Array-Comparative Genomic Hybridization Reveals Loss of SOCS6 Is Associated with Poor Prognosis in Primary Lung Squamous Cell Carcinoma

BACKGROUND: Primary tumor recurrence commonly occurs after surgical resection of lung squamous cell carcinoma (SCC). Little is known about the genes driving SCC recurrence. METHODS: We used array comparative genomic hybridization (aCGH) to identify genes affected by copy number alterations that may be involved in SCC recurrence. Training and test sets of resected primary lung SCC were assembled. aCGH was used to determine genomic copy number in a training set of 62 primary lung SCCs (28 with recurrence and 34 with no evidence of recurrence) and the altered copy number of candidate genes was confirmed by quantitative PCR (qPCR). An independent test set of 72 primary lung SCCs (20 with recurrence and 52 with no evidence of recurrence) was used for biological validation. mRNA expression of candidate genes was studied using qRT-PCR. Candidate gene promoter methylation was evaluated using methylation microarrays and Sequenom EpiTYPER analysis. RESULTS: 18q22.3 loss was identified by aCGH as being significantly associated with recurrence (p = 0.038). Seven genes within 18q22.3 had aCGH copy number loss associated with recurrence but only SOCS6 copy number was both technically replicated by qPCR and biologically validated in the test set. SOCS6 copy number loss correlated with reduced mRNA expression in the study samples and in the samples with copy number loss, there was a trend for increased methylation, albeit non-significant. Overall survival was significantly poorer in patients with SOCS6 loss compared to patients without SOCS6 loss in both the training (30 vs. 43 months, p = 0.023) and test set (27 vs. 43 months, p = 0.010). CONCLUSION: Reduced copy number and mRNA expression of SOCS6 are associated with disease recurrence in primary lung SCC and may be useful prognostic biomarkers

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

EphA2 as a Glioma-Associated Antigen: A Novel Target for Glioma Vaccines

EphA2 is a receptor tyrosine kinase and is frequently overexpressed in a wide array of advanced cancers. We demonstrate in the current study that the EphA2 protein is restrictedly expressed in primary glioblastoma multiforme and anaplastic astrocytoma tissues in comparison to normal brain tissues. To evaluate the possibility of targeting EphA2 in glioma vaccine strategies, we stimulated human leukocyte antigen (HLA) A2(+) peripheral blood mononuclear cells (PBMCs) obtained from healthy donors and glioma patients with autologous dendritic cells (DCs) loaded with synthetic EphA2(883–891) peptide (TLADFDPRV), which has previously been reported to induce interferon-γ in HLA-A2(+) PBMCs. Stimulated PBMCs demonstrated antigen-specific cytotoxic T lymphocyte (CTL) responses as detected by specific lysis of T2 cells loaded with the EphA2(883) peptide as well as HLA-A2(+) glioma cells, SNB19 and U251, that express EphA2. Furthermore, in vivo immunization of HLA-A2 transgenic HHD mice with the EphA2(883–891) peptide resulted in the development of an epitope-specific CTL response in splenocytes, despite the fact that EphA2(883–891) is an autoantigen in these mice. Taken together, these data suggest that EphA2(883–891) may be an attractive antigen epitope for molecularly targeted glioma vaccines

Monitoring Programs of the U.S. Gulf of Mexico: Inventory, Development and Use of a Large Monitoring Database to Map Fish and Invertebrate Spatial Distributions

Since the onset of fisheries science, monitoring programs have been implemented to support stock assessments and fisheries management. Here, we take inventory of the monitoring programs of the U.S. Gulf of Mexico (GOM) surveying fish and invertebrates and conduct a gap analysis of these programs. We also compile a large monitoring database encompassing much of the monitoring data collected in the U.S. GOM using random sampling schemes and employ this database to fit statistical models to then map the spatial distributions of 61 fish and invertebrate functional groups, species and life stages of the U.S. GOM. Finally, we provide recommendations for improving current monitoring programs and designing new programs, and guidance for more comprehensive use and sharing of monitoring data, with the ultimate goal of enhancing the inputs provided to stock assessments and ecosystem-based fisheries management (EBFM) projects in the U.S. GOM. Our inventory revealed that 73 fisheries-independent and fisheries-dependent programs have been conducted in the U.S. GOM, most of which (85%) are still active. One distinctive feature of monitoring programs of the U.S. GOM is that they include many fisheries-independent surveys conducted almost year-round, contrasting with most other marine regions. A major sampling recommendation is the development of a coordinated strategy for collecting diet information by existing U.S. GOM monitoring programs for advancing EBFM

Outras famílias: a construção social da conjugalidade homossexual no Brasil Different families: the social construction of homosexual conjugality in Brazil

Este artigo propõe uma reflexão sobre a construção social da conjugalidade homossexual no Brasil contemporâneo, especialmente no âmbito do Poder Legislativo, espaço privilegiado de discussão acerca do projeto de lei que institui a parceria civil entre pessoas do mesmo sexo. A análise dos elementos estruturantes nos embates ideológicos decorrentes das disputas em torno do reconhecimento social e jurídico das uniões homossexuais como entidades familiares, também é perpassada por discursos originários da Igreja Católica e de representantes da população homossexual.<br>This article presents some reflections on the social construction of homosexual conjugality in contemporary Brazil, particularly concerning the Legislative sphere - where most of the debate on the law project for civil partnership between people of the same sex has taken place. The main objective is to analyze the structuring elements of the ideological struggles stemming from the disputes around the social and juridical recognition of homosexual unions as familial entities. The discourses that come from the Catholic Church and those of homosexual representatives are also given priority in the analysis