Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges.

Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting.

Computational Biology Helps Understand How Polyploid Giant Cancer Cells Drive Tumor Success.

Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. Newly formed cells end up accessing numerous multicellular and unicellular programs that enable metastasis, drug resistance, tumor recurrence, and self-renewal or diverse clone formation. An integrative literature review was carried out, searching articles in several sites, including: PUBMED, NCBI-PMC, and Google Academic, published in English, indexed in referenced databases and without a publication time filter, but prioritizing articles from the last 3 years, to answer the following questions: (i) "What is the current knowledge about polyploidy in tumors?"; (ii) "What are the applications of computational studies for the understanding of cancer polyploidy?"; and (iii) "How do PGCCs contribute to tumorigenesis?"

Translational Bioinformatics Applied to the Study of Complex Diseases.

Translational Bioinformatics (TBI) is defined as the union of translational medicine and bioinformatics. It emerges as a major advance in science and technology by covering everything, from the most basic database discoveries, to the development of algorithms for molecular and cellular analysis, as well as their clinical applications. This technology makes it possible to access the knowledge of scientific evidence and apply it to clinical practice. This manuscript aims to highlight the role of TBI in the study of complex diseases, as well as its application to the understanding and treatment of cancer. An integrative literature review was carried out, obtaining articles through several websites, among them: PUBMED, Science Direct, NCBI-PMC, Scientific Electronic Library Online (SciELO), and Google Academic, published in English, Spanish, and Portuguese, indexed in the referred databases and answering the following guiding question: "How does TBI provide a scientific understanding of complex diseases?" An additional effort is aimed at the dissemination, inclusion, and perpetuation of TBI knowledge from the academic environment to society, helping the study, understanding, and elucidating of complex disease mechanics and their treatment.

Serum albumin and vascular endothelial growth factor in epithelial ovarian cancer: looking at adnexal tumor drainage.

PURPOSE: This study aims to analyze serum albumin levels (SAL) in relation to concentrations of vascular endothelial growth factor (VEGF) from peripheral plasma, infundibular plasma, peritoneal fluids and the peritoneal burden of VEGF of patients with epithelial ovarian cancer. METHODS: Exploratory analyses of SAL in 39 patients and its relation to mean concentrations of VEGF from the origins are described above. Statistical analyses comprised Student's t test, Mann-Whitney test and Pearson's and Spearman's correlation coefficient. RESULTS: Both infundibular concentrations of VEGF and the peritoneal burden of VEGF showed significant differences between SAL dichotomized at 3 g/dl. Concentrations of VEGF in peritoneal fluids were not significant in relation to SAL. Peripheral plasma VEGF levels did not show any linear correlation with SAL. Indeed, SAL showed a significant negative linear correlation (p < 0.001) to infundibular plasma as well as the peritoneal burden of VEGF (p = 0.004). CONCLUSIONS: Infundibular mean concentrations of VEGF may contribute to reduce SAL in advanced staging rather than the peripheral plasma concentrations of this glycoprotein. The peritoneal burden of VEGF may also aid in decreasing levels of serum albumin.

Peritoneal VEGF burden as a predictor of cytoreductive surgery outcome in women with epithelial ovarian cancer.

OBJECTIVE: To determine whether peripheral plasma concentration, peritoneal fluid concentration, and/or peritoneal vascular endothelial growth factor (VEGF) burden can predict the possibility of optimal cytoreduction in women with epithelial ovarian carcinoma (EOC); and if so, to determine cutoff values below which optimal cytoreduction is likely to occur. METHODS: We measured plasma VEGF concentration, peritoneal VEGF concentration, and VEGF burden in 46 women undergoing cytoreductive surgery. Univariate analysis, bivariate analysis, correlation tests, and stepwise regression were performed with cytoreduction as the outcome. RESULTS: The VEGF burden best predicted the outcome. The area under the curve was 0.84 and the log-transformed cutoff value was 15.52 log pg. Overall, the chance of optimal cytoreduction was 11 times greater when the VEGF burden was less than 15.52 log pg. For women with advanced disease, the chance was 6 times greater below this value. CONCLUSION: The VEGF burden may quantify tumor activity, and it could be used when selecting patients likely to benefit from induction chemotherapy before undergoing cytoreductive surgery.

Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathway.

Preclinical studies have shown the potential antitumour efficacy of monoclonal antibodies (MAbs) directed to the epidermal growth factor receptor (EGFR). In this report, we investigated the cytotoxic effects of the MAb matuzumab (EMD 72000) towards A431 cells and compared it to cetuximab. While cetuximab induced cell cycle arrest and inhibited A431 cell proliferation, matuzumab did not. Both MAbs inhibited growth factor induced EGFR, HER2 and AKT phosphorylation; however, only cetuximab inhibited ERK 1/2 phosphorylation. Taken together, the data indicate that each antibody may elicit different responses on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival. When combined, MAbs synergistically inhibited cell proliferation and induced EGFR down-regulation with a strong inhibition of ERK1/2 and AKT phosphorylation. In addition, both MAbs efficiently inhibited VEGF expression and induced ADCC, highlighting their therapeutic potential in vivo when used either as a single agent or in combination.

Clotrimazole decreases human breast cancer cells viability through alterations in cytoskeleton-associated glycolytic enzymes.

Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. Glycolysis is known to be controlled by allosteric regulators, as well as by reversible binding of glycolytic enzymes to cytoskeleton. Clotrimazole is an anti-fungal azole derivative recently recognized as a calmodulin antagonist with promising anti-cancer effect. Here, we show that clotrimazole induced morphological and functional alterations on human breast cancer derived cell line, MCF-7. The drug decreased cell viability in a dose- and time-dependent manner, exhibiting an IC50 of 88.6+/-5.3 microM and a t0.5 of 89.7+/-7.2 min, with 50 microM clotrimazole. Morphological changes were evident as observed by scanning electron microscopy, which revealed the completely loss of protrusion responsible for cell adhesion after a 180 min of treatment with 50 microM clotrimazole. Giemsa stained cells observed by optical microscopy show morphological alterations and a marked nuclear condensation. These changes occurred in parallel to the detachment of the glycolytic enzymes, 6-phosphofructo-1-kinase and aldolase, from cytoskeleton. After a 45 min treatment with 50 microM clotrimazole, the remaining activities in a cytoskeleton enriched fraction was 16.4+/-3.6% and 41.0+/-15.6% of control for 6-phosphofructo-1-kinase and aldolase, respectively. Immunocytochemistry experiments revealed a decrease in the co-localization of 6-phosphofructo-1-kinase and F-actin after clotrimazole treatment, suggesting the site of detachment of the enzymes. Altogether, our results support evidence for apoptotic events that might be started by clotrimazole involving inhibition of glycolytic flux in MCF-7 cells and makes this drug a promising agent in the fight against human breast cancer.