Small extracellular vesicles derived from PD-L1-modified mesenchymal stem cell promote Tregs differentiation and prolong allograft survival.

We aimed to explore whether programmed cell death protein-1 ligand (PD-L1) modification on small extracellular vesicles (sEVs) could promote T regulatory cells (Tregs) differentiation. In this study, it was confirmed that under physiological conditions, PD-L1 expression was minimal in the MSCs and absent in the MSC-sEVs. A vector harboring the PD-L1 gene was constructed and transfected into bone marrow mesenchymal stem cells (BM-MSCs). By extracting the sEVs of these modified BM-MSCs and monitoring the expression of the PD-L1 protein, however, PD-L1 expression was substantially increased in the MSCs and concentrated in the sEVs. Then, the rat naïve CD4 + T cells were cocultured with the sEVs derived from the PD-L1-modified MSCs (sEVsPD-L1). By flow cytometry, a higher percentage of Tregs and anti-inflammatory downstream cytokines (including IL-2, IFN-γ, TGF-ß, IL-10) was detected in the sEVsPD-L1 group than that in the control group treated by either sEVs in wild type, modified by empty vector, or blank control. Suppressive effect on CD4 + T cell proliferation serves as additional evidence to support the immunoregulation capacity of sEVsPD-L1. The animal model of vascularized composite allograft further confirmed that PD-L1-modified sEVs induce an immune tolerance, by clinically observation, histopathology, T cell fate and cell product. In conclusion, sEVsPD-L1 efficiently promotes Treg cell differentiation in vitro and in vivo, which suggests their therapeutic potential in the treatment of allograft rejection.

Complication of osteo reconstruction by utilizing free vascularized fibular bone graft.

The success of free vascularized fibular bone graft (FVFBG) has accelerated the osteo reconstruction which results from trauma, resection of a tumor or an infectious bone segment, or correction of congenital deformity. But the complication behind should not be overlooked. The failure could necessitate a second surgery, which prolong the rehabilitation period and produce further health cost. Worst, the patients may suffer a permanent impaired ankle function, or a sustained morpho-functional loss on reconstructive area which are hard to save. To provide an overview of the complication related to reconstruction by FVFBG, a narrative review is conducted to identify the complications including their types and rates, the contributing factors, the approaches to measure and the techniques to avoid. Methodologically, by quick research on Pubmed and abstract reading of reviews, we characterize five reconstructive areas where FVFBG were most frequently applied: extremities, mandible, spine, osteonecrosis of femoral head, and penile. Following, the complications on different reconstructive areas are retrieved, studied and presented in five (or more specifically, six) separate sections. By the way, meaningful difference between FVFBG and other bone flap was presented in a few words if necessary. Donor-site morbidities were studied and summarized as a whole. In these literatures, the evidences documented on limb and mandibular reconstruction have the fullest detail, followed by the spine and lastly the penile. In conclusion, FVFBG, though a mature technique, needs further deep and comprehensive study and maybe device-based assistance to achieve better reconstructive effect and minimize donor-site damage.

Evaluation of the prognostic value of paraoxonase 1 in the recurrence and metastasis of hepatocellular carcinoma and establishment of a liver-specific predictive model of survival.

BACKGROUND: Hepatocellular carcinoma is a malignant tumor with a highly invasive and metastatic phenotype, and the detection of potential indicators associated with its recurrence and metastasis after surgical resection is critical for patient survival. METHODS: Transcriptome data for large cohorts (n = 1432) from multicenter sources were comprehensively analyzed to explore such potential signatures. The prognostic value of the selected indicators was investigated and discussed, and a comparison with conventional clinicopathological features was performed. A survival predictive nomogram for 5-year survival was established with the selected indicator using the Cox proportional hazards regression. To validate the indicator at the protein level, we performed immunohistochemical staining with paraffin-embedded slides of hepatocellular carcinoma samples (n = 67 patients) from our hospital. Finally, a gene set enrichment analysis (GSEA) was performed to detect the underlying biological processes and internal mechanisms. RESULTS: The liver-specific protein paraoxonase 1 (PON1) was found to be the most relevant indicator of tumor recurrence, invasiveness, and metastasis in the present study, and the downregulation of PON1 might reveal poor survival for patients with hepatocellular carcinoma. The C-index of the PON1-related nomogram was 0.714, thus indicating a more effective predictive performance than the 7th American Joint Committee on Cancer (AJCC) tumor stage (0.534), AJCC T stage (0.565), or alpha-fetoprotein (0.488). The GSEA revealed that PON1 was associated with several hepatocellular carcinoma-related pathways, including the cell cycle, DNA replication, gap junction and p53 downstream pathways. CONCLUSIONS: The downregulation of paraoxonase 1 may suggest worse outcomes and a higher recurrence rate. Thus, paraoxonase 1 might represent an indicator for predicting the survival of patients with hepatocellular carcinoma.

