bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4032: Targeting the isoprenoid biosynthetic pathway in a murine model of metastatic prostate cancer
Authors: Reilly Jacqueline E. , Neighbors Jeffrey D. , Bannick Nadine , Henry Michael D. , Kuder Craig H. , Hohl Raymond J. 
Published: May 2015

Abstract
The isoprenoid biosynthetic pathway (IBP) provides substrates for the post-translational modification of key proteins in regulating malignant cell properties, including proliferation, migration, and invasion. Several studies have found broad inhibitors of the IBP, such as statins, to significantly reduce the risk of advanced prostate cancer (PCa), potentially through their induced-reduction of geranylgeranylated proteins. However, such inhibition of the entire IBP is limited by side effects resulting from depletion of all isoprenoids and their products. We have developed a novel compound, geranylgeraniol bisphosphonate (GGOHBP), selectively targeting geranylgeranyl diphosphate synthase (GGDPS) and reducing the post-translational modification of geranylgeranylated proteins. Luciferase-expressing human-derived 22Rv1 PCa cells were injected into the left ventricle of 20 mice using bioluminescence imaging (BLI) to visualize tumor development. After three weeks 18/20 mice had developed tumors and daily subcutaneous (SQ) injections of 1.5mg/kg GGOHBP were given for one month. All 18 mice developed mandible tumors, 13 developed adrenal gland tumors, 4 developed intestinal tumors, 2 developed femoral tumors, 2 developed liver tumors, and 1 developed a tumor in an unidentified location in the chest cavity. Ex vivo photon count analyses revealed an 80% (p=0.1458) reduction in adrenal gland tumors of the treated mice as compared to vehicle-treated controls. This corresponded to a 54% (p=0.0007) reduction in total adrenal gland tumor weight in the treated as compared to the control mice. Western blot analysis of the adrenal gland tumors and one intestinal tumor showed a reduction in Rap1A geranylgeranylation in the treated mice and not the control mice, while non-tumorous tissues showed no Rap1A alteration. A follow-up study of non-tumor bearing mice given SQ injections of 1.25 or 1.5 mg/kg GGOHBP daily did not reveal alterations in Rap1A geranylgeranylation in the adrenal glands, kidneys, liver, or heart. Our findings detail a novel compound capable of preferentially altering the IBP in the adrenal gland tumors of a murine model of metastatic PCa. Future work defining the mechanism behind this focal effect and the adrenal gland isoprenoid environment will allow compound optimization and further understanding of the IBP's role in PCa metastasis.
Citation Format: Jacqueline E. Reilly, Jeffrey D. Neighbors, Nadine Bannick, Michael D. Henry, Craig H. Kuder, Raymond J. Hohl. Targeting the isoprenoid biosynthetic pathway in a murine model of metastatic prostate 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 4032. doi:10.1158/1538-7445.AM2014-4032
Abstract 4074: Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation
Authors: Kim Hyemin , Kim Yejin , Choi Jiwon , Jang Mirim , Choi Jiyea , Hwang Young-il , Kang Jae Seung , Lee Wang Jae 
Published: May 2015

Abstract
It is recently reported that CD40-CD40 ligand (CD40L) interaction is important to Th17 development. Also, it is known that transforming growth factor-beta (TGF-β) promotes tumorigenesis as an immunosuppressive cytokine and is crucial for the development of Th17. In this study, we investigated the role of CD40 on breast cancer cells and its role on the immune suppressive function and tumor progression. CD40 stimulation on breast cancer cell line, MDA-MB231, caused up-regulation of TGF-β, and direct CD40-CD40L interaction between breast cancer cells and activated T cells increased TFG-β production. Moreover, direct interaction of CD40-CD40L induced the production of IL-17, which increased the proliferation of MDA-MB231 cells via the activation of STAT3. Therefore, direct CD40-CD40L interaction of breast tumor and activated T cells increases the TGF-β production and the differentiation of Th17 cells, which promote the proliferation of breast cancer cells.
Citation Format: Hyemin Kim, Yejin Kim, Jiwon Choi, Mirim Jang, Jiyea Choi, Young-il Hwang, Jae Seung Kang, Wang Jae Lee. Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation. [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 4074. doi:10.1158/1538-7445.AM2014-4074
Abstract 4075: LAG3 and PD1 co-inhibitory molecules directly interact to limit CD8+ T cell signaling
Authors: Huang Ruea-Yea , Eppolito Cheryl , Fadiel Ahmed , Hamza Adel , Lele Shashikant , Mastuzaki Junko , Odunsi Kunle 
Published: May 2015

