A Human Head and Neck Squamous Cell Carcinoma Cell Line with Acquired cis-Diamminedichloroplatinum-Resistance Shows Remarkable Upregulation of BRCA1 and Hypersensitivity to Taxane

Recently, an inverse relationship between resistance to platinum-based chemotherapeutic agents and taxanes has been implicated in breast and ovarian cancers, and a possible pivotal role for BRCA1 has also been suggested. Because cis-diamminedichloroplatinum (CDDP) and taxanes are the most active antitumor agents against head and neck squamous cell carcinoma (HNSCC), we analyzed the sensitivity of nine HNSCC cell lines and their previously established derived CDDP-resistant cell lines to two representative taxanes: docetaxel and paclitaxel. None of the nine original cell lines showed any cross resistance between CDDP and taxanes, but one of the CDDP-resistant cell lines, RPMI2650CR, demonstrated hypersensitivity to both taxanes when compared to the parental cell line, RPMI2650. Furthermore, RPMI2650CR exhibited increased expression of BRCA1. These data suggest that (i) taxanes are a good candidate for a second-line therapeutic drug for HNSCC patients with acquired CDDP resistance and (ii) BRCA1 can be a candidate marker for predicting an inverse CDDP/taxane sensitivity phenotype in HNSCC

Ocorrencia de toxinas em carne bovina salgada e levemente dessecada, embalada a vacuo e inoculada Staphylococcus aureus ou Clostridium botulinum

Orientador: Pedro Eduardo de FelicioDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de AlimentosResumo: Produtos cárneos com baixo teor de sal e alta atividade de água têm vida de prateleira reduzida à temperatura ambiente. A carne de sol, um produto tipicamente brasileiro, é elaborada de forma artesanal e tem uma duração média de três a cinco dias. Os princípios de boas práticas de fabricação, associados ao armazenamento refrigerado adequado e à embalagem a vácuo, permitem a conservação de produtos cárneos tradicionais de baixo teor de sal, por um tempo maior, para a comercialização a longas distâncias. O presente trabalho foi realizado com o objetivo de avaliar a segurança microbiológica de uma carne bovina salgada e levemente dessecada, com características físico-químicas similares à carne-de-sol, com teor de sal compatível ao paladar humano, sem necessidade de dessalga e acondicionada em dois tipos de embalagem a vácuo, de acordo com suas permeabilidades ao oxigênio (9,6cc02/m2/dia vs 40,Occ02/m2/dia). No processamento utilizou-se o coxão-mole bovino, cortado em fatias de 5,Ocm de espessura, salgadas com 4% de sal e mantidas a 0°C por quatro horas. Ems eguida, foi realizada a secagem em câmara climatizada durante quatro horas a uma temperatura média de 24,5°e e umidade relativa do ar de 52,3% ...Observação: O resumo, na íntegra poderá ser visualizado no texto completo da tese digital.Abstract: Meat products with low salt content and high water activity have a short shelf-life at ambient temperature. A typical Brazilian beef product, "carne-de-sol", is traditionally made in small quantities at local markets and has an average time for consumption of three to five days. Principies of good manufacturing practices associated with proper cold storage and vacuum packaging could allow the preservation of low salt traditional meat products for longer time to make possible their marketing to distant areas. However, it is important to take into account the potential hazard of toxin formation in these products at abusive temperatures. This research work was carried out to evaluate the microbiological safety of a beef product with physico-chemical characteristics similar to "carne-de-sol", having salt levei compatible to consumers acceptance without desalting, vacuum packaged in two types of packaging films according to their oxygen barrier (9.6ccO2/m2/diavs. 40.0ccO2/m2/dia).Boxed beef top round wholesale cuts were sliced in 5 cm thick steaks, added of 4% salt and kept in the cooler (O°C ] for four hours ...Note: The complete abstract is available with the full electronic digital thesis or dissertations.MestradoMestre em Tecnologia de Alimento

Attempts to remodel the pathways of gemcitabine metabolism: Recent approaches to overcoming tumours with acquired chemoresistance

Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine resistance is regulated by various factors, including aberrant genetic and epigenetic controls, metabolism of gemcitabine, the microenvironment, epithelial-to-mesenchymal transition, and acquisition of cancer stem cell properties. In many situations, results using cell lines offer valuable lessons leading to the first steps of important findings. In this review, we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance, including nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ATP-binding cassette transporters, and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance

Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings

Duodenal neuroendocrine tumor after bilateral breast cancer with type 1 neurofibromatosis: a case report