Association between non-alcoholic fatty liver disease and risk of sarcopenia: a systematic review and meta-analysis.

OBJECTIVES: To determine the association of non-alcoholic fatty liver disease (NAFLD) with the incidence of sarcopenia. DESIGN: Systematic review and meta-analysis of observational clinical studies. SETTING AND PARTICIPANTS: Adults with NAFLD. METHODS: Databases such as PubMed, Embase, Cochrane and Web of Science were searched for eligible studies published from the inception of each database up to 4 April 2023. All cross-sectional studies on the association between NAFLD and sarcopenia were included in this study. The quality of the included studies and risk of bias was assessed using the Agency for Healthcare Research and Quality checklist. STATA V.15.1 software was used for statistical analysis. RESULTS: Of the 1524 retrieved articles, 24 were included in this review, involving 88 609 participants. Our findings showed that the prevalence of sarcopenia was higher in the NAFLD group than in the control group (pooled OR 1.74, 95% CI 1.39 to 2.17). In a subgroup analysis by region, patients with NAFLD showed an increased risk of sarcopenia (pooled OR 1.97, 95% CI 1.54 to 2.51) in the Asian group, whereas patients with NAFLD had no statistically significant association with the risk of sarcopenia in the American and European groups, with a pooled OR of 1.31 (95% CI 0.71 to 2.40) for the American group and a pooled OR of 0.99 (95% CI 0.21 to 4.69) for the European group. Similar results were observed in the sensitivity analysis, and no evidence of publication bias was observed. CONCLUSIONS AND IMPLICATIONS: The current study indicated a significant positive correlation between NAFLD and sarcopenia, which may be affected by regional factors. This study provides the correlation basis for the relationship between NAFLD and sarcopenia and helps to find the quality strategy of sarcopenia targeting NAFLD.

Neurexin dysfunction in neurodevelopmental and neuropsychiatric disorders: a PRIMSA-based systematic review through iPSC and animal models.

Background: Neurexins, essential synaptic proteins, are linked to neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD) and schizophrenia. Objective: Through this systematic review, we aimed to shed light on the relationship between neurexin dysfunction and its implications in neurodevelopmental and neuropsychiatric manifestations. Both animal and human-induced pluripotent stem cell (hiPSC) models served as our primary investigative platforms. Methods: Utilizing the PRISMA 2020 guidelines, our search strategy involved scouring articles from the PubMed and Google Scholar databases covering a span of two decades (2003-2023). Of the initial collection, 27 rigorously evaluated studies formed the essence of our review. Results: Our review suggested the significant ties between neurexin anomalies and neurodevelopmental and neuropsychiatric outcomes, most notably ASD. Rodent-based investigations delineated pronounced ASD-associated behaviors, and hiPSC models derived from ASD-diagnosed patients revealed the disruptions in calcium dynamics and synaptic activities. Additionally, our review underlined the integral role of specific neurexin variants, primarily NRXN1, in the pathology of schizophrenia. It was also evident from our observation that neurexin malfunctions were implicated in a broader array of these disorders, including ADHD, intellectual challenges, and seizure disorders. Conclusion: This review accentuates the cardinal role neurexins play in the pathological process of neurodevelopmental and neuropsychiatric disorders. The findings underscore a critical need for standardized methodologies in developing animal and hiPSC models for future studies, aiming to minimize heterogeneity. Moreover, we highlight the need to expand research into less studied neurexin variants (i.e., NRXN2 and NRXN3), broadening the scope of our understanding in this field. Our observation also projects hiPSC models as potent tools for bridging research gaps, promoting translational research, and fostering the development of patient-specific therapeutic interventions.

