Platelet reactivity evaluated with the VASP assay following ticagrelor loading dose in acute coronary syndrome patients undergoing percutaneous coronary intervention

Background

The level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS).

Objective

We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI.

Methods

We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index ≥ 50%.

Results

One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17 ± 14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6–22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index < 16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p = 0.9).

Conclusion

In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index < 16%.     

Bridging Hepatocellular Carcinoma to Transplant: Transarterial Chemoembolization Response,Tumor Biology,and Recurrence after Transplantation in a 12-Year Transplant Cohort

PurposeTo evaluate tumor response to transarterial chemoembolization as well as biologic characteristics of the tumor as predictors of recurrence after transplantation in patients with hepatocellular carcinoma (HCC) who were bridged or down-staged to liver transplantation.Materials and MethodsAn institutional review board-approved, Health Insurance Portability and Accountability Act-compliant, single-institution retrospective analysis was performed on all patients with HCC who were treated with the use of conventional transarterial chemoembolization or transarterial chemoembolization with drug-eluting embolics (DEE) over a 12-year period and who subsequently underwent liver transplantation (n = 142). Treatment response was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) imaging criteria and then correlated with tumor characteristics and recurrence. Of the 142 patients followed after transplantation, 127 had imaging after transarterial chemoembolization but before transplantation. Imaging response and post-transplantation recurrence were correlated with patient demographics, liver function, and tumor morphology. HCC recurred in 9 patients (mean time from transplantation, 526 days). Recurrence was analyzed with the use of univariate and multivariate statistics. Kaplan-Meier recurrence-free survival curves were calculated based on immediate imaging response before transplantation with the use of the log-rank test.ResultsBefore transplantation, 57% of patients (72/127) demonstrated complete response (CR) and 24% (31/127) showed partial response (PR). Complete pathologic necrosis occurred in 54% (39/72) of CR patients and 20% (6/31) of PR patients. Poor treatment response, defined as stable disease (SD) or progressive disease (PD), occurred in 18% of patients (24/127) before transplantation and was present in 67% of cases of recurrence (6/9; P < .001). Post-transplantation recurrence was present in 1.4% of patients (1/71) with CR and in 6.5% of patients (2/31) with PR. In patients with SD after transarterial chemoembolization, HCC recurred in 18.8% of transplant patients (3/16) and in 43% of patients (3/7) with PD. Larger pretreatment tumor size (P = .05), higher Child-Pugh score (P = .002), higher tumor grade at explantation (P = .04), and lymphovascular invasion at explantation (P = .008) also were associated with increased incidence of post-transplantation recurrence.ConclusionsPoor tumor response to transarterial chemoembolization before transplantation identifies patients at increased risk for post-transplantation recurrence.     

Locoregional Therapy of Hepatocellular-Cholangiocarcinoma versus Hepatocellular Carcinoma: A Propensity Score–Matched Study

PurposeTo compare outcomes of unresectable hepatocellular-cholangiocarcinoma (HCC-CC) with hepatocellular carcinoma (HCC) after locoregional therapy (LRT).Materials and MethodsConsecutive patients with histologically confirmed HCC-CC or HCC treated with LRT between 2007 and 2017 were retrospectively reviewed. Ten patients (8 men; median age, 60 y) with 12 HCC-CCs (mean diameter, 4.2 cm ± 1.9; mean number, 3.7 ± 3.3) treated with chemoembolization (n = 6), yttrium-90 radioembolization (n = 2), RF ablation (n = 1), or chemoembolization/RF ablation (n = 1) were compared with 124 patients (92 men; median age, 59 y) with 134 HCCs (mean diameter, 4.8 cm ± 4.0; mean number, 2.6 ± 2.2) treated with chemoembolization (n = 51), yttrium-90 radioembolization (n = 17), RF ablation (n = 41), or chemoembolization/RF ablation (n = 15). Propensity score–matched analysis with conditional logistic regression adjusted for age, sex, LRT modality, tumor-specific features, and Child-Pugh class. Tumor-volume doubling time (TVDT) before LRT and objective response rates were compared by Kruskal-Wallis and Fisher exact test; progression-free survival (PFS) and transplant-free survival (TFS) were compared by Cox proportional hazards model.ResultsOn univariate analysis, HCC-CC was associated with lower median TVDT (2.4 months vs 5.2 months, P = .03), objective response (30% vs 71%, P = .01), and median PFS (2.4 months vs 7.4 months, HR 4.3, 95% CI 2.2–8.4, P < .0001). Propensity score–matched analysis demonstrated greater distant progression (60% vs 30%, P = .003) and significantly shorter median PFS (2.4 months vs 6.0 months, HR 3.3, 95% CI 1.3–8.9, P = .017) for HCC-CC. No significant difference was observed in TFS (7.5 months vs 13.8 months, HR 1.5, 95% CI 0.4–6.1).ConclusionsHCC-CC was associated with reduced PFS and greater distant progression after LRT compared with HCC, indicating a need for adjunctive treatment strategies to improve outcomes.     

