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61.
【摘要】 目的 明确1个LEOPARD综合征家系的PTPN11基因突变。方法 对中国科学院大学宁波华美医院确诊的1例LEOPARD综合征先证者的家系进行现场调查。提取家系内4例患者、2例健康成员及与该家系无关的100例健康对照外周血标本。PCR扩增PTPN11基因所有外显子,使用Sanger测序法进行突变位点分析。结果 该家系3代14人,其中6人患病(男3例,女3例),符合常染色体显性遗传。患者皮损主要分布于面部、躯干和四肢,具有特殊面容及心血管系统异常。4例患者存在PTPN11基因的错义突变c.1632G>T(p.R558L),导致第558位由精氨酸变为亮氨酸,该突变既往未曾报道。该家系2例健康成员及100例健康对照未发现PTPN11基因突变。结论 该LEOPARD综合征家系患者PTPN11基因13号外显子发生c.1632G>T错义突变,可能是该家系患者发病的分子基础。 相似文献
62.
Weiyu Ye Anna Olsson-Brown Robert A. Watson Vincent T. F. Cheung Robert D. Morgan Isar Nassiri Rosalin Cooper Chelsea A. Taylor Umair Akbani Oliver Brain Rubeta N. Matin Nicholas Coupe Mark R. Middleton Mark Coles Joseph J. Sacco Miranda J. Payne Benjamin P. Fairfax 《British journal of cancer》2021,124(10):1661
Background Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10−6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma 相似文献
63.
目的 本研究通过网络药理学及分子对接方法研究苦参治疗慢性乙型肝炎的物质基础与分子机制。方法 依据中药系统药理学数据库和分析平台(TCMSP)筛选苦参有效化学成分及靶点基因。检索GeneCards数据库及OMIM数据库获取慢性乙型肝炎(CHB)相关靶点基因。采用Cytoscape3.7.2构建苦参治疗CHB的“相关活性成分-潜在作用靶点”网络并进行拓扑结构分析,利用STRING平台进行蛋白质相互作用分析,构建PPI网络,通过R 3.6.2进行基因富集分析。依据AutoDock vina将关键活性成分与核心靶点进行分子对接。结果 获得苦参治疗CHB的相关活性成分23个,潜在作用靶点97个。网络分析结果提示苦参可能通过作用于IL-6、ESR1、AR、RELA、PPARG和CASP3 6个核心靶点及相关通路以达到治疗CHB的目的。分子对接预测结果提示关键活性成分与核心靶点稳定结合。结论 本研究初步揭示了苦参治疗慢性乙型肝炎多成分、多靶点、多通路的作用机制,为苦参的临床开发提供基础。 相似文献
64.
65.
Xiaofei Ye Fangyuan Hu Yinghong Zhai Yingyi Qin Jinfang Xu Xiaojing Guo Yonglong Zhuang Jia He 《Hematological oncology》2020,38(4):565-575
Immune checkpoint inhibitors (ICIs) have shown remarkable clinical effects in many cancer types. However, ICIs could also induce severe organ system toxicities, including those of the hematological system. The present study aimed to extensively characterize the hematological toxicities of ICIs immunotherapy. Data were extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1, 2014, to March 31, 2019. Disproportionality analysis, including information component (IC) and reporting odds ratio (ROR), was used to detect potential disproportionality signal. The lower boundary of the 95% confidence interval of IC (IC025) exceeding zero or that of ROR (ROR025) exceeding one was considered statistically significant for detecting disproportionality signal. A total of 29 294 335 records were extracted from the database, with 132 573 related to ICIs. Overall, hematological adverse events (AEs) were more frequently reported in ICIs (IC025: 0.81; ROR025: 1.80). On further analysis, hematological AEs were overreported in female patients (female vs male, ROR025: 1.04) and anti-CTLA-4 monotherapy groups (anti-CTLA-4 vs anti-PD-1, ROR025: 1.33) and polytherapy groups (polytherapy vs monotherapy, ROR: 1.20, ROR025: 1.11). Moreover, class-specific hematological AEs were also detected and differed in unique ICI regimens. Notably, disseminated intravascular coagulation had the highest proportion of death outcomes among the top 10 most frequently reported ICI-associated hematological AEs. Our study shows a high reporting frequency of hematological AEs induced by ICI monotherapy (especially by anti-CTLA-4 therapy) and reinforced by polytherapy. A spectrum of class-specific disproportionality signal was also detected; some were fatal and reported for the first time. The heterogeneous clinical spectrum of hematological toxicities, including the non-negligible proportion of death as reported outcome, are warranted to be reminded by clinicians. Early recognition and management of ICI-related hematological AEs are highly important and further studies are needed to confirm the results of our study. 相似文献
66.
