Predictive biomarkers for checkpoint inhibitor-based immunotherapy: The Galectin-3 signature in NSCLCs

Checkpoint inhibitor-based immunotherapy is opening a promising scenario in oncology, with objective responses registered in multiple cancer types. However, reliable predictive markers of tumor responsiveness are still lacking. These markers need to be urgently identified for a better selection of patients that can be candidates for immunotherapy. In this pilot study, a cohort of 34 consecutive patients bearing programmed death-ligand 1 (PD-L1)-positive non-small cell lung carcinoma (NSCLC), treated with pembrolizumab, was considered. The retrospective immuno-phenotypic analysis performed on the original tumor biopsies allowed for the identification of a specific “galectin signature”, which strongly correlated with tumor responsiveness to anti PD-1 immunotherapy. We observed that the large majority of patients (about 90%) with high galectin-3 tumor expression (score 3+) showed an early and dramatic progression of the disease after three cycles of treatments. In contrast, all patients with negative or low/intermediate expression of galectin-3 in tumor cells showed an early and durable objective response to pembrolizumab, indicating galectin-3 as an interesting predictive marker of tumor responsiveness. The galectin-3 signature, at least in NSCLCs, promises a better selection of patient candidates for immunotherapy, reducing unnecessary treatment exposures and social costs. A large multicenter study is ongoing to validate this finding

GMO Guidelines project.

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Diagnostic delay does not influence survival of pancreatic cancer patients

Background: Most pancreatic ductal adenocarcinoma patients present with advanced disease. Whether it is possible to increase survival by earlier diagnosis is unclear. Objective: The purpose of this study was to investigate the association between presenting complaints and risk factors for pancreatic cancer with diagnostic delay, stage and survival. Methods: This was a single-centre retrospective cohort study. Consecutive patients were interviewed and data on demographics, medical history, risk factors and complaints leading to pancreatic ductal adenocarcinoma diagnosis and disease stage were recorded. Diagnostic delay was considered as time between first complaint and diagnosis. Patients received appropriate treatments and their outcome was recorded in a dedicated database. The Chi-square test for comparison of categorical variables and the Mann–Whitney test for continuous variables were employed with Bonferroni corrections. Correlation between continuous variables was evaluated by means of the Spearman correlation coefficient. Survival analysis was performed with the Kaplan–Meier method and a log-rank test. Results: The median diagnostic delay for 477 pancreatic ductal adenocarcinoma patients was two months (interquartile range 1–5), being significantly shorter for patients presenting with jaundice compared with those with pain, weight loss, diabetes (p < 0.001). The global rate of metastatic disease at diagnosis was 40%, being only 22% in those presenting with jaundice. The median diagnostic delay, however, was not significantly different among disease stages but was significantly longer in patients with a body mass index>25 kg/m2. The median survival time was seven months. Factors associated with worse survival at the multivariable analysis were older age (hazard ratio 1.02 per year), metastatic disease (hazard ratio 2.12) and pain as presenting complaint (hazard ratio 1.32), while diagnostic delay was not. Conclusion: While some complaints are associated with a shorter diagnostic delay and less advanced disease stage, we could not demonstrate that delay is associated with survival, possibly suggesting that prevention rather than early recognition is important to tackle pancreatic cancer lethality

A novel BRCA2 splice variant identified in a young woman

Background: BRCA1/2 VUSs represent an important clinical issue in risk assessment for the breast/ovarian cancer families (HBOC) families. Among them, some occurring within the intron-exon boundary may lead to aberrant splicing process by altering or creating de novo splicing regulatory elements or unmasking cryptic splice site. Defining the impact of these potential splice variants at functional level is important to establish their pathogenic role. Methods: Genomic DNA was extracted from peripheral blood sample of a young woman affected with breast cancer belonging to a HBOC family and the entire coding regions of the BRCA1 and BRCA2 genes were amplified using the Ion AmpliSeq BRCA1 and BRCA2 Panel. The BRCA2 c.682-2delA variant has been characterized by RT-PCR analysis performed on mRNA extracted from blood and lymphoblastoid cell line. Results: We demonstrated that a novel BRCA2 c.682-2delA variant at the highly conserved splice consensus site in intron 8 disrupts the canonical splice acceptor site generating a truncated protein as predicted by several bioinformatics tools. Segregations analysis in the family and LOH performed on proband breast cancer tissue further confirmed its classification as pathogenic variant. Conclusion: Combining different methodologies, we characterized this new BRCA2 variant and provided findings of clinical utility for its classification as pathogenic variant

