Subpopulations of regulatory T cells are associated with subclinical atherosclerotic plaques,levels of LDL,and cardiorespiratory fitness in the elderly

Background:Atherosclerosis forms the pathological basis for the development of cardiovascular disease.Since pathological processes initially develop without clinically relevant symptoms,the identification of early markers in the subclinical stage plays an important role for initiating early interventions.There is evidence that regulatory T cells(Tregs)are involved in the development of atherosclerosis.Therefore,the present study aimed to identify and investigate associations with Tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques(SAP).In addition,various lifestyle and risk factors,such as cardiorespiratory fitness,were investigated as associated signatures.Methods:A cross-sectional study was performed in 79 participants(male:n=50;age=63.6±3.7 years;body mass index=24.9±3.1 kg/m2;mean±SD)who had no previous diagnosis of chronic disease and were not taking medication.Ultrasound of the carotids to identify SAP,cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were performed.Additionally,tests were conducted to assess blood lipids and determine glucose levels.Immunophenotyping of Tregs and their subtypes(resting(rTregs)and effector/memory(mTregs))was performed by 8-chanel flow cytometry.Participants were categorized according to atherosclerotic plaque status.Linear and logistic regression models were used to analyze associations between parameters.Results:SAP was detected in a total of 29 participants.The participants with plaque were older(64.8±3.6 years vs.62.9±3.5 years)and had higher peripheral systolic blood pressure(133.8±14.7 mmHg vs.125.8±10.9 mmHg).The participants with SAP were characterized by a lower percentage of rTregs(28.8%±10.7%vs.34.6%±10.7%)and a higher percentage of mTregs(40.3%±14.7%vs.30.0%±11.9%).Multiple logistic regression identified age(odds ratio(OR)=1.20(95%confidence interval(95%CI):1.011.42))and mTregs(OR=1.05(95%CI:1.021.10))as independent risk factors for SAP.Stepwise linear regression could reveal an association of peak oxygen uptake(β=0.441),low-density lipoprotein(LDL)(β=0.096),and SAP(β=6.733)with mTregs and LDL(β=0.104)with rTregs.Conclusion:While at an early stage of SAP,the total proportion of Tregs gives no indication of vascular changes,this is indicated by a shift in the Treg subgroups.Factors such as serum LDL or cardiopulmonary fitness may be associated with this shift and may also be additional diagnostic indicators.This could be used to initiate lifestyle-based preventive measures at an early stage,which may have a protective effect against disease progression.

Contraindications for video capsule endoscopy

Video capsule endoscopy(VCE) has been applied in the last 15 years in an increasing field of applications. Although many contraindications have been put into perspective, some precautions still have to be considered. Known stenosis of the gastrointestinal tract is a clear contraindication for VCE unless surgery is already scheduled or at least has been considered as an optional treatment modality. In patients with a higher incidence of stenosis, as in an established diagnosis of Crohn's disease, clinical signs of obstruction, prior radiation or surgical small bowel resection, a preceding test with the self-dissolving patency capsule can override this contraindication. Endoscopic placement of the capsule should be considered in patients with swallowing disorders to avoid aspiration. Esophageal or gastric motility disorders may require endoscopic capsule transport or application of prokinetics if the real-time viewer proofs delayed transit. In pregnant women, VCE should be restricted to urgent cases where diagnosis cannot be postponed after delivery, as data on safety are missing. There is theoretical and clinical evidence that patients with implanted cardiac devices such as a pacemaker, cardioverters or left heart assist devices, can safely undergo VCE in spite of still existing contraindication by manufacturers. Children from the age of 2 years have safely undergone VCE. Although video capsules are not proven safe with magnetic resonance imaging(MRI), first single cases of patients incidentally undergoing MRI with an incorporated capsule have been reported, showing susceptibility artifacts but no signs of clinical harm.

