Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells

Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders.Although both cell populations have been already studied and used for their regenerative potentials,recently their special immunoregulatory features have brought much more attention.Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response,particularly T cell proliferation,activation,and cytokine production.This makes them suitable choices for allogeneic stem cell transplantation.Nevertheless,these two cells do not have equal immunoregulatory activities.Many elements including their extraction sources,age/passage,expression of different markers,secretion of bioactive mediators,and some others could change the efficiency of their immunosuppressive function.However,to our knowledge,no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells.This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression,deactivation,cytokine production,and regulatory T cells induction capacities.Moreover,it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.

Nanoscale Stiffness Distribution in Bone Metastasis

Nanomechanical heterogeneity is expected to have an effect on elasticity, injury and bone remodelling. In normal bone, we have two types of cells (osteoclasts and osteoblasts) working together to maintain existing bone. Bone cancers can produce factors that make the osteoclasts work harder. This means that more bone is destroyed than rebuilt, and leads to weakening of the affected bone. We report here the first demonstration of the nanoscale stiffness distribution in bone metastases before and after treatment of animals with the bisphosphonate Risedronate, a drug which is currently used for the treatment of bone metastases in patients with advanced cancers. The strategy used here is applicable to a wide class of biological tissues and may serve as a new reflection for biologically inspired scaffolds technologies.

A novel regulatory region controls IgH locus transcription and switch recombination to a subset of isotypes

Class switch recombination(CSR)occurs at the IgH locus and replaces the immunoglobulin(Ig)isotype expressed from IgM to IgG,IgE or IgA,endowing the B cell receptor with novel effector functions.CSR is triggered by activation-induced cytidine deaminase(AID),1 an enzyme that deaminates cytosines to uracils in single-stranded DNA exposed by transcription.The distinct antibody isotypes are encoded in the IgH locus in individual transcription units composed of a cytokine-inducible promoter,an intronic exon,and a switch region(Sx),followed by the exons encoding the constant region(Cx)(Fig.S1a).During CSR,the choice of recombination to a particular isotype is determined by the stimulation-dependent activation of specific promoters,triggering the generation of noncoding germline transcripts(GLTs).2 Thus far,the transcriptional regulation of the IgH locus is known to be controlled by the Eμenhancer,located downstream of the variable region and upstream of the donor switch region(Sμ),and the 3′regulatory region(3′RR)super-enhancer located downstream of Cα.

Concurrent PIEZO1 activation and ATP2B4 blockade effectively reduce the risk of cerebral malaria and inhibit in vitro Plasmodium falciparum multiplication in red blood cells

Malaria caused by the Plasmodium falciparum parasite is responsible for more than 240 million cases per year and killed 627,000 people in 2020,mostly African children.The malaria parasite is transmitted by mosquitos belonging to the genus Anopheles.After an asymptomatic liver stage,the parasite is released into the bloodstream to invade red blood cells(RBCs)and replicate asexually.This erythrocytic phase is associated with a variety of clinical manifestations,including mild and severe malaria.Cerebral malaria(CM)is one of the most severe forms,characterized by the sequestration of parasitized RBCs in the small capillaries of the brain and the local development of cytokine-mediated inflammation.Genetic variants in genes encoding proteins involved in red blood cell physiology are protective factors against severe malaria,as clearly demonstrated for the sickle cell variant of hemoglobin(HbS).

The quest for optimal and reliable guidelines based on robust evidence for the treatment of cholangiocarcinoma

In 1991,Gordon H.Guyatt described the evidence-based medicine(EBM)as“a focus on educating front-line clinicians in assessing the credibility of research evidence,understanding the results of clinical studies,and determining how best to apply the results to their everyday practice”(1).In 2010,Graham et al.defined clinical guidelines as“statements that include recommendations intended to optimize patient care that are informed by a systematic review of the evidence and an assessment of the benefits and harms of alternative care options”(2).Since 2010,the number of clinical guidelines increased exponentially,and the query on PubMed with the term“new guidelines”produces 59,773 results.

