WEE1 kinase inhibition triggers severe chromosome pulverization in aneuploid cells

Abstract Aneuploidy, a hallmark of cancer, is a prominent feature associated with poor prognosis in breast cancer. Here, we screened a panel of cell cycle kinase inhibitors to identify novel targets for highly aneuploid breast cancers. We show that increasing aneuploidy in breast cancer cells sensitizes to the inhibition of WEE1 kinase. Upon exposure to WEE1 inhibitor, aneuploid cells exhibit aberrant mitosis characterized by the detachment of centromere proteins from centromeric DNA and pulverization of chromosomes. The occurrence of such phenotype is driven by excessive levels of replication stress and DNA damage during S-phase, that in turn trigger major defects in the subsequent mitosis. We show that DNA2 helicase/nuclease, that regulates replication of centromeric DNA, is the key player responsible for severe chromosome pulverization in mitosis. The heightened vulnerability of aneuploid cells to WEE1 inhibition, coupled with underlying molecular mechanisms, provides a rationale for clinical exploration of WEE1-targeted therapies against aneuploid breast cancers. Impact Statement Increased vulnerability of aneuploid cells to WEE1 inhibition is orchestrated by the DNA2 nuclease/helicase. These findings open new therapeutic strategies in the context of personalized medicine in breast cancer

Microtubule-Associated Protein ATIP3, an Emerging Target for Personalized Medicine in Breast Cancer

Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician’s therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer

Detection of DNA damage by alkaline comet assay in mouse colonic mucosa

We recently characterized the association between DNA damage and immunoresponse in vivo in colonic mucosa of mice infected with a Salmonella Typhimurium strain expressing a genotoxin, known as typhoid toxin. In this protocol, we describe the specific steps for assessing DNA damage by the alkaline comet assay of colonic mucosal samples. The description of the comet assay protocol follows the international guidelines (Minimum Information for Reporting on the Comet Assay [Moller et al., 2020]). For complete details on the use and execution of this protocol, please refer to Martin et al. (2021)

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells

Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastric carcinogenesis. Methods: Using three different gastric epithelial cell lines, a non-cancerous (HFE-145) and two different subtypes of gastric cancer (AGS and MKN74), we analyzed the modulation of Nrf2 expression over time. After invalidation of Nrf2 by CRISPR-cas9, we assessed its role in H. pylori-induced epithelial-to-mesenchymal transition (EMT). Finally, we evaluated the expression of Nrf2 and ZEB1, a central EMT transcription factor, in human gastric tissues. Results: We first demonstrated that the Nrf2 signaling pathway is differentially regulated depending on the infection stage. Rapidly and transiently activated, Nrf2 was downregulated 24 h post-infection in a VacA-dependent manner. We then demonstrated that Nrf2 invalidation leads to increased EMT, which is even exacerbated after H. pylori infection. Finally, Nrf2 expression tended to decrease in human patients’ gastric mucosa infected with H. pylori. Conclusions: Our work supports the hypothesis that Nrf2 downregulation upon H. pylori infection participates in EMT, one of the most important events in gastric carcinogenesis

Systematic Proteomic Approach to Characterize the Impacts of Chemical Interactions on Protein and Cytotoxicity Responses to Metal Mixture Exposures

Chemical interactions have posed a big challenge in toxicity characterization and human health risk assessment of environmental mixtures. To characterize the impacts of chemical interactions on protein and cytotoxicity responses to environmental mixtures, we established a systems biology approach integrating proteomics, bioinformatics, statistics, and computational toxicology to measure expression or phosphorylation levels of 21 critical toxicity pathway regulators and 445 downstream proteins in human BEAS-2B cells treated with 4 concentrations of nickel, 2 concentrations each of cadmium and chromium, as well as 12 defined binary and 8 defined ternary mixtures of these metals in vitro. Multivariate statistical analysis and mathematical modeling of the metal-mediated proteomic response patterns showed a high correlation between changes in protein expression or phosphorylation and cellular toxic responses to both individual metals and metal mixtures. Of the identified correlated proteins, only a small set of proteins including HIF-1α is likely to be responsible for selective cytotoxic responses to different metals and metals mixtures. Furthermore, support vector machine learning was utilized to computationally predict protein responses to uncharacterized metal mixtures using experimentally generated protein response profiles corresponding to known metal mixtures. This study provides a novel proteomic approach for characterization and prediction of toxicities of metal and other chemical mixtures