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing:roles,opportunities and challenges

Skin wounds are characterized by injury to the skin due to trauma,tearing,cuts,or contusions.As such injuries are common to all human groups,they may at times represent a serious socioeconomic burden.Currently,increasing numbers of studies have focused on the role of mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)in skin wound repair.As a cell-free therapy,MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy.Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures,including the regeneration of vessels,nerves,and hair follicles.In addition,MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization,wound angiogenesis,cell proliferation,and cell migration,and by inhibiting excessive extracellular matrix production.Additionally,these structures can serve as a scaffold for components used in wound repair,and they can be developed into bioengineered EVs to support trauma repair.Through the formulation of standardized culture,isolation,purification,and drug delivery strategies,exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair.In conclusion,MSCderived EV-based therapies have important application prospects in wound repair.Here we provide a comprehensive overview of their current status,application potential,and associated drawbacks.

Methyltransferase-like 3(METTL3)inhibition potentiates anti-tumor immunity:a novel strategy for improving anti-PD1 therapy

In a recent article published in Cancer Discovery,Guirguis et al.demonstrated that enzymatic inhibitors of the m6 A methyltransferase METTL3 induced a formation of immunostimulatory doublestranded mRNAs(dsRNAs)in cancer cells,which triggered a profound tumor-cell-intrinsic interferon response leading to an enhanced antigen presentation and thereby increased killing of tumor cells by cytotoxic CD8+T-lymphocytes.The inhibition of METTL3 synergized with anti-PD1 immunotherapy,highlighting its potential for improving cancer treatment.

Genome-wide MicroRNA Expression Profiles in COPD: Early Predictors for Cancer Development

Chronic obstructive pulmonary disease （COPD） significantly increases the risk of developing cancer. Biomarker studies frequently follow a case-control set-up in which patients diagnosed with a disease are compared to controls. Longitudinal cohort studies such as the COPD-centered German COPD and SYstemic consequences-COmorbidities NETwork （COSYCONET） study provide the patient and biomaterial base for discovering predictive molecular markers. We asked whether microRNA （miRNA） profiles in blood collected from COPD patients prior to a tumor diagnosis could support an early diagnosis of tumor development independent of the tumor type. From 2741 participants of COSYCONET diagnosed with COPD, we selected 534 individuals including 33 patients who developed cancer during the follow-up period of 54 months and 501 patients who did not develop cancer, but had similar age, gender and smoking history. Genome-wide miRNA profiles were generated and evaluated using machine learning techniques. For patients developing cancer we identified nine miRNAs with significantly decreased abundance （two-tailed unpaired t-test adjusted for multiple testing P 〈 0.05）, including members of the miR-320 family. The identified miRNAs regulate different cancer-related pathways including the MAPK pathway （P - 2.3 × 10 -5）. We also observed the impact of confounding factors on the generated miRNA profiles, underlining the value of our matched analysis. For selected miRNAs, qRT-PCR analysis was applied to validate the results. In conclusion, we identified several miRNAs in blood of COPD patients, which could serve as candidates for biomarkers to help identify COPD patients at risk of developing cancer.

A novel role for mitochondrial fission in macrophages: trained innate immunity induced by beta-glucan

In a recent paper published in Nature Immunology,Ding et al.provided new insights into the mechanism of how trained innate immunity could eradicate cancer.The authors demonstrated that yeast-derived whole beta-glucan particles(WGP)increased the responsiveness of lung interstitial macrophages to tumor-derived factors associated with the subsequent inhibition of tumor metastasis through enhanced cytotoxicity to cancer cells.The authors identified the metabolic sphingolipid–mitochondrial fission axis in WGP-trained macrophages as the key pathway responsible for this phenomenon and categorized it as a mechanism of trained innate immunity[1].

Fumarate hydratase:a new checkpoint of metabolic regulation in inflammatory macrophages

A recent article published by Hooftman et al.1 in Nature identified a crucial function for fumarate hydratase(FH)in bone marrow-derived macrophages(BMDMs).Pharmacological inhibition or genetic ablation of FH led to increased fumarate levels and downstream suppression of mitochondrial respiration implying the importance of cellular metabolic states and cytokine balance shift in innate immunity.

Local tissue development of type 1 innate lymphoid cells:guided by interferon-gamma

A recent article published in Science by Bai et a I.1 identified interferon-Y(IFN-y)secreted by type 1 innate lymphoid cells(ILCIs)self-perpetuated their own local development from resident hematopoietic stem cells(HSCs)in adult liver.