精准健康管理模式在2型糖尿病中的应用研究进展

2型糖尿病在全球发病率明显增高,已成为第三大慢性非传染性疾病,严重影响了患者的生命质量,且给社会带来了严重的医疗负担。传统的健康管理模式已经不能满足人们日益增长的健康需求,亟待采取有针对性的干预措施,提高疾病的防治率。本文基于精准医学的视角,对国内外有关2型糖尿病的精准诊断、预测、建档、健康改善、绩效评价模式的应用现状进行综述,以期推动健康管理工作向精准化、个性化发展。     

Cell type–specific spatial and functional coupling between mammalian brain Kv2.1 K+ channels and ryanodine receptors

The Kv2.1 voltage‐gated K⁺ channel is widely expressed throughout mammalian brain, where it contributes to dynamic activity‐dependent regulation of intrinsic neuronal excitability. Here we show that somatic plasma membrane Kv2.1 clusters are juxtaposed to clusters of intracellular ryanodine receptor (RyR) Ca²⁺‐release channels in mouse brain neurons, most prominently in medium spiny neurons (MSNs) of the striatum. Electron microscopy–immunogold labeling shows that in MSNs, plasma membrane Kv2.1 clusters are adjacent to subsurface cisternae, placing Kv2.1 in close proximity to sites of RyR‐mediated Ca²⁺ release. Immunofluorescence labeling in transgenic mice expressing green fluorescent protein in specific MSN populations reveals the most prominent juxtaposed Kv2.1:RyR clusters in indirect pathway MSNs. Kv2.1 in both direct and indirect pathway MSNs exhibits markedly lower levels of labeling with phosphospecific antibodies directed against the S453, S563, and S603 phosphorylation site compared with levels observed in neocortical neurons, although labeling for Kv2.1 phosphorylation at S563 was significantly lower in indirect pathway MSNs compared with those in the direct pathway. Finally, acute stimulation of RyRs in heterologous cells causes a rapid hyperpolarizing shift in the voltage dependence of activation of Kv2.1, typical of Ca²⁺/calcineurin‐dependent Kv2.1 dephosphorylation. Together, these studies reveal that striatal MSNs are distinct in their expression of clustered Kv2.1 at plasma membrane sites juxtaposed to intracellular RyRs, as well as in Kv2.1 phosphorylation state. Differences in Kv2.1 expression and phosphorylation between MSNs in direct and indirect pathways provide a cell‐ and circuit‐specific mechanism for coupling intracellular Ca²⁺ release to phosphorylation‐dependent regulation of Kv2.1 to dynamically impact intrinsic excitability. J. Comp. Neurol. 522:3555–3574, 2014. © 2014 Wiley Periodicals, Inc.     

Correlative 3D superresolution fluorescence and electron microscopy reveal the relationship of mitochondrial nucleoids to membranes

Microscopic images of specific proteins in their cellular context yield important insights into biological processes and cellular architecture. The advent of superresolution optical microscopy techniques provides the possibility to augment EM with nanometer-resolution fluorescence microscopy to access the precise location of proteins in the context of cellular ultrastructure. Unfortunately, efforts to combine superresolution fluorescence and EM have been stymied by the divergent and incompatible sample preparation protocols of the two methods. Here, we describe a protocol that preserves both the delicate photoactivatable fluorescent protein labels essential for superresolution microscopy and the fine ultrastructural context of EM. This preparation enables direct 3D imaging in 500- to 750-nm sections with interferometric photoactivatable localization microscopy followed by scanning EM images generated by focused ion beam ablation. We use this process to "colorize" detailed EM images of the mitochondrion with the position of labeled proteins. The approach presented here has provided a new level of definition of the in vivo nature of organization of mitochondrial nucleoids, and we expect this straightforward method to be applicable to many other biological questions that can be answered by direct imaging.     

The hinge region in androgen receptor control

The region between the DNA-binding domain and the ligand-binding domain of nuclear receptors is termed the hinge region. Although this flexible linker is poorly conserved, diverse functions have been ascribed to it. For the androgen receptor (AR), the hinge region and in particular the (629)RKLKKL(634) motif, plays a central role in controlling AR activity, not only because it acts as the main part of the nuclear translocation signal, but also because it regulates the transactivation potential and intranuclear mobility of the receptor. It is also a target site for acetylation, ubiquitylation and methylation. The interplay between these different modifications as well as the phosphorylation at serine 650 will be discussed here. The hinge also has an important function in AR binding to classical versus selective androgen response elements. In addition, the number of coactivators/corepressors that might act via interaction with the hinge region is still growing. The importance of the hinge region is further illustrated by the different somatic mutations described in patients with androgen insensitivity syndrome and prostate cancer. In conclusion, the hinge region serves as an integrator for signals coming from different pathways that provide feedback to the control of AR activity.     

