Epigenetic regulation of cGAS and STING expression in cancer.

Although cancer immunotherapy has become a successful therapeutic strategy in a certain range of solid cancer and hematological malignancies, this efficacy of immunotherapy is impeded by limited success rates due to an immunologically "cold" state. The cGAS-STING signaling pathway is an evolutionarily conserved system which can find cytoplasmic DNA to regulate the innate immune and adaptive immune response. Beyond the host defense and autoimmune disorders, recent advances have now expanded the roles of cGAS-STING that is precise activated and tight regulated to improve anticancer immunity. Mounting evidence now has shown the crucial role of epigenetic regulation in mediating the expression of key genes associated with the cGAS-STING signaling pathway. In this review, we highlight the structure and cellular localization of cGAS and STING as well as intracellular cascade reaction of cGAS-STING signal transduction. We further summarize recent findings of epigenetic regulatory mechanisms that control the expression of cGAS and STING in cancer. The review aims to offer theoretical basis and reference for targeting the epigenetic mechanisms that control cGAS and STING gene expression to promote the development of more effective combination therapeutic regimens to enhance the efficacy of cancer immunotherapy in clinical practice and cancer clinical and cancer research workers.

Safety of SGLT2 Inhibitors in Three Chronic Diseases.

This study aimed to assess the safety of SGLT2 inhibitors in type 2 diabetes, chronic kidney disease, and chronic heart failure considering the number needed to treat (NNT).Methods: Data were obtained from 10 morbidity-mortality trials and were pooled to calculate the NNTs. The number needed to treat to benefit (NNTB) is used to express beneficial outcomes, whereas the number needed to treat to be harmed (NNTH) is used for harmful outcomes. The eight safety outcomes of interest were fracture, diabetic ketoacidosis, amputation, urinary tract infection, genital infection, acute kidney injury, severe hypoglycemia, and volume depletion.A total of 10 trials involving 76319 patients were included in this meta-analysis. The mean follow-up was 2.35 years. SGLT2 inhibitors play a positive role in acute kidney injury and severe hypoglycemia, with the corresponding mean NNTBs being 157 and 561, respectively. SGLT2 inhibitors significantly increased the risk of diabetic ketoacidosis, genital infection, and volume depletion, with the corresponding mean NNTHs being 1014, 41, and 139. It was found that the safety of SGLT2 inhibitors was the same in three diseases and five SGLT2 inhibitors.SGLT2 inhibitors have a positive impact on acute kidney injury and severe hypoglycemia, but they increase the incidence of diabetic ketoacidosis, genital infection, and volume depletion.

Corrigendum: Benefits and risks of antihypertensive medication in adults with different systolic blood pressure: A meta-analysis from the perspective of the number needed to treat.

[This corrects the article DOI: 10.3389/fcvm.2022.986502.].

Effect of alirocumab and evolocumab on all-cause mortality and major cardiovascular events: A meta-analysis focusing on the number needed to treat.

Aims: The efficacy of anti-proprotein convertase subtilisin/Kexin type 9 (PCSK9) monoclonal antibodies in patients with atherosclerotic cardiovascular disease (ASCVD) remains unclear. Therefore, this study aims to assess the effect of PCSK9 inhibitors (alirocumab and evolocumab) on ASCVD patients considering the number needed to treat (NNT). Methods: We reviewed randomized controlled trials (RCTs) which compared the effects of alirocumab or evolocumab and placebo or standards of care. All articles were published in English up to May 2022. Using random effect models, we estimated risk ratios (RRs), NNT, and 95% confidence intervals (CI). Results: We incorporated 12 RCTs with 53 486 patients total, of which 27 674 received PCSK9 inhibitors and 25 812 received placebos. The mean follow-up duration was 1.56 years. The effect of PCSK9 inhibitors on major adverse cardiovascular events (MACE) was statistically significant, and the corresponding mean NNT was 36. Alirocumab reduced the risk of MACE, stroke, and coronary revascularization; the corresponding mean NNT were 37, 319, and 107, respectively. Evolocumab positively affected MACE, myocardial infarction, stroke, and coronary revascularization; the corresponding mean NNT were 32, 78, 267, and 65, respectively. The effects of alirocumab or evolocumab on all-cause mortality and cardiovascular mortality were not statistically significant. Conclusion: This study suggests that preventing one patient from MACE needed to treat 36 patients with ASCVD with PCSK9 inhibitors for 1.56 years. Both alirocumab and evolocumab reduced MACE, stroke, and coronary revascularization. Evolocumab had a positive effect on myocardial infarction, but no effects were noted for alirocumab. In addition, alirocumab may not be as effective as evolocumab. NNT visualizes the magnitude of efficacy to assist in clinical decisions. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=344908], identifier [CRD42022344908].

Benefits and risks of antihypertensive medication in adults with different systolic blood pressure: A meta-analysis from the perspective of the number needed to treat.

Background: The blood pressure (BP) threshold for initial pharmacological treatment remains controversial. The number needed to treat (NNT) is a significant indicator. This study aimed to explore the benefits and risks of antihypertensive medications in participants with different systolic BPs (SBPs), and cardiovascular disease status from the perspective of the NNT. Methods: We conducted a meta-analysis of 52 randomized placebo-controlled trials. The data were extracted from published articles and pooled to calculate NNTs. The participants were divided into five groups, based on the mean SBP at entry (120-129.9, 130-139.9, 140-159.9, 160-179.9, and ≥180 mmHg). Furthermore, we stratified patients into those with and without cardiovascular disease. The primary outcomes were the major adverse cardiovascular events (MACEs), and adverse events (AEs) leading to discontinuation. Results: Antihypertensive medications were not associated with MACEs, however, it increased AEs, when the SBP was <140 mmHg. For participants with cardiovascular disease or at a high risk of heart failure and stroke, antihypertensive treatment reduced MACEs when SBP was ≥130 mmHg. Despite this, only 2-4 subjects had reduced MACEs per 100 patients receiving antihypertensive medications for 3.50 years. The number of individuals who needed to treat to avoid MACEs declined with an increased cardiovascular risk. Conclusion: Pharmacological treatment could be activated when SBP reaches 140 mmHg. For people with cardiovascular disease or at a higher risk of stroke and heart failure, 130 mmHg may be a better therapeutic threshold. It could be more cost-effective to prioritize antihypertensive medications for people with a high risk of developing cardiovascular disease.

Circulating mature dendritic cells homing to the thymus promote thymic epithelial cells involution via the Jagged1/Notch3 axis.

Multiple proinflammatory conditions, including chemotherapy, radiotherapy, transplant rejection, and microbial infections, have been identified to induce involution of the thymus. However, the underlying cellular and molecular mechanisms of these inflammatory conditions inducing apoptosis of thymic epithelial cells (TECs), the main components of the thymus, remain largely unknown. In the circulation, mature dendritic cells (mDCs), the predominant initiator of innate and adaptive immune response, can migrate into the thymus. Herein, we demonstrated that mDCs were able to directly inhibit TECs proliferation and induce their apoptosis by activating the Jagged1/Notch3 signaling pathway. Intrathymic injection of either mDCs or recombinant mouse Jagged1-human Fc fusion protein (rmJagged1-hFc) into mice resulted in acute atrophy of the thymus. Furthermore, DAPT, a γ-secretase inhibitor, reversed the effects induced by mDC or rmJagged1-hFc. These findings suggest that acute or aging-related thymus degeneration can be induced either by mass migration of circulating mDCs in a short period of time or by a few but constantly homing mDCs.