IFN‐γ protects from apoptotic neutrophil‐mediated tissue injury during acute Listeria monocytogenes infection

Listeria monocytogenes (LM) is a foodborne Gram‐positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN‐γ‐producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN‐γ. IFN‐γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng^?/? mice. Moreover, IFN‐γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM‐induced neutrophil apoptosis and spleen damage. In addition to this, IFN‐γ could effectively drive macrophage‐mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF‐β secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN‐γ at the early stage of LM infection, which is characterized by both LM elimination and tissue‐protective effects.     

Distinct Biomarker Profiles in Ex Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection versus CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation

Various approaches have been developed for ex vivo T cell depletion in allogeneic stem cell transplantation to prevent graft-versus-host disease (GVHD). Direct comparisons of T cell depletion strategies have not been well studied, however. We evaluated cellular and plasma biomarkers in 2 different graft manipulation strategies, CD3⁺CD19⁺ cell depletion (CD3/19D) versus CD34⁺ selection (CD34S), and their associations with clinical outcomes. Identical conditions, including the myeloablative preparative regimen, HLA-identical sibling donor, GVHD prophylaxis, and graft source, were used in the 2 cohorts. Major clinical outcomes were similar in the 2 groups in terms of overall survival, nonrelapse mortality, and cumulative incidence of relapse; however, the cumulative incidence of acute GVHD trended to be higher in the CD3/19D cohort compared with the CD34S cohort. A distinct biomarker profile was noted in the CD3/19D cohort: higher levels of ST2, impaired Helios^? FoxP3⁺Treg reconstitution, and rapid reconstitution of naïve, Th2, and Th17 CD4 cells in the early post-transplantation period. In vitro graft replication studies confirmed that CD3/19D disproportionately depleted Tregs and other CD4 subset repertoires in the graft. This study confirms the utility of biomarker monitoring, which can be directly correlated with biological consequences and possible future therapeutic indications.     

主动脉弓分支的数字减影血管造影解剖学变异及其意义

目的:讨论数字减影(DSA)下主动脉弓及其分支的解剖变异情况,为血管疾病介入诊断和治疗提供形态学依据.方法:从本院2000年2月～2008年6月行血管造影的所有患者中,选取造影片中主动脉弓及其分支的DSA图像资料完整者共534例,进行观察分析,描述所见主动脉弓及其分支的不同变异情况,统计发生率.结果:主动脉弓分支结构"正常"者占92.17%;左椎动脉迷走者占4.49%;左颈总动脉与头臂干共干者占1.50%;无头臂干,主动脉弓各分支均起自主动脉弓者占1.68%;右位主动脉弓者占0.19%.上述各种类型又有不同的变异亚型.结论:中国人主动脉弓及其分支变异种类繁多,影响血管疾病诊断和治疗.     

Leukotrienes in pulmonary arterial hypertension

Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism and are markers and mediators of pulmonary inflammation. Research over the past two decades has established that LTs modulate inflammation in pulmonary arterial hypertension (PAH). The purpose of this review was to summarize the current knowledge of LTs in the pathophysiology of PAH and to highlight a recent study that advances our understanding of how leukotriene B₄ (LTB₄) specifically contributes to pulmonary vascular remodeling. The results of these studies suggest that pharmacological inhibition of LT pathways, especially LTB₄, has high potential for the treatment of PAH.     

Role of T cell-derived exosomes in immunoregulation

Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells. They are composed of a lipid bilayer containing transmembrane proteins and enclosing cytosolic proteins and RNA, mediating intercellular communication between different cell types in the body, and thus influencing various physiological and pathological functions of both recipient and parent cells. For their nanolevel structures with a stable nature and various biological functions, studies of exosomes have been the subject of increasing interest in the past few years. It is widely known that different T cell subsets play important roles in cellular and humoral immunity, and their exosomes were also reported to exert similar biological functions. While several groups reported the secretion of exosomes by various T cells, the systematic summary involved in these exosomes are deficient. In this review, we will summarize the structure and functions of exosomes derived from T cells in recent reports, discuss emerging therapeutic opportunities, and consider the associated challenges.     

