Gene expression changes associated with chemotherapy resistance in Ewing sarcoma cells

Ewing Sarcoma (ES) is a highly aggressive bone and soft tissue childhood cancer. The development of resistance to chemotherapy is common and remains the main cause of treatment failure. We herein evaluated the expression of genes associated with chemotherapy resistance in ES cell lines. A set of genes (CCAR1, TUBA1A, POLDIP2, SMARCA4 and SMARCB1) was data-mined for resistance against doxorubicin and vincristine, which are the standard drugs used in the treatment of patients with ES. The expression of each gene in SK-ES-1 ES cells was reported before and after exposure to a drug resistance-inducing protocol. There was a significant downregulation of CCAR1 and TUBA1A in doxorubicin-resistant cells, with low expression of TUBA1A in vincristine-resistant cells. By contrast, POLDIP2 was significantly upregulated in cells resistant to either drug, and the expression of the SMARCB1 and SMARCA4 genes was upregulated in doxorubicin-resistant cells. These findings indicate that resistance to specific chemotherapeutic agents was accompanied by differential changes in gene expression in ES tumors

Glioblastoma: molecular profile and immunophenotypic analysis as prognostic tools for tailored therapy and decision making in a recent surgical series

Objective: Despite combined approaches the prognosis of Glioblastoma remains poor. However, different variants of this tumor might show different prognostic characteristics. Aim of the study is to investigate the role of molecular prognostic factors in predicting clinical outcomes in patients treated for glioblastoma. The study focuses on therapeutic and prognostic value of IDH1 gene mutations and MGMT promoter methylation status. Methods: 115 patients diagnosed and treated for glioblastoma at our institution within a period of five years (2013–2018) were included. All patients received pre-operative MRI, gross-total surgical resection and adjuvant treatments (chemotherapy and radiotherapy). Immunohistochemical analysis of histological samples was performed for IDH1 gene R132H mutations and MGMT promoter methylation status. Follow-up was conducted through clinical examination and MRI scans for a period of 60 months. Results: Mean population age was 59.21 ± 13.9 [19–85]. Overall median survival was 14 months, range 12–16. IDH1 gene mutation was identified in 30 patients (26%) and positively correlated with survival (IDH1 mutated: 32 months 95%C.I. [12–16] vs IDH1 wild type: 12 months, 95%C.I. [11–14]; p < 0.001). MGMT promoter methylation was identified in 51 patients (44%) and was positively correlated to overall survival (met-MGMT: 16 months 95%C.I. [14–19] vs non-met-MGMT: 12 months 95%C.I. [11–16]; p < 0.05). Conclusions: Our findings highlighted that molecular characterization of tumor profile provides a prognostic tool to predict clinical efficacy of treatments and prognosis. Peculiar molecular features and immunophenotypic analysis will enhance reliability and promote personalized therapeutic decision-making in order to increase global survival and quality of life in patients diagnosed and treated for glioblastoma. Keywords: Glioblastoma, IDH, MDMT, Overall survival, Free progression surviva

Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions

Background: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber’s hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. Case presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation

Aumento da Incidência de Recidiva Bioquímica após Prostatectomia Radical em Centro de Formação em Urologia Oncológica no Brasil: Doenças mais Avançadas estão sendo submetidas à Cirurgia?

Introdução: O câncer de próstata e a neoplasia maligna mais incidente em homens, representando 29% dos diagnósticos da doença no Brasil, segundo o Instituto Nacional de câncer Jose Alencar Gomes da Silva (INCA). Esse câncer e suspeito em alterações do toque retal e/ou do nível sérico do antígeno prostático especifico (PSA) total, sendo o diagnóstico definitivo feito por estudo histopatológico. Objetivo: Verificar a associação entre parâmetros clínicos e anatomopatológicos após prostatectómica radical com recidiva bioquímica ao longo do seguimento. Método: Estudo retrospectivo observacional dos parâmetros clínicos (idade, PSA inicial, toque retal, classificação histopatológica da International Society of Urological Pathology (ISUP), escala de D’Amico e estádio clínico) e anatomopatológicos (grau ISUP da peça cirúrgica, margens cirúrgicas, extensão extracapsular tumoral e presença de linfonodos acometidos), de 177 pacientes submetidos a prostatectomia radical em serviço de uro-oncologia de junho/2010-maio/2018. Resultados: A recidiva bioquímica ocorreu em 44,1% dos casos no tempo de seguimento médio de 34,9 meses. A análise univariada demonstrou PSA inicial >9 ng/mL, toque retal alterado, classificação patológica ISUP 4 e 5, risco D’Amico alto e estagio clinico TNM T3 como fatores diretamente associados a recidiva bioquímica. As margens cirúrgicas foram positivas em 46,3%; em 47,7%, identificou-se extensão extraprostática tumoral. Linfonodos positivos em 10,9% e vesículas seminais comprometidas ocorreram em 21,8%. Conclusão: Fatores clinico-patológicos podem ser preditores de recidiva bioquímica. Nesses casos, foi identificado padrão clinico pré-tratamento supostamente mais agressivo em comparação a literatura em geral. Além disso, deve-se considerar a curva de aprendizado dos cirurgiões em formação no serviço, o que pode resultar em maiores taxas de margens cirúrgicas positivas

Correlação entre os Parâmetros Clínicos, Patológicos e a Sobrevida Livre de Doença de Pacientes com Câncer Renal Tratados com Cirurgia em um Centro Oncológico do Sistema Público de Curitiba

Introdução: O câncer renal corresponde a 13a neoplasia mais incidente no mundo, sendo o terceiro tipo de câncer geniturinário mais comum. A maioria dos pacientes e assintomática, ocorrendo o diagnóstico de maneira incidental durante a realização de exames de imagem. O tratamento padrão-ouro e o cirúrgico. Objetivo: Correlacionar os parâmetros clínicos e patológicos com a sobrevida livre de doença em pacientes com câncer renal submetidos à nefrectomia. Método: Estudo retrospectivo com 99 pacientes submetidos a tratamento cirúrgico do câncer renal no período de 2010 a 2020. Foram comparados os parâmetros clínicos e patológicos com o desfecho clinico oncológico após nefrectomia. Resultados: Os 99 pacientes tiveram seguimento pós-operatório médio de 26,9 meses, sendo a sobrevida livre de doença (media) de 61,9%. A análise univariada demonstrou que as variáveis tamanho de tumor >7 cm e graus de Fuhrman III e IV estiveram relacionadas a progressão de doença após a nefrectomia (p=0,046 e IC=1,017-7,083; p=0,005 e IC=1,725-23,004, respectivamente). Na análise multivariada, o tamanho do tumor >7 cm (p=0,014 e IC=1,290-9,326) e os graus de Fuhrman III e IV (p=0,028 e IC=1,174-16,616) foram identificados como fatores preditores a progressão. Conclusão: O tamanho tumoral >7 cm e/ou os graus III ou IV de Fuhrman são fatores de risco para recorrência tumoral após o tratamento cirúrgico do câncer renal

Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats

Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondria! biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein +3% leucine]). After 20 days of tumour evolution, the animals underwent (18)-fludeoxyglucose positron emission computed tomography (F-18-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (F-18-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondria! density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação302863/2013-3; 302425/2016-92012/06955-0; 2014/13334-7; 2015/21890-0; 2017/02739-

