A platform for oncogenomic reporting and interpretation.

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we introduce a Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework that facilitates the interpretation and reporting of somatic variants in cancer. PORI integrates reporting and graph knowledge base tools combined with support for manual curation at the reporting stage. PORI represents an open-source platform alternative to commercial reporting solutions suitable for comprehensive genomic data sets in precision oncology. We demonstrate the utility of PORI by matching 9,961 pan-cancer genome atlas tumours to the graph knowledge base, calculating therapeutically informative alterations, and making available reports describing select individual samples.

Cell-to-cell communication mediates glioblastoma progression in Drosophila.

Glioblastoma (GB) is the most aggressive and lethal tumour of the central nervous system (CNS). GB cells grow rapidly and display a network of projections, ultra-long tumour microtubes (TMs), that mediate cell to cell communication. GB-TMs infiltrate throughout the brain, enwrap neurons and facilitate the depletion of the signalling molecule wingless (Wg)/WNT from the neighbouring healthy neurons. GB cells establish a positive feedback loop including Wg signalling upregulation that activates cJun N-terminal kinase (JNK) pathway and matrix metalloproteases (MMPs) production, which in turn promote further TMs infiltration, GB progression and neurodegeneration. Thus, cellular and molecular signals other than primary mutations emerge as central players of GB. Using a Drosophila model of GB, we describe the temporal organisation of the main cellular events that occur in GB, including cell-to-cell interactions, neurodegeneration and TM expansion. We define the progressive activation of JNK pathway signalling in GB mediated by the receptor Grindelwald (Grnd) and activated by the ligand Eiger (Egr)/TNFα produced by surrounding healthy brain tissue. We propose that cellular interactions of GB with the healthy brain tissue precede TM expansion and conclude that non-autonomous signals facilitate GB progression. These results contribute to deciphering the complexity and versatility of these incurable tumours.

Patient selection for a developmental therapeutics program using whole genome and Transcriptome analysis.

Introduction Given the high level of uncertainty surrounding the outcomes of early phase clinical trials, whole genome and transcriptome analysis (WGTA) can be used to optimize patient selection and study assignment. In this retrospective analysis, we reviewed the impact of this approach on one such program. Methods Patients with advanced malignancies underwent fresh tumor biopsies as part of our personalized medicine program (NCT02155621). Tumour molecular data were reviewed for potentially clinically actionable findings and patients were referred to the developmental therapeutics program. Outcomes were reviewed in all patients, including those where trial selection was driven by molecular data (matched) and those where there was no clear molecular rationale (unmatched). Results From January 2014 to January 2018, 28 patients underwent WGTA and enrolled in clinical trials, including 2 patients enrolled in two trials. Fifteen patients were matched to a treatment based on a molecular target. Five patients were matched to a trial based upon single-gene DNA changes, all supported by RNA data. Ten cases were matched on the basis of genome-wide data (n = 4) or RNA gene expression only (n = 6). With a median follow-up of 6.7 months, the median time on treatment was 8.2 weeks. Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA.

Selected toxicities of targeted therapies: presentation and management.

The introduction of targeted therapy has changed the landscape of metastatic renal cell carcinoma (mRCC) but has also brought challenges. One such challenge of treating this chronic disease is long-term therapy, which produces ongoing toxicity. Knowledge of the spectrum of toxicity from targeted therapy and appropriate and timely intervention is required to maintain adequate dosing required for optimal outcome. This article addresses some of the major toxicities of newer agents in RCC and discusses management strategies.

Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study.

Mammalian cell culture systems are used predominantly for the production of therapeutic monoclonal antibody (mAb) products. A number of alternative platforms, such as Pichia engineered with a humanized N-linked glycosylation pathway, have recently been developed for the production of mAbs. The glycosylation profiles of mAbs produced in glycoengineered Pichia are similar to those of mAbs produced in mammalian systems. This report presents for the first time the comprehensive characterization of an anti-human epidermal growth factor receptor 2 (HER2) mAb produced in a glycoengineered Pichia, and a study comparing the anti-HER2 from Pichia, which had an amino acid sequence identical to trastuzumab, with trastuzumab. The comparative study covered a full spectrum of preclinical evaluation, including bioanalytical characterization, in vitro biological functions, in vivo anti-tumor efficacy and pharmacokinetics in both mice and non-human primates. Cell signaling and proliferation assays showed that anti-HER2 from Pichia had antagonist activities comparable to trastuzumab. However, Pichia-produced material showed a 5-fold increase in binding affinity to FcγIIIA and significantly enhanced antibody dependant cell-mediated cytotoxicity (ADCC) activity, presumably due to the lack of fucose on N-glycans. In a breast cancer xenograft mouse model, anti-HER2 was comparable to trastuzumab in tumor growth inhibition. Furthermore, comparable pharmacokinetic profiles were observed for anti-HER2 and trastuzumab in both mice and cynomolgus monkeys. We conclude that glycoengineered Pichia provides an alternative production platform for therapeutic mAbs and may be of particular interest for production of antibodies for which ADCC is part of the clinical mechanism of action.

Avaliação da qualidade de queijos de coalho comercializados no entorno da cidade universitária, Recife, PE / Evaluation of quality of cheese commercialized around the city university, Recife, PE

O objetivo deste trabalho foi avaliar a qualidade dos queijos de coalho comercializados em padarias localizadas no entorno da Cidade Universiária, Recife/PE em relação à legislação vigente. O material estudado compreendeu 18 amostras de queijo de coalho, provenientes de cinco fornecedores do interior de Pernambuco, coletadas em seis estabelecimentos. Estavam impróprias para o consumo 100 por cento e 83,3 por cento das amostras quanto aos parâmetros microbiológicos e microscópicos, respectivamente. Evidenciou-se que 50,0 por cento das amostras encontravam em não conformidade com a legislação vigente quanto ao teor de gordura do extrato seco, e 17,0 por cento quanto ao teor de umidade. (...) Foram observadas falhas na aplicação das boas práticas de manipulação na área de frios das padarias. Estes dados denunciam a necessidade de um aperfeiçoamento quanto á normalização do processo de fabricação e das ações de controle higiênico-sanitário, uma vez que o elevado índice de contaminação do queijo de coalho representa um potencial risco à saúde da população consumidora.

Aspectos legais do uso de aditivos químicos em alimentos / Legal aspects of the use of chemical additives in food

Os produtos industrializados ocupam uma parcela cada vez maior do mercado de alimentos haja vista, principalmente, a mudança dos hábitos alimentares nos últimos anos. Sem o uso de aditivos químicos, a variedade destes alimentos disponíveis e seu tempo de vida em manter-se em condições de consumo seriam muito reduzidos. Contudo, o uso de aditivos é um tema controverso, com alegações de que estes são tóxicos e que podem desencadear reações adversas nos consumidores. Entretanto, todos os aditivos permitidos no Brasil são considerados seguros, de acordo com as normas da Agência Nacional de Vigilância Sanitária se utilizados nas quantidades estabelecidas pela mesma. Não obstante ao cumprimento das recomendações da legislação, ressalta-se que a indústria de alimentos deve estar sempre atenta ás constantes investigações e descobertas nesta área, de forma a fornecer ao mercado alimentos sempre seguros. Este trabalho teve o intuito de abordar os aspectos legais vigentes no Brasil quanto á regulamentação do uso de aditivos químicos em alimentos.