La-Wei Yang Xian-Jin Wu Yi Liang Guang-Qing Ye Yuchuan Che Xue-Zhen Wu Xiao-Jie Zhu Huo-Liang Fan Xiang-Ping Fan Jun-Fa Xu 《Molecular carcinogenesis》2020,59(4):447-461
Effective therapeutic targets for triple-negative breast cancer (TNBC), a special type of breast cancer (BC) with rapid metastasis and poor prognosis, are lacking, especially for patients with chemotherapy resistance. Decitabine (DCA) is a Food and Drug Administration-approved DNA methyltransferase inhibitor that has been proven effective for the treatment of tumors. However, its antitumor effect in cancer cells is limited by multidrug resistance. Cancer stem cells (CSCs), which are thought to act as seeds during tumor formation, regulate tumorigenesis, metastasis, and drug resistance through complex signaling. Our previous study found that miR-155 is upregulated in BC, but whether and how miR-155 regulates DCA resistance is unclear. In this study, we demonstrated that miR-155 was upregulated in CD24−CD44+ BC stem cells (BCSCs). In addition, the overexpression of miR-155 increased the number of CD24−CD44+ CSCs, DCA resistance and tumor clone formation in MDA-231 and BT-549 BC cells, and knockdown of miR-155 inhibited DCA resistance and stemness in BCSCs in vitro. Moreover, miR-155 induced stemness and DCA resistance by inhibiting the direct target gene tetraspanin-5 (TSPAN5). We further confirmed that overexpression of TSPAN5 abrogated the effect of miR-155 in promoting stemness and DCA resistance in BC cells. Our data show that miR-155 increases stemness and DCA resistance in BC cells by targeting TSPAN5. These data provide a therapeutic strategy and mechanistic basis for future possible clinical applications targeting the miR-155/TSPAN5 signaling axis in the treatment of TNBC. 相似文献
67.
68.
Xinping Zhou Chen Mei Jin Zhang Ying Lu Jianping Lan Shengyun Lin Yuefeng Zhang Yuemin Kuang Yanling Ren Liya Ma Juying Wei Li Ye Weilai Xu Kongfei Li Chenxi Lu Jie Jin Hongyan Tong 《Hematological oncology》2020,38(4):531-540
Patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) or higher-risk MDS have limited treatment options and poor prognosis. Our previous single-center study of decitabine followed by low dose idarubicin and cytarabine (D-IA) in patients with myeloid neoplasms showed promising primary results. We therefore conducted a multicenter study of D-IA regimen in AML evolving from MDS and higher-risk MDS. Patients with AML evolving from MDS or refractory anemia with excess blasts type 2 (RAEB-2) (based on the 2008 WHO classification) were included. The D-IA regimen (decitabine, 20 mg/m2 daily, days 1 to 3; idarubicin, 6 mg/m2 daily, days 4 to 6; cytarabine 25 mg/m2 every 12 hours, days 4 to 8; granulocyte colony stimulating factor [G-CSF], 5 μg/kg, from day 4 until neutrophil count increased to 1.0 × 109/L) was administered as induction chemotherapy. Seventy-one patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS and 27 (38.0%) had RAEB-2. Twenty-eight (63.6%) AML patients achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi): 14 (31.8%) patients had CR and 14 (31.8%) had CRi. Six (22.2%) MDS patients had CR and 15 (55.6%) had marrow complete remission. The median overall survival (OS) was 22.4 months for the entire group, with a median OS of 24.2 months for AML and 20.0 months for MDS subgroup. No early death occurred. In conclusion, the D-IA regimen was effective and well tolerated, representing an alternative option for patients with AML evolving from MDS or MDS subtype RAEB-2. 相似文献
69.