Differential expression and subcellular localization of Prohibitin 1 are related to tumorigenesis and progression of non-small cell lung cancer

Lung cancer remains the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer. With a variety of biological functions, Prohibitin1 (PHB1) has been proved tumor-associated. But there are conflicting data regarding the involvement of PHB1 in tumorigenesis and few studies regarding the role of PHB1 in lung cancer. The studies reported herein used a combination of clinical observations and molecular methods to investigate the possible role of PHB1 in NSCLC tissues and cell lines. PHB1 expression was evaluated by RT-PCR, RT-qPCR, Western blotting and immunohistochemistry analysis. Flow cytometric analysis was used to determine the surface expression profiles of PHB1 in lung cell lines. The results showed that PHB1 expression were generally increased in lung cancer tissues when compared with matched noncancerous tissues and closely related with tumor differentiation and lymph node invasion. PHB1 expression levels was also increased in three lung cancer cell lines (SK-MES-1, NCI-H157 and NCI-H292) as compared with BEAS-2B cells. Moreover, there were various subcellular localization of PHB1 in different lung cancer cells and the presence of PHB1 on the surface of lung cancer cells was significantly reduced. In conclusion, PHB1 expression is increased in NSCLC and the up-regulation of PHB1 is associated with clinically aggressive phenotype. The different subcellular localization of PHB1 in NSCLC cells and the loss of the membrane-associated PHB1 probably related to the tumorigenesis and progression of NSCLC and suggests that PHB1 may play different roles in various types of NSCLC.     

运用精细肝脏外科理念治疗肝血管瘤

目的：探讨运用精细肝脏外科理念治疗肝血管瘤的价值。 方法：回顾性分析行肝切除的52例肝血管瘤患者的临床资料,其中采用精细肝切除术23例,传统肝切除术29例。 结果：52例患者均手术成功,术后顺利康复,术中及围手术期无严重并发症,无死亡发生。精细肝切除组与传统肝切除组比较,前者手术时间延长[（128.0±25.7）min vs.（100.9±20.4）min]（P<0.05）,术中出血、输血例数比例差异均无统计学意义（均P>0.05）,术后住院时间明显缩短[（7.0±1.5）d vs.（8.6±1.5）d]（P<0.05）,术后丙氨酸氨基转移酶（ALT）峰值[（277.5± 189.3）U/L vs.（960.0 ±635.0）U/L],门冬氨酸氨基转移酶（AST）峰值[（254.2 ±191.4）U/L vs. （838.5±677.1）U/L]以及术后并发症发生率均明显降低（8.7% vs. 31.0%）（均P<0.05）。 结论：运用精细肝脏外科理念治疗肝血管瘤安全有效,较传统肝切除术具有明显优势。     

改良Glisson肝蒂法在精准肝切除术中的应用

目的探讨改良Glisson肝蒂法在肝癌患者肝切除术中应用的可行性。方法对60例肝切除术后病理学检查证实的肝细胞癌患者进行分组研究。实验组（Glisson组）经过术前精确评估后,术中采取改良Glisson肝蒂法首先阻断肝段肝蒂,然后按照术中B超定位肝静脉主干及分支作为肝内断肝平面,采取精细钳夹法切除单一以及联合肝段。对照组（Prigle组）行常规术前检查及评估,术中采取传统Prigle法阻断第一肝门后,以超声刀不显露肝静脉按照术中B超定位平面切除单一或联合肝段。结果术中出血量、输血量、手术时间和术后肝功能指标、术后恢复时间及术后白蛋白用量2组间差异均无统计学意义（P〉0.05）;Glisson组术后并发症发生率（23.3%）低于Prigle组（50.0%）,P〈0.05;Glisson组术后病理标本切缘距肿瘤距离为（2.3±0.7）cm,大于Prigle组的（1.5±0.6）cm,P〈0.05。Glisson组术后1年的肿瘤复发率略低于Prigle组〔10.0%（3/30）比16.7%（5/30）〕,但差异没有统计学意义（P〉0.05）。结论改良Glisson肝蒂法肝切除在肝癌患者中的应用具有与传统Prigle法同样的安全性,且可减少术后并发症的发生,保证手术切缘,同时理论上可以降低术后复发率。     

肝门部胆管癌的精准外科手术治疗

医学及相关领域学科的持续发展推动着传统外科向以精确决策和精准操作为特征的精准外科转化.最大化清除病灶、最小创伤侵袭和最大程度脏器保护是精准外科的追求目标.由于特殊的解剖学位置和生物学特性,肝门部胆管癌的治疗极具挑战性.为了达到精准外科的要求,术前需对肝门部解剖结构、肿瘤的生物学特征以及肝脏功能储备情况等予以充分了解,同时对于术前预处理、肝切除技术和血管、胆管重建技术应予充分掌握.