Utility of next‐generation sequencing methods to identify the novel HLA alleles in potential stem cell donors from Chinese Marrow Donor Program

The human leucocyte antigen (HLA) is the most polymorphic region of the human genome. Compared with Sanger‐sequencing‐based typing (SBT) methods, next‐generation sequencing (NGS) has significantly higher throughput and depth sequencing characteristics, having dramatic impacts on HLA typing in clinical settings. Here, we performed NGS technology with Ion Torrent S5 platform to evaluate the potential four novel HLA alleles detected in five donors from Chinese Marrow Donor Program (CMDP, Shaanxi Province) during routine Sanger SBT testing. We also predicted the highest estimated relative frequency novel allele‐bearing haplotypes according to their phenotypes and HaploStats database. NGS assays, as it provided the phase‐defined and complete sequencing information, undoubtedly increase novel allele identification which will greatly enrich HLA database and provide more information for donor selection.     

A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy

Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here we show that exosomes, endogenous nano-sized membrane vesicles secreted by most cell types, can deliver chemotherapeutics such as doxorubicin (Dox) to tumor tissue in BALB/c nude mice. To reduce immunogenicity and toxicity, mouse immature dendritic cells (imDCs) were used for exosome production. Tumor targeting was facilitated by engineering the imDCs to express a well-characterized exosomal membrane protein (Lamp2b) fused to αv integrin-specific iRGD peptide (CRGDKGPDC). Purified exosomes from imDCs were loaded with Dox via electroporation, with an encapsulation efficiency of up to 20%. iRGD exosomes showed highly efficient targeting and Dox delivery to αv integrin-positive breast cancer cells in vitro as demonstrated by confocal imaging and flow cytometry. Intravenously injected targeted exosomes delivered Dox specifically to tumor tissues, leading to inhibition of tumor growth without overt toxicity. Our results suggest that exosomes modified by targeting ligands can be used therapeutically for the delivery of Dox to tumors, thus having great potential value for clinical applications.     

LRIG1 Enhances Chemosensitivity by Modulating BCL-2 Expression and Receptor Tyrosine Kinase Signaling in Glioma Cells

Purpose

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) are an inhibitor of receptor tyrosine kinases (RTKs) that was discovered in recent years, and many studies showed that LRIG1 is a tumor suppressor gene and may be related to tumor drug resistance. In this study, we explored whether LRIG1 protein expression can improve the chemosensitivity of glioma cells and what was its mechanism.

Materials and Methods

We collected 93 cases of glioma tissues and detected the expression of LRIG1 and BCL-2. We constructed a multidrug resistance cell line U251/multidrug resistance (MDR) and examined the change of LRIG1 and BCL-2 at mRNA and protein expression levels. LRIG1 expression was upregulated in U251/MDR cells and we detected the change of multidrug resistance. Meanwhile, we changed the expression of LRIG1 and BCL-2 and explored the relationship between LRIG1 and BCL-2. Finally, we also explored the relationship between LRIG1 and RTKs.

Results

LRIG1 was negatively correlated with BCL-2 expression in glioma tissue and U251/MDR cells, and upregulation of LRIG1 can enhance chemosensitivity and inhibit BCL-2 expression. Furthermore, LRIG1 was negatively correlated with RTKs in U251/MDR cells.

Conclusion

These results demonstrated that LRIG1 can improve chemosensitivity by modulating BCL-2 expression and RTK signaling in glioma cells.     

Association of nuclear annexin A1 with prognosis of patients with esophageal squamous cell carcinoma

Although recent progress has been made in the diagnosis and treatment of cancer, the prognosis of esophageal squamous cell carcinoma (ESCC) remains poor. The identification of biomarkers for ESCC prognosis is important for treatment decisions. The aim of this study was to evaluate the relationship between the expressions of Annexin A1 (ANXA1), three prime repair exonuclease 1 (TREX1) and apurinic/apyrimidinic endonuclease-1 (APE1) and clinical outcome of patients with ESCC. The expressions of ANXA1, TREX1 and APE1 in 93 pairs of ESCC and paracancerous tissues were tested using immunohistochemistry. ANX1, TREX1 and APE1 were dysregulated in ESCC. Nuclear expressions of ANXA1 and APE1 were significantly associated with pathologic type (P = 0.004 and 0.040, respectively). Patients with low expression of nuclear ANXA1 had a better prognosis than those with high expression of nuclear ANXA1 (HR = 0. 448, 95% CI 0.236-0.849, P = 0.014), especially for those with histologic grade 1 and 2 (HR = 0.303, 95% CI: 0.155-0.593, P < 0.001). In conclusion, nuclear ANXA1 may be potentially used as a prognostic biomarker for ESCC.