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Background: Chronic kidney disease (CKD) significantly increases stroke risk and severity, posing challenges in both acute management and long-term outcomes. CKD contributes to cerebrovascular pathology through systemic inflammation, oxidative stress, endothelial dysfunction, vascular calcification, impaired cerebral autoregulation, and a prothrombotic state, all of which exacerbate stroke risk and outcomes. Methods: This review synthesizes evidence from peer-reviewed literature to elucidate the pathophysiological mechanisms linking CKD and stroke. It evaluates the efficacy and safety of acute reperfusion therapies—intravenous thrombolysis and endovascular thrombectomy—in CKD patients with acute ischemic stroke. Considerations, such as renal function, drug dosage adjustments, and the risk of contrast-induced nephropathy, are critically analyzed. Evidence-based recommendations and research priorities are drawn from an analysis of current practices and existing knowledge gaps. Results: CKD influences stroke outcomes through systemic and local pathophysiological changes, necessitating tailored therapeutic approaches. Reperfusion therapies are effective in CKD patients but require careful monitoring of renal function to mitigate risks, such as contrast-induced nephropathy and thrombolytic complications. The bidirectional relationship between stroke and CKD highlights the need for integrated management strategies to address both conditions. Early detection and optimized management of CKD significantly reduce stroke-related morbidity and mortality. Conclusion: Optimizing stroke care in CKD patients requires a comprehensive understanding of their pathophysiology and clinical management challenges. This article provides evidence-based recommendations, emphasizing individualized treatment decisions and coordinated care. It underscores the importance of integrating renal considerations into stroke treatment protocols and highlights the need for future research to refine therapeutic strategies, address knowledge gaps, and consider tailored interventions to improve outcomes and quality of life for this high-risk population. [ABSTRACT FROM AUTHOR]

Single-stranded DNA binding proteins (SSBs) regulate multiple DNA transactions, including replication, transcription, and repair. We recently identified SSB1 as a novel protein critical for the initiation of ATM signaling and DNA double-strand break repair by homologous recombination. Here we report that germline Ssb1(-/-) embryos die at birth from respiratory failure due to severe rib cage malformation and impaired alveolar development, coupled with additional skeletal defects. Unexpectedly, Ssb1(-/-) fibroblasts did not exhibit defects in Atm signaling or γ-H2ax focus kinetics in response to ionizing radiation (IR), and B-cell specific deletion of Ssb1 did not affect class-switch recombination in vitro. However, conditional deletion of Ssb1 in adult mice led to increased cancer susceptibility with broad tumour spectrum, impaired male fertility with testicular degeneration, and increased radiosensitivity and IR-induced chromosome breaks in vivo. Collectively, these results demonstrate essential roles of Ssb1 in embryogenesis, spermatogenesis, and genome stability in vivo.

Aim: Chronic Kidney Disease (CKD) is a common comorbidity among acute ischaemic stroke (AIS) patients undergoing reperfusion therapies, including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). Acknowledging CKD's prevalence in this cohort and understanding its influence on outcomes is crucial for prognosis and optimizing care. This study aims to determine the prevalence of CKD among anterior circulation AIS (acAIS) patients undergoing reperfusion therapies and to analyse the role of CKD in mediating outcomes. Methods: A random‐effects meta‐analysis was conducted to pool and examine prevalence data. A total of 263 633 patients were included in the meta‐analysis. The study assessed CKD's association with functional outcomes, symptomatic intracranial haemorrhage (sICH) and mortality. Results: The overall pooled prevalence of CKD among acAIS ranged from 30% to 56% in IVT‐treated patients and 16%–42% for EVT‐treated patients. CKD was associated with increased odds of unfavourable functional outcome at 90 days in both IVT (OR 1.837; 95% CI: [1.599; 2.110]; p <.001) and EVT (OR 1.804; 95% CI: [1.525; 2.133]; p <.001) groups. In IVT‐treated patients, CKD was associated with increased odds of 30‐day mortality (OR 6.211; 95% CI: [1.105; 34.909]; p =.038). CKD in IVT‐treated patients exhibited increased odds of sICH, albeit statistically non‐significant (OR 1.595; 95% CI: [0.567; 3.275]). Conclusions: The high prevalence of CKD and its significant impact on outcomes in acAIS patients treated with reperfusion therapies underscore its clinical significance. This insight can guide personalised care strategies and potentially improve the prognosis in the management of acAIS. [ABSTRACT FROM AUTHOR]

The increasing prevalence of diabetes and stroke is a major global public health concern. Specifically, acute stroke patients, with pre‐existing diabetes, pose a clinical challenge. It is established that diabetes is associated with a worse prognosis after acute stroke and the various biological factors that mediate poor recovery profiles in diabetic patients is unknown. The level of association and impact of diabetes, in the setting of reperfusion therapy, is yet to be determined. This article presents a comprehensive overview of the current knowledge of the role of diabetes in stroke, therapeutic strategies for primary and secondary prevention of cardiovascular disease and/or stroke in diabetes, and various therapeutic considerations that may apply during pre‐stroke, acute, sub‐acute and post‐stroke stages. The early diagnosis of diabetes as a comorbidity for stroke, as well as tailored post‐stroke management of diabetes, is pivotal to our efforts to limit the burden. Increasing awareness and involvement of neurologists in the management of diabetes and other cardiovascular risk factors is desirable towards improving stroke prevention and efficacy of reperfusion therapy in acute stroke patients with diabetes. [ABSTRACT FROM AUTHOR]

