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Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to palbociclib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to palbociclib enhances G 1 cell cycle arrest and cellular senescence in tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2 and Cyclin E2 caused by palbociclib and enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and palbociclib was also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo . However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/palbociclib combination, suggesting one molecular route that could lead to drug resistance.

HORMAD1 expression is usually restricted to germ-line cells but is also aberrantly expressed in 60% of triple-negative breast cancers (TNBCs), where it is bi-modally expressed and associated with genomic instability. Here, we show that out-of-context HORMAD1 expression in mitotic cells perturbs mitotic arrest and generates aneuploidy. These phenotypes are caused by out-of-context HORMAD1 expression driving a weakening of the spindle assembly checkpoint (SAC) and/or in kinetochore-microtubule error correction. These mitotic effects of HORMAD1 are MAD2L1-independent, but instead caused by a HORMAD1/Aurora B interaction and defective Aurora B/INCENP signalling. Consistent with this mechanism, aberrant HORMAD1 expression causes sensitivity to MPS1, Aurora B or BUB1 inhibitors currently being investigated as cancer treatments. Our data suggests how out-of-context expression of a meiotic gene imparts genomic instability upon tumour cells and also identifies several associated dependencies as mechanism-based therapeutic targets for a large, biomarker-defined, subset of cancers. HORMAD1 expression is typically restricted to germline cells where it has an important role in meiotic recombination but has been shown to be upregulated in triple negative breast cancer (TNBC). Here, the authors report that aberrant HORMAD1 expression weakens the spindle assembly checkpoint, driving sensitivity to AURORA kinase inhibition.

Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects most of the adult population and persists for life after the initial contact. The extreme success of the virus is attributed to its bipartite life cycle, which consists of a dormant-like state of latency, with periodical reactivation to the virus producing, lytic phase. Zta (BZLF1, Z, Zebra or EB1) is a multifunctional viral protein that belongs to the bZIP family of transcription factors and is known as the master lytic regulator of EBV. Together with transcriptional activation, Zta has been shown to be involved in DNA binding-dependent transcriptional repression, particularly of the host class II major histocompatibility complex transactivator, CIITA. Distinct protein domains, as well as various post translational modifications, like phosphorylation of Serine 209 by the viral protein kinase (VPK), have been linked to different functional roles of Zta. In the present study, it was shown that VPK can partially inhibit SUMOylation of Zta on Lysine 12, in a manner which was not dependent on Serine 209 phosphorylation. However, no direct interaction of VPK and Zta could be observed and no significant effect of either proteins on histone H2AX phosphorylation was seen. Interestingly, in vitro reporter assays revealed that fusion of a SUMO moiety to the amine-terminus of Zta inhibited repression of the CIITA promoter, but not the activation of the viral BHLF1 promoter, pointing at divergent mechanisms of action of transcriptional repression and activation by Zta. Moreover, truncation of the carboxy-terminal dimerisation domain of Zta (crucial for protein-DNA interaction) abrogated BHLF1 transactivation but not CIITA down-regulation, revealing underlying diffe rences in DNA binding requirements for the two processes. Further in silico sequence analysis, coupled with a mutation approach of the CIITA promoter, confirmed that an alternate route to the Zta DNA binding-dependent repression exists. Finally, no single promoter element could be linked to down-regulation of CIITA, suggesting sequestration of a possible, yet unknown cofactor, by Zta.

Even if political agendas always had youth's social inclusion as an important item, in the last two decades this issue became critical. For this age group, in recent years, unemployment reached very high levels (21.8% in 2010 and 21.9% in 2011). According to Eurostat data, youth represent one fifth of total European Union population. Regardless of the exceptional opportunities available for young people in modern societies, they also face extreme challenges related to the educational and training systems and their labour market access. The decrease in the number of permanent jobs due to the crisis had a disproportionate effect on the youth, this group been overrepresented in the temporary contracts category. Even if, under normal circumstances, temporary contracts represent the first step to more stable forms of employment, they can also create segmented labour markets, young people being trapped in the lower segments with less training on the job, lower payment and worse openings for long-term employment and career. In order to achieve the Strategy \"Europe 2020\" objective of 75% employment for the age group 20-64, new approaches are needed concerning the measures and the ways to boost young people's transition to the labour force. As a result of reduced youth participation to the labour force, both the Romanian National Strategy for Social Protection and Social Inclusion 2008-2010 and the Romanian National Development Plan 2007-2013 considered youth integration into the labour market as a major challenge and main priority. This paper briefly describes European Union labour market and further presents an analysis of the Romanian youth labour market peculiarities compared to that in the EU-27 and other EU countries; some possible solutions are listed.

Water reservoirs are critical components of hydrological systems that mitigate floods and droughts, but their long-term performance under climate change and variable socioeconomic conditions remain insufficiently documented. This study examines the Bahlui River basin (northeastern Romania), where 17 reservoirs constructed mainly between the 1960s and 1980s have been operational for more than five decades. Using the most recent technical reservoir reports, land-use evolution, and present operational functions, the contribution of man-made reservoirs to flood attenuation and drought buffering over time was appraised. Flood mitigation is the most consistent and reliable function, with peak-flow reductions commonly exceeding 60–90% of design discharges at the basin scale. Engineered drought mitigation functions (irrigation and industrial water supply) have decreased significantly as a result of socioeconomic changes started in 1989. However, the gradual expansion of green infrastructure, such as wetlands and riparian vegetation, has improved passive water retention and low-flow buffering capacity. These unanticipated developments have resulted in variable levels of hybrid hydrological resilience. The findings show that, while artificial reservoirs have strong flood-control capacity over long periods of time, their contribution to drought mitigation is increasingly dependent on the integration of ecological components, emphasizing the importance of green-gray interactions in long-term reservoir management.