目的:检测miR-34c-3p与M2型肿瘤相关巨噬细胞(tumor-associated macrophage,TAM)在三阴性乳腺癌(triple negative breast cancer,TNBC)中的表达,并探讨其在乳腺癌发病中的意义。方法:选择2017年2月至2018年1月于西京医院就诊的68例TNBC患者作为实验组(A组),以同期就诊的70例乳腺纤维腺瘤患者作为对照组(B组)。采用Real-time RT-PCR 检测组织标本中miR-34c-3p的表达;流式细胞检测M2型TAM的表达;ELISA法检测血清中IL-10的表达。并进一步分析miR-34c-3p的表达与乳腺癌M2型TAM及血清IL-10水平的相关性。结果:A、B组miR-34c-3p的相对表达量分别为0.84±0.08、1.29±0.71,A组明显低于B组,差异有统计学意义(P<0.05)。与B组比较,A组M2型TAM(CD68+CD163+)细胞比例显著升高(P<0.05)。A组血清IL-10的表达[(19.69±4.93) pg/ml]较B组[(17.26±3.51) pg/ml]显著升高,差异有统计学意义(P<0.05)。TNBC组织中miR-34c-3p的表达与M2型TAM比例及血清IL-10表达均呈显著负相关(r=-0.508,r=-0.656,P<0.05)。结论:TNBC组织中miR-34c-3p的表达下调,M2型TAM比例及血清IL-10表达均显著升高,促进TNBC进展。 相似文献
70.
目的:分析原发性干燥综合征(primary Sjögren’s syndrome,pSS)合并自身免疫性肝病(autoimmune liver disease,ALD)的临床特点和预后。方法:回顾性分析浙江大学医学院附属第一医院2014年2月至2017年12月住院的pSS患者,比较pSS伴或不伴ALD两组间的临床表现和预后的差异。结果:共纳入203例pSS患者,其中合并ALD者68例(自身免疫性肝炎31例,原发性胆汁性胆管炎37例),不合并ALD者135例。两组间年龄、性别比例、口干、眼干、疼痛、乏力、淋巴结肿大、涎腺肿大、皮疹、肺部病变、肾脏受累等临床表现,其他免疫性疾病(如自身免疫性甲状腺疾病、类风湿关节炎和血管炎)的发生率,抗核抗体(antinuclear antibody,ANA)滴度,抗干燥综合征A抗体(Sjögren’s syndrome A antibody,SSA)、SSA52、抗干燥综合征B抗体(Sjögren’s syndrome B antibody,SSB)阳性率,红细胞沉降率和C反应蛋白水平差异均无统计学意义。pSS合并ALD的患者病程较短、抗线粒体-M2抗体 (anti-mitochondrial M2 antibody, AMA-M2)和抗着丝点抗体阳性率高,IgG、IgM水平高,C3水平低,血细胞减少,肝脏相关血清学指标(如谷丙转氨酶、谷草转氨酶、谷氨酰转肽酶、碱性磷酸酶、总胆红素、直接胆红素、间接胆红素)水平升高,肝硬化的比例增加,死亡事件明显增多(死亡率13.24% vs. 2.96%, P=0.013),预后更差。二元Logistic回归分析发现,pSS合并ALD的患者出现死亡事件的不良因素为肝硬化、EULAR干燥综合征疾病活动性指数评分(the EULAR Sjögren’s syndrome disease activity index,ESSDAI)和总胆红素水平。Kaplan-Meier生存曲线提示合并ALD的患者生存率低于对照组。结论:pSS合并ALD的患者病情更重、死亡事件发生率高,需要临床重视并加强对症治疗。 相似文献