Human IgG1 antibodies suppress angiogenesis in a target-independent manner

Aberrant angiogenesis is implicated in diseases affecting nearly 10%of the world’s population.The most widely used antiangiogenic drug is bevacizumab,a humanized IgG1 monoclonal antibody that targets human VEGFA.Although bevacizumab does not recognize mouse Vegfa,it inhibits angiogenesis in mice.Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI(CD64)and c-Cbl,impairing macrophage migration.Other approved humanized or human IgG1 antibodies without mouse targets(adalimumab,alemtuzumab,ofatumumab,omalizumab,palivizumab and tocilizumab),mouse IgG2a,and overexpression of human IgG1-Fc or mouse IgG2a-Fc,also inhibited angiogenesis in wild-type and FcγR humanized mice.This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown,Fc cleavage,IgG-Fc inhibition,disruption of Fc-FcγR interaction,or elimination of FcRγ-initated signaling.Furthermore,bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice.Finally,mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis.These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

Interaction of Diet/Lifestyle Intervention and TCF7L2 Genotype on Glycemic Control and Adiposity among Overweight or Obese Adults:Big Data from Seven Randomized Controlled Trials Worldwide

Objective.The strongest locus which associated with type 2 diabetes(T2D)by the common variant rs7903146 is the transcription factor 7-like 2 gene(TCF7L2).We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits,body weight,or waist circumference in overweight or obese adults in several randomized controlled trials(RCTs).Methods.From October 2016 to May 2018,a large collaborative analysis was performed by pooling individualparticipant data from 7 RCTs.These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults.Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies.Results.In the joint analysis,a total of 7 eligible RCTs were included(n=4,114).Importantly,we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose.Compared with the control group,diet/lifestyle interventions were related to lower fasting glucose by-3.06(95%CI,-5.77 to-0.36)mg/dL(test for heterogeneity and overall effect:I^(2)=45:1%,p<0:05;z=2:20,p=0:028)per one copy of the TCF7L2 T risk allele.Furthermore,regardless of genetic risk,diet/lifestyle interventions were associated with lower waist circumference.However,there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele.Conclusions.Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.

丙型肝炎病毒分类的临床与治疗意义

Background &Aims: Blood mononuclear cells (BMCs) frequently are infected by hepatitis C virus (HCV) variants that are not found in plasma. The influence of this compartmentalization on the natural and therapeutic outcome of hepatitis C is unknown. Methods: We studied 119 patients with previously untreated chronic HCV infection. Sixty-five of these patients started first-line treatment with pegylated interferon-alfa and ribavirin after enrollment in the study. The internal ribosomal entry site (IRES) of HCV RNA was amplified and compared between plasma and BMCs by means of single-strand conformational polymorphism(SSCP) analysis, line-probe assay, and cloning sequencing. Results: The IRES SSCP patterns differed between plasma and BMCs in 54 (48%) of 113 assessable patients. Twenty-seven (24%) of these patients were co-infected by 2 HCV types or subtypes, only 1 of which was detectable in BMCs (n = 25) or in plasma(n = 2). SSCP-defined compartmentalization was more frequent in former drug users than in others (35/56 [60%] vs 19/56 [34%]; P < .01), and less frequent in patients with genotype 1 HCV in plasma (26/73 [24%] vs 28/40 [65%]; P < .01). The only variables that were independently predictive of a sustained virologic response were SSCP-defined comparmtentalization (25/31 vs 10/32; P = .0001) and genotype 2 or 3 infection of BMCs (22/31 vs 8/34; P = .002). Conclusions: A significant proportion of patients with hepatitis C are co-infected by 2 or more HCV variants with distinct IRES sequences and distinct cellular tropism. This compartmentalization is a strong independent predictor of treatment efficacy.

HIV reservoir: antiviral immune responses and immune interventions for curing HIV infection

Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.

Advances in Research on COVID-19 Vaccination for People Living with HIV

Introduction In December 2019,multiple cases of aggravated pneumonia of unidentified origin were reported inWuhan,China.These were confirmed to be caused by a novel coronavirus.The World Health Organization(WHO)named the disease coronavirus disease 2019(COVID-19).The International Committee on Taxonomy of Viruses officially identified the novel virus severe acute respiratory syndrome coronavirus 2(SARSCoV-2).[1]Although China is now a low endemic areawith a downward trend in the number of confirmed and suspected cases,[2]the threat of the COVID-19 pandemic remains critical.By mid-March 2022,the cumulative number of reported confirmed cases of COVID-19 worldwide exceeded 450 million,with more than 6 million deaths.[3]Since there is no specific therapeutic drug for the treatment of COVID-19,it is important to control the epidemic by actively promoting SARS-CoV-2 vaccination globally,reducing the risk of viral transmission and the incidence of severe COVID-19,thus improving prognoses.[4]