Abstract
Increasing evidence indicate that dual blockade of Lymphocyte Activation Gene-3 (LAG3) and programmed cell death 1 (PD1) synergistically enhances autoimmunity and anti-tumor immunity. Despite the fact that these co-inhibitory receptors individually attenuate T cell receptor signaling, it is not clear whether they interact at the physical, biochemical and/or molecular levels, to regulate the functional fate of T cells. To answer these questions, we first simulated possible direct interaction of LAG3 and PD1 using in-silico molecular docking techniques. Using confocal microscopy and ImageStream analyses, we demonstrated that LAG3 and PD1 molecules co-localized in a subset of activated murine CD8+ T cells. The co-localization occurred at the trans-Golgi vesicles, early/recycling endosomal compartments, lysosomes, and microtubule organizing center (MTOC). Importantly, LAG3 and PD1 cluster with pLck at the immunological synapse of CD8+ T cell and dendritic cell conjugates. Reciprocal immunoprecipitation of the T cell extracts with specific antibodies for LAG3 and PD1 revealed a physical association between LAG3 and PD1 and this interaction was absent in T cells isolated from LAG3 and PD1 knockout mice. Finally, LAG3 protein was also associated with Src family tyrosine phosphatase-2 (SHP2) that is recruited by PD1 during T cell signaling. The recruitment of phosphatases is additively reduced in CD8+ T cells deficient in both LAG3 and PD1. Taken together, our data suggest that LAG3 interacts and collaborates with PD1, following T cell activation, for rapid translocation from early/recycling endosomal compartments to the immunological synapse, leading to a synergistic inhibitory effect on T cell signaling.
Citation Format: Ruea-Yea Huang, Cheryl Eppolito, Ahmed Fadiel, Adel Hamza, Shashikant Lele, Junko Mastuzaki, Kunle Odunsi. LAG3 and PD1 co-inhibitory molecules directly interact to limit CD8+ T cell signaling. [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 4075. doi:10.1158/1538-7445.AM2014-4075
Abstract 4078: EZH2 marks polyfunctional memory T cells and controls tumor immunity
Authors: Zhao Ende , Maj Tomasz , Kryczek Ilona , Zhao Lili , Wei Shuang , Wan Shanshan , Crespo Joel , Szeliga Wojciech , Vatan Linda , Wu Ke , Chinnaiyan Arul M. , Welling Theodore H. , Marquez Victor E. , Kotarski Jan , Zhang Yi , Liu Rebecca , Tao Kaixiong , Wang Guobin , Zou Weiping 
Published: May 2015

Abstract
Polyfunctional T cells mediate potent anti-viral immunity. However, the nature and molecular mechanisms controlling their functional signature remain poorly understood. Here we report that polyfunctional T cells are characterized by high proliferative capacity and apoptotic resistance. Enhancer of zeste homolog 2 (EZH2) phenotypically marks them and functionally controls their survival and expansion. Notch signaling regulates effector T cell function. We show that EZH2 represses Numb and Fbxw7, two Notch repressors, activates Notch signaling, and Notch subsequently stimulates Bcl-2 expression and protects EZH2+ T cells from apoptosis via trimethylating histone H3 on lysine 27. Moreover, EZH2 targets T cell cycling repressors and promotes their expansion. EZH2+CD8+ T cells mediate anti-tumor immunity and are associated with improved long-term cancer survival. Together, the data reveal a novel role and mechanism for EZH2 in controlling polyfunctional T cells. Thus, manipulation of EZH2 signaling in T cells may have therapeutic potential in treating cancer patients.
Citation Format: Ende Zhao, Tomasz Maj, Ilona Kryczek, Lili Zhao, Shuang Wei, Shanshan Wan, Joel Crespo, Wojciech Szeliga, Linda Vatan, Ke Wu, Arul M. Chinnaiyan, Theodore H. Welling, Victor E. Marquez, Jan Kotarski, Yi Zhang, Rebecca Liu, Kaixiong Tao, Guobin Wang, Weiping Zou. EZH2 marks polyfunctional memory T cells and controls tumor immunity. [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 4078. doi:10.1158/1538-7445.AM2014-4078
Abstract 41: 47 kda CXCR4: A marker for highly invasive neuroblastoma
Authors: Shankar Vipin , Qi Lei , Kihira Kentaro , Komada Yoshihiro , Hori Hiroki 
Published: May 2015

