Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications.

About 75% of all breast cancers are hormone receptor-positive (HR+). However, the efficacy of endocrine therapy is limited due to the high rate of either pre-existing or acquired resistance. In this work we reconstructed the pathways around estrogen receptor (ER), mTOR, and cyclin D in order to compare the effects of CDK4/6 and PI3K/AKT/mTOR inhibitors.

Different Cardiotoxicity of Palbociclib and Ribociclib in Breast Cancer: Gene Expression and Pharmacological Data Analyses, Biological Basis, and Therapeutic Implications.

Breast cancer is the most frequent tumor in women. The recent advent of cyclin-dependent kinase (CDK) 4/6 inhibitors palbociclib and ribociclib has represented a major step forward for patients with hormone receptor-positive breast cancer. These two agents have showed similar efficacy in terms of breast cancer outcome but different cardiotoxic effects.

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role.

Clinical impact of different exosomes' protein expression in pancreatic ductal carcinoma patients treated with standard first line palliative chemotherapy.

Introduction: Pancreatic ductal adenocarcinoma is associated to dismal prognosis despite the use of palliative chemotherapy, partly due to the lack of knowledge of biological processes underlying disease progression. Exosomes have been identified as biomarkers sources in different cancer types. Aim of the study was to analyse the contents of circulating exosomes in patients with pancreatic cancer who received palliative chemotherapy.

KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to Enhanced -Glutathionylation of Distinct Structural and Regulatory Proteins.

Loss-of-function mutations in the KRIT1 gene are associated with the pathogenesis of cerebral cavernous malformations (CCMs), a major cerebrovascular disease still awaiting therapies. Accumulating evidence demonstrates that KRIT1 plays an important role in major redox-sensitive mechanisms, including transcriptional pathways and autophagy, which play major roles in cellular homeostasis and defense against oxidative stress, raising the possibility that KRIT1 loss has pleiotropic effects on multiple redox-sensitive systems. Using previously established cellular models, we found that KRIT1 loss-of-function affects the glutathione (GSH) redox system, causing a significant decrease in total GSH levels and increase in oxidized glutathione disulfide (GSSG), with a consequent deficit in the GSH/GSSG redox ratio and GSH-mediated antioxidant capacity.

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways.

Glutathione is considered the major non-protein low molecular weight modulator of redox processes and the most important thiol reducing agent of the cell. The biosynthesis of glutathione occurs in the cytosol from its constituent amino acids, but this tripeptide is also present in the most important cellular districts, such as mitochondria, nucleus, and endoplasmic reticulum, thus playing a central role in several metabolic pathways and cytoprotection mechanisms. Indeed, glutathione is involved in the modulation of various cellular processes and, not by chance, it is a ubiquitous determinant for redox signaling, xenobiotic detoxification, and regulation of cell cycle and death programs.

Emerging Biomarkers in Bladder Cancer Identified by Network Analysis of Transcriptomic Data.

Bladder cancer is a very common malignancy. Although new treatment strategies have been developed, the identification of new therapeutic targets and reliable diagnostic/prognostic biomarkers for bladder cancer remains a priority. Generally, they are found among differentially expressed genes between patients and healthy subjects or among patients with different tumor stages.

LncRNA co-expression network analysis reveals novel biomarkers for pancreatic cancer.

High mortality and low survival rates for pancreatic ductal adenocarcinoma (PDAC) mainly result from the delay in diagnosis and treatment. Therefore, there is an urgent need to identify early PDAC biomarkers and new therapeutic targets. In this study, we applied a commonly used systems biology approach, the weighted gene co-expression network analysis (WGCNA), on lncRNA expression data.

A possible S-glutathionylation of specific proteins by glyoxalase II: An in vitro and in silico study.

Unlabelled: Glyoxalase II, the second of 2 enzymes in the glyoxalase system, is a hydroxyacylglutathione hydrolase that catalyses the hydrolysis of S-d-lactoylglutathione to form d-lactic acid and glutathione, which is released from the active site. The tripeptide glutathione is the major sulfhydryl antioxidant and has been shown to control several functions, including S-glutathionylation of proteins. S-Glutathionylation is a way for the cells to store reduced glutathione during oxidative stress, or to protect protein thiol groups from irreversible oxidation, and few enzymes involved in protein S-glutathionylation have been found to date.

Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient's prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples.

Epithelial to Mesenchymal Transition in Renal Cell Carcinoma: Implications for Cancer Therapy.

Epithelial-to-mesenchymal transition (EMT) is a developmentally vital reversible process by which fully differentiated cells lose their epithelial features and acquire a migratory mesenchymal phenotype. EMT contributes to the metastatic potential of tumors. The expression profile and other biological properties of EMT suggest potential targets for cancer therapy, including in renal-cell carcinoma (RCC).

Glyoxalase II promotes "in vitro" S-glutathionylation.

S-glutathionylation involves the reversible formation of a mix disulphide-bridge between specific cysteine and a molecule of glutathione, the major non-protein antioxidant compound in the cell. Mechanisms of protein S-glutathionylation are far to be completely understood and several reactions can promote it, either spontaneously or catalyzed. For the first time Glo II enzyme was studied as a new potential candidate to promote S-glutathionylation.

Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma.

Clear cell Renal Cell Carcinoma (ccRCC) is due to loss of von Hippel-Lindau (VHL) gene and at least one out of three chromatin regulating genes BRCA1-associated protein-1 (BAP1), Polybromo-1 (PBRM1) and Set domain-containing 2 (SETD2). More than 350, 700 and 500 mutations are known respectively for BAP1, PBRM1 and SETD2 genes. Each variation damages these genes with different severity levels.

BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies.

Several novel recurrent mutations of histone modifying and chromatin remodeling genes have been identified in renal cell carcinoma. These mutations cause loss of function of several genes located in close proximity to VHL and include PBRM1, BAP1 and SETD2. PBRM1 encodes for BAF180, a component of the SWI/SNF chromatin remodeling complex, and is inactivated in, on average, 36% of clear cell renal cell carcinoma (ccRCC).

KRAS mutation status is associated with specific pattern of genes expression in pancreatic adenocarcinoma.

Aims: To evaluate potential differences at a molecular level between KRAS mutant tumors (MT) and KRAS wild-type (WT) pancreatic tumors and the biological and prognostic significance of different KRAS mutations.

Materials & Methods: Expression of a panel of 29 genes was analyzed in KRAS WT and MT tumors. Effects of KRAS mutation and gene expression levels were assessed on patients' survival.

Lgr5 expression, cancer stem cells and pancreatic cancer: results from biological and computational analyses.

Aims: To determine the relationship between Lgr5 and other stemness markers and pathologic features in pancreatic ductal adenocarcinoma (PDAC) samples.

Materials & Methods: In 69 samples, Lgr5 was analyzed by qRT-PCR together with a panel of 29 genes. Bioinformatic analysis was carried out to identify a possible pathway regulating Lgr5 expression in PDAC.

Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer.

Introduction: Signal transducer and activator of transcription 3 (STAT3) mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in several cellular processes such as cell growth and apoptosis. Deregulation of the STAT3 activity has been shown in many malignancies, including breast, head and neck, prostate, pancreas, ovarian and brain cancers and melanoma. Thus, STAT3 may represent an ideal target for cancer therapy.

ExportAid: database of RNA elements regulating nuclear RNA export in mammals.

Motivation: Regulation of nuclear mRNA export or retention is carried out by RNA elements but the mechanism is not yet well understood. To understand the mRNA export process, it is important to collect all the involved RNA elements and their trans-acting factors.

Results: By hand-curated literature screening we collected, in ExportAid database, experimentally assessed data about RNA elements regulating nuclear export or retention of endogenous, heterologous or artificial RNAs in mammalian cells.

How much do we know about the coupling of G-proteins to serotonin receptors?

Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes.

Strawberry intake increases blood fluid, erythrocyte and mononuclear cell defenses against oxidative challenge.

The health promoting effects of a regular consumption of strawberries deserve attention, and a direct or indirect antioxidant role of strawberry bioactive compounds is among the most probable mechanisms underlying their beneficial properties. In the present study, we evaluated the overall effects of a 2-week daily consumption of strawberries on plasma antioxidant status, membrane lipid susceptibility to ex vivo-induced oxidation, and erythrocyte and mononuclear cell resistance to oxidative damage in apparently healthy volunteers. After strawberry intake, a moderate increase in fasting plasma antioxidant capacity and vitamin C was observed, together with a significant increase in the lag phase preceding plasma lipid oxidation.

Oncogenic H-Ras up-regulates acid β-hexosaminidase by a mechanism dependent on the autophagy regulator TFEB.

The expression of constitutively active H-RasV12 oncogene has been described to induce proliferative arrest and premature senescence in many cell models. There are a number of studies indicating an association between senescence and lysosomal enzyme alterations, e.g.

Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists.

Specific modulation of serotonin 5-HT(2C) G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. The different efficacy of drugs targeting these receptors are due to the presence of genetic variants in population and this variability is still hard to predict. Therefore, in order to administer the more suitable drug, taking into account patient genotype, it is necessary to know the molecular effects of its gene nucleotide variations.

S-D-Lactoylglutathione can be an alternative supply of mitochondrial glutathione.

The mitochondrial pool of GSH (glutathione) is considered the major redox system in maintaining matrix redox homeostasis, preserving sulfhydryl groups of mitochondrial proteins in appropriate redox state, in defending mitochondrial DNA integrity and protecting mitochondrial-derived ROS, and in defending mitochondrial membranes against oxidative damage. Despite its importance in maintaining mitochondrial functionality, GSH is synthesized exclusively in the cytoplasm and must be actively transported into mitochondria. In this work we found that SLG (S-D-lactoylglutathione), an intermediate of the glyoxalase system, can enter the mitochondria and there be hydrolyzed from mitochondrial glyoxalase II enzyme to D-lactate and GSH.

Cellular redox imbalance and changes of protein S-glutathionylation patterns are associated with senescence induced by oncogenic H-ras.

H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and transform cells. In fact, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. In our experimental model, human fibroblasts transfected with H-RasV12 show a dramatic modification of morphology.