Dissociation kinetics of the thyrotropin-receptor complex. Characterization of a slowly dissociable component

The kinetics of the dissociation of thyrotropin (TSH) from human thyroid plasma membranes were studied in an attempt to further understand the molecular dynamics of the TSH--receptor interaction. Dissociation of bound [125I]TSH from thyroid plasma membranes was a biphasic process consisting of rapidly and slowly dissociable components, RDC and SDC, respectively. The dilution induced dissociation of bound [125I]TSH was enhanced by the addition of excess TSH (DEC). DEC was proportional to the dose of unlabeled TSH and its magnitude increased linearly with temperature. These results are in contrast to those reported for the kinetics of [125I]insulin dissociation. The functional significance of DEC remains largely unexplained. It was found that the fraction of SDC was dependent upon time of association in a temperature-dependent and apparently saturable process. It could not be attributed to alterations in the electrophoretic, immunologic or binding properties of [125I]TSH. Furthermore, no correlation was observed between generation of SDC and change in the Scatchard profile of TSH binding, in contrast to studies on growth hormone. These data suggest that, like some other polypeptide hormones, binding of TSH to its receptor does not proceed according to laws describing simple, rapidly reversible, bimolecular reactions. Furthermore, bound TSH undergoes a receptor-mediated conversion from a rapidly to a slowly dissociable state with time of incubation.     

两种补片修补TRAM皮瓣切取后腹壁缺损的临床效果比较

目的:比较聚丙烯网片与膨体聚四氟乙烯补片修补TRAM皮瓣切取后腹壁缺损的有效性及安全性。方法:回顾性分析85例游离TRAM皮瓣切取术后腹壁缺损的修补,比较两组患者术后并发症的发生率。结果:两组患者均无腹壁疝发生;聚丙烯网片组患者腹壁膨出率为6.3%,膨体聚四氟乙烯补片组为5.7%,无显著性差异;膨体聚四氟乙烯补片组术后感染率及积血积液率略高于聚丙烯网片组,无显著性差异;聚丙烯网片组患者术后疼痛不适及异物感发生率为34.4%,高于膨体聚四氟乙烯组的3.8%,差异具有统计学意义。结论:两种补片对于修复TRAM皮瓣切取后腹壁缺损都是有效的,膨体聚四氟乙烯补片更佳。     

Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients

Background:

PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown.

Methods:

The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays.

Results:

The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2).

Conclusions:

The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy.     

Outcome of tricuspid valve surgery in the presence of permanent pacemaker

Objectives

Given the paucity of available literature, we sought to evaluate the mechanisms of tricuspid regurgitation and the outcomes of tricuspid valve surgery in the presence of permanent pacemakers.

Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P= 0.044). Kaplan-Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCC-specific overall survival (HR, 2.799; 95% CI, 1.346–5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.