Abstract
Neuroblastoma; a pediatric cancer of the sympathetic nervous system, which accounts for 15% of childhood cancer deaths, presents with metastatic disease of the bone and the bone marrow at diagnosis in 70% of the cases. Although studies have shown that the CXCL12 chemokine receptor CXCR4 mediates the process of metastasis in many cancer types, its role in the bone marrow metastasis of neuroblastoma is unclear. In an effort to better understand the role of the CXCR4- CXCL12 axis in bone marrow metastasis of neuroblsatoma, we screened 20 neuroblastoma cell lines for their invasive potential, and expression of CXCR4, and sought to identify a correlation between tumor invasiveness and CXCR4 expression. Western blot analyses of cell lysates revealed the presence of multiple CXCR4 isoforms with 3 prominent species at about 35 kda, 47 kda and 62 kda. Cell lines expressing the 47 kda isoform showed higher secretion of MMP9 in gelatin zymography and higher migration and invasion towards mesenchymal stem cells (MSCs) and MSC-conditioned-RPMI, in transwell migration/invasion studies. Far western blot analysis with immuno-precipitated CXCR4, showed that the 47kda protein bound with CXCL12 at a higher rate. Blocking CXCR4 with AMD3100 or a neutralizing antibody against the 47 Kda isoform decreased the secretion of MMP9, the expression of integrin α3 and integrin β1 and the invasive potential of the cell. These data suggest that the 47 kda CXCR4 plays a prominent role in the bone marrow metastasis of neuroblastoma and could possibly be used as a diagnostic marker for highly invasive neuroblastoma and the development of minimal residual disease.
Citation Format: Vipin Shankar, Lei Qi, Kentaro Kihira, Yoshihiro Komada, Hiroki Hori. 47 kda CXCR4: A marker for highly invasive neuroblastoma. [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 41. doi:10.1158/1538-7445.AM2014-41
Abstract 4103: Biomarkers of thyroid function and autoimmunity associated with thyroid cancer risk: A nested case-control study
Authors: Kim Jeongseon , Cho Young Ae , Shin Aesun , Lee Jeonghee , Kong Sun-Young , Lee Eun Kyung , Lee You Jin 
Published: May 2015

Abstract
Background & Objective: The incidence of thyroid cancer has been increased in several countries. However, the markers to predict for high-risk group have not been fully established. We aim to investigate the potential association between the biomarkers of thyroid function/autoimmunity and the risk of thyroid cancer in Korean population, where the incidence rate of thyroid cancer is one of the highest in the world.
Design: This study was a nested case-control study within the Cancer Screenee Cohort study, which consisted of 257 incident thyroid cancer patients who were ascertained during mean of 2.2 years of follow-up and 257 controls. Total triidothyronine (TT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and thyroglobulin (Tg), and two markers of thyroid autoimmunity (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb] antibodies) were measured. Logistic regression models were used to examine the association between these biomarkers and thyroid cancer risk. Stratified analyses were conducted by sex, BMI, and smoking status.
Results: When the markers were categories by tertile distribution of the levels of controls group, highest tertile of FT4 (OR [95% CI] = 1.73[1.11, 2.69]) and middle tertile of TSH (OR [95% CI] = 1.77[1.14, 2.74]) were associated with thyroid cancer risk in multivariate analyses. In addition, normal (30-60 U/mL) (OR [95% CI] = 8.47 [5.39, 13.33]) or elevated levels (60 &gt; U/mL) (OR [95% CI] = 4.48 [2.59, 7.76]) of TPOAb showed an elevated risk for thyroid cancer. Stratified analyses implied that some of these associations could be differed by sex, BMI, or smoking status.
Conclusions: This study represented that the levels of biomarkers of thyroid function/autoimmunity, particularly the presence of TPOAb, may be used as diagnostic adjuncts for predicting thyroid cancer risk.
Citation Format: Jeongseon Kim, Young Ae Cho, Aesun Shin, Jeonghee Lee, Sun-Young Kong, Eun Kyung Lee, You Jin Lee. Biomarkers of thyroid function and autoimmunity associated with thyroid cancer risk: A nested case-control 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 4103. doi:10.1158/1538-7445.AM2014-4103
Abstract 4107: Efficient delivery of dietary compound modulates mcp-1 in murine prostate cancer cells
Authors: Mishra Manoj K. , Stokes James A. , Salaam Amanee , Nyairo Elijah , Singh Udai , Dean Derrick 
Published: May 2015

