Targeting SMYD3 to sensitize homologous recombination-proficient tumors to PARP-mediated synthetic lethality

SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors

Data monitoring roadmap. The experience of the Italian Multiple Sclerosis and Related Disorders Register

Introduction Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked.This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register.MethodsThe Register collects, through a standardized Web-based Application, unique patients.Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated.ResultsThe Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients.The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were >= 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2).Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months.ConclusionsData from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications

Nitrification and coupled nitrification-denitrification at shallow depths are responsible for early season N2O emissions under alternate wetting and drying management in an Italian rice paddy system

There is increasing pressure to reduce water use in irrigated rice production to save water, reduce methane emissions and reduce grain arsenic uptake arising from anaerobic conditions. However, under such practices emissions of nitrous oxide (N2O) often increase. Rice systems generally exhibit strong stratification of environmental conditions that drive the balance between N2O production and consumption, and ultimately the emissions of N2O. We investigated how the introduction of alternate wetting and drying (AWD) relative to conventional flood (FLD) irrigation modifies the depth distribution of environmental conditions and nutrients (NO3-, NH4+, dissolved organic carbon, soil redox (Eh) and water filled pore space, (WFPS)). We then examined how these variables related to N2O production and consumption via the measurement of delta N-15-N2Oemitted/poreair, delta N-15-NO3-, N2Oturnover and subsurface N2O fluxes at five depths (5, 12.5, 25, 50 and 80 cm). These measurements, together with N2O surface emissions were taken on six days surrounding a broadcast urea fertilizer application and for six days surrounding the onset of final drainage. The highest emissions were observed in the AWD treatment at the onset of measurements. These emissions were driven by high NH4+ availability and could mainly be attributed to nitrification directly or indirectly via coupled nitrification-denitrification in the upper depths. In both irrigation treatments, an increase in NO3- and dissolved N2O concentrations and a drop in delta N-15-NO3- values indicated rapid and ephemeral nitrification following the fertilization, but without significant effects on N2O surface emissions. At 50 and 80 cm, delta N-15-N2Oporeair, was enriched relative to upper depths, pointing to N2O reduction at these depths in both treatments. We conclude that the increased N2O emissions under AWD compared to FLD management were associated with enhanced nitrification in the upper soil layers during plant establishment and thus related to basal N fertilization and mineralization of native soil N rather than in-season fertilization

Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality

SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors