NF-κB Mediates Tumor Necrosis Factor α-Induced Expression of Optineurin, a Negative Regulator of NF-κB

Optineurin is a ubiquitously expressed multifunctional cytoplasmic protein encoded by OPTN gene. The expression of optineurin is induced by various cytokines. Here we have investigated the molecular mechanisms which regulate optineurin gene expression and the relationship between optineurin and nuclear factor κB (NF-κB). We cloned and characterized human optineurin promoter. Optineurin promoter was activated upon treatment of HeLa and A549 cells with tumor necrosis factor α (TNFα). Mutation of a putative NF-κB-binding site present in the core promoter resulted in loss of basal as well as TNFα-induced activity. Overexpression of p65 subunit of NF-κB activated this promoter through NF-κB site. Oligonucleotides corresponding to this putative NF-κB-binding site showed binding to NF-κB. TNFα-induced optineurin promoter activity was inhibited by expression of inhibitor of NF-κB (IκBα) super-repressor. Blocking of NF-κB activation resulted in inhibition of TNFα-induced optineurin gene expression. Overexpressed optineurin partly inhibited TNFα-induced NF-κB activation in Hela cells. Downregulation of optineurin by shRNA resulted in an increase in TNFα-induced as well as basal NF-κB activity. These results show that optineurin promoter activity and gene expression are regulated by NF-κB pathway in response to TNFα. In addition these results suggest that there is a negative feedback loop in which TNFα-induced NF-κB activity mediates expression of optineurin, which itself functions as a negative regulator of NF-κB.     

弥漫大B细胞淋巴瘤临床病理特征及预后分析

[目的]探讨弥漫大B细胞淋巴瘤(DLBCL)预后的相关因素.[方法]回顾性分析58例DLBCL患者的临床资料,采用单因素及Cox多因素分析DLBCL预后的相关因素.[结果]单因素分析显示,与DL-BCL患者预后相关的影响因素有患者的年龄、临床分期、血清LDH、PS分级、近期疗效及结外病灶数;Cox回归分析显示,与DLBCL患者预后相关的独立危险因素为年龄、近期疗效及临床分期;低危组、低中危组、高中危组及高危组的5年生存率分别是68.75％(11/16)、57.41％(12/21)、36.36％(4/11)、10.00％(1/10),随危险程度增高5年生存率依次降低(P＜0.05).[结论]与DLBCL患者预后相关的独立危险因素为患者的年龄、近期疗效及临床分期,应根据相关因素制定相应的治疗方案,以提高患者生存率.     

miR-21在弥漫大B细胞淋巴瘤肿瘤组织中的表达及临床意义

本研究旨在检测弥漫大B细胞淋巴瘤（DLBCL）患者肿瘤石蜡组织中miR-21的差异性表达与PTEN相关性及其临床意义。采用Real-time-PCR方法检测26例DLBCL患者及10名正常对照的miR-21表达,应用聚合物免疫组化检测系统检测PTEN蛋白水平。结果表明,26例DLBCL石蜡组织中miR-21的表达量为6．586（1．10,38．22）,显著高于正常对照[0．791（0．35,2．87）]（P〈0．05）,在26例DLBCL中有6例PTEN蛋白（23％）阳性,而在20例（77％）中为阴性。DLBCL中miR-2l表达水平与PTEN蛋白水平呈负相关,其高表达与DLBCL血清LDH水平呈正相关、Ⅲ／Ⅳ期患者miR-21表达水平明显高于Ⅰ／Ⅱ期患者（P〈0．05）,与临床亚型无关（P〉0．05）。结论：在DLBCL中miR-21表达升高可能提示肿瘤恶性程度高,预后不良,PTEN可能是miR-21的靶基因。     

MicroRNA-21在弥漫大B细胞淋巴瘤中的表达及其意义

本研究旨在检测弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma,DLBCL）细胞株中miR-21（micro RNA-21）的表达以及调控PDCD4及PTEN 2种基因对肿瘤生长、浸润及转移能力的影响,并探讨以miR-21作为靶分子对DLBCL基因治疗的可能性。首先,使用荧光定量PCR（qRT-PCR）检测3种DLBCL细胞株中miR-21的表达水平;利用转染anti-miR-21来降低miR-21的表达量,研究miR-21对DLBCL的生物行为可能产生的作用;通过荧光素酶报告基因检测,定量RT-PCR和Western blot来验证miR-21与PDCD4和PTEN的关系。结果表明：ABC-型DLBCL细胞株中miR-21的表达明显高于GCB-型DLBCL;RNA反义抑制技术特异性降低OCI-LY3和OCILY10细胞miR-21表达后,细胞增殖、侵袭能力受到明显抑制,凋亡增加;荧光素酶报告、定量RT-PCR和Western blot检测表明,PDCD4及PTEN是miR-21靶基因。结论：miR-21可能涉及DLBCL的发病机制,可能为一种新的DLBCL治疗靶分子。     