Inhibition of HIV-1 replication by small interfering RNAs directed against Glioma Pathogenesis Related Protein (GliPR) expression

Background: Previously, we showed that glioma pathogenesis related protein (GliPR) is induced in CEM T cells upon HIV-1 infection in vitro. To examine whether GliPR plays a role as HIV dependency factor (HDF), we tested the effect of GliPR suppression by siRNA on HIV-1 replication. Results: Induction of GliPR expression by HIV-1 was confirmed in P4-CCR5 cells. When GliPR was suppressed by siRNA, HIV-1 replication was significantly reduced as measured by HIV-1 transcript levels, HIV-1 p24 protein levels, and HIV-1 LTR-driven reporter gene expression, suggesting that GliPR is a cellular co-factor of HIV-1. Microarray analysis of uninfected HeLa cells following knockdown of GliPR revealed, among a multitude of gene expression alterations, a down-regulation of syndecan-1, syndecan-2, protein kinase C alpha (PRKCA), the catalytic subunit beta of cAMP-dependent protein kinase (PRKACB), nuclear receptor co-activator 3 (NCOA3), and cell surface protein CD59 (protectin), all genes having relevance for HIV-1 pathology. Conclusions: The up-regulation of GliPR by HIV-1 and the early significant inhibition of HIV-1 replication mediated by knockdown of GliPR reveal GliPR as an important HIV-1 dependency factor (HDF), which may be exploited for HIV-1 inhibition

Avaliação ambiental integrada para licenciamento de operação de áreas de pesquisa (Loap) com plantas geneticamente modificadas: estudo de caso do mamão geneticamente modificado para resistência ao vírus da mancha anelar.

O Brasil possui oportunidades, competência, infra-estrutura institucional e legislação que permitem desenvolver a biotecnologia agropecuária com satisfatórias condições de biossegurança. A incorporação de construções genéticas para resistência a pragas e doenças, adaptação de variedades a condições ambientais adversas, com acréscimo de valor nutricional ou inclusão de características de valor farmacêutico, podem consolidar a posição do país na produção de grãos, fibras e oleaginosas de maior valor agregado. Ao lado dos estudos de segurança alimentar, são necessárias respostas que garantam a segurança de produtos geneticamente modificados para o meio ambiente. Para tanto, métodos científicos devem ser utilizados na construção de cenários que possibilitem determinar o alcance dos efeitos ambientais de organismos geneticamente modificados, com potencial de causar impacto ambiental negativo, antes mesmo que sejam realizados testes de campo. O estudo destas possíveis influências pode ser realizado empregando-se avaliações de impactos ambientais (AIAs), que definem-se como procedimentos para a previsão, a análise e a seleção de tecnologias, projetos e políticas de desenvolvimento, que minimizem alterações negativas da qualidade ambiental.bitstream/CNPMA/5663/1/boletim_30.pd

Acima dos confrontos sobre os transgênicos: uma experiência piloto de consulta pública.