Sarcopenia and risk of cardio-cerebrovascular disease: A two-sample Mendelian randomization study.

Based on the association between sarcopenia and the risk of developing cardio-cerebrovascular disease (CCVD) established by a meta-analysis by Fang et al.(Biosci Trends. 2023; 17:293-301), we have used Mendelian randomization (MR) analysis to test the authenticity and accuracy of such an association. In this MR study, appendicular lean mass, handgrip strength, and walking pace were used as sarcopenia-related traits, with cardiovascular diseases and stroke set as outcomes of CCVD. MR analysis was performed using inverse-variance weighting, the MR Egger, weighted median, simple mode, and weighted mode. No heterogeneity or horizontal pleiotropy in MR estimates was observed (Cochran's Q P value > 0.05, MR-PRESSO global test P value > 0.05, and MR-Egger intercept P value > 0.05). Results of that analysis proved a causal relationship between sarcopenia-related traits and cardio-cerebrovascular disease, with a causal association between appendicular lean mass and cardiovascular diseases and an inverse causal relationship between appendicular lean mass and stroke. However, such a relationship was absent in the case of handgrip strength and the risk of cardiovascular diseases as well as in the case of walking pace and lacunar/ischemic stroke. Therefore, the effect of sarcopenia on CCVD should be carefully explained.

Revisiting regulatory T cells as modulators of innate immune response and inflammatory diseases.

Regulatory T cells (Treg) are known to be critical for the maintenance of immune homeostasis by suppressing the activation of auto- or allo-reactive effector T cells through a diverse repertoire of molecular mechanisms. Accordingly, therapeutic strategies aimed at enhancing Treg numbers or potency in the setting of autoimmunity and allogeneic transplants have been energetically pursued and are beginning to yield some encouraging outcomes in early phase clinical trials. Less well recognized from a translational perspective, however, has been the mounting body of evidence that Treg directly modulate most aspects of innate immune response under a range of different acute and chronic disease conditions. Recognizing this aspect of Treg immune modulatory function provides a bridge for the application of Treg-based therapies to common medical conditions in which organ and tissue damage is mediated primarily by inflammation involving myeloid cells (mononuclear phagocytes, granulocytes) and innate lymphocytes (NK cells, NKT cells, γδ T cells and ILCs). In this review, we comprehensively summarize pre-clinical and human research that has revealed diverse modulatory effects of Treg and specific Treg subpopulations on the range of innate immune cell types. In each case, we emphasize the key mechanistic insights and the evidence that Treg interactions with innate immune effectors can have significant impacts on disease severity or treatment. Finally, we discuss the opportunities and challenges that exist for the application of Treg-based therapeutic interventions to three globally impactful, inflammatory conditions: type 2 diabetes and its end-organ complications, ischemia reperfusion injury and atherosclerosis.

Double-pivot proper digital artery perforator flap for fingertip reconstruction.

BACKGROUND: Dorsal flap based on proper digital artery perforator has been commonly used in wound coverage of fingertip; yet a small diameter and short length poses a risk of pedicle kinking or occlusion. The present study aims to present our preliminary results of using a double-pivot perforator flap based on the end dorsal branch of proper digital artery to repair finger pulp defect. METHODS: We designed a double-pivot flap based on the end-dorsal perforator branch of proper digital artery, raised from the dorsal aspect of the middle phalanx, with inclusion of both the perforator and a section of the trunk of the artery. This modified procedure forms a pedicle with a larger diameter and length than traditional designs. Twelve patients (12 fingers) each with a soft-tissue defect of the fingertip were successfully treated and followed up in this retrospective study. RESULTS: All the flaps survived without showing any signs of necrosis; three cases presented with transient venous flow disorder, these self-resolving without requiring any additional treatment. At final follow-up (12-33 months, mean 20 months), mean static two-point discrimination on the flap was 7.0 mm (range, 6-9). CONCLUSION: The double-pivot proper digital artery flap serves as a reliable option in fingertip reconstruction offering added benefits of having greater rotation flexibility, a lower risk of vessel kinking or occlusion, and good recovery of cutaneous sensation.

Combined transfer by several perforator skin flaps to cover an extensive and multiplanar wound on the foot and ankle.