CD4+ T Cell–mediated Granulomatous Pathology in Schistosomiasis Is Downregulated by a B Cell–dependent Mechanism Requiring Fc Receptor Signaling

The effector functions of CD4⁺ T lymphocytes are generally thought to be controlled by distinct populations of regulatory T cells and their soluble products. The role of B cells in the regulation of CD4-dependent host responses is less well understood. Hepatic egg granuloma formation and fibrosis in murine schistosomiasis are dependent on CD4⁺ lymphocytes, and previous studies have implicated CD8⁺ T cells or cross-regulatory cytokines produced by T helper (Th) lymphocytes as controlling elements of this pathologic process. In this report, we demonstrate that B cell–deficient (μMT) mice exposed to Schistosoma mansoni develop augmented tissue pathology and, more importantly, fail to undergo the spontaneous downmodulation in disease normally observed during late stages of infection. Unexpectedly, B cell deficiency did not significantly alter T cell proliferative response or cause a shift in the Th1/Th2 balance. Since schistosome-infected Fc receptor–deficient (FcR γ chain knockout) mice display the same exacerbated egg pathology as that observed in infected μMT mice, the B cell– dependent regulatory mechanism revealed by these experiments appears to require receptor-mediated cell triggering. Together, the data demonstrate that humoral immune response/FcR interactions can play a major role in negatively controlling inflammatory disease induced by CD4⁺ T cells.     

T Cell Receptor–γ/δ Cells Protect Mice from Herpes Simplex Virus Type 1–induced Lethal Encephalitis

Increased numbers of T cell receptor (TCR)-γ/δ cells have been observed in animal models of influenza and sendai virus infections, as well as in patients infected with human immunodeficiency virus and herpes simplex virus type 1 (HSV-1). However, a direct role for TCR-γ/δ cells in protective immunity for pathogenic viral infection has not been demonstrated. To define the role of TCR-γ/δ cells in anti–HSV-1 immunity, TCR-α^−/− mice treated with anti– TCR-γ/δ monoclonal antibodies or TCR-γ/δ × TCR-α/β double-deficient mice were infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-γ/δ cells limited severe HSV-1–induced epithelial lesions and greatly reduced mortality by preventing the development of lethal viral encephalitis. The observed protection resulted from TCR-γ/δ cell–mediated arrest of both viral replication and neurovirulence. The demonstration that TCR-γ/δ cells play an important protective role in murine HSV-1 infections supports their potential contribution to the immune responses in human HSV-1 infection. Thus, this study demonstrates that TCR-γ/δ cells may play an important regulatory role in human HSV-1 infections.     

原发扁桃体弥漫性大 B 细胞淋巴瘤 7 例临床分析简

扁桃体是头颈部非霍奇金淋巴瘤（NHL）好发部位,弥漫性大B细胞淋巴瘤（DLBCL）是其最常见病理类型.本研究目的为总结原发扁桃体DLBCL的临床特征、免疫表型、预后因素及治疗策略.回顾性分析2009年10月至2013年2月7例初诊原发扁桃体DLBCL患者临床资料.结果表明,所有患者均因咽部不适或咽部疼痛就诊,Ann Arbor分期Ⅰ期42.8％ （3/7）,Ⅱ期57.1％ （4/7）.病理免疫组织化学检测显示,CD10阳性率100％、BCLL-2阳性率83.3％、BCL-6阳性率71.4％、Ki-67阳性率≥70％,为66.7％.放化疗对所有患者均有效,随访4-40个月,患者均存活.结论：原发扁桃体DLBCL分期早,在发病年龄、临床表现、病理组织学类型方面都有明显的特征,患者对放化疗敏感,预后较好,多数患者可长期生存.     

Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+ T Cells and Granulocyte/Macrophage Colony–stimulating Factor

We analyzed the ability of interferon (IFN)-γ knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-γ impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD8 and natural killer cells. Analysis of the tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFN- inducible protein 10 and monokine induced by γ-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage colony–stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes infiltrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that GM-CSF can substitute for IFN-γ in maintaining the CD8–polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection.     

Optimizing Workflows for Fast and Reliable Metabolic Tumor Volume Measurements in Diffuse Large B Cell Lymphoma

Molecular Imaging and Biology - This pilot study aimed to determine interobserver reliability and ease of use of three workflows for measuring metabolic tumor volume (MTV) and total lesion...