May progesterone receptor membrane component 1 (PGRMC1) predict the risk of breast cancer?

Objective: Our and other studies have pointed on an important role of progesterone receptor membrane component 1 (PGRMC1) in development of breast cancer, especially in hormone therapy. To investigate if PGRMC1 could be used to predict the risk for getting breast cancer, we assessed in tissues of patients with primary invasive breast cancer, if the expression of PGRMC1 may be associated with the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), and ki67.

Methods: Samples from 109 patients with breast cancer between the years 2008 and 2014 were obtained with the patients’ consent. Each sample was evaluated for the ERα, PR, Ki67, and PGRMC1 expression by immunohistochemistry using serial sections from the ame paraffin block comparing malignant tissue to benign tissue.

Results: Expression of PGRMC1 is increased in tumor area compared with non-cancerous tissue and positively correlates with ERα expression (OR?=?1.42 95%CI 1.06–1.91, p?=?0.02). No association was obtained between expression of PGRMC1 and PR or Ki67.

Conclusion: It can be suggested that women with breast epithelium highly expressing PGRMC1 and in interaction with ERα may have an increased risk to develop breast cancer, especially when treated with hormone therapy.     

靶向S1PR3基因shRNA慢病毒表达载体构建及功能鉴定

目的：构建靶向小鼠S1PR3基因的shRNA慢病毒表达载体,并验证其对内皮祖细胞迁移能力的影响。方法依照shRNA设计原则,合成对应的shRNA序列,将其克隆到PHBLV载体中,使用三载体系统进行病毒包装,收集制备成功的病毒,并用荧光显微镜法测定病毒滴度,使用病毒感染EPC后,测定各组细胞中S1PR3蛋白表达情况,选择合适的病毒感染EPC后,测定其对EPC迁移能力的影响。结果成功将shRNA序列克隆到慢病毒表达载体PHBLV-U6-RFP,表达质粒与辅助质粒共转染293细胞后48 h就可以看到细胞中成功表达红色荧光。收集培养成功病毒感染小鼠EPC,可以不同程度干扰细胞中S1PR3蛋白表达,S1PR3蛋白表达受到抑制后,EPC的迁移能力明显减弱。结论我们成功构建了可以有效干扰S1PR3表达的慢病毒载体,并初步观察了其对EPC细胞的迁移能力的影响,为后续进一步调控S1PR3相关的细胞功能的研究奠定了基础。     

The avidity of PR3‐ANCA in patients with granulomatosis with polyangiitis during follow‐up

The objective of this study is to investigate whether the avidity of proteinase‐3‐anti‐neutrophil cytoplasmic antibody (PR3‐ANCA) changes during follow‐up in different subgroups of patients with granulomatosis with polyangiitis (GPA). We selected 10 patients with renal relapsing GPA, 10 patients with renal non‐relapsing GPA and 10 patients with non‐renal relapsing GPA. In all patients, an ANCA rise occurred during remission. The avidity was measured using a chaotropic approach at the time of an ANCA rise and at the time of a relapse in relapsing patients or time‐matched during remission in non‐relapsing patients. No difference was observed in the avidity at the ANCA rise between renal relapsing patients [26·2% (15·5–47·5)], renal patients without a relapse [39·6% (21·2–63·4)] and non‐renal relapsing patients [34·2% (21·6–59·5)]. In renal relapsing patients, the avidity increased significantly from the moment of the ANCA rise to the relapse [difference 6·4% (0·0–17·1), P = 0·0273]. The avidity did not increase after an ANCA rise in renal non‐relapsing patients [difference 3·5 (?6·0 to 10·1), P = 0·6250] or in non‐renal relapsing patients [difference ?3·1% (?8·0 to 5·0), P = 0·5703]. The avidity of PR3‐ANCA increases after an ANCA rise during follow‐up in renal relapsing patients, but not after an ANCA rise in renal patients who remain in remission or in non‐renal relapsing patients.     

