TGF‐β1‐Modified Hyaluronic Acid/Poly(glycidol) Hydrogels for Chondrogenic Differentiation of Human Mesenchymal Stromal Cells

In cartilage regeneration, the biomimetic functionalization of hydrogels with growth factors is a promising approach to improve the in vivo performance and furthermore the clinical potential of these materials. In order to achieve this without compromising network properties, multifunctional linear poly(glycidol) acrylate (PG‐Acr) is synthesized and utilized as crosslinker for hydrogel formation with thiol‐functionalized hyaluronic acid via Michael‐type addition. As proof‐of‐principle for a bioactivation, transforming growth factor‐beta 1 (TGF‐β1) is covalently bound to PG‐Acr via Traut's reagent which does not compromise the hydrogel gelation and swelling behavior. Human mesenchymal stromal cells (MSCs) embedded within these bioactive hydrogels show a distinct dose‐dependent chondrogenesis. Covalent incorporation of TGF‐β1 significantly enhances the chondrogenic differentiation of MSCs compared to hydrogels with supplemented noncovalently bound TGF‐β1. The observed chondrogenic response is similar to standard cell culture with TGF‐β1 addition with each medium change. In general, multifunctional PG‐Acr offers the opportunity to introduce a range of biomimetic modifications (peptides, growth factors) into hydrogels and, thus, appears as an attractive potential material for various applications in regenerative medicine.     

CDH1/E-cadherin and solid tumors. An updated gene-disease association analysis using bioinformatics tools

Cancer is a group of diseases that causes millions of deaths worldwide. Among cancers, Solid Tumors (ST) stand-out due to their high incidence and mortality rates. Disruption of cell–cell adhesion is highly relevant during tumor progression. Epithelial-cadherin (protein: E-cadherin, gene: CDH1) is a key molecule in cell–cell adhesion and an abnormal expression or/and function(s) contributes to tumor progression and is altered in ST. A systematic study was carried out to gather and summarize current knowledge on CDH1/E-cadherin and ST using bioinformatics resources. The DisGeNET database was exploited to survey CDH1-associated diseases. Reported mutations in specific ST were obtained by interrogating COSMIC and IntOGen tools. CDH1 Single Nucleotide Polymorphisms (SNP) were retrieved from the dbSNP database.DisGeNET analysis identified 609 genes annotated to ST, among which CDH1 was listed. Using CDH1 as query term, 26 disease concepts were found, 21 of which were neoplasms-related terms. Using DisGeNET ALL Databases, 172 disease concepts were identified. Of those, 80 ST disease-related terms were subjected to manual curation and 75/80 (93.75%) associations were validated. On selected ST, 489 CDH1 somatic mutations were listed in COSMIC and IntOGen databases. Breast neoplasms had the highest CDH1-mutation rate. CDH1 was positioned among the 20 genes with highest mutation frequency and was confirmed as driver gene in breast cancer. Over 14,000 SNP for CDH1 were found in the dbSNP database.This report used DisGeNET to gather/compile current knowledge on gene-disease association for CDH1/E-cadherin and ST; data curation expanded the number of terms that relate them. An updated list of CDH1 somatic mutations was obtained with COSMIC and IntOGen databases and of SNP from dbSNP. This information can be used to further understand the role of CDH1/E-cadherin in health and disease.     

Intramarrow injection of β-catenin-activated,but not na?ve mesenchymal stromal cells stimulates self-renewal of hematopoietic stem cells in bone marrow

Bone marrow mesenchymal stromal cells (MSCs) have been implicated in the microenvironmental support of hematopoietic stem cells (HSCs) and often co-transplanted with HSCs to facilitate recovery of ablated bone marrows. However, the precise effect of transplanted MSCs on HSC regeneration remains unclear because the kinetics of HSC self-renewal in vivo after co-transplantation has not been monitored. In this study, we examined the effects of intrafemoral injection of MSCs on HSC self-renewal in rigorous competitive repopulating unit (CRU) assays using congenic transplantation models in which stromal progenitors (CFU-F) were ablated by irradiation. Interestingly, naïve MSCs injected into femur contributed to the reconstitution of a stromal niche in the ablated bone marrows, but did not exert a stimulatory effect on the in-vivo self-renewal of co-transplanted HSCs regardless of the transplantation methods. In contrast, HSC self-renewal was four-fold higher in bone marrows intrafemorally injected with β-catenin-activated MSCs. These results reveal that naïve MSCs lack a stimulatory effect on HSC self-renewal in-vivo and that stroma must be activated during recoveries of bone marrows. Stromal targeting of wnt/β-catenin signals may be a strategy to activate such a stem cell niche for efficient regeneration of bone marrow HSCs.     

