Synaptopodin-2 induces assembly of peripheral actin bundles and immature focal adhesions to promote lamellipodia formation and prostate cancer cell migration

Synaptopodin-2 (Synpo2), an actin-binding protein and invasive cancer biomarker, induces formation of complex stress fiber networks in the cell body and promotes PC3 prostate cancer cell migration in response to serum stimulation. The role of these actin networks in enhanced cancer cell migration is unknown. Using time-course analysis and live cell imaging of mock- and Synpo2-transduced PC3 cells, we now show that Synpo2 induces assembly of actin fibers near the cell periphery and Arp2/3-dependent lamellipodia formation. Lamellipodia formed in a non-directional manner or repeatedly changed direction, explaining the enhanced chemokinetic activity of PC3 cells in response to serum stimulation. Myosin contraction promotes retrograde flow of the Synpo2-associated actin filaments at the leading edge and their merger with actin networks in the cell body. Enhanced PC3 cell migration correlates with Synpo2-induced formation of lamellipodia and immature focal adhesions (FAs), but is not dependent on myosin contraction or FA maturation. The previously reported correlation between Synpo2-induced stress fiber assembly and enhanced PC3 cell migration therefore reflects the role of Synpo2 as a newly identified regulator of actin bundle formation and nascent FA assembly near the leading cell edge.     

Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status,and it regulates cell proliferation by inhibiting Erk1/2 phosphorylation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Significantly downregulated histidine-rich glycoprotein (HRG) during the dynamic stages (WB, WB7, and WB11) of neoplastic transformation of WB F344 hepatic oval-like cells was screened out by iTRAQ labeling followed by 2DLC-ESI-MS/MS analysis. HRG expression was significantly lower in HCC tissues. HRG overexpression in Huh7 and MHCC-97H hepatoma cell lines led to decreased cell proliferation, colony-forming ability, and tumor growth, and increased cell apoptosis. HRG could inhibit cell proliferation via the FGF-Erk1/2 signaling pathway by reducing Erk1/2 phosphorylation. On the other hand, the functional expression of HRG was also dependent on the glycosylation status at its N-terminal, especially at the glycosylation site Asn 125. The glycosylation of HRG may play a key competitive role in the interaction between HRG and heparin sulfate for binding bFGF and activating the FGF receptor. These findings provide novel insights into the molecular mechanism of HRG in HCC.     

MicroRNA-29B (mir-29b) regulates the Warburg effect in ovarian cancer by targeting AKT2 and AKT3

Epithelial ovarian cancer (EOC) is the most lethal and aggressive gynecological malignancy, and abnormal cellular metabolism significantly contributes to cancer onset and progression. Here, we report that miR-29b negatively regulates AKT2/AKT3 expression, causing HK2/PKM2 downregulation and leading to a decreased Warburg effect and slowed ovarian cancer progression. Compared to normal ovaries, ovaries with epithelial cancer exhibited lower miR-29b expression at both cellular/histological levels. Glucose consumption and lactate production experiments confirmed miR-29b''s regulation of EOC metabolism. A luciferase reporter assay confirmed the direct binding of miR-29b to AKT2/AKT3 3′ UTRs. miR-29b silencing correlated with increased expression of AKT2/3, pAKT2/3, HK2, and PKM2. Pyruvic acid and NAD+/NADH levels also changed when miR-29b expression was suppressed; this effect could be blocked by specific AKT inhibitors, suggesting the miR-29b-AKT axis regulates the Warburg effect in ovarian cancer. In xenograft mouse models, miR-29b inhibited tumor formation in vivo. In vivo imaging also demonstrated that miR-29b agomir inhibited the relative uptake of ¹⁸F-FDG in the xenograft tumors, suggesting that miR-29b over-expression could negatively modulate tumor glucose metabolism in vivo. Taken together, our study suggests that miR-29b regulates the Warburg effect in EOC via AKT2/AKT3 and may provide novel options for future treatments for EOC.     