RESUMO: A tecnologia do DNA recombinante abriu, juntamente com um horizonte ilimitado de possibilidades de inovações, polêmicas que não podem ser ignoradas ou resolvidas por meio de uma difusão linear de informações. Ações multidisciplinares e multi-institucionais têm sido implementadas, com sucesso, em diversos países, para estabelecer novas formas de comunicação entre peritos e leigos. Isso permite identificar possíveis restrições e benefícios nas trajetórias tecnológicas, e assim entender e negociar eventuais conflitos. No Brasil, esse tipo de abordagem não tem recebido atenção significativa. A metodologia Problem Formulation and Options Assessment (PFOA), articulada no contexto do projeto internacional Genetically Modified Organisms - Environmental Risk Assessment (GMO-ERA), e sintonizada com as novas tendências de envolvimento dos diversos setores de interesse (stakeholders) ligados a uma tecnologia, propõe integrar na análise de risco as perspectivas ambiental, social, econômica e ética. A equipe de implementação de uma experiência piloto do PFOA foi formada pelo grupo do GMOERA - ligado ao Projeto Rede de Biossegurança (BioSeg), da Empresa Brasileira de Pesquisa Agropecuária (Embrapa), pelo Instituto de Pesquisa em Riscos e Sustentabilidade, da Universidade Federal de Santa Catarina (Iris-UFSC), e pelo Centro de Gestão de Estudos Estratégicos do Ministério da Ciência e Tecnologia (CGEE/MCT). O caso utilizado como modelo foi o feijão geneticamente modificado resistente ao mosaico-dourado, que vem sendo desenvolvido pela Embrapa. O piloto, financiado pelo CGEE/MCT, contou com a participação de diversos stakeholders. Dentre as conclusões, recomenda-se o uso de sistemas de informação não unidirecionados, mais transparentes e abertos, baseados em uma ciência rigorosa, para subsidiar as instâncias científicas e políticas nas tomadas de decisão. abstract: Recombinant DNA technology, together with an unlimited horizon of possibilities of innovation, triggered a discussion, among stakeholders, that cannot be ignored or solved through a linear difusion of information. Multidisciplinary and multi-institutional actions are being successfully adopted in several countries to establish new communication strategies between specialists and stakeholders. These strategies allow the identification of possible constraints and benefits of a technology during its development and, consequently, understanding and negotiation of conflicts. In Brazil this approach is not being used yet. The Problem Formulation and Options Assessment (PFOA) methodology was proposed by the Genetically Modified Organisms - Environmental Risk Assessment (GMO-ERA) project, aligned with the new trend of involving stakeholders in the risk assessment of a new technology. PFOA integrates the environmental, social, economic and ethical perspectives into the risk assessment of a technology. PFOA's pilot experience was conducted by a group formed by the GMO-ERA team associated with the Biosafety Network (BioSeg) project of the Brazilian Agricultural Research Corporation (Embrapa), by the Institute of Research in Risk and Sustainability from the Federal University of Santa Catarina (Iris-UFSC) and by the Center for Strategic Management and Studies in Science, Technology and Innovation of the Ministry of Science and Technology (CGEE/ MCT). The case study was a genetically modified bean resistant to the golden mosaic disease, which is being developed by Embrapa. This pilot was funded by CGEE/MCT and gathered representatives of several stakeholders. It could be concluded that the use of non-directed, transparent, open and science-based communication approaches is of great value for scientific and political decision making instances

Electrochemotherapy for solid tumors: literature review and presentation of a novel endoscopic approach

Background: Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive and long-lasting antitumoral results that are receiving the attention of the scientific community. It is a local treatment that combines the use of electroporation and the administration of cytotoxic drugs to induce cell death in the target tissue. ECT is largely used for the treatment of cutaneous and subcutaneous lesions, and good results have been reported for the treatment of deep visceral tumors. The latest literature review is provided. Moreover, in line with its development for the treatment of visceral tumors in this article, we describe a novel approach of ECT: endoscopic treatment of colorectal cancer. Endoscopic ECT application was combined with systemic chemotherapy in the treatment of obstructing rectal cancer without prospective surgery. A good response after ECT was described: concentric involvement of the rectum was reduced, and no stenosing lesions were detected. Conclusions: Clinical studies have demonstrated that ECT is a very effective treatment for tumors of different histologic types and localizations. Endoscopic treatment for gastrointestinal cancer is an innovative application of ECT. The combination of systemic treatment and ECT was safe and highly effective in the treatment of colorectal cancer, especially when obstructive, giving the patient a significant gain in quality of life