Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.     

肝移植术后早期肠内肠外营养支持的随机对比研究

目的观察早期肠内营养（enteral nutrition,EN）对维持和改善肝移植术后患者营养状态的影响。方法将30例肝移植术后早期（术后1～7 d）患者,按随机数字表法分成肠外营养（parenteral nutrition,PN）组、EN,每组各15例,各组营养支持均为等热量和等氮量。各组患者分别于术前、术后第1天、术后第8天检测营养指标,测定术后每天氮平衡并计算累计氮平衡,统计术后感染及营养支持并发症的发生率,进行对照研究。结果术后第8天,EN组的白蛋白和前白蛋白水平显著高于PN组（P〈0.05）;总胆红素、谷丙转氨酶和谷草转氨酶比较,EN组显著低于PN组（P〈0.01）;EN组的血糖水平及胆汁引流量显著优于PN组（P〈0.05）。术后第4天起,患者每日氮平衡比较,EN组显著优于PN组（P〈0.05）;术后7 d累计氮平衡比较,EN组显著优于PN组（P〈0.01）。术后早期感染比较,EN组显著低于PN组（P〈0.05）。肛门排气时间和平均营养支持费用比较,EN组显著低于PN组（P〈0.01）。EN组的住院时间显著低于PN组（P〈0.05）。EN组无严重营养支持并发症的发生。结论肝移植术后早期的肠内营养营养支持治疗是安全、可行的,与PN相比,EN能更有效地改善患者术后营养状况,促进移植肝的功能恢复,降低术后感染率和医疗费用。     

Layered MoS2 Hollow Spheres for Highly‐Efficient Photothermal Therapy of Rabbit Liver Orthotopic Transplantation Tumors

Combining photothermal therapy (PTT) with clinical technology to kill cancer via overcoming the low tumor targeting and poor therapy efficiency has great potential in basic and clinical researches. A brand‐new MoS₂ nanostructure is designed and fabricated, i.e., layered MoS₂ hollow spheres (LMHSs) with strong absorption in near‐infrared region (NIR) and high photothermal conversion efficiency via a simple and fast chemical aerosol flow method. Owing to curving layered hollow spherical structure, the as‐prepared LMHSs exhibit unique electronic properties comparing with MoS₂ nanosheets. In vitro and in vivo studies demonstrate their high photothermal ablation of cell and tumor elimination rate by single NIR light irradiation. Systematic acute toxicity study indicates that these LMHSs have negligible toxic effects to normal tissues and blood. Remarkably, minimally invasive interventional techniques are introduced to improve tumor targeting of PTT agents for the first time. To explore PTT efficiency on orthotopic transplantation tumors, New Zealand white rabbits with VX₂ tumor in liver are used as animal models. The effective elimination of tumors is successfully realized by PTT under the guidance of digital subtraction angiography, computed tomography, and thermal imaging, which provides a new way for tumor‐targeting delivery and cancer theranostic application.     

Mesenchymal Stem Cell-Laden Composite β Cell Porous Microgel for Diabetes Treatment

Type 1 diabetes mellitus is a chronic metabolic condition characterized by the autoimmune damage of pancreatic β cells. As an alternative to continuous exogenous insulin administration of insulin, β cell transplantation is shown to provide an alternative approach for controlling hyperglycemia in diabetes. However, β cell transplantation faces significant challenges of low β cell proliferation and immunologic insults. Thus, novel approaches capable of promoting the islet microenvironment for sustainability is highly desired. This study develops mesenchymal stem cell (MSC)-laden composite β cell porous microgels (MGs) to address sustainability for the treatment of diabetes. The MGs are prepared via microfluidic droplet templates encapsulating both MSCs and β cells with porogen for creating a porous structure. In addition to offering a suitable microenvironment for nutrient delivery, the porous structure promoted β cell growth and insulin secretion. The outstanding anti-apoptotic and immunomodulatory roles of MSCs further provide a favorable environment for β cell survival and function. On this basis, the therapeutic performance of the MGs in reducing hyperglycemia and achieving sustained glycemic control in diabetic mice is demonstrated. Collectively, these results show that the novel MGs have great potential for the treatment of diabetes providing a promising platform for clinical β cell transplantation.     

GAD65基因修饰的神经干细胞移植治疗癫痫的实验研究

目的:将谷氨酸脱羧酶65(GAD65)基因修饰的神经干细胞移植到海仁酸颞叶癫痫模型大鼠海马中,检测目的基因在脑内的表达以及基因工程化细胞移植对癫痫的影响.方法:建立海仁酸致癫痫大鼠模型,完全随机分为GAD-NSCs移植组、单纯NSCs移植组、生理盐水对照组,每组20只.在移植后1、2、3天,1、2、4、8周各时间点,通...     

