B7 homolog 3 in pancreatic cancer

Despite advances in cancer treatment,pancreatic cancer(PC)remains a disease with high mortality rates and poor survival outcomes.The B7 homolog 3(B7-H3)checkpoint molecule is overexpressed among many malignant tumors,including PC,with low or absent expression in healthy tissues.By modulating various immunological and nonimmunological molecular mechanisms,B7-H3 may influence the progression of PC.However,the impact of B7-H3 on the survival of patients with PC remains a subject of debate.Still,most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC.Furthermore,it has been demonstrated that B7-H3 stimulates the migration,invasion,and metastasis of PC cells,and enhances resistance to chemotherapy.In preclinical models of PC,B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibodydependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site.Finally,PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies.This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.

Clinical correlation of B7-H3 and B3GALT4 with the prognosis of colorectal cancer

AIM To investigate the expression and clinical significance of B7 homolog 3(B7-H3) and β-1,3-galactosyltransferase-4(B3 GALT4) in colorectal cancer(CRC) patients.METHODS Using tissue microarray, we identified the expression of B7-H3 and B3 GALT4 in 223 CRC patient samples by immunohistochemistry and evaluated the possible correlation between B7-H3 and B3 GALT4 and clinicaloutcomes. Further, the m RNA and protein expression were identified to establish the regulatory relationship of B7-H3 with B3 GALT4 in vitro.RESULTS A significant positive correlation between B7-H3 and B3 GALT4 was observed in CRC specimens(r = 0.219, P = 0.001). High expression of B7-H3 was identified as a significant independent predictor of poor overall survival(OS) [hazard ratio(HR) = 1.781; 95%CI: 1.027-3.089; P = 0.040]. Moreover, high expression of B3 GALT4 was also recognized as an independent predictor of inferior OS(HR = 1.597; 95%CI: 1.007-2.533; P = 0.047). Additionally, CRC patients expressing both high B7-H3 and high B3 GALT4 contributed to a significant decrease in OS(HR = 2.283; 95%CI: 1.289-4.042; P = 0.005). In CRC cell lines with stable expression of high B7-H3, the m RNA and protein expressions of B3 GALT4 were significantly upregulated. Similarly, the expression of B3 GALT4 was significantly reduced when expression of B7-H3 was knocked down.CONCLUSION The expression of B3 GALT4 in CRC is positively correlated with B7-H3 expression in vitro. B7-H3/B3 GLAT4 may be used as dual prognostic biomarkers for CRC.

Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis

Viral myocarditis(VMC)is one of the most common acquired heart diseases in children and teenagers.However,its pathogenesis is still unclear,and effective treatments are lacking.This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes(CMCs)induced by coxsackievirus B3(CVB3).CVB3 was utilized for inducing the VMC mouse model and cellular model.Cardiac echocardiography,left ventricular ejection fraction(LVEF),and left ventricular fractional shortening(LVFS)were implemented to assess the cardiac function.In CVB3-induced VMC mice,cardiac insufficiency was observed,as well as the altered levels of ferroptosis-related indicators(glutathione) peroxidase 4(GPX4),glutathione(GSH),and malondialdehyde(MDA).However,exosomes derived from human umbilical cord mesenchymal stem cells(hucMSCs-exo)could restore the changes caused by CVB3 stimulation.Let-7a-5p was enriched in hucMSCs-exo,and the inhibitory ffect of hucMSCs-exoa-ie-pmimo on CVB3-induced ferroptosis was higher than that of hucMSCs-exommie N(NC:negative control).Mothers against decapentaplegic homolog 2(SMAD2)increased in the VMC group,while the expression of zinc-finger protein 36(ZFP36)decreased.Let-7a-5p was confirmed to interact with SMAD2 messenger RNA(mRNA),and the SMAD2 protein interacted directly with the ZFP36 protein.Silencing SMAD2 and overexpressing ZFP36 inhibited the expression of ferroptosis-related indicators.Meanwhile,the levels of GPX4,solute carrier family 7,member 11(SLC7A11),and GSH were lower in the SMAD2 overexpression plasmid(oe-SMAD2)+let-7a-5p mimic group than in the oe-NC+let-7a-5p mimic group,while those of MDA,reactive oxygen species(ROS),and Fe^(2+)increased.In conclusion,these data showed that ferroptosis could be regulated by mediating SMAD2 expression.Exo-let-7a-5p derived from hucMSCs could mediate SMAD2 to promote the expression of ZFP36,which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.

Effect of vitamin B12 on cleft palate induced by 2,3.7.8-tetrachlorodibenzo-p-dioxin and dexamethasone in mice

The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin （TCDD） and dexamethasone （DEX）. We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules （trans- forming growth factor-β3 （TGF-β3） and TGF-β3 type I receptor （activin receptor-like kinase 5, ALK5）） during pala- togenesis among a control group （Group A）, TCDD＋DEX exposed group （Group B）, and TCDD＋DEX＋vitamin B12 exposed group （Group C）. While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD＋DEX treatment, the expression levels of key signaling molecules （TGF-~3 and ALK5） during palatogenesis were significantly modulated. In TCDD＋DEX exposed and TCDD＋DEX＋vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX＋TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD.

DJ-1在心肌缺血再灌注损伤中的研究进展

心肌缺血再灌注损伤(MIRI)是心肌梗死后冠状动脉再通治疗的常见并发症,严重影响急性心肌梗死患者心功能恢复,导致患者预后不良,同时也增加了患者主要不良心血管事件的发生率和病死率。帕金森病相关蛋白7(PARK7/DJ-1)作为一种多功能蛋白,参与氧化应激、细胞自噬与凋亡调控、线粒体稳态维持、信号转导等与MIRI密切相关的病理生理过程。人第10号染色体缺失的磷酸酶及张力蛋白同源基因/磷脂酰肌醇-3-激酶/蛋白激酶B信号通路及核转录因子红系2相关因子2信号通路均在MIRI中发挥重要作用,而DJ-1作为上述通路的重要启动元件,可直接参与MIRI的发生、发展。MIRI病理机制复杂,进一步研究DJ-1在MIRI中的作用,可能为有效防治MIRI提供新的靶点和潜在研究方向。

Tumor immune checkpoints and their associated inhibitors

Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.