Abstract Background Thrombospondin-4 (THBS4) is a member of the extracellular calcium-binding protein family and is involved in cell adhesion and migration. The aim of this study was to evaluate the potential role of deregulation of THBS4 expression in colorectal carcinogenesis. Of particular interest was the possible silencing of expression by methylation of the CpG island in the gene promoter. Methods Fifty-five sporadic colorectal tumours stratified for the CpG Island Methylator Phenotype (CIMP) were studied. Immunohistochemical staining of THBS4 protein was assessed in normal and tumour specimens. Relative levels of THBS4 transcript expression in matched tumours and normal mucosa were also determined by quantitative RT-PCR. Colony forming ability was examined in 8 cell lines made to overexpress THBS4. Aberrant promoter hypermethylation was investigated as a possible mechanism of gene disruption using MethyLight. Methylation was also assessed in the normal colonic tissue of 99 patients, with samples biopsied from four regions along the length of the colon. Results THBS4 expression was significantly lower in tumour tissue than in matched normal tissue. Immunohistochemical examination demonstrated that THBS4 protein was generally absent from normal epithelial cells and tumours, but was occasionally expressed at low levels in the cytoplasm towards the luminal surface in vesicular structures. Forced THBS4 over-expression caused a 50-60% repression of tumour colony growth in all eight cell lines examined compared to control cell lines. Tumours exhibited significantly higher levels of methylation than matched normal mucosa, and THBS4 methylation correlated with the CpG island methylator phenotype. There was a trend towards decreased gene expression in tumours exhibiting high THBS4 methylation, but the correlation was not significant. THBS4 methylation was detectable in normal mucosal biopsies where it correlated with increasing patient age and negatively with the occurrence of adenomas elsewhere in the colon. Conclusions THBS4 shows increased methylation in colorectal cancer, but this is not strongly associated with altered gene expression, either because methylation has not always reached a critical level or because other factors influence THBS4 expression. THBS4 may act as a tumour suppressor gene, demonstrated by its suppression of tumour colony formation in vitro. THBS4 methylation is detectable in normal colonic mucosa and its level may be a biomarker for the occurrence of adenomas and carcinoma.

Abstract Background SnoN is an important regulator of the transforming growth factor beta (TGFβ) signalling pathway and has been shown to exhibit both tumour promotion and suppression activity. Methods To further explore the role of this complex molecule in colorectal tumorigenesis, we examined 52 paired normal and tumour colorectal specimens stratified by level of microsatellite instability; 18 with high-level microsatellite instability (MSI-H) and 34 microsatellite stable (MSS). SnoN transcript expression was quantitated by real-time PCR and analysed with respect to clinical indicators of prognosis. Results Within the MSI-H subgroup, SnoN was commonly either up-regulated (6/18, 33%) or down-regulated (7/18, 39%). A significantly different distribution of SnoN expression was observed in MSS cancers compared with MSI-H (P ≤ 0.001). Whilst 17/34 (50%) of MSS tumours demonstrated up-regulation, none showed down-regulated expression. Within the MSI-H subgroup, up-regulation was significantly correlated with lack of repeat tract mutation in the TGFβRII gene (P ≤ 0.025), suggesting that SnoN is more frequently up-regulated in the presence of functional TGFβ signalling. Conclusion Together these data support the notion that SnoN has both oncogenic and tumour suppressive properties depending on other genetic changes within the tumour, and that the MSI-H pathway of colorectal tumorigenesis presents an excellent model for the study of these opposing functions.

Colorectal cancer is a major cause of cancer death and approximately 20% arises within serrated polyps, which are under-recognized and poorly understood. Human serrated colorectal polyps frequently exhibit both oncogenic BRAF mutation and widespread DNA methylation changes, which are important in silencing genes restraining neoplastic progression. Here, we investigated whether in vivo induction of mutant Braf is sufficient to result in coordinated promoter methylation changes for multiple cancer-related genes. The BrafV637E mutation was induced in murine intestine on an FVB;C57BL/6J background and assessed for morphological and DNA methylation changes at multiple time points from 10 days to 14 months. Extensive intestinal hyperplasia developed by 10 days post-induction of the mutation. By 8 months, most mice had murine serrated adenomas with dysplasia and invasive cancer developed in 40% of mice by 14 months. From 5 months onwards, Braf mutant mice showed extensive, gene-specific increases in DNA methylation even in hyperplastic mucosa without lesions. This demonstrates that persistent oncogenic Braf signaling is sufficient to induce widespread DNA methylation changes. This occurs over an extended period of time, mimicking the long latency followed by rapid progression of human serrated neoplasia. This study establishes for the first time that DNA methylation arises slowly in direct response to prolonged oncogenic Braf signaling in serrated polyps; this finding has implications both for chemoprevention and for understanding the origin of DNA hypermethylation in cancer generally. [ABSTRACT FROM AUTHOR]