新辅助化疗治疗肢体软组织肉瘤28例报告

目的分析探讨新辅助化疗治疗肢体软组织肉瘤(soft tissue sarcoma,STS)的临床疗效及价值。方法选取2009年5月至2012年6月,我科经新辅助化疗[术前顺铂+异环磷酰胺+阿霉素(cisplatin+ifosfamide+adriamycin,DDP+IFO+ADM,DIA)化疗2个周期+手术治疗+术后DIA化疗6个周期]治疗的28例肢体STS患者,其中男18例,女10例;年龄15~62岁,中位年龄35岁。DIA 1个周期的化疗方案为:第1天DDP 120 mg/m2,第7~9天每天按序均给予ADM 30 mg/m2、IFO 2.0 g/m2,第10~11天IFO2.0 g/m2。对所有患者进行随访,复查肺部CT及病变部位X线片,记录复发、转移、死亡情况。参照实体瘤疗效评价标准(response evaluation criteria in solid tumour,RECIST)1.1评价化疗疗效;按照化疗常见不良反应事件评价标准(common terminology criteria for adverse events,CTCAE)4.0对化疗期间的不良反应进行评价。结果本组28例手术均进行顺利,总失血量50~600 ml,平均260 ml,切口如期愈合。DIA化疗方案进行了术前2个周期、术后6个周期化疗,持续时间为38周,28例共进行了224个化疗周期。28例随访12~59个月,随访结束时,存活23例,其中无瘤生存20例,带瘤生存3例。本组2年无瘤生存率71.4%,2年总生存率82.1%。术后转移5例,均肺部转移而死亡;4例术后复发,复发率12.3%。4例复发患者与3例肺转移患者,于发现后先辅助三维适行放疗。经过术前化疗,肿瘤体积平均缩小(30.2±11.3)%,尤其肿瘤直径>15 cm的22例,肿瘤体积平均缩小(42.7±7.8)%;28例中完全缓解(complete remssion,CR)0例,部分缓解(partial remission,PR)12例,稳定(stable disease,SD)14例,疾病进展(progression diseas,PD)2例,客观缓解率(objective response rate,ORR)为42.9%,疾病控制率(disease control rate,DCR)为92.9%;患者对化疗耐受性良好,主要化疗不良反应均为一过性,经用药对症处理后症状消失。结论新辅助化疗方案治疗肢体STS,术前化疗可明显缩小STS的体积,减轻肿瘤周围的软组织水肿,可控制微小转移灶,很好地配合STS的手术切除;能够提高患者的总生存率及无瘤生存率,有利于肢体STS的保肢治疗;其近、中期疗效满意,不良反应可耐受,是治疗STS重要有效的方法。     

Phosphodiesterase 4D gene polymorphism is associated with ischaemic and haemorrhagic stroke

It has been reported that the variants of the PDE4D (phosphodiesterase 4D) gene are associated with stroke, especially with the combination of cardio-embolic and carotid stroke in the Icelandic population, but it is still very controversial as to whether PDE4D is a susceptible gene for stroke in other populations. In the present study, we tested whether the PDE4D gene variation also confers stroke risk in a Chinese population. Our hypothesis was tested in a case-control study of a Chinese population comprising 639 stroke patients (including 253 with cerebral thrombosis, 171 with lacunar infarction and 215 with intracerebral haemorrhage) and 887 healthy controls. Three SNPs (single nucleotide polymorphisms) (rs966221, rs456009 and rs2910829) in PDE4D were chosen based on the significant association with stroke reported previously in a Western population, and these were genotyped using PCR/RFLP (restriction-fragment-length polymorphism) and confirmed by sequencing. We found that only SNP83 (rs966221) was associated with stroke. Allele C of rs966221 is a risk allele, conferring an increased risk for atherothrombotic strokes [OR (odds ratio), 1.51; 95% CI (confidence interval), 1.09-2.10] independent of conventional risk factors. Haplotype analysis confirmed that haplotype G-C-C was associated with increased risk for atherothrombotic stroke (OR, 1.80; 95% CI, 1.300-2.491). Our findings support that SNP83 of PDE4D is a genetic risk factor for atherothrombotic strokes in a Chinese population.     

Serum cytochrome c level as a prognostic indicator in patients with systemic inflammatory response syndrome

BACKGROUND: Apoptosis may play an important role in the development of systemic inflammatory response syndrome (SIRS) and progression to multiple organ dysfunction syndrome (MODS). To quantify the extent of apoptosis in these morbidities, we developed a sandwich ELISA system to measure serum cytochrome c (cyt-c) levels and we investigated the prognostic significance of cyt-c concentration in SIRS/MODS patients. METHODS: Cyt-c concentrations in patients with SIRS (n=53) with or at risk for MODS were measured and compared with those of control subjects (n=14). RESULTS: Cyt-c concentrations in SIRS/MODS patients increased (0.24-210 ng/ml), whereas those in control subjects were under detection limits (0.1 ng/ml). Cyt-c concentrations in non-survivors increased significantly compared with those in survivors both on the day of admission and on the fifth hospital day. A significant positive correlation was found between cyt-c concentration and two representative organ dysfunction scores, APACHE II and multi-organ failure (MOF) score. Cyt-c concentrations increased earlier than MOF score during the exacerbation phase and rapidly decreased during the convalescence phase in a survivor, but the level continued to be high in a non-survivor. CONCLUSIONS: Determination of serum cyt-c concentrations may be useful to assess the severity of organ dysfunction and to predict the prognosis of SIRS/MODS patients.     