受体SLCO1B1 rs2291075位点多态性对肝移植术后早期他克莫司剂量校正谷浓度的影响

目的：探索肝移植术后早期SLCO1B1 rs2291075基因型对他克莫司（FK506）剂量校正谷浓度（dose-corrected trough concentration,C/D,ng·mL-1·mg-1·kg-1）的影响作用。方法：利用PCR扩增和DNA测序技术对210例肝移植受体及其供体进行SLCO1B1 rs2291075位点以及FK506代谢经典生物标志物CYP3A5 rs776746位点基因分型,分析多态性与FK506代谢表型C/D值的相关性。根据肝功能恢复和C/D值变化情况,肝移植术后早期分为恢复期（1～14 d）和平稳期（15～28 d）,分别进行统计分析。结果：供体和受体CYP3A5 rs776746联合分析可将FK506代谢表型区分为快（EM）、中（IM）、慢（PM）代谢3组,形成E-I-P分型体系。受体SLCO1B1 rs2291075 CC、CT+TT基因型患者C/D值在术后恢复期（P=0.019 5）和平稳期（P=0.015 2）差异均有统计学意义;供体SLCO1B1 rs2291075基因型与FK506 C/D值无关联。多因素分析显示FK506日剂量、总胆红素、E-I-P分型和受体SLCO1B1 rs2291075进入恢复期FK506剂量C/D值预测模型;而在平稳期,受体SLCO1B1 rs2291075未能进入C/D值多因素预测模型。PM亚组分析,排除供体和受体CYP3A5 rs776746影响后,受体SLCO1B1 rs2291075基因型在术后恢复期和稳定期均是FK506 C/D值的独立影响因素（P分别为0.030,0.040）。结论：受体SLCO1B1 rs2291075位点可能是影响肝移植早期FK506 C/D值的新遗传位点,其与供体和受体CYP3A5 rs776746基因型相结合,有助于形成精准用药指导体系。     

Caspase inhibitors increase the rate of recovery of neural stem/progenitor cells from post-mortem rat brains stored at room temperature

To match the demand of regenerative medicine for nerve system, collection of stem cells from the post-mortem body is one of the most practical ways. In this study, the storage condition of the post-mortem body was examined. We prepared neural stem/progenitor cells (NSPCs) from post-mortem rat brains stored at different temperatures. When brains were stored at 4 °C, for one week, we were able to obtain neurospheres (a spheroid body containing NSPCs) by stimulation of cells with epidermal growth factor (EGF). Incremental increases in storage temperature decreased the rate of appearance of neurospheres. Within 48 h at 15 °C, 24 h at 25 °C, in both condition, we were able to recover NSPCs from post-mortem rat brains. At 15 °C, 90% of neurosphere-forming activity was lost within 24 h. However, even after 24 h at 25 °C, 2% neurosphere-forming activity remained. After 6 h of death, there was very little difference between the rates of NSPC recovery at 4 °C and 25 °C. Addition of caspase inhibitors to both the rat brain storage solution and the NSPC culture medium increased the rate of neurosphere-forming activity. In particular, an inhibitor of caspase-8 activity increased the NSPC recovery rate approximately three-fold, with no accompanying detrimental effects on neural differentiation in vitro.     

Thermo-responsive cell culture carriers based on poly(vinyl methyl ether)—the effect of biomolecular ligands to balance cell adhesion and stimulated detachment

Abstract

Two established material systems for thermally stimulated detachment of adherent cells were combined in a cross-linked polymer blend to merge favorable properties. Through this approach poly(N-isopropylacrylamide) (PNiPAAm) with its superior switching characteristic was paired with a poly(vinyl methyl ether)-based composition that allows adjusting physico-chemical and biomolecular properties in a wide range. Beyond pure PNiPAAm, the proposed thermo-responsive coating provides thickness, stiffness and swelling behavior, as well as an apposite density of reactive sites for biomolecular functionalization, as effective tuning parameters to meet specific requirements of a particular cell type regarding initial adhesion and ease of detachment. To illustrate the strength of this approach, the novel cell culture carrier was applied to generate transplantable sheets of human corneal endothelial cells (HCEC). Sheets were grown, detached, and transferred onto planar targets. Cell morphology, viability and functionality were analyzed by immunocytochemistry and determination of transepithelial electrical resistance (TEER) before and after sheet detachment and transfer. HCEC layers showed regular morphology with appropriate TEER. Cells were positive for function-associated marker proteins ZO-1, Na⁺/K⁺-ATPase, and paxillin, and extracellular matrix proteins fibronectin, laminin and collagen type IV before and after transfer. Sheet detachment and transfer did not impair cell viability. Subsequently, a potential application in ophthalmology was demonstrated by transplantation onto de-endothelialized porcine corneas in vitro. The novel thermo-responsive cell culture carrier facilitates the generation and transfer of functional HCEC sheets. This paves the way to generate tissue engineered human corneal endothelium as an alternative transplant source for endothelial keratoplasty.     

Peripheral Nerve Injuries and Transplantation of Olfactory Ensheathing Cells for Axonal Regeneration and Remyelination: Fact or Fiction?

Successful nerve regeneration after nerve trauma is not only important for the restoration of motor and sensory functions, but also to reduce the potential for abnormal sensory impulse generation that can occur following neuroma formation. Satisfying functional results after severe lesions are difficult to achieve and the development of interventional methods to achieve optimal functional recovery after peripheral nerve injury is of increasing clinical interest. Olfactory ensheathing cells (OECs) have been used to improve axonal regeneration and functional outcome in a number of studies in spinal cord injury models. The rationale is that the OECs may provide trophic support and a permissive environment for axonal regeneration. The experimental transplantation of OECs to support and enhance peripheral nerve regeneration is much more limited. This chapter reviews studies using OECs as an experimental cell therapy to improve peripheral nerve regeneration.     

基于PIC18单片机的铁轨检测系统

该文论述了基于PIC18系列单片机设计的一种铁轨监测系统,该系统可以自动监测铁轨上是否存在裂纹。着重说明了系统的构成和工作原理,并论述了在具有硬件堆栈的PIC18F2420单片机上移植uCOS的方法。