ER、PR、HER-2、Ki-67与乳腺癌新辅助化疗疗效相关性分析

目的  探讨雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2（HER-2）、Ki67抗原（Ki-67）与乳腺癌新辅助化疗疗效相关性分析。方法  采用免疫组织化学方法检测81例乳腺癌新辅助化疗前后ER、PR、HER-2、Ki-67的表达情况,并评估其与乳腺癌新辅助化疗有效率的关系。结果  81例患者中临床RR79％,术后pCR（9.9％）,tpCR（6.2％）。达到pCR+tpCR率,（ER阴性）23.0%>（ER阳性）12.7%,（PR阴性）28.6%>（PR阳性）9.4%;ER、PR、HER-2及Ki67等与新辅助化疗疗效之间差异无统计学意义。新辅助化疗前后ER、PR、HER-2的状态改变不明显,差异无统计学意义（P >0.05）,而Ki67的表达数量有统计学意义（P <0.05）,其降低了Ki67的表达水平。结论  乳腺癌新辅助化疗可有效控制肿瘤,ER或PR阴性者较阳性者可获得更高的pCR+tpCR率,Ki67可作为化疗药物敏感性和耐药性的预测指标。

     

Involvement of an Orphan Transporter,SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells

The SLC22A18 gene, which encodes an orphan transporter, is located at the 11p15.5 imprinted region, an important tumor suppressor gene region. However, the role of SLC22A18 in tumor suppression remains unclear. Here, we investigated the involvement of SLC22A18 in cell growth, invasion, and drug resistance of MCF7 human breast cancer cell line. Western blot analysis indicated that SLC22A18 is predominantly expressed at intracellular organelle membranes. Quantitative proteomics showed that knockdown of SLC22A18 significantly altered the expression of 578 (31.0%) of 1867 proteins identified, including proteins related to malignancy and poor prognosis of breast cancer. SLC22A18 knockdown (1) increased MCF7 cell growth concomitantly with a >7-fold increase of annexin A8 (involved in cell growth and migration; a predictor of poor prognosis), (2) induced spherical morphology of MCF7 cells concomitantly with a nearly 3-fold increase of CD44 (involved in regulation of malignant phenotypes), and (3) increased chemosensitivity to vinca alkaloids concomitantly with a >80% reduction of doublecortin-like kinase 1 (involved in regulation of microtubule polymerization). Our results suggest that SLC22A18 may act as a tumor suppressor by regulating the expression levels of cell growth–related proteins, and vinca alkaloids might show therapeutic efficacy against low-SLC22A18–expressing breast cancer.     

敲除S1PR3可缓解小鼠的急性肺损伤：基于抑制MAPK信号通路

目的 探讨敲除S1PR3是否通过抑制丝裂原活化蛋白激酶（MAPKs）途径改善脂多糖（LPS）诱导的小鼠急性肺损伤。方法 用LPS诱导小鼠急性肺损伤模型。雄性C57BL/6J和S1PR3敲除小鼠,随机分为4组：C57 NS组（C57,生理盐水处理）、C57 LPS组（C57,LPS诱导）、S1PR3-/- NS组（S1PR3敲除鼠,生理盐水处理）、S1PR3-/- LPS组（S1PR3敲除鼠,LPS诱导）,8只/组。RT-qPCR检测S1PR3,IL-β和IL-18表达,HE染色检测肺部组织损伤,流式细胞术检测细胞凋亡水平,Western blot法检测caspase-1,GSDMD,p-JNK,p-ERK p-p38 蛋白表达水平。同时,Ⅱ型肺泡上皮细胞（MLE-12 细胞）铺板后分为 4 组：PBS 组、LPS 组、CYM5541组（仅加入S1PR3激动剂）、CYM5541+LPS组（加入S1PR3激动剂+LPS）,检测各组细胞焦亡水平及MAPK信号通路分子的表达水平。结果 急性肺损伤小鼠肺组织S1PR3表达上调（P<0.001）;血清IL-1β和IL-18因急性肺损伤而明显升高（P<0.05）。急性肺损伤小鼠因敲除S1PR3肺出血、炎症渗出明显改善,肺湿干比重下降,细胞凋亡比例和焦亡相关蛋白如clv-caspase-1,GSDMD表达均降低（P<0.05）。MLE-12细胞因加入S1PR3激动剂,细胞焦亡相关蛋白表达均升高（P<0.05）。此外,MAPKs家族（JNK,ERK p38）的激活因S1PR3敲除后受到抑制,因加入S1PR3激动剂而表达明显升高（P<0.05）。结论 敲除S1PR3可通过抑制MAPK信号通路改善急性肺损伤。