ASSOCIAÇÃO DE HERBICIDAS PARA O MANEJO DE PLANTAS DANINHAS EM MILHO

Corn is an important crop for agriculture, playing a fundamental role in animal and human feed and energy production. Therefore, the purpose of this study was evaluate the effectiveness, selectivity and effects on corn physiological and productive characteristics after herbicide application either isolated or in tank mix. The procedure adopted was randomized blocks design, with four replications each. The treatments, glyphosate, [atrazine + simazine], nicosulfuron, mesotrione, tembotrione, plus a weeded control were used alone or in a tank mixture. It was evaluated the herbicide phytotoxicity in AG 9025 PRO3 hybrid corn, as well as the weed control of alexander grass and crabgrass at 7, 14, 21 and 28 days after treatment (DAT). At 50 DAT, variables related to the grain physiological characteristics were also measured. Finally, during harvest, grain yield was determined. All evaluations showed that phytotoxicity caused by herbicides was not visually perceptible in AG 9025 PRO3 corn hybrid. The control was effective in treatments that presented in tank mix treatments glyphosate with nicosulfuron and tembotrione. The physiological characteristic affected after herbicide application was photosynthesis, which, when compared to other treatments, showed better results with nicosulfuron and mesotrione. Herbicides did not interfere in corn grain yield. Glyphosate associated with other herbicides used in corn crops shows to be a valuable practice to improve and accelerate the weed control studied with selectivity to the crop.O uso de herbicidas para o controle de plantas daninhas na cultura do milho tem sido uma prática muito comum pelos produtores, sendo aplicados de modo isolado ou em mistura em tanque. Diante disso, o objetivo do trabalho foi avaliar a eficiência, a fitotoxicidade, o efeito em características fisiológicas e produtivas do milho após a aplicação de herbicidas de modo isolado ou em mistura em tanque. O experimento foi instalado a campo, no delineamento de blocos casualizados, com quatro repetições. Como tratamentos foram utilizados de forma isolada ou em mistura em tanque o glyphosate, [atrazine+simazine], nicosulfuron, mesotrione, tembotrione, mais uma testemunha capinada. Avaliou-se a fitotoxicidade dos herbicidas ao híbrido de milho AG 9025 PRO3, a eficiência no controle de papuã (Urochloa plantaginea) e milhã (Digitaria ciliaris) aos 7, 14, 21 e 28 dias após a aplicação dos tratamentos (DAT). Aos 50 DAT aferiu-se ainda as variáveis referentes às características fisiológicas do milho e na colheita determinou-se a produtividade de grãos. A fitotoxicidade ocasionada pelos herbicidas não foi perceptível ao híbrido de milho AG 9025 PRO3. O controle foi eficiente nos tratamentos que apresentaram a mistura em tanque de glyphosate com nicosulfuron e tembotrione. A taxa fotossintética aumentou com a aplicação de nicosulfuron e mesotrione ao se comparar com os demais tratamentos. A concentração interna de CO2, taxa de transpiração, condutância estomática de vapores de água, eficiência de carboxilação e uso eficiente da água não foram alteradas ao se usar os herbicidas isolados ou em mistura. A aplicação dos herbicidas não interferiu na produtividade de grãos de milho. A associação de glyphosate com outros herbicidas demonstra ser prática favorável para melhorar a eficácia de controle

Interference and threshold level of Sida rhombifolia in transgenic soybean cultivars

This study aimed to assess the interference and threshold level (TL) of Sida rhombifolia, the arrowleaf sida, competing with different soybean cultivars. The treatments comprised different soybean cultivars (NS 6909, NA 5909, DM 5958, Brasmax ELITE, Brasmax LANÇA, and SYN 13561) and densities of arrowleaf sida plants per square meter (m-2) (0, 2, 3, 4, 9, 15, 16, 23, 22, and 58; 0, 2, 3, 3, 6, 6, 10, 11, 18, and 47; 0, 3, 4, 7, 8, 10, 11, 13, 15, and 24; 0, 1, 4, 6, 12, 18, 19, 31, 44, and 50; 0, 4, 5, 6, 9, 13, 17, 20, 20, and 47; 0, 2, 3, 5, 9, 11, 15, 18, 29, and 30, respectively) for each cultivar. Cultivars NS 6909, NA 5909, and Brasmax Lança were more competitive than DM 5958, Brasmax Elite, and SYN 13561. The TL values varied from 0.55 to 0.95 plants m-2 for cultivars NS 6909, NA 5909, and Brasmax Lança, which exhibited greater competitiveness with arrowleaf sida. The lowest values of TL varied from 0.26 to 0.61 plants m-2 for cultivars DM 5958, Brasmax Elite, and SYN 13561, which had less competitiveness with weed