Investigation of TNBC in vitro Antiproliferative Effects of Versatile Pirrolo[1,2-a]quinoxaline Compounds

he triple-negative breast cancer (TNBC) is characterized by a more aggressive nature and poorer prognosis, nowadays none pharmaceutical approach is still available. For this reason, the research of new active compounds and attractive targets represents an interesting field. In this context MDA- MB-231 cell line was selected to evaluate the antiproliferative effects of new [1,2-a]-pyrroloquinoxaline derivatives. The MTT assay revealed that the amine forms of synthesized molecules were more active compared to iminic ones at 72 h of incubation. The antiproliferative effect of the most promising compounds highlighted the formation of autophagic vacuoles

RAD51 and mitotic function of MUS81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death

International support for the Arab uprisings: Understanding sympathetic collective action using theories of social dominance and social identity

Inspired by the popular Arab protests against oppressive regimes that began in 2010, people around the world protested in sympathy with the Arab peoples. The present research draws on two major theories of intergroup relations to develop an initial integrative model of sympathetic collective action. We incorporate social dominance theory’s (SDT) concept of (rejectionist) legitimizing myths with the solidarity and emotional mediation concept of the social identity model of collective action (SIMCA) to understand motivations for sympathetic collective action among bystanders. Using data from 12 nations (N = 1,480), we tested three models: (a) SIMCA (i.e., solidarity, anger, and efficacy), (b) a social dominance theory model of collective action (i.e., social dominance orientation and ideologies concerning Arab competence), and (c) an integrated model of sympathetic collective action combining both theories. Results find the greatest support for an integrated model of collective action. Discussion focuses on theoretical pluralism and suggestions for future research

Discovery of a novel quinoxalinhydrazide with a broad-spectrum anticancer activity

Previously, we discovered a novel class of salicylhydrazide compounds with remarkable activity in hormone-dependent and -independent human cancer cells. We then designed and synthesized numerous analogues. Among these analogues, a quinoxalinhydrazide compound, SC144, exhibited desirable physicochemical and drug-like properties and therefore was selected for further preclinical investigation. In the present study, we evaluated the in vitro activity of SC144 in a range of drug-sensitive and -resistant cancer cell lines as well as its in vivo efficacy in MDA-MB-435 and HT29 mice xenograft models. The broad-spectrum cytotoxicity of SC144 is especially highlighted by its potency in ovarian cancer cells resistant to cisplatin, breast-cancer cells resistant to doxorubicin, and colon cancer cells resistant to oxaliplatin. Furthermore, its activity was independent of p53, HER-2, estrogen and androgen receptor expressions. We also examined the effect of SC144 on cell cycle progression and apoptosis in select cell lines. Considering its cytotoxicity profile in a variety of in vitro and in vivo cancer models as well as its effects on cell cycle regulation and apoptosis, SC144 appears to represent a promising agent for further clinical development

Neck subcutaneous nodule as first metastasis from broad ligament leiomyosarcoma: a case report and review of literature

Leiomyosarcoma usually develops in the myometrium and is characterized by a high recurrence rate, frequent hematogenous dissemination, and poor prognosis. Metastasis is usually to lungs, liver, and bone, and occasionally to the brain, but seldom to the head and neck region. Primary leiomyosarcoma very rarely arises in the broad ligament

Development of quercetin-DHA ester-based pectin conjugates as new functional supplement. Effects on cell viability and migration

A quercetin derivative with remarkable biological performance was successfully synthesized by chemical modification of the flavonoid with docosahexaenoic acid to synthesize 2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate (3), deeply characterized by NMR spetroscopy. Modified quercetin and pectin were involved in a grafting process by an ecofriendly radical procedure able to preserve the biological features of the quercetin derivative. Antioxidant performances of the conjugate were evaluated both in term of total phenolic amount and scavenger activity in organic and aqueous environments. Additionally, in vitro acute oral toxicity was also tested against Caco-2 cells and 3T3 fibroblasts, confirming that pectin conjugate does not have any effect on cell viability at the dietary use concentrations. Finally, in vitro experiments highlighted the ability of the conjugate to counteract the migratory properties of Caco-2 and HepG2 cells, indicating its feature in the reduction of the migration of tumour cells. These data showed that the covalent binding of the quercetin derivative to the pectin chain represents a very interesting strategy to improve the bioavailability of the quercetin, representing an effective means of protecting and to transporting polyphenol molecules

Profiling RNA editing in human tissues: towards the inosinome Atlas

Adenine to Inosine RNA editing is a widespread co- and post-transcriptional mechanism mediated by ADAR enzymes acting on double stranded RNA. It has a plethora of biological effects, appears to be particularly pervasive in humans with respect to other mammals, and is implicated in a number of diverse human pathologies. Here we present the first human inosinome atlas comprising 3,041,422 A-to-I events identified in six tissues from three healthy individuals. Matched directional total-RNA-Seq and whole genome sequence datasets were generated and analysed within a dedicated computational framework, also capable of detecting hyper-edited reads. Inosinome profiles are tissue specific and edited gene sets consistently show enrichment of genes involved in neurological disorders and cancer. Overall frequency of editing also varies, but is strongly correlated with ADAR expression levels. The inosinome database is available at: http://srv00.ibbe.cnr.it/editing/