BACKGROUND: This study aimed to assess the feasibility and effectiveness of using combined transfer by two or three large skin flaps to cover a single extensive and multiplanar wound on the foot and ankle to achieve full coverage of the wound and primary donor-site closure. PATIENTS AND METHODS: Seventeen patients with extensive wounds around their foot and ankle were treated. The flap could either be anterolateral femoral perforator (ALTP) flap, deep inferior epigastric artery perforator (DIEP) flap, or thoracodorsal artery perforator (TDAP) flap. According to the dimensions and shape of the wound and the availability of donor sites, we classified the reconstruction into three different types. Based on the type, the soft-tissue defect was divided into two or three parts to guide the corresponding perforator skin flaps to be harvested within the maximum width and length of the donor sites. RESULTS: All 17 patients were successfully reconstructed, with a total of 35 flaps in 37 paddles. Vascular compromise occurred in one patient and was saved by venous thrombectomy. In total, four flaps experienced a partial loss and were treated either conservatively or by a skin graft. No ulceration due to abrasion occurred on any flap during the entire follow-up. All donor sites were directly closed and healed uneventfully, except for one needing coverage by a skin graft and another experiencing dehiscence and scar widening. CONCLUSION: Combined transfer by several skin perforator flaps is a flexible reconstructive option for resurfacing extensive and multiplanar wounds on the foot and ankle. The benefit lies in a well-reconstructed contour, an anti-frictional property, a permission of a normal shoe wearing in the reconstructed foot, and meanwhile a primary closure on donor site.

Regionalized coverage of the totally degloved foot by a combination of "Boat sock" style free flap and skin graft.

INTRODUCTION: To maximize the morpho-functional recovery on the totally degloved foot while not excessively introducing the technical complexity of microsurgery, we present a regionalized reconstruction, in which the highly functional subunit (weight-bearing area and ankle-around area) is covered by free skin flaps, and the less functional subunit (dorsum) by skin graft. METHODS: From June 2011 to December 2017, 10 patients who had total degloving injury on foot underwent reconstruction based on regionalized coverage. As the shape of combined flaps resemble a boat sock in high-heeled shoe, we name it as "Boat Sock" flaps. Complication like vascular compromise, partial or total flap loss, Equinus deformity and delayed plantar ulceration were documented elaborately. Secondary surgeries were also recorded. Foot function was evaluated by Maryland foot score at the last follow up. RESULTS: Twenty-one free skin flaps were used for "Boat sock" coverage on highly functional subunits. Flap dimension ranged from 19×5cm2 to 28×8cm2 (mean 151cm2). Among these flaps, one experienced partial necrosis which was treated conservatively, one experienced burn due to lack of protective sensation. Complication like Equinus deformity or delayed plantar ulceration did not occur. Secondary surgery included debulking on two cases. Mean Maryland foot score was 90.4. CONCLUSION: This regionalized coverage by "Boat Sock" flaps and skin graft could serve as a standard procedure for reconstruction of the totally degloved foot, by offering the benefits of multi-plane coverage, a well-contoured ankle, an abrasion-tolerant planta, and eclectic surgical complexities.

Identification of the hsa_circ_0039466/miR-96-5p/FOXO1 regulatory network in hepatocellular carcinoma by whole-transcriptome analysis.

