Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors 1 . Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2 V617F (JAK2 VF ) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease 1,2 . Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2 VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2 VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2 VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2 VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.Atherosclerotic cardiovascular disease (ACVD) is the major cause of death and disability in the developed world 3 . A large burden of residual ACVD risk remains despite current therapies, including intensive lowering of low-density lipoprotein levels 3 , which highlights the need for new treatments. In the Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS), inhibition of IL-1β reduced cardiovascular events, thereby validating the contribution of inflammation to ACVD 4 . However, canakinumab therapy was associated with a small risk of infections and has not been approved for cardiovascular conditions. Thus, a more precise way to identify patients who may benefit most from anti-inflammatory therapy is required. Clonal haematopoiesis usually arises from somatic mutations in haematopoietic stem and progenitor cells (HSPCs) in one of four genes (TET2, ASXL1, DNMT3A or JAK2), which lead to clonal expansion of haematopoietic cells. The prevalence of clonal haematopoiesis increases with age, and it affects more than 10% of people who are over 70 years old 1 . Although clonal haematopoiesis conferred an increased risk of haematological malignancies of 0.5-1% per year, this modest increase was not nearly enough to account for the 40% incr...

The skin, which serves as the first barrier of the human body, is particularly susceptible to exogenous injuries. Skin wounds, including acute burns and chronic non-healing ulcers, are commonly observed in clinics. Healing of skin wounds is a complex process, consisting of infiltration of inflammatory cells, cellular proliferation, and tissue remodeling phases, which restore the integrity and functions of the skin. Epithelialization is involved in wound healing through re-establishing an intact keratinocyte layer. Epidermal stem cells are indispensable for epithelialization, and they are regulated by multiple proinflammatory cytokines or growth factors. In this review, we summarize recent advances in the effect of these cytokines on migration, proliferation, and differentiation processes of epidermal stem cells. We also introduce promising therapeutic strategies targeting epidermal stem cells or related proinflammatory cytokines for patients with skin wounds.

Introduction We conducted a presurgical trial to assess the tissue-related effects of metformin in overweight/obese breast cancer (BC) patients. Methods Metformin 1,500 mg daily was administered to 35 nondiabetics with stage 0–III BC, body mass index (BMI) ≥ 25 kg/m2. The primary endpoint was tumor proliferation change (i.e., ki-67). Tumor proliferation change was compared to untreated historical controls, matched by age, BMI, and stage. Results There was no reduction in ln(ki-67) after metformin (p = .98) or compared to controls (p = .47). There was a significant reduction in BMI, cholesterol, and leptin. Conclusion Despite no proliferation changes, we observed reductions in other relevant biomarkers.

BackgroundBreast cancer risk assessment including genetic testing can be used to classify people into different risk groups with screening and preventive interventions tailored to the needs of each group, yet the implementation of risk-stratified breast cancer prevention in primary care settings is complex.ObjectiveTo address barriers to breast cancer risk assessment, risk communication, and prevention strategies in primary care settings, we developed a Web-based decision aid, RealRisks, that aims to improve preference-based decision-making for breast cancer prevention, particularly in low-numerate women.MethodsRealRisks incorporates experience-based dynamic interfaces to communicate risk aimed at reducing inaccurate risk perceptions, with modules on breast cancer risk, genetic testing, and chemoprevention that are tailored. To begin, participants learn about risk by interacting with two games of experience-based risk interfaces, demonstrating average 5-year and lifetime breast cancer risk. We conducted four focus groups in English-speaking women (age ≥18 years), a questionnaire completed before and after interacting with the decision aid, and a semistructured group discussion. We employed a mixed-methods approach to assess accuracy of perceived breast cancer risk and acceptability of RealRisks. The qualitative analysis of the semistructured discussions assessed understanding of risk, risk models, and risk appropriate prevention strategies.ResultsAmong 34 participants, mean age was 53.4 years, 62% (21/34) were Hispanic, and 41% (14/34) demonstrated low numeracy. According to the Gail breast cancer risk assessment tool (BCRAT), the mean 5-year and lifetime breast cancer risk were 1.11% (SD 0.77) and 7.46% (SD 2.87), respectively. After interacting with RealRisks, the difference in perceived and estimated breast cancer risk according to BCRAT improved for 5-year risk (P=.008). In the qualitative analysis, we identified potential barriers to adopting risk-appropriate breast cancer prevention strategies, including uncertainty about breast cancer risk and risk models, distrust toward the health care system, and perception that risk assessment to pre-screen women for eligibility for genetic testing may be viewed as rationing access to care.ConclusionsIn a multi-ethnic population, we demonstrated a significant improvement in accuracy of perceived breast cancer risk after exposure to RealRisks. However, we identified potential barriers that suggest that accurate risk perceptions will not suffice as the sole basis to support informed decision making and the acceptance of risk-appropriate prevention strategies. Findings will inform the iterative design of the RealRisks decision aid.

Background: LNK/SH2B3 inhibits JAK/STAT signaling by hematopoietic cytokine receptors. GWAS have shown association of a common SNP in LNK (R262W, T allele) with neutrophilia, thrombocytosis and coronary artery disease (CAD). We have shown that LNK(TT) reduces LNK function and that LNK deficient mice display prominent platelet−neutrophil aggregates, accelerated atherosclerosis and thrombosis. Platelet−neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of neutrophil extracellular traps (NETs) in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency. Methods: We bred mice with combined deficiency of Lnk and the NETosis-essential enzyme peptidylarginine deiminase4 (PAD4) and transplanted their bone marrow into Ldlr −/− mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2 V617F ). Results: Lnk deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated Lnk −/− platelets promoted increased NETosis when incubated with Lnk −/− neutrophils compared to WT platelets or WT neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from Lnk −/− platelets, as well as increased priming and response of Lnk −/− neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06−scFv). E06−scFv reversed accelerated NETosis, atherosclerosis and thrombosis in Lnk −/− mice. We also showed increased NETosis when human induced pluripotent stem cell (iPSC) derived LNK(TT) neutrophils were incubated with LNK(TT) platelet/megakaryocytes, but not in isogenic LNK(CC) controls, confirming human relevance. Using data from UK Biobank we found that individuals with the JAK2 VF mutation only showed increased CAD when also carrying the LNK R262W allele. Mice with hematopoietic Lnk +/- and Jak2 VF clonal hematopoiesis, showed accelerated arterial thrombosis but not atherosclerosis compared to Jak2VFLnk +/+ controls. Conclusions: Hematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils promoting NETosis, and increases CAD risk in humans carrying JAK2 VF mutations. Therapies targeting OxPL may be beneficial for CAD in genetically defined human populations.