沉默TRIM23基因抑制骨肉瘤细胞的增殖

目的 探讨TRIM23基因对骨肉瘤细胞增殖能力的影响.方法 应用Western blot实验检测TRIM23基因在骨肉瘤细胞中的表达;应用shRNA质粒转染骨肉瘤细胞系U2OS,通过MTT与平板克隆形成实验评估细胞增殖能力;应用Westernblot实验检测U2OS细胞Akt/P53/P21通路的表达改变.结果 TRIM23蛋白在骨肉瘤细胞中的表达高于成骨细胞;沉默TRIM23基因可以抑制骨肉瘤细胞的增殖能力;沉默TRIM23基因下调P-Akt表达,但总Akt的表达无明显改变,上调P53与P21的表达.结论 TRIM23在骨肉瘤细胞中表达升高,TRIM23能通过调节Akt/P53/P21通路影响骨肉瘤细胞的增殖.     

Tumor-specific lytic path “hyperploid progression mediated death”: Resolving side effects through targeting retinoblastoma or p53 mutant

A major advance was made to reduce the side effects of cancer therapy via the elucidation of the tumor-specific lytic path “hyperploid progression-mediated death” targeting retinoblastoma (Rb) or p53-mutants defective in G1 DNA damage checkpoint. The genetic basis of human cancers was uncovered through the cloning of the tumor suppressor Rb gene. It encodes a nuclear DNA-binding protein whose self-interaction is regulated by cyclin-dependent kinases. A 3D-structure of Rb dimer is shown, confirming its multimeric status. Rb assumes a central role in cell cycle regulation and the “Rb pathway” is universally inactivated in human cancers. Hyperploidy refers to a state in which cells contain one or more extra chromosomes. Hyperploid progression occurs due to continued cell-cycling without cytokinesis in G1 checkpoint-defective cancer cells. The evidence for the triggering of hyperploid progression-mediated death in RB-mutant human retinoblastoma cells is shown. Hence, the very genetic mutation that predisposes to cancer can be exploited to induce lethality. The discovery helped to establish the principle of targeted cytotoxic cancer therapy at the mechanistic level. By triggering the lytic path, targeted therapy with tumor specificity at the genetic level can be developed. It sets the stage for systematically eliminating side effects for cytotoxic cancer therapy.     

PD-L1高表达晚期非小细胞肺癌患者单纯免疫治疗与免疫联合化疗疗效比较

背景与目的以免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）为代表的免疫治疗越来越广泛地应用于肺癌治疗。然而，对于程序性死亡受体配体1（programmed cell death-ligand 1, PD-L1）高表达，即肿瘤比例评分（tumor proportion score, TPS）≥50%的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者，采用单纯免疫治疗还是免疫联合化疗在临床上仍存争议。本研究旨在评估PD-L1高表达的晚期NSCLC患者接受单纯免疫治疗与免疫联合化疗的疗效。方法本研究回顾性分析了49例PD-L1高表达晚期NSCLC患者的临床资料。PD-L1表达采用22C3抗体行免疫组化染色，按TPS判读PD-L1表达水平。比较不同临床特征分组患者的客观缓解率（objective response rate，ORR）和无进展生存时间（progression free survival, PFS）。结果免疫单药与免疫联合化疗组的ORR分别为47.1%（8/17）和43.8%（14/32），差异无统计学意义（P=0.825）。免疫单药与免疫联合化疗组的中位PFS分别为8.0个月和6.8个月，差异无统计学意义（P=0.502）。并对本组PD-L1高表达患者免疫治疗的预测因素进行了分析，结果显示，一线免疫治疗ORR（12/19, 63.2%）显著优于二线及以上免疫治疗（10/30, 33.3%），差异有统计学意义（P=0.041），二者间PFS无差异。年龄、性别、吸烟史、功能状态评分（performance status, PS）、病理类型、肿瘤大小、肿瘤淋巴结转移（tumor node metastasis, TNM）分期与ORR和PFS不相关。结论PD-L1高表达的晚期NSCLC患者接受免疫单药和免疫联合化疗的疗效相近。PD-L1高表达患者一线免疫治疗的ORR更佳。对此类人群的最佳治疗方案有待于前瞻性临床研究进一步探索。     