Background: Circular RNAs (circRNAs) are important for the process of cancer initiation and progression. However, the role of circRNAs in hepatocellular carcinoma (HCC) remains incompletely understood. Therefore, we further explored the expression network of circRNAs in HCC. Methods: Whole-transcriptome microarrays of HCC and paired normal liver tissues were obtained from the Gene Expression Omnibus (GEO) database. The structures of tumor-associated circRNAs were acquired by the Cancer-Specific CircRNA Database (CSCD). StarBase, circBank, and R packages (miRNAtap and multiMiR) were used to predict miRNA targets of circRNAs and downstream molecules of miRNAs. Expression relationships between RNA-RNA interactions were evaluated by data from The Cancer Genome Atlas (TCGA) and GEO databases. ClusterProfiler and DOSE R packages were used for pathway enrichment to explore the biological functions of potential target genes. Finally, a possible circRNA-miRNA-mRNA regulatory network was established based on the competing endogenous RNA (ceRNA) hypothesis. Results: The differentially expressed circRNAs (DECs) were matched with cancer-specific circRNAs in the CSCD database and a screening analysis was performed to obtain 5 cancer-specific circRNAs. A total of 329 possible target miRNAs for 5 cancer-specific circRNAs were predicted by the circBank database, and intersection analysis with differentially expressed miRNAs (DEmiRNAs) revealed that miR-6746-3p and miR-96-5p were the two most suitable miRNAs targets for our selected circRNAs. Further expression verification and prediction of base complementary paired binding sites demonstrated the hsa_circ_0039466/miR-96-5p axis as a crucial pathway in HCC. Next, we found that FOXO1 and LEPR were two potential downstream molecules of the hsa_circ_0039466/miR-96-5p axis through target gene prediction analysis, differential expression analysis, and intersection analysis. The pathway enrichment results suggested that the hsa_circ_0039466/miR-96-5p axis affects the progression and outcome of HCC through the insulin resistance pathway. Finally, through multi-data crossover analysis and data analysis of HCC samples further confirmed the existence of the hsa_circ_0039466/miR-96-5p/FOXO1 ceRNA regulatory network and that the axis was closely related to clinical stage. Conclusions: hsa_circ_0039466 facilitates the expression of FOXO1 by sponging miR-96-5p, and ultimately inhibits tumor progression. These results provide a theoretical basis for further understanding of the gene expression network of HCC.

Expression and prognostic value of SULT1A2 in bladder cancer.

Sulfotransferase Family 1A Member 2 (SULT1A2) is a protein coding gene. Several studies have reported that SULT1A2 may have a chemical carcinogenic effect if expressed as a functional protein. The present study aimed to investigate the expression and potential role of SULT1A2 in bladder cancer (BC). Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to analyze SULT1A2 expression in BC. In addition, reverse transcription-quantitative PCR and western blot analyses were performed to detect SULT1A2 expression in BC cells and tissues. Immunohistochemistry analysis was performed on 100 formalin-fixed, paraffin-embedded BC tissues and corresponding adjacent normal bladder tissues (ANBTs) to verify SULT1A2 expression and determine the clinical significance of SULT1A2 in BC. Gene set enrichment analysis (GSEA) was performed to determine the potential biological processes and internal molecular mechanisms. The results demonstrated that SULT1A2 was highly expressed in BC tissues compared with ANBTs. Furthermore, high SULT1A2 expression was significantly associated with the staging of BC. Analyses of TCGA datasets and BC tissue microarray indicated that high SULT1A2 expression was significantly associated with a favorable overall survival in patients with BC. In addition, GSEA revealed pathways, diseases and biological processes associated with SULT1A2. Taken together, the results of the present study suggest that SULT1A2 acts as an oncogene in BC, and thus may serve as a biomarker for tumor staging and prognosis in patients with BC.

ZIPK activates the IL-6/STAT3 signaling pathway and promotes cisplatin resistance in gastric cancer cells.

Gastric cancer is one of the most common malignant cancers globally. Chemotherapy resistance remains a major obstacle in the treatment of gastric cancer, and the molecular mechanisms underlying drug resistance are still not well understood. We previously reported that Zipper interacting protein kinase (ZIPK), also known as death-associated protein kinase3, exerts an oncogenic effect on gastric cancer via activation of Akt/NF-κB signaling and promotion of stemness. Here, we explored the roles of ZIPK in cisplatin resistance. We report that ZIPK enhances cell proliferation and invasion and reduces the antitumor activity of cisplatin in gastric cancer. In addition, our western blot data suggest that ZIPK activated the IL-6/STAT3 signaling pathway. Furthermore, ZIPK increased the expression of IL-6 and multidrug-resistance genes. Using the STAT3 inhibitor stattic to block the IL-6/STAT3 signaling pathway strongly increased the sensitivity of ZIPK-expressed cells to cisplatin. In conclusion, ZIPK may play a role in cisplatin resistance through activation of the IL-6/ STAT3 signaling pathway. Inhibition of STAT3 in gastric cancer overexpressing ZIPK might have potential to improve the efficacy of cisplatin.

Algorithm for covering circumferential wound on limbs with ALTP or/and DIEP flaps based on chain-linked design and combined transplantation.

