 1.1–2.8) with a P value for trend of 0.01). A marginally significant positive association was observed with androstenedione (p = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients (ICCs) for measurements of serial annual blood donations from the same individual were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls).
Conclusions: Premenopausal concentrations of testosterone and free testosterone are positively associated with breast cancer risk. Results from other prospective studies are consistent with our results. Testosterone and free testosterone are also highly reliable (i.e. a single measurement is reflective of a woman's average level over time). Future studies should examine the contribution of including testosterone and free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A3.