A web-based nomogram to predict overall survival for postresection leiomyosarcoma patients with lung metastasis.

To investigate the overall survival of post-resection leiomyosarcoma (LMS) patients with lung metastasis, data of post-resection LMS patients with lung metastasis between 2010 and 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The clinical characteristics and survival data for post-resection LMS patients with lung metastasis at Tianjin Medical University Cancer Hospital & Institute (TJMUCH) between October 2010 and July 2018 were collected. Patients derived from the SEER database and TJMUCH were divided into training and validation cohorts, respectively. Univariate and multivariate Cox regression analyses were performed and a nomogram was established. The area under the curve (AUC) and the calibration curve were used to evaluate the nomogram. A web-based nomogram was developed based on the established nomogram. Eventually, 226 patients from the SEER database who were diagnosed with LMS and underwent primary lesion resection combined with lung metastasis were enrolled in the training cohort, and 17 patients from TJMUCH were enrolled in the validation cohort. Sex, race, grade, tumor size, chemotherapy, and bone metastasis were correlated with overall survival in patients with LMS. The C-index were 0.65 and 0.75 in the SEER and Chinese set, respectively. Furthermore, the applicable AUC values of the ROC curve in the SEER cohort to predict the 1-, 3-, 5- years survival rate were 0.646, 0.682, and 0.689, respectively. The corresponding AUC values in the Chinese cohort were 0.970, 0.913, and 0.881, respectively. The calibration curve showed that the nomogram performed well in predicting the overall survival in post-resection LMS patients with lung metastasis. A web-based nomogram (https://weijunqiang.shinyapps.io/survival_lms_lungmet/) was established. The web-based nomogram (https://weijunqiang.shinyapps.io/survival_lms_lungmet/) is an accurate and personalized tool for predicting the overall survival of post-resection LMS with lung metastasis.

Web-based nomogram to predict postresection risk of distant metastasis in patients with leiomyosarcoma: retrospective analysis of the SEER database and a Chinese cohort.

OBJECTIVES: This study investigated risk factors and constructed an online tool to predict distant metastasis (DM) risk in patients with leiomyosarcoma (LMS) after surgical resection. METHODS: Data regarding patients with LMS who underwent surgical resection between 2010 and 2018 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Data were collected regarding patients with LMS who underwent surgical resection at Tianjin Medical University Cancer Hospital and Institute (TJMUCH) between October 2010 and July 2018. Patients were randomly divided into training and validation sets. Logistic regression analyses were performed; a nomogram was established. The area under the curve (AUC) and calibration curve were used to evaluate the nomogram, which served as the basis for a web-based nomogram. RESULTS: This study included 4461 and 76 patients from the SEER database and TJMUCH, respectively. Age, ethnicity, grade, T stage, N stage, radiotherapy, and chemotherapy were associated with DM incidence. C-index values were 0.815 and 0.782 in the SEER and Chinese datasets, respectively; corresponding AUC values were 0.814 and 0.773, respectively. A web-based nomogram (https://weijunqiang-leimyosarcoma-seer.shinyapps.io/dynnomapp/) was established. CONCLUSIONS: Our web-based nomogram is an accurate and user-friendly tool to predict DM risk in patients with LMS; it can aid clinical decision-making.

Clinicopathologic features, prognostic factors, and outcomes of visceral sarcomas: A retrospective 12-year single-center study.

