Contribution of plasma levels of VEGF-A and angiopoietin-2 in addition to a genetic variant in KCNAB1 to predict the risk of bevacizumab-induced hypertension
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Hybrid model of tumor growth, angiogenesis and immune response yields strategies to improve antiangiogenic therapy
Solid tumors harbor a complex and dynamic microenvironment that hinders the delivery and efficacy of therapeutic interventions. In this study, we developed and utilized a hybrid, discrete-continuous mathematical model to explore the interplay between solid tumor growth, immune response, tumor-induced angiogenesis, and antiangiogenic drugs. By integrating published data with anti-angiogenic drugs, we elucidate three primary mechanisms by which anti-angiogenesis influences tumor progression and treatment outcomes: reduction in tumor growth rate by mitigating and temporally delaying angiogenesis, normalization of blood vessel structure and function, and improving immune cell extravasation and activation. Our results indicate a significant increase in functional blood vessels and perfusion following anti-angiogenic treatment, which in turn improves the intratumoral distribution of immune cells. The normalization window, or optimal time frame for anti-angiogenic drug administration, and the dose of the drug arise naturally in the model and are highlighted as crucial factors in maximizing treatment benefits. Prolonged anti-angiogenic treatment triggers cancer cell migration into healthy tissue and induces immunosuppression due to hypoxia, potentially leading to negative effects because these cancer cells will rapidly proliferate upon treatment termination. In conclusion, the positive contribution of anti-angiogenic treatment must balance the possible negative effects by choosing a proper treatment protocol as well as combining it with proper anti-cancer treatment. Our findings provide valuable insights and a framework for the design of protocols with anti-angiogenic treatment, targeted immunotherapy, and non-targeted anti-cancer therapies.
Self-reported hypertension prevalence, risk factors, and knowledge among South Africans aged 24 to 40 years old
Although hypertension is a significant public health burden in South Africa (SA), less is known about its prevalence, risk factors, and possible preventative strategies among young adults. We assessed the prevalence, possible risk factors, and knowledge associated with self-reported hypertension among young adults from SA. A cross-sectional online survey was conducted among 1000 young South African adults (24–40 years; 51.0% women). We administered a socio-demographic questionnaire and collected information on measures of socio-economic status (SES) (e.g. asset wealth index), self-reported medical history, and lifestyle risk factors. Furthermore, a modified version of the hypertension evaluation of lifestyle and management questionnaire was used to assess participants’ hypertension knowledge. The overall prevalence of self-reported hypertension was 24.0%, with significant differences between women and men (27.5% and 20.4% respectively, p = 0.033). Only 16.8% of the respondents had good hypertension knowledge. There was a positive association between good knowledge of hypertension and being hypertensive (OR = 1.43 CI:1.23–3.12), monthly blood pressure check-ups (OR = 2.03 CI:1.78–3.23), knowing the side effects of uncontrolled blood pressure (OR = 1.28 CI:1.07–1.89) and having a biological mother with hypertension (OR = 1.79 CI:1.53–2.21). Being employed full-time (OR = 0.74 CI:0.69–0.80), having a higher SES (wealth index 4 (OR = 0.70 CI:0.59–0.97) and 5 (OR = 0.65 CI:0.48–0.81)), exercising 6 to 7 days per week (OR = 0.83 CI:0.71–0.94), and not consuming alcohol at all (OR = 0.73 CI:0.67–0.89), were all found to be protective against hypertension. The high hypertension prevalence, lack of hypertension knowledge, and reported risk factors among this group highlight the need for early robust preventative strategies to mitigate hypertension risk among this population.
Epigenomics and transcriptomics association study of blood pressure and incident diagnosis of hypertension in twins
Hypertension is the most frequent health-related condition worldwide and is a primary risk factor for renal and cardiovascular diseases. However, the underlying molecular mechanisms are still poorly understood. To uncover these mechanisms, multi-omics studies have significant potential, but such studies are challenged by genetic and environmental confounding – an issue that can be effectively reduced by studying intra-pair differences in twins. Here, we coupled data on hypertension diagnoses from the nationwide Danish Patient Registry to a study population of 740 twins for whom genome-wide DNA methylation and gene expression data were available together with measurements of systolic and diastolic blood pressure. We investigated five phenotypes: incident hypertension cases, systolic blood pressure, diastolic blood pressure, hypertension (140/90 mmHg), and hypertension (130/80 mmHg). Statistical analyses were performed using Cox (incident cases) or linear (remaining) regression analyses at both the individual-level and twin pair-level. Significant genes (p < 0.05) at both levels and in both types of biological data were investigated by bioinformatic analyses, including gene set enrichment analysis and interaction network analysis. Overall, most of the identified pathways related to the immune system, particularly inflammation, and biology of vascular smooth muscle cell. Of specific genes, lysine methyltransferase 2 A (KMT2A) was found to be central for incident hypertension, ataxia-telangiectasia mutated (ATM) for systolic blood pressure, and beta-actin (ACTB) for diastolic blood pressure. Noteworthy, lysine methyltransferase 2A (KMT2A) was also identified in the systolic and diastolic blood pressure analyses. Here, we present novel biomarkers for hypertension. This study design is surprisingly rare in the field of hypertension.
Investigation and management of resistant hypertension: British and Irish Hypertension Society position statement
People living with resistant hypertension (RH) are at high risk of adverse cardiovascular events. The British and Irish Hypertension Society has identified suspected RH as a condition for which specialist guidance may improve rates of blood pressure control and help clinicians identify those individuals who may benefit from specialist review. In this position statement we provide a practical approach for the investigation and management of adults with RH. We highlight gaps in the current evidence and identify important future research questions. Our aim is to support the delivery of high-quality and consistent care to people living with RH across the UK and Ireland.
FBXO22 promotes HCC angiogenesis and metastasis via RPS5/AKT/HIF-1α/VEGF-A signaling axis
The gene F-box only protein 22 (FBXO22) has been discovered to promote the development of liver cancer tumors. Nevertheless, there remains considerable ambiguity regarding the involvement of FBXO22 in the processes of angiogenesis and metastasis in hepatocellular carcinoma (HCC). Our study has confirmed a significant upregulation of FBXO22 expression in both HCC samples and cellular models. The increased level of FBXO22 correlates strongly with the number of tumors, presence of vascular invasion, and poor prognosis. Experimental investigations have shown that FBXO22 significantly enhances angiogenesis and metastasis of HCC both in vitro and in vivo. Mechanistically, FBXO22 interacts with and ubiquitinates 40S ribosomal protein S5 (RPS5) on Lys85, thereby promoting its K48-linked ubiquitin-mediated degradation in the cytoplasm. Following a decrease in the expression of RPS5, activation of downstream PI3K/AKT signaling pathway occurs, leading to elevated levels of HIF-1α and vascular endothelial growth factor A (VEGF-A). Our study has shown that FBXO22 facilitates HCC angiogenesis and metastasis via the RPS5/AKT/HIF-1α/VEGF-A signaling axis. Notably, inhibition of FBXO22 enhances the efficacy of Lenvatinib both in vitro and in vivo. Therefore, FBXO22 may present itself as a potential target for therapeutic intervention in the treatment of HCC.
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