胃癌组织细胞程序性死亡配体1表达情况和CD8+肿瘤浸润T淋巴细胞密度及其与患者临床病理特征和预后的关系研究

背景 目前,胃癌组织细胞程序性死亡配体1（PD-L1）表达情况和CD8+肿瘤浸润T淋巴细胞（TILs）密度是否可作为胃癌患者预后的评估指标尚不明确。 目的 分析胃癌组织PD-L1表达情况、CD8+ TILs密度及其与患者临床病理特征和预后的关系。 方法 选择2016年1月至2018年3月在南阳市第一人民医院行手术治疗的胃癌患者125例,采用实时荧光定量反转录聚合酶链反应检测其胃癌组织PD-L1 mRNA相对表达量,采用免疫组化方法检测其胃癌组织CD8+ TILs密度。分析胃癌组织PD-L1 mRNA相对表达量、CD8+ TILs密度与患者临床病理特征的关系;胃癌组织PD-L1 mRNA相对表达量与CD8+ TILs密度的相关性分析采用Pearson相关分析;通过电话随访至术后36个月,以患者死亡或失访为终点事件,绘制Kaplan-Meier曲线以进行生存分析;胃癌患者预后的影响因素分析采用单因素和多因素Cox回归分析。 结果 所有患者胃癌组织平均PD-L1 mRNA相对表达量为3.1,癌巢内平均CD8+ TILs数量为36个,最终归为低水平组73例（PD-L1 mRNA相对表达量<3.1）和高水平组52例（PD-L1 mRNA相对表达量≥3.1）,低密度组55例（CD8+ TILs数量<36个）和高密度组70例（CD8+ TILs≥36个）。低水平组与高水平组患者淋巴结转移、脉管侵犯、腹膜转移情况比较,差异有统计学意义（P<0.05）;低密度组与高密度组患者浸润深度、淋巴结转移、脉管侵犯、腹膜转移情况比较,差异有统计学意义（P<0.05）。Pearson相关分析结果显示,胃癌组织PD-L1 mRNA相对表达量与CD8+ TILs密度呈负相关（r=-0.412,P<0.001）。中位随访时间为36.0个月,125例患者中预后不良37例,预后良好88例;低水平组与高水平组、低密度组与高密度组患者Kaplan-Meier曲线比较,差异均有统计学意义（P<0.05）。多因素Cox回归分析结果显示,高水平PD-L1 mRNA〔HR=3.021,95%CI（1.632,5.045）〕、低密度CD8+ TILs〔HR=2.158,95%CI（1.854,4.632）〕为胃癌患者预后不良的独立危险因素（P<0.05）。 结论 高水平PD-L1 mRNA、低密度CD8+ TILs均是胃癌患者预后不良的独立危险因素,有望成为胃癌患者预后不良的生物标志物。     

Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis

Intercellular cross-talk between osteoblasts and osteoclasts is important for controlling bone remolding and maintenance. However, the precise molecular mechanism by which osteoblasts regulate osteoclastogenesis is still largely unknown. Here, we show that osteoblasts can induce Ca(2+) oscillation-independent osteoclastogenesis. We found that bone marrow-derived monocyte/macrophage precursor cells (BMMs) lacking inositol 1,4,5-trisphosphate receptor type2 (IP(3)R2) did not exhibit Ca(2+) oscillation or differentiation into multinuclear osteoclasts in response to recombinant receptor activator of NF-kappaB ligand/macrophage colony-stimulating factor stimulation. IP(3)R2 knockout BMMs, however, underwent osteoclastogenesis when they were cocultured with osteoblasts or in vivo in the absence of Ca(2+) oscillation. Furthermore, we found that Ca(2+) oscillation-independent osteoclastogenesis was insensitive to FK506, a calcineurin inhibitor. Taken together, we conclude that both Ca(2+) oscillation/calcineurin-dependent and -independent signaling pathways contribute to NFATc1 activation, leading to efficient osteoclastogenesis in vivo.     

Binding-Induced Fluorescence of Serotonin Transporter Ligands: A Spectroscopic and Structural Study of 4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP+) and APP+ Analogues

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头颈部鳞癌程序性死亡配体-1的共表达基因及 调控网络的生物信息学分析

目的 运用生物信息学的方法绘制头颈部鳞癌（HNSCC）中程序性死亡配体-1（PD-L1）共表达基因关系网络,筛选潜在的PD-L1的协同标志物,寻找可能的PD-L1基因调控肿瘤免疫状态的基因和通路。方法 利用癌症和肿瘤基因图谱（TCGA）中的大样本HNSCC的转录组学数据,在cBioPortal数据平台进行基因集的检索,筛选PD-L1共表达基因,在R语言的clusterProfiler中进行GO-BP和KEGG富集分析,再进行分子关系网络分析,提取重要节点基因（hub基因）,再进行生存分析。结果 筛选出共表达基因117个,共表达基因主要富集在免疫调节和病毒反应过程。网络节度分析得到了10个hub基因,依次为STAT1、IFNG、CXCL10、CCR5、FCGR3A、CXCL9、GBP5、CD86、GZMB、IRF1。生存分析显示：CCR5、CXCL9、GZMB是HNSCC预后相关的重要基因。这些基因均参与了免疫过程,其表达与PD-L1相关（Pearson相关系数为0.30、0.35、0.39,P值均小于0.01）。这些基因高表达在HNSCC中均为保护因素。结论 HNSCC中的PD-L1共表达的主要基因均为免疫相关基因,其中CCR5、CXCL9、GZMB与PD-L1存在共表达关系,与预后相关,其可能与程序性死亡受体-1（PD-1）/PD-L1介导的肿瘤免疫逃避相关,为进一步研究PD-1/PD-L1的作用机制和精准靶向治疗提供了新的参考。     

