A selective p53 activator and anticancer agent to improve colorectal cancer therapy

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.We thank PT national funds (FCT/MCTES , Fundação para a Ciência e a Tecnologia , and Ministério da Ciência, Tecnologia e Ensino Superior ) through grants UIDB/50006/2020 , UID/BIO/04469/2019 , UIDB/04539/2020 , and UIDP/04539/2020 ( CIBB ); BioTecNorte operation ( NORTE-01-0145-FEDER-000004 ) and Porto Neurosciences and Neurologic Disease Research Initiative at I3S ( Norte-01-0145-FEDER-000008 ) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte ; Masaryk University ( Project MUNI/A/1127/2019 ) and Ministry of Education, Youth and Sports of the Czech Republic (project nos. LQ1605 and LM2018125 ); FCT financial support through the fellowships SFRH/BD/119144/2016 (H.R.) and SFRH/BD/117949/2016 (L.R.); Fondazione AIRC ( IG#18985 , A.I.); and the Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences , PD/00016/2012 ). We thank Dario Rizzotto for assistance in preparing the libraries for RNA sequencing. Funding: This work was supported by PT National Funds (FCT/MCTES, Fundação para a Ciência e Tecnologia , and Ministério da Ciência, Tecnologia e Ensino Superior ) via the projects UIDB/50006/2020 ( LAQV/REQUIMTE ), UIDB/00313/2020 , and UIDP/00313/2020 , co-funded by COMPETE2020-UE

Proteomics-Based Systems Biology Modeling of Bovine Germinal Vesicle Stage Oocyte and Cumulus Cell Interaction

BACKGROUND: Oocytes are the female gametes which establish the program of life after fertilization. Interactions between oocyte and the surrounding cumulus cells at germinal vesicle (GV) stage are considered essential for proper maturation or 'programming' of oocytes, which is crucial for normal fertilization and embryonic development. However, despite its importance, little is known about the molecular events and pathways involved in this bidirectional communication. METHODOLOGY/PRINCIPAL FINDINGS: We used differential detergent fractionation multidimensional protein identification technology (DDF-Mud PIT) on bovine GV oocyte and cumulus cells and identified 811 and 1247 proteins in GV oocyte and cumulus cells, respectively; 371 proteins were significantly differentially expressed between each cell type. Systems biology modeling, which included Gene Ontology (GO) and canonical genetic pathway analysis, showed that cumulus cells have higher expression of proteins involved in cell communication, generation of precursor metabolites and energy, as well as transport than GV oocytes. Our data also suggests a hypothesis that oocytes may depend on the presence of cumulus cells to generate specific cellular signals to coordinate their growth and maturation. CONCLUSIONS/SIGNIFICANCE: Systems biology modeling of bovine oocytes and cumulus cells in the context of GO and protein interaction networks identified the signaling pathways associated with the proteins involved in cell-to-cell signaling biological process that may have implications in oocyte competence and maturation. This first comprehensive systems biology modeling of bovine oocytes and cumulus cell proteomes not only provides a foundation for signaling and cell physiology at the GV stage of oocyte development, but are also valuable for comparative studies of other stages of oocyte development at the molecular level

Are social norms associated with smoking in French university students? A survey report on smoking correlates

<p>Abstract</p> <p>Background</p> <p>Knowledge of the correlates of smoking is a first step to successful prevention interventions. The social norms theory hypothesises that students' smoking behaviour is linked to their perception of norms for use of tobacco. This study was designed to test the theory that smoking is associated with perceived norms, controlling for other correlates of smoking.</p> <p>Methods</p> <p>In a pencil-and-paper questionnaire, 721 second-year students in sociology, medicine, foreign language or nursing studies estimated the number of cigarettes usually smoked in a month. 31 additional covariates were included as potential predictors of tobacco use. Multiple imputation was used to deal with missing values among covariates. The strength of the association of each variable with tobacco use was quantified by the inclusion frequencies of the variable in 1000 bootstrap sample backward selections. Being a smoker and the number of cigarettes smoked by smokers were modelled separately.</p> <p>Results</p> <p>We retain 8 variables to predict the risk of smoking and 6 to predict the quantities smoked by smokers. The risk of being a smoker is increased by cannabis use, binge drinking, being unsupportive of smoke-free universities, perceived friends' approval of regular smoking, positive perceptions about tobacco, a high perceived prevalence of smoking among friends, reporting not being disturbed by people smoking in the university, and being female. The quantity of cigarettes smoked by smokers is greater for smokers reporting never being disturbed by smoke in the university, unsupportive of smoke-free universities, perceiving that their friends approve of regular smoking, having more negative beliefs about the tobacco industry, being sociology students and being among the older students.</p> <p>Conclusion</p> <p>Other substance use, injunctive norms (friends' approval) and descriptive norms (friends' smoking prevalence) are associated with tobacco use.</p> <p>University-based prevention campaigns should take multiple substance use into account and focus on the norms most likely to have an impact on student smoking.</p

Being lonely or using substances with friends? A cross-sectional study of Hungarian adolescents’ health risk behaviours

BACKGROUND: Studying adolescents' health risk behaviours is oddly significant in Central and Eastern European countries, where the prevalence of smoking and drinking among 14-18 year old students is significantly high. The goal of our study is to examine the role of social psychological and social behavioural variables in health risk behaviours among Hungarian adolescents. METHODS: Our sample was comprised of three high schools of Debrecen (the second largest city of Hungary). In all, 501 students filled in the questionnaire from 22 classes (14-22 years old). Students aged above 18 years were excluded for the purpose of the study, giving a total sample size of 471 high school students. Descriptive statistics and binary logistic regression analyses were conducted. RESULTS: According to our results (1) social behavioural factors (namely, smoking and alcohol use of the best friend and peer group) proved to be better predictors of adolescents' health risk behaviours as compared to the included social psychological attributes (2); among the latter ones, loneliness and shyness were negatively related with both smoking and drinking, while competitiveness was a predictor of drinking prevalence among boys. CONCLUSIONS: The findings suggest that social behavioural factors, including smoking and drinking of friends, are oddly important predictors of Hungarian adolescents' health risk behaviours. According to our results, health policy should pay more attention to peer norms related to smoking and drinking during school health promotion. Developing health protective social norms may be an indispensable component of effective health promotion in high schools

Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms

Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2&alpha; (Topo2&alpha;), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy

Coordination-Driven Self-Assembly on Polymer Surfaces for Efficient Synthesis of [Au(SPh)](n) Coordination Polymer-Based Films

SSCI-VIDE+CDFA+TTS:ADM:SVDInternational audience--

An intrinsic dual-emitting gold thiolate coordination polymer, [Au( plus I)(p-SPhCO2H)](n), for ratiometric temperature sensing

SSCI-VIDE+CDFA+OVE:ADMInternational audienc