Abstract
Monocyte chemo-attractant protein (MCP-1) is a chemokine, which recruits monocytes, neutrophils, and lymphocytes in response to trauma and proinflammatory cytokines such as TNF-α. MCP-1 generally is not expressed in healthy individuals, but in response to various stressful stimuli it gets up-regulated, which in turn contributes to increased inflammation. MCP-1 has been implicated in mediating apoptosis by producing a proapoptotic protein designated MCP-induced protein (MCPIP). Resveratrol (RES), a polyphenolic compound found in the skin of red fruits, exhibits anti-inflammatory, anti-oxidative, anti-cancer, and anti-proliferative characteristics. In this study, we hypothesized that the functionalization of RES with detonated nano-diamond (DND, hereafter called fDND) will enhance the effective delivery of RES to tumor cell and impact the modulation of molecular mechanisms in murine prostate cancer (PCa) cells. This hypothesis was tested on mouse PCa cell lines, derived from transgenic adenocarcinoma of mouse prostate (TRAMP), in C57/B6 mice. Interestingly, TRAMP-C1 and TRAMP-C2 form tumor while TRAMP-C3 fails to develop tumor. TRAMP cells were treated with different concentrations of fDND at different time points and analyzed for underlying cellular and molecular mechanisms such as cell viability/proliferation, mitochondrial membrane potential, cytokines and growth factors production. The initial results indicate that the fDND significantly induce molecular signatures in TRAMP-C3 cells in comparison with TRAMPC1 and C2. Interestingly, the level of MCP-1 was significant elevated in TRAMP C1 and C2 cells. Thus, suggesting a major role of MCP-1 in the regulation of cancer progression and clearance. This data also suggest that the functionality of dietary compounds can be enhanced by conjugating or functionalizing them with DND, which can be used as a therapeutic carrier.
Citation Format: Manoj K. Mishra, James A. Stokes, Amanee Salaam, Elijah Nyairo, Udai Singh, Derrick Dean. Efficient delivery of dietary compound modulates mcp-1 in murine prostate cancer cells. [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 4107. doi:10.1158/1538-7445.AM2014-4107
Abstract 4124: Ovarian cancer survival by tumor subtype
Authors: Poole Elizabeth M. , Cramer Daniel W. , Vitonis Allison F. , Terry Kathryn L. 
Published: May 2015