INTRODUCTION: Coverage of circumferential wounds on limbs is a challenging reconstructive job. Here, we propose a skin flap-based algorithm to reconstruct circumferential wound with the chain-linked design and combined transplantation of ALTP and DIEP flap, which could achieve full-coverage and simultaneously primary donor-site closure. PATIENT AND METHODS: From December 2007 to December 2018, 14 patients with circumferential would on upper or lower limbs underwent reconstruction with ALTP or DIEP flap, by the technique of combined transplantation or chain-linked design, or both. The wound was classified into five different types according to the width compared to the donor site (overall magnitudes and regularity), which was separately reconstructed by five different wound decomposition and corresponding flap design. Flap survivorship, complication on recipient or donor site and any secondary surgeries have been recorded. RESULTS: 14 patients were successfully treated with 22 flaps, including seven patients reconstructed with one flap (4 bi-pedicled, 2 tri-pedicled), 6 patients reconstructed with two flaps (1 in mono-pedicled, 5 in multi-pedicled), one with 3 flaps and skin grafts. Only one donor site was not directly closed, and one experienced dehiscence but finally healed. All flaps survived uneventfully but three had minor edge necrosis and later treated with skin graft. CONCLUSION: The algorithm is practical in circumferential wound resurfacing on limbs for allowing flexible design, sufficient coverage, and low donor site morbidity.

Comparison of free vascularized iliac bone flap grafting versus pedicled iliac bone flap grafting for treatment of osteonecrosis of the femoral head.

BACKGROUND: A high incidence of osteonecrosis of the femoral head (ONFH), a commonly seen and intractable disease, has been reported. This retrospective study aims to compare the reconstructive outcomes by free vascularized iliac bone flap (FVIBF) with those by vascularized pedicled iliac bone flap (PIBF) to determine which one is better for ONFH patients. METHODS: From January 2010 to December 2017, 35 patients (40 hips) were treated by PIBF grafting, and 32 patients (36 hips) were treated by FVIBF grafting. The two groups were then compared in terms of the preoperative baseline conditions, intraoperative data, and postoperative Harris hip score (HHS). RESULTS: In the PIBF group, the operating time was significantly longer than the FVIBF group (195.5 ±â€¯26.4 vs 147.2 ±â€¯17.7 min, respectively), and the intra-operative blood loss was significantly heavier (330.0 ±â€¯63.9 vs 240.3 ±â€¯37.5 ml, respectively). Meanwhile, the recipient site morbidity rate in the PIBF group outnumbered that in the FVIBF group (27.5% vs 8.3%, respectively), and a higher rate of lateral femoral cutaneous nerve (LFCN) injury was observed in the PIBF group than in the FVIBF group (27.5% vs 8.3%, respectively). No difference was found in postoperative HHS score between the two groups. In both groups, the recovery effect of the patients in stage II was better than that in stage III. CONCLUSION: While maintaining a similar clinical effect, the FVIBF grafting exhibited a distinct advantage over the PIBF grafting, in terms of shorter operative time, less blood loss, and lower risk of LFCN injury.

Nudix hydrolase 1 is a prognostic biomarker in hepatocellular carcinoma.

We investigated the prognostic significance of Nudix hydrolase 1 (NUDT1) in hepatocellular carcinoma (HCC). NUDT1 mRNA and protein levels were significantly higher in HCC tissues than normal liver tissues. The level of NUDT1 expression correlated with tumor grade, stage, size, differentiation, degree of vascular invasion, overall survival (OS), and disease-free survival (DFS) in HCC patients. Multivariate analysis showed that NUDT1 expression was an independent prognostic factor for OS and DFS in HCC patients. We constructed a prognostic nomogram with NUDT1 expression, AFP levels, vascular invasion, Child-Pugh classification, age, sex, AJCC staging, and tumor differentiation as variables. This nomogram was highly accurate in predicting the 5-year OS of HCC patients (c-index= 0.709; AUC= 0.740). NUDT1 silencing in HCC cells significantly reduced their survival, colony formation, migration, and invasiveness. Gene set enrichment analysis showed that biological pathways related to cell cycle, fatty acid metabolism, bile acid and bile salt metabolism, and PLK1 signaling were associated with NUDT1, as were the gene ontology terms "DNA binding transcription activator activity," "RNA polymerase II," "nuclear division," and "transmembrane transporter activity." Our study thus demonstrates that NUDT1 is a prognostic biomarker with therapeutic potential in HCC patients.