Abstract Background Young women with NF1 are at a high risk of developing breast cancer. Although they are at risk for abdominal tumors, such as gastrointestinal stromal tumors and neuroendocrine tumors, follow-up strategies for other tumors after breast cancer have not yet been established. Here, we present a case of duodenal neuroendocrine tumor found during follow-up after bilateral mastectomy for breast cancer with type 1 neurofibromatosis (NF1), for which pancreaticoduodenectomy (PD) and lymphadenectomy were performed. Case presentation A 46-year-old woman with NF1 was referred to our hospital for treatment of a duodenal submucosal tumor. Her previous operative history included bilateral mastectomy for breast cancer: right total mastectomy and left partial mastectomy performed 9 and 5 years ago, respectively. Her daughter was confirmed to have NF1, but her parents were unclear. Although she had no recurrence or symptoms during the follow-up for her breast cancer, she wished to undergo 18-fluorodeoxyglucose–positron emission tomography (FDG–PET) for systemic screening. FDG–PET demonstrated FDG accumulation in the duodenal tumor with a maximum standardized uptake value of 5.78. Endoscopy revealed a 20-mm-diameter tumor in the second duodenal portion, and endoscopic biopsy suggested a NET G1. We performed PD and lymphadenectomy for complete. She was doing well without recurrence and was followed up with PET tomography–computed tomography. Conclusions Early detection of gastrointestinal tumors is difficult, because most of them are asymptomatic. Gastrointestinal screening is important for patients with NF1, and PD with lymphadenectomy is feasible for managing duodenal neuroendocrine tumors, depending on their size

Disruption of Tacc3 function leads to in vivo tumor regression

The formation of the bipolar spindle is responsible for accurate chromosomal segregation during mitosis. The dynamic instability of microtubules has an important role in this process, and has been shown to be an effective target for cancer chemotherapy. Several agents that target non-microtubule mitotic proteins, including the motor protein Eg5, Aurora kinases and Polo-like kinases, are currently being developed as chemotherapeutic drugs. However, because the efficacies of these drugs remain elusive, new molecular targets that have essential roles in tumor cells are desired. Here, we provide in vivo evidence that transforming acidic coiled-coil-3 (Tacc3) is a potential target for cancer chemotherapy. Using MRI, we showed that Tacc3 loss led to the regression of mouse thymic lymphoma in vivo, which was accompanied by massive apoptosis. By contrast, normal tissues, including the thymus, showed no overt abnormalities, despite high Tacc3 expression. in vitro analysis indicated that Tacc3 depletion induced multi-polar spindle formation, which led to mitotic arrest, followed by apoptosis. Similar responses have been observed in Burkitt\u27s lymphoma and T-ALL. These results show that Tacc3 is a vulnerable component of the spindle assembly in lymphoma cells and is a promising cancer chemotherapy targe

Long Non-Coding RNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

Long non-coding RNAs (lncRNAs) have emerged as a significant player in various cancers, including pancreatic cancer. However, how lncRNAs are aberrantly expressed in cancers is largely unknown. We hypothesized that lncRNAs would be regulated by signaling pathways and contribute to malignant phenotypes of cancer. In this study, to understand the significance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), which is a major aberrant signaling pathway in pancreatic cancer, for the expression of lncRNAs, we performed comparative transcriptome analyses between pancreatic cancer cell lines with or without activation of MAPK. We identified 45 lncRNAs presumably associated with MAPK in pancreatic cancer cells; among these, LINC00941 was consistently upregulated by MAPK. The immediate genomic upstream region flanking LINC00941 was identified as a promoter region, the activity of which was found to be preferentially associated with MAPK activity via ETS-1 binding site. LINC00941 promoted cell proliferation in vitro. Moreover, TCGA data analysis indicated that high expression of LINC00941 was associated with poor prognosis of patients with pancreatic cancer. Transcriptomes comparing transcriptions between cells with and without LINC00941 knockdown revealed 3229 differentially expressed genes involved in 44 biological processes, including the glycoprotein biosynthetic process, beta-catenin-TCF complex assembly, and histone modification. These results indicate that MAPK mediates the aberrant expression of lncRNAs. LINC00941 is the lncRNA by MAPK most consistently promoted, and is implicated in the dismal prognosis of pancreatic cancer. MAPK-associated lncRNAs may play pivotal roles in malignant phenotypes of pancreatic cancer, and as such might represent both potentially valid therapeutic targets and diagnostic biomarkers