Osteoprotegerin in diabetic osteopathy

AimThe aim of this study is to evaluate the relationship between OPG and the degree of glycaemic control in a population of elderly subjects.Methods and resultsData presented included 172 elderly subjects, of whom 107 were hospitalized for a hip fracture and 65 were non fractured outpatients. All participants received a multidimensional geriatric evaluation and underwent blood sampling. HbA1c, OPG, CTX and OC were measured and DXA scans were performed. Carotid intima-media thickness (IMT) was measured in all outpatients. Diabetic patients had more comorbidities, higher mean values of lumbar spine and femoral neck BMD and T-score, lower circulating levels of OC and CTX, and higher circulating levels of OPG compared to non-diabetic subjects. OPG was directly correlated with HbA1c. This association was most evident in non-fractured elderly subjects. Moreover, diabetic patients with IMT>1.5 mm had greater mean values of OPG than non-diabetic subjects with high IMT and than elderly subjects with IMT < 1.5 mm, with and without T2DM.ConclusionsDiabetic patients have reduced circulating levels of OC and CTX, and elevated serum levels of OPG, suggesting a state of low bone turnover. Reduced bone turnover causes an increase of BMD and could lead to a poor bone quality. OPG and HbA1c were directly correlated and OPG mean values were higher in diabetic patients with poor glucose control. Diabetic osteopathy could be considered a late complication of T2DM, directly related with the degree of glucose control and the duration of the disease.     

Chemokine (C-X-C motif) ligand 1 (CXCL1) protein expression is increased in high-grade prostate cancer

Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may enhance tumor epithelial-stromal interactions facilitating tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, however, no study to date has been reported describing CXCL1 in human prostate tumors. Herein, we set out to describe the expression pattern of CXCL1 in human prostate tumors.     

Molecular mechanisms for bone resorption by gingipains: Degradation of osteoprotegerin by lysine-specific gingipain is a key factor for enhanced osteoclastogenesis

BackgroundPeriodontitis is a chronic inflammatory disease accompanied by alveolar bone loss. Porphyromonas gingivalis, which plays a key role in the etiology of periodontitis, produces cysteine proteases called gingipains to promote proteolysis. Gingipains are classified into two groups based on their cleavage site specificity, specifically arginine-specific gingipains (Rgps) and lysine-specific gingipains (Kgps).HighlightWe found that osteoclast differentiation induced by active vitamin D₃, Toll-like receptor ligands including lipopolysaccharide, and inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β was enhanced by a secreted Kgp in co-cultures of mouse osteoblasts and bone marrow cells, whereas RgpB had no effect on osteoclast differentiation under the same experimental conditions. The effect of Kgp on osteoclast differentiation was completely blocked by an inhibitor of Kgp. Further, osteoprotegerin (OPG), a protein that regulates osteoclast differentiation, was degraded by Kgp. Kgp-mediated osteoclast differentiation was not observed in co-cultures of OPG-deficient osteoblasts and bone marrow cells.ConclusionOur data suggests that degradation of OPG by Kgp is a crucial event in the progression of osteolysis in periodontitis.     

渴络欣胶囊联合培哚普利治疗早期糖尿病肾病的临床研究

目的 探讨渴络欣胶囊联合培哚普利治疗早期糖尿病肾病的临床疗效。方法 选取2021年6月—2023年1月郑州大学第五附属医院收治的168例早期糖尿病肾病患者,按随机数字表法将患者分为对照组和治疗组,每组各84例。对照组晨服培哚普利叔丁胺片,4 mg/d,1次/d。治疗组在对照组基础上口服渴络欣胶囊,4粒/次,3次/d。两组疗程12周。比较两组临床疗效,治疗前后中医症状积分、肾功能指标[24 h尿蛋白定量（24 h UP）等]、相关量表[肾脏病生活质量量表1.3（KDQOL-SF 1.3）、简式抑郁-焦虑-压力量表（DASS-21）]评分及血清血管生成抑制蛋白1（VASH-1）、高迁移率族蛋白B1（HMGB1）、CXC趋化因子配体10（CXCL10）水平。结果 治疗后,治疗组总有效率是94.05%,显著高于对照组的84.52%（P＜0.05）。治疗后,两组气短乏力积分、咽干口渴积分、肢体麻木积分、肢体麻木积分、腰膝酸软积分、畏寒肢冷积分均较治疗前显著降低（P＜0.05）;治疗后,治疗组中医症状积分低于对照组（P＜0.05）。治疗后,两组血肌酐（Scr）、24 h UP、尿蛋白排泄率（UAER）低于同组治疗前（P＜0.05）;治疗后,治疗组肾功能指标改善优于对照组（P＜0.05）。治疗后,两组KDQOL-SF 1.3评分均显著增高,而DASS-21评分均显著降低（P＜0.05）;治疗后,治疗组KDQOL-SF 1.3评分和DASS-21评分改善优于对照组（P＜0.05）。治疗后,两组血清VASH-1、HMGB1、CXCL10水平均显著降低（P＜0.05）;治疗后,治疗组血清VASH-1、HMGB1、CXCL10水平低于对照组（P＜0.05）。结论 渴络欣胶囊联合培哚普利治疗早期糖尿病肾病具有良好的疗效,能有效缓解机体炎症反应、控制肾组织纤维化,在患者症状和负面情绪减轻、肾功能和生活质量改善方面获得更佳效果,值得临床推广应用。     

Diagnostic utility of programmed cell death ligand 1 (clone SP142) immunohistochemistry for malignant lymphoma and lymphoproliferative disorders: A brief review

The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune control and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and -negative subgroups, but their clinicopathological significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.