Extracellular vesicles from human urine-derived stem cells inhibit glucocorticoid-induced osteonecrosis of the femoral head by transporting and releasing pro-angiogenic DMBT1 and anti-apoptotic TIMP1.

Osteonecrosis of the femoral head (ONFH) frequently occurs after glucocorticoid (GC) treatment. Extracellular vesicles (EVs) are important nano-sized paracrine mediators of intercellular crosstalk. This study aimed to determine whether EVs from human urine-derived stem cells (USC-EVs) could protect against GC-induced ONFH and focused on the impacts of USC-EVs on angiogenesis and apoptosis to explore the mechanism by which USC-EVs attenuated GC-induced ONFH. The results in vivo showed that the intravenous administration of USC-EVs at the early stage of GC exposure could rescue angiogenesis impairment, reduce apoptosis of trabecular bone and marrow cells, prevent trabecular bone destruction and improve bone microarchitecture in the femoral heads of rats. In vitro, USC-EVs reversed the GC-induced suppression of endothelial angiogenesis and activation of apoptosis. Deleted in malignant brain tumors 1 (DMBT1) and tissue inhibitor of metalloproteinases 1 (TIMP1) proteins were enriched in USC-EVs and essential for the USC-EVs-induced pro-angiogenic and anti-apoptotic effects in GC-treated cells, respectively. Knockdown of TIMP1 attenuated the protective effects of USC-EVs against GC-induced ONFH. Our study suggests that USC-EVs are a promising nano-sized agent for the prevention of GC-induced ONFH by delivering pro-angiogenic DMBT1 and anti-apoptotic TIMP1. STATEMENT OF SIGNIFICANCE: This study demonstrates that the intravenous injection of extracellular vesicles from human urine-derived stem cells (USC-EVs) at the early stage of glucocorticoid (GC) exposure efficiently protects the rats from the GC-induced osteonecrosis of the femoral head (ONFH). Moreover, this study identifies that the promotion of angiogenesis and inhibition of apoptosis by transferring pro-angiogenic DMBT1 and anti-apoptotic TIMP1 proteins contribute importantly to the USC-EVs-induced protective effects against GC-induced ONFH. This study suggests the promising prospect of USC-EVs as a new nano-sized agent for protecting against GC-induced ONFH, and the potential of DMBT1 and TIMP1 as the molecular targets for further augmenting the protective function of USC-EVs.

Free vascularized iliac bone flap based on deep circumflex iliac vessels graft for the treatment of osteonecrosis of femoral head.

BACKGROUND: To investigate the feasibility and clinical efficacy of free vascularized iliac bone flap based on deep iliac circumflex vessels graft for the treatment of osteonecrosis of femoral head (ONFH) in young adults. METHODS: Eighteen patients (19 hips) undergoing ONFH were included from January 2016 to May 2017. After the debridement of the necrotic bones, the contralateral vascularized iliac bone flap was designed and harvested before grafting, in which the deep circumflex iliac vessels and the transverse branch (or ascending branch) of the lateral circumflex femoral artery and their accompanying veins were anastomosed. X-ray was obtained at 1, 3, 6, 9, and 12 months respectively for evaluation of the bone flap healing. Hip function was evaluated with Harris hip score at 18 months postoperatively. RESULTS: None of the patients is lost to follow-up. All the hips healed well except for four complications: one patient developed superficial wound infection, one patient had subcutaneous hematoma, and two patients developed anterolateral femoral cutaneous nerve injury. X-ray films at 12 months showed improvement in 13 hips (68.4%), five hips (26.3%) were unchanged, and one femoral head collapse with conversion to total hip arthroplasty (THA) at 14 months postoperatively (5.3%). Postoperative mean Harris hip scores were significantly improved compared to the preoperative results (P < 0.05). CONCLUSION: Free vascularized iliac bone flap based on deep circumflex iliac vessels graft is an acceptable treatment option for young adult ONFH in mid-late stage with low conversion to THA rate at short-term follow-up.