Abstract
Introduction: Epithelial ovarian cancer is heterogeneous, with subgroups defined by cell of origin (ovary vs. fallopian tube), histology, and carcinogenic pathway (the etiologic pathway through which tumors arise: type I tumors develop on the ovarian surface and are low grade serous or mucinous histology; type II tumors develop through endometriotic implantation and are clear cell or endometrioid histology; type III tumors originate in the fallopian tube and are high grade serous histology). Although differences in associations have been observed with risk of incident ovarian cancer, few studies have examined differences in survival by subtype. In the New England Case-Control Study of ovarian cancer (NECC), we examined differences in survival by tumor dominance (a surrogate for cell of origin), histology, and carcinogenic pathway.
Methods: Among 2076 women with epithelial ovarian cancer (1991-2008), 892 deaths were observed. Cox proportional hazards regression was used to calculate hazards ratios (HRs) and 95% confidence intervals (95% CI) for the association of ovarian cancer subtype with overall survival, adjusting for age at diagnosis, study phase, year of diagnosis (as a proxy for treatment), BMI, and smoking status.
Results: Serous invasive tumors were more likely to be non-dominant (likely fallopian origin) and type III. Compared to serous invasive tumors, all other tumor histologies had statistically significantly improved survival. Similarly, dominant tumors (i.e., likely ovarian origin) had greater survival than non-dominant tumors (HR: 0.38; 95% CI: 0.31-0.47). Type I (mucinous and low grade serous) and type II (endometrioid and clear cell) tumors had better survival than type III (high grade serous) tumors (HR: 0.21; 95%CI: 0.16-0.28 and HR: 0.23; 95% CI: 0.18-0.29, respectively).
Conclusion: Regardless of how subtype was defined, high grade, invasive serous tumors had worse survival compared to other tumor subtypes. This underscores the need for prevention and treatment targeted at these aggressive tumors.
Table.Associations between tumor subtype and overall survivalSubtypeDeaths/CasesMedian Survival (years)HR (95% CI)HistologySerous invasive654/9683.21.00 (ref.)Serous borderline25/25010.10.35 (0.18-0.67)Mucinous36/2427.10.38 (0.25-0.58)Endometrioid68/3314.70.28 (0.21-0.37)Clear cell29/1163.40.30 (0.21-0.44)DominanceNon-dominant268/3853.31.00 (ref.)Dominant162/6034.00.38 (0.31-0.47)PathwayType III596/8563.21.00 (ref.)Type II97/4474.00.23 (0.18-0.29)Type I60/2915.70.21 (0.16-0.28)
Citation Format: Elizabeth M. Poole, Daniel W. Cramer, Allison F. Vitonis, Kathryn L. Terry. Ovarian cancer survival by tumor subtype. [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 4124. doi:10.1158/1538-7445.AM2014-4124
Abstract 4136: Comparison of overall survival of Chronic Lymphocytic Leukemia (CLL) patients referred or not referred to a specialized CLL clinic: A Canadian population-based study
Authors: Beiggi Sara , Banerji Versha , Deneka Angela , Griffith Jane , Gibson Spencer , Johnston James 
Published: May 2015

Abstract
Chronic Lymphocytic Leukemia (CLL) patients in Manitoba are either referred to the CancerCare Manitoba (CCMB) CLL clinic or receive care from other hematologists/general practitioners. However, it is unknown whether referral to the CLL-specialized clinic alters patients' outcome.
All CLL/SLL diagnoses in Manitoba 2007-2011 were obtained from the Manitoba Cancer Registry to create an immunophenotipically confirmed population-based cohort. Referred patients to the CLL-specialized clinic were identified from the CCMB charts. Association between age and treatment was measured by chi-squared test. Hazard ratio (HR) was determined using Cox Proportional Hazard Regression model.
Of 555 CLL/SLL diagnoses, 281 (51%) were referred to the CLL-specialized clinic. For referred and non-referred patients the median age was 68y (39-99) and 72y (45-96), treated patients were 77 (27%) and 31 (11%), time to first treatment was 5m (0-5.5y) and 3m (0-2.5y), respectively. M:F was 1.7:1 for both groups. CLL was the primary cause of death in both referred and non-referred patients (57% and 35%, respectively). Comorbidities such as cardiovascular diseases had equal contributions to mortality in both populations (7% and 9.5% in referred and non-referred patients, respectively). When patients older than 70 years were investigated, elderly patients that were referred to the clinic were more likely to receive treatment (p = 0.0002).
When adjusted for age (≥80y HR 10.79, p: &gt;0.0001; 71-79y HR 5.44, p: 0.0007; 62-70y HR 4.07, p: 0.0051; &lt;62 HR 1.00), gender (male HR 1.61, p: 0.0414), pre-CLL cancer (HR 1.85, p: 0.0187) and post-CLL Cancer (HR 2.31 p: 0.0208), patients seen by CLL-specialists had a &gt;2-fold increased OS compared to non-referred patients (HR 2.39, p: 0.0003) in the Manitoba population. In the non-referred population, there was a striking correlation between advancing age and decreasing OS. This correlation was almost eliminated in the referred population.
Thus, patients seen in a specialized clinic have an improved survival compared to non-referred patients and this appears to be primarily related to improved OS in the elderly. Whether this observation is related to improved therapy/supportive care in the specialized clinic or to referral bias is under investigation.
Citation Format: Sara Beiggi, Versha Banerji, Angela Deneka, Jane Griffith, Spencer Gibson, James Johnston. Comparison of overall survival of Chronic Lymphocytic Leukemia (CLL) patients referred or not referred to a specialized CLL clinic: A Canadian population-based 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 4136. doi:10.1158/1538-7445.AM2014-4136