骨填充网袋椎体成形术与经皮椎体后凸成形术治疗Kümmell病的疗效比较

目的比较骨填充网袋椎体成形术（Vesselplasty）与经皮椎体后凸成形术（percutaneous kyphoplasty，PKP）治疗 Kümmell 病的临床疗效。方法2015 年 1 月—2018 年 12 月收治 63 例 Kümmell 病患者，其中 28 例采用 Vesselplasty 治疗（Vesselplasty 组），35 例采用 PKP 治疗（PKP 组）。两组患者性别、年龄、病程、骨密度 T 值、骨折节段及术前疼痛视觉模拟评分（VAS）、Oswestry 功能障碍指数（ODI）、伤椎前缘高度、后凸 Cobb 角等一般资料比较，差异均无统计学意义（P>0.05），具有可比性。记录两组手术时间、术中透视时间、骨水泥注射量、骨水泥渗漏率、骨水泥弥散面积率和随访期间并发症发生情况，以及术前、术后 1 d、末次随访时 VAS 评分、ODI、伤椎前缘高度、后凸 Cobb 角。 结果两组患者均获随访，随访时间 12～36 个月，平均 24.2 个月。Vesselplasty 组手术时间、术中透视时间、骨水泥注射量、骨水泥弥散面积率均明显小于 PKP 组（P<0.05）。Vesselplasty 组骨水泥渗漏率（7.14%）明显低于 PKP 组（34.29%）（χ²=5.153，P=0.023）。两组患者术后 1 d 及末次随访时 VAS 评分、ODI、伤椎前缘高度、后凸 Cobb 角均较术前显著改善（P<0.05），术后两组间比较差异均无统计学意义（P>0.05）。随访期间两组均未见术椎再塌陷，Vesselplasty 组邻椎骨折发生率（7.14%）与 PKP 组（14.29%）比较，差异无统计学意义（χ²=0.243，P=0.622）。 结论Vesselplasty 和 PKP 治疗 Kümmell 病疗效相似，均能有效缓解患者疼痛症状，改善生活质量，部分恢复伤椎高度，矫正椎体后凸。但前者具有手术时间短、术中透视时间少、骨水泥渗漏少等优势。     

Clinicopathological aspects of therapy-related acute myeloid leukemia and myelodysplastic syndrome

Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions.     

蓝莓花青素对人胃腺癌BGC-823细胞增殖、侵袭的影响及机制研究

目的:探讨蓝莓花青素(BA)对人胃腺癌BGC-823细胞增殖、侵袭的影响及相关机制。方法:低、中、高剂量实验组与对照组人胃腺癌BGC-823细胞分别以25、50、100μg/mL BA与等量生理盐水处理,分别处理12 h、24 h、48 h。采用噻唑蓝(MTT)与流式细胞仪检测人胃腺癌BGC-823细胞增殖与凋亡;采用Transwell小室实验与免疫细胞化学法检测人胃腺癌BGC-823细胞侵袭与P53、半胱氨酸蛋白酶-3(Caspase-3)蛋白表达。结果:干预48 h时,对照组、低、中、高剂量实验组人胃腺癌BGC-823细胞P53与Caspase-3蛋白阳性细胞百分比分别为(11.12±1.01)%,(24.31±2.18)%,(47.56±2.91)%,(66.49±5.14)%与(15.04±1.23)%,(28.22±3.09)%,(69.36±5.42)%,(86.52±6.15)%。实验组胃腺癌BGC-823细胞增殖抑制率随BA浓度增大而逐渐升高;与对照组比较,低、中、高剂量实验组人胃腺癌BGC-823细胞凋亡率、P53与Caspase-3蛋白阳性细胞百分比均显著升高,侵袭率降低,呈浓度依赖性(均P0.05)。结论:BA可有效抑制胃腺癌BGC-823细胞增殖,诱导其凋亡,并降低侵袭能力,其机制可能与上调P53与Caspase-3蛋白表达有关。     

The Clinical and Prognostic Implications of Pluripotent Stem Cell Markers Expression and Their Correlation with the WNT signal pathway in Hepatocellular Carcinoma

Objectives: This study aimed to investigate the expression of SOX2, SOX9, p53, and β-catenin in hepatocellular carcinoma (HCC) and their correlation with clinicopathological parameters of prognostic importance. Materials and Methods: Seventy-five patients were enrolled in this study. All patients had full clinical and follow-up data and available paraffin blocks. Immunohistochemical analysis was performed and correlated with clinicopathological factors and patient survival. Results: We detected the positive expression of SOX2, SOX9, p53, and β-catenin in 76%, 50.7%, 50.7%, and 77.9% of HCC specimens respectively. All studied markers showed a significant increase in the expression in tumor tissue specimens compared to non-tumor tissue. Both SOX2 and SOX9 expressions were significantly associated with adverse prognostic factors in HCC. Significant positive correlations were found between SOX2 and SOX9 and both p53 and β-catenin expression (r= 0.528, 0.485 and; r = 0.253, 0.327, respectively; p < 0.0001 for both of them). Regarding survival, we found that HCC patients with positive SOX2 and SOX9 expressions had significantly shorter overall survival (p=0.0001, each). Additionally, larger tumor size, tumor grade, high stage, tumor multiplicity, presence of cirrhosis, tumor necrosis, high p53 expression, and positive β-catenin expression were independent predictors of worse survival. A multivariate Cox analysis revealed that tumor grade, stage, p53, and SOX2 expression were independent predictors of unfavorable prognosis in overall survival (p=0.0001, p=0.0001,p=0.033; and p=0.003, respectively). Conclusions: Our findings might provide an insight into SOX2 and SOX9’s role in HCC and suggest that SOX2 might be targeted for HCC therapy.     

Molecular profiling of Chinese R-CHOP treated DLBCL patients: Identifying a high-risk subgroup

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.     

A trip through the signaling pathways of melanoma

Many cellular signaling pathways are involved in the development of cancer. Depending on the tumor entity, the nature as well as the mode of activation can differ. Some signaling pathways frequently show changes as all tumor cells have to fulfill some basic requirements such as independence from growth factors or insensitivity against apoptosis. In this review, the possibilities of a tumor to manipulate signaling pathways to reach these goals are exemplified based on an archetypical melanoma cell. In addition, new therapeutic options based on the knowledge of signaling pathways will be discussed.