MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells

The resistance of cancer cells to a variety of structurally non-related cytotoxic drugs is known as multidrug resistance phenomenon (MDR). In cellular membranes an activity of MDR transporters such as P-glycoprotein (ABCB1) is affected by their lipid environment. Many various compounds have been examined for their ability to restore drug-sensitivity of resistant cancer cells. Statins, inhibitors of the key enzyme of mevalonate pathway HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase are drugs commonly prescribed in order to reduce serum level of cholesterol and to diminish the risk of cardiovascular disease. Statins as drugs that influence lipid composition of cell membrane and in that way they also exert influence on lipid bilayer properties appear to be good candidates as MDR modulators. In this work it was shown that statins - mevastatin and simvastatin exert antiproliferative, pro-apoptotic and reversing drug resistance effect in human colon adenocarcinoma cell line LoVo and its drug-resistant subline LoVo/Dx. A hypothesis was also checked whether flavones, which as it is well known are able to influence the biosynthesis of cholesterol, may change the anticancer activity of statins. Our investigations have revealed that combined use of statins and studied flavonoids results in enhanced cell growth inhibition and apoptosis and lower cancer cell proliferation as compared to the application only statins alone. Moreover, in drug resistant LoVo/Dx cells a stronger decrease of resistance to doxorubicine was observed in the presence of statins in combination with flavones as compared to the effect observed for statins only.

Dissecção de aorta pós‐troca valvar mitral: o papel da ecocardiografia intraoperatória no diagnóstico

According to the most recent guidelines, the use of intraoperative transesophageal echocardiography in valvular surgeries is well established, as well as its use in the diagnosis, management, and rescue of perioperative complications. The aim of this case report is to illustrate a condition in which its intraoperative use had a positive influence on the outcome.

Aortic dissection after mitral valve replacement: the role of intraoperative echocardiography in this diagnosis

PARAPLEGIA CRURAL INCOMPLETA OCASIONADA POR HISTOPLASMOSE CEREBRAL E MEDULAR EM PACIENTE SEM IMUNODEFICIÊNCIA: RELATO DE CASO

Novel Biocompatible Polymers for Biomedical Applications

Exploring collagen remodeling and regulation as prognosis biomarkers in stable heart failure

We assessed the predictive ability of circulating biomarkers involved in collagen synthesis (procollagen type I N-terminal propeptide [PINP], and procollagen type III N-terminal propeptide [PIIINP], collagen degradation (c-terminal telopeptide of collagen type I [CTx] and mediators of cardiac fibrosis (Galectin-3 and soluble suppression of tumorigenicity 2 protein or sST2) as prognosis markers in 182 subjects with chronic heart failure (HF). In univariate analysis, all markers predicted mortality (except for PINP). A multivariate baseline model was fitted including variables potentially associated with mortality in HF patients. The baseline regression model included age, clinical data and biomarkers. We created four models from the baseline model augmented with the levels of hs-cTnT, CRP and NT-proBNP (model 1), CTx/PIIINP ratio, sST2 and Galectine-3 (model 2), NT-proBNP and sST2 (model 3) and NT-proBNP, CTx/PIIINP ratio and sST2 (model 4), to test whether these biomarkers have an incremental value for predicting mortality. After the addition of all biomarkers to the baseline model, age, CTx/PIIINP ratio and sST2 remained significant predictors. By contrast, Galectin-3 was not significantly associated with mortality. A multimarker strategy, demonstrated that the greatest prognostic improvement was attained with the combined addition of CTx/PIIINP ratio and sST2 highlighting the potential role of fibrosis pathways in risk stratification.

Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial Corentin Curinier, Kamila Solecki, Anne Dupuy, Cyril Breuker, Manuela Lotierzo, Laetitia Zerkowski, Eran Kalmanovich, Mariama Akodad, Jérôme Adda, Pascal Battistella, et al.

Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns

Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.

β-TrCP- and Casein Kinase II-Mediated Degradation of Cyclin F Controls Timely Mitotic Progression

Orderly progressions of events in the cell division cycle are necessary to ensure the replication of DNA and cell division. Checkpoint systems allow the accurate execution of each cell-cycle phase. The precise regulation of the levels of cyclin proteins is fundamental to coordinate cell division with checkpoints, avoiding genome instability. Cyclin F has important functions in regulating the cell cycle during the G2 checkpoint; however, the mechanisms underlying the regulation of cyclin F are poorly understood. Here, we observe that cyclin F is regulated by proteolysis through β-TrCP. β-TrCP recognizes cyclin F through a non-canonical degron site (TSGXXS) after its phosphorylation by casein kinase II. The degradation of cyclin F mediated by β-TrCP occurs at the G2/M transition. This event is required to promote mitotic progression and favors the activation of a transcriptional program required for mitosis.

The AMSH3 ESCRT-III-Associated Deubiquitinase Is Essential for Plant Immunity

Plant "nucleotide-binding leucine-rich repeat" receptor proteins (NLRs) detect alterations in host targets of pathogen effectors and trigger immune responses. The Arabidopsis thaliana mutant pen1 syp122 displays autoimmunity, and a mutant screen identified the deubiquitinase "associated molecule with the SH3 domain of STAM3" (AMSH3) to be required for this phenotype. AMSH3 has previously been implicated in ESCRT-mediated vacuolar targeting. Pathology experiments show that AMSH3 activity is required for immunity mediated by the CC-NLRs, RPS2 and RPM1. Co-expressing the autoactive RPM1 D505V and the catalytically inactive ESCRT-III protein SKD1 E232Q in Nicotiana benthamiana supports the requirement of ESCRT-associated functions for this CC-NLR-activated immunity. Meanwhile, loss of ESCRT function in A. thaliana is lethal, and we find that AMSH3 knockout-triggered seedling lethality is "enhanced disease susceptibility 1" (EDS1) dependent. Future studies may reveal whether AMSH3 is monitored by a TIR-NLR immunity receptor.