Neurobiologia do transtorno de humor bipolar e tomada de decisão na abordagem psicofarmacológica

O Transtorno do Humor Bipolar (THB) caracteriza-se por oscilações do humor que causam prejuízos significativos no âmbito biopsicossocial. O interesse da comunidade científica por este transtorno vem aumentando nos últimos cinco anos em função de sua crescente prevalência associada ao refinamento diagnóstico, à ampliação do arsenal terapêutico e ao conhecimento dos avanços nas pesquisas da neurobiologia do transtorno. A presente revisão aborda questões diagnosticas e terapêuticas aplicadas à neurobiologia dos THB, relacionando-as diretamente à terapêutica dos quadros de mania, hipomania, estados mistos, depressão bipolar e ciclagem rápida, da infância à idade adulta. São revisados criticamente importantes estudos realizados com diferentes fármacos potencialmente eficazes como estabilizadores do humor, nos diversos subdiagnósticos do THB. São analisados fármacos, tais como o lítio, anticonvulsivantes, antipsicóticos, benzodiazepínicos, bloqueadores dos canais de cálcio e hormônio tireoideo, bem como as possíveis bases biológicas para seus efeitos terapêuticos. Em síntese, este trabalho aborda os avanços da psicofarmacologia cuja eficácia é comprovada nos subtipos do THB, procurando relacioná-los com a neurobiologia deste transtorno.Bipolar Disorder (BD) is characterized by mood swings that cause significant impairment in social, occupational, or other areas of functioning. During the last years, new insights have been provided in the diagnosis, etiology, neurobiological basis and treatment of bipolar disorder. This paper emphasizes recent studies related to some diagnostic and therapeutic aspects during manic episode, hypomanic, mixed episode, bipolar depression and rapid cycling, in children, adolescents and adults. Studies using proposed mood stabilizers, which present adequate metodological basis, including double–blind, controlled studies and which presented a significant number of patients were included and critically evaluated in this revision. Drugs such as the lithium, anticonvulsants, antipsychotics, benzodiazepines, calcium channels blockers and thyroid augmentation are proposed to be effective in certain diagnostic profiles. The possible biological bases for these drugs therapeutic effects are also revised. In summary, this article focuses on recent and important psychopharmacological progresses on the treatment of BD subtypes. Furthermore, the revision presents possible biological basis to explain the therapeutic profile of these drugs

Proceedings of the 3rd International Conference on Community Engagement and Education for Sustainable Development

This proceeding contains articles on the various ideas of the academic community presented at The 3rd International Conference on Community Engagement and Education for Sustainable Development (ICCEESD 2022) organized by the Universitas Gadjah Mada, Indonesia on 7th-8th December 2022.  ICCEESD is a biannual forum for sharing, benchmarking, and discussing HEI’s activities in developing Education for Sustainable Development towards community engagement. Education for Sustainability as a teaching strategy for resolving community challenges through formal, informal, or non-formal education is expected to benefit from various community service best practices by academics, researchers, and students. The 3rd ICCEESD has “Strengthening Education for Sustainability Towards Better Community Engagement” as its theme this year. It is expected that the 3rd ICCEESD will provide a forum for the presenters and participants to exchange best practices, policies, and conceptual implementation of Education for Sustainability towards better community engagement and explore ideas to address community needs.  Conference Title: 3rd International Conference on Community Engagement and Education for Sustainable DevelopmentConference Theme: Strengthening Education for Sustainability Towards Better Community EngagementConference Acronyms: ICCEESD 2022Conference Date: 7th-8th December 2022Conference Location: Grand Rohan Jogja Yogyakarta, IndonesiaConference Organizer: Universitas Gadjah Mada, Indonesi