氟橡胶246B作为胆管替代物的可行性

目的:氟橡胶246B具有比聚乙烯、聚丙烯更好的组织相容性,类似于较为广泛的膨体聚四氟乙烯,而又具有比膨体聚四氟乙烯更好的硬度,自身不易发生形变.通过对氟橡胶246B进行新鲜胆汁浸泡、常规方式消毒和大鼠体内植入实验,明确氟橡胶246B作为人体内植入物、人工胆管替代物的可行性.方法:实验于2006-06/2007-03在吉林大学超分子结构与材料教育部重点实验室完成.①制作50 mm×10 mm×0.5 mm矩形氟橡胶246B薄片,放入盛有新鲜胆汁的烧杯内浸泡,并放入37℃恒温箱内保存,浸泡30 d后取出,测量拉伸强度、热分解温度、玻璃化转变温度,与浸泡前测得值进行对比,以明确氟橡胶246B长期处于胆汁环境内是否改变其理化性质.②制作50 mm×10 mm×0.5 mm矩形氟橡胶246B薄片,进行煮沸法、甲醛蒸气熏蒸法和甲醛溶液浸泡法消毒,然后测量拉伸强度、热分解温度、玻璃化转变温度,与消毒前测得值进行对比,以明确氟橡胶246B是否可以进行消毒使用.③将氟橡胶246B、膨体聚四氟乙烯、聚丙烯、聚乙烯制成大小、厚度相等薄片分别植入大鼠腹腔内,30 d后开腹取薄片周围组织制作病理切片,观察其在大鼠腹腔内与周围组织是否存在变态反应及炎症反应情况.结果:①氟橡胶246B在新鲜胆汁浸泡30 d后,与浸泡前相比,热分解温度、玻璃化转变温度和拉伸强度均改变微小,差异无显著性意义(P > 0.05).②氟橡胶246B在胆汁浸泡前后、消毒前后均可较好的对抗机械性应力.③对氟橡胶246B进行煮沸法、甲醛蒸气熏蒸法和甲醛溶液浸泡法消毒处理后,测得热分解温度、玻璃化转变温度和拉伸强度与消毒前相比也无明显改变,差异无显著性意义(P > 0.05).④氟橡胶246B在大鼠体内植入后未出现明显变态或过敏反应,与周围组织炎症轻微,与膨体聚四氟乙烯相似,差异无显著性意义(P > 0.05).结论:氟橡胶246B与胆汁长期接触后的主要理化性质未发生明显改变,能够对抗机械性应力,能够消毒使用,不引起变态或过敏反应.因此,氟橡胶246B可以作为胆管替代物材料.     

Prevalence of the metabolic syndrome in patients with borderline personality disorder: results from a cross-sectional study

Metabolic syndrome (MetS) is an important risk factor for the development of type-2 diabetes and coronary artery disease. We aimed to compare the MetS prevalence in patients with borderline personality disorder (BPD) with comparison subjects followed in primary care from a similar region. One hundred and thirty-five BPD patients according to DSM-IV diagnostic criteria were compared to 1009 subjects from primary care. We used the American Heart Association/National Heart, Lung and Blood Institute criteria to determine the rate of MetS. The age-standardized prevalence of MetS was more than double in patients with BPD compared to comparison subjects (23.3 vs. 10.6 %, p < 0.05). Regarding individual MetS criteria, hyperglycemia was significantly more prevalent in both genders (p < 0.05). Abdominal obesity (p < 0.05) and hypertriglyceridemia (p < 0.05) were significantly higher only in women with BPD. Within BPD patients, an increased rate of MetS was associated with higher BMI (p = 0.004), age (p = 0.03), treatment with second-generation antipsychotics (quetiapine, olanzapine and clozapine; p = 0.032), dysthymia (p = 0.031), panic disorder (p = 0.032), benzodiazepine dependency (p = 0.015) and binge eating disorder p = 0.02). Our results demonstrate an increased MetS rate, dysregulated glucose and lipid metabolism in patients with BPD. Cardiometabolic monitoring and careful screening for physical health conditions among people with BPD is warranted.