A Copolymer Scaffold Functionalized with Nanodiamond Particles Enhances Osteogenic Metabolic Activity and Bone Regeneration

Functionalizing polymer scaffolds with nanodiamond particles (nDPs) has pronounced effect on the surface properties, such as improved wettability, an increased active area and binding sites for cellular attachment and adhesion, and increased ability to immobilize biomolecules by physical adsorption. This study aims to evaluate the effect of poly(l ‐lactide‐co‐ε‐caprolactone) (poly(LLA‐co‐CL)) scaffolds, functionalized with nDPs, on bone regeneration in a rat calvarial critical size defect. Poly(LLA‐co‐CL) scaffolds functionalized with nDPs are also compared with pristine scaffolds with reference to albumin adsorption and seeding efficiency of bone marrow stromal cells (BMSCs). Compared with pristine scaffolds, the experimental scaffolds exhibit a reduction in albumin adsorption and a significant increase in the seeding efficiency of BMSCs (p = 0.027). In the calvarial defects implanted with BMSC‐seeded poly(LLA‐co‐CL)/nDPs scaffolds, live imaging at 12 weeks discloses a significant increase in osteogenic metabolic activity (p = 0.016). Microcomputed tomography, confirmed by histological data, reveals a substantial increase in bone volume (p = 0.021). The results show that compared with conventional poly(LLA‐co‐CL) scaffolds those functionalized with nDPs promote osteogenic metabolic activity and mineralization capacity. It is concluded that poly(LLA‐co‐CL) composite matrices functionalized with nDPs enhance osteoconductivity and therefore warrant further study as potential scaffolding material for bone tissue engineering.

     

Effects of physical activity on quality of life and physical function in postoperative patients with gastrointestinal cancer

Objectives: This study was to clarify changes in physical function and quality of life (QOL) for postoperative, and to examine the influence of the amount of physical activity on these variables. Methods: This study included 29 patients who underwent gastrointestinal cancer surgery. The QOL measurement was used to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for preoperative and 2nd and 4th postoperative weeks. Physical function measured knee extension strength, 4 m walk time, 5 times sit-to-stand test, and 6-minute walk for preoperative and 1st and 2nd postoperative weeks. The amount of physical activity score was based on METs-hours, which is estimated from cumulative physical activity. As basic characteristics were investigated cancer stage, comorbidities and complications, and operative. Statistical analysis was repeated measures analysis of variance was performed to observe postoperative changes in physical function and QOL. Furthermore, stepwise multiple regression analysis was used to the parameters of physical function and QOL affected by the physical activity score were investigated. Results: Physical function decreased postoperatively and generally improved 2nd postoperative week. Though scores on the QOL functional scales improved, some items did not improve sufficiently. Multiple regression analysis showed that physical activity score had an effect on constipation and emotion functioning. Conclusions: Improvement in symptom scales is not sufficient in a short period of time, and they need to be followed up by increasing the amount of physical activity and promoting instantaneous exercise.     

Design,Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.     

人脂肪干细胞复合珊瑚支架在三维培养下成骨活性的初步研究

目的探讨人脂肪干细胞（ADSCs）作为种子细胞复合珊瑚支架材料在体外三维培养下的成骨活性。方法取行脂肪抽吸术患者的脂肪组织,I型胶原酶消化进行培养,贴壁细胞传代,取第2代细胞进行诱导,培养基中添加成骨诱导剂地塞米松、β-甘油磷酸钠、抗坏血酸和维生素D3。成骨诱导后复合珊瑚继续培养,以未诱导的ADSCs复合物为对照,进行生长曲线、DIO染色后的共聚焦荧光显微镜、碱性磷酸酶（AKP）和骨钙蛋白（OCN）生物化学定量检测。结果7～8d后ADSCs在材料上生长进入平台期,诱导ADSCs复合珊瑚7d后生长良好。诱导ADSCsAKP表达随着时间的推移不断增强,而且在检测的各个时间点,诱导ADSCsAKP表达水平均明显高于未诱导ADSCs（均P〈0．05）。诱导ADSCs在珊瑚支架上第7天后检测到OCN表达,并一直增高,且从第7天开始OCN表达均明显高于未诱导ADSCs（均P〈0.05）。结论脂肪干细胞复合珊瑚支架在三维培养下能够向成骨细胞表型分化。