Urbanization fundamentally fractures the natural water cycle, leading to a cascade of interconnected problems including increased flood risk, degraded water quality, stressed groundwater resources, and inefficient distribution networks. Traditional, fragmented management approaches that address these issues in isolation have proven inadequate. This research argues for a paradigm shift towards an Integrated Urban Water Management (IUWM) framework anchored in the concept of the “river-aquifer-pipe network continuum”, treating these components as a single, dynamic hydrological and infrastructural entity. Drawing upon a series of detailed case studies from Eastern Romania, this paper synthesizes the systemic impacts of development across the entire urban water system. Evidence from the Prut, Olt, and Bahlui river basins demonstrate how channelization exacerbates flood peaks and leads to severe biochemical degradation. Hydrogeological modeling of the Gherăești-Bacău wellfield reveals the vulnerabilities of over-extraction, while analysis of the Iași water network highlights the challenge of water losses in the aging infrastructure. In response, a modern, multi-tool approach is consolidated into a practical, three-stage framework for action: Diagnose, Prescribe, and Optimize. This framework advocates for (1) a comprehensive diagnosis using a suite of predictive numerical models (a “digital twin”); (2) the prescription of foundational, nature-based solutions, such as floodplain restoration, to heal core ecological functions; and (3) the continuous optimization of engineered infrastructure using smart, real-time control technologies. The synthesis concludes that an integrated, data-driven, and collaborative approach is the only sustainable path forward. Future research should focus on formally coupling these diagnostic models to create true Digital Twins of urban water systems—an essential step towards building resilient, water-secure cities for the 21st century.

Background and Objectives: Groin hernia repair surgery (GHRS) is among the most common elective interventions. The aim of this three-year nationwide study on GHRS is to provide a thorough analysis of the impact that the COVID-19 pandemic had on the Romanian Health System in regard to elective procedures. Materials and Methods: 46,795 groin hernia cases obtained between 2019 and 2021 from the DRG database using ICD-10 diagnostic codes. The data were collected from all 261 GHRS performing hospitals nationwide, including 227 public hospitals (PbH) and 34 private hospitals (PvH). The 42 variables taken into account were processed using Microsoft Excel 2021, applying Chi square, F-Test Two-Sample for variances, and Two Sample t-Test. The significance threshold considered was p < 0.001. Results: Of the grand total of cases, 96.2% were inguinal hernias, 86.8% were performed on men, 15.2% were laparoscopic procedures, and 6.88% were in PvH. Overall, due to the pandemic, the total number of GHRS decreased with 44.45% in 2020 and with 29.72% in 2021 compared to pre-pandemic year 2019. April 2020 shows the steepest decrease in GHRS (91 procedures nationwide). In the private sector, there was an opposite trend with increases in the number of cases by 12.21% and a 70.22% in both pandemic years. The mean admission period (MAP) for all procedures was 5.5 days. There was a significant difference between PbH and PvH (5.75 vs. 2.8 days, p < 0.0001). During the pandemic, the MAP in PbH decreased (6.02 in 2019, 5.82 in 2020 and 5.3 in 2021), remaining stable for PvH (2.9 days in 2019, 2.85 days in 2020 and 2.74 days in 2021). Conclusion: The COVID-19 pandemic significantly reduced the overall number of GHRS performed in Romania in 2020 and 2021, compared to 2019. However, the private sector thrived with an actual increase in the number of cases. There was a significant lower MAP in the PvH compared to PbH throughout the three-year period.

Background: Upper esophageal perforations are life-threatening conditions associated with a high risk of mediastinitis, sepsis, and multiorgan failure. Standard management often requires extensive surgical intervention, which carries substantial morbidity. Methods: We report the case of a 56-year-old male with an iatrogenic cervical esophageal perforation complicated by cervicomediastinal abscess formation. Due to anatomical constraints preventing standard endoluminal approaches, a hybrid organ-preserving strategy was employed, consisting of surgical drainage combined with an externally adapted vacuum-assisted closure (VAC) system applied adjacent to the esophageal defect. Results: The patient demonstrated progressive clinical improvement without the need for esophageal diversion or major reconstructive surgery. Inflammatory markers were monitored serially and showed a downward trend, serving as adjunctive indicators of treatment response. The esophageal defect healed successfully, was confirmed radiologically, and no treatment-related complications were observed. Conclusions: This case suggests that externally adapted VAC therapy may represent a potential organ-preserving option in selected patients with complex cervical esophageal perforations when conventional techniques are not feasible. Further studies are required to validate this approach.

This manuscript introduces a river segmentation method and explores the impact of human interventions through a long-term study of total nitrogen, total phosphorus, chemical oxygen demand, and biochemical oxygen demand. An indicator linking parameter concentrations to the river’s flow rate was used to assess the development of the examined parameters. The analysis spanned from 2011 to 2022, considering both seasonal and yearly variations. Normal probability plots served as statistical tools to evaluate whether the data followed normal distributions and identify outliers. The proposed segmentation divided the Bahlui River into four segments, each defined by anthropogenic stressors. It was found that, due to human activity, each river segment could be viewed as an “independent” river. This supports the idea that river segments can be analyzed separately as distinct components. The proposed segmentation approach represents an alternative approach in river water quality research, moving from traditional continuous system models to fragmented system analysis, which better reflects the reality of heavily modified river systems. The study’s findings are important for understanding how anthropogenic modifications affect river ecosystem functioning in the long term.