Background: Visceral sarcomas are a rare form of soft tissue sarcoma. This study aimed to evaluate the survival and prognostic factors and effective treatments for visceral sarcomas. Methods: All patients with visceral sarcoma referred to our center between January 2010 and December 2021 were retrospectively analyzed. The Kaplan-Meier method and a log-rank test were used for survival analysis. Results: A total of 53 patients with visceral sarcoma were analyzed in this study with the median age at diagnosis of 57 (range, 24-77) years. Among them, 37 (69.8%) and 16 (30.2%) patients had localized and metastatic diseases at the initial presentation, respectively, and 44 patients underwent surgical resection. The median follow-up, event-free survival (EFS) and overall survival (OS) were 63.0 (range, 2-130), 42.0 months (95% confidence interval [CI] 10.879-73.121) and 45.0 months (95% CI 9.938-80.062), respectively. The 5-year EFS and OS rates were 44% and 46%, respectively. Univariate analysis of prognostic indicators illustrated that metastasis at presentation, surgery, surgical margin and the types of surgery were significantly associated with OS and EFS. In this study, combined chemotherapy or radiotherapy had no effects on EFS and OS. Conclusion: Primary visceral sarcoma is an uncommon and aggressive malignant tumor with a higher rate of local recurrence. In the largest cohort of visceral sarcomas in China to date, we identified metastases at presentation, surgery, surgical margin, and the types of surgery as independent predictors of survival. The combination of chemotherapy and radiotherapy did not affect survival.

The efficacies and biomarker investigations of antiprogrammed death-1 (anti-PD-1)-based therapies for metastatic bone and soft tissue sarcoma.

OBJECTIVE: Sarcomas are a group of rare malignancies with various subtypes. Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies, including anti-programmed death-1 (PD-1)-based therapies. METHODS: We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15, 2016 to December 30, 2019. These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments. Furthermore, 8 patients underwent panel DNA and whole transcript sequencing. RESULTS: Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group. The median follow-up time was 5.77 months. The median progression-free survival was 7.59 months, the overall response rate was 16.7% and the disease control rate was 55.6%. Based on whole exome and transcript sequencing data, there was no association between TMB, TNB, MSI, HLA-LOH, and PD-L1 expressions and sarcoma types with clinical responses. Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity (ITH) in progressive disease (PD) patients and lower ITH in partial response (PR) and stable disease patients. A higher percentage of immune cell infiltration, especially monocytes, was observed in PR patients. Active stromal gene expression was increased in PD patients but decreased in PR patients. Enrichment analysis revealed that an increased TGF-ß signaling pathway was reversely correlated with anti-PD-1 efficacy, while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy. CONCLUSIONS: Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated. ITH, monocyte ratio, stroma subtypes, and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.

Efficacy and safety of the VEGFR2 inhibitor Apatinib for metastatic soft tissue sarcoma: Chinese cohort data from NCT03121846.

BACKGROUND: There is no standard treatment for stage IV soft tissue sarcoma (STS) after the failure of Adriamycin-based chemotherapy. This phase II study (NCT03121846) assessed the efficacy and safety of apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV STS after chemotherapy failure. METHODS: Forty-two subjects with stage IV STSs who had failed chemotherapy and who received Apatinib were recruited between September 2015 and February 2018. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the PFS rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. RESULTS: Forty-two subjects were evaluated for AEs and 38 subjects were evaluated for efficacy. At 12 weeks, the PFR, ORR, and DCR were 70%, 26.32% (10/38), and 86.84% (33/38), respectively. Regarding overall responses, the ORR and DCR were 23.68% (9/38) and 57.89% (22/38), respectively. The median PFS was 7.87 months, and the median overall survival (OS) was 17.55 months. The most common AEs included hypertension (n = 18, 42.86%), hand-foot-skin reaction (n = 15, 35.71%), apositia (n = 13, 30.95%), and proteinuria (n = 11, 26.19%). No subjects had grade 4 AEs and 11 subjects (26.19%) experienced grade 3 AEs, mainly hypertension, hand-foot-skin reaction, proteinuria, apositia, fatigue, pain, and dysgeusia. Notably, the subjects who experienced hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (P = 0.0003). CONCLUSION: With the largest Chinese STS cohort to date, we report that apatinib show good efficacy in advanced STS subjects with significant higher ORR and some adverse events may predict prognosis.

Effect of combined treatment including surgery and postoperative adjuvant therapy on spinal metastases of Tomita type 7.

OBJECTIVES: Identify the efficacy of multidisciplinary treatment including palliative spinal surgery on patients with Tomita type 7 spinal metastases. PATIENTS AND METHODS: A retrospective analysis of surgery treated spinal metastatic patients from January 2013 to December 2016 in Tianjin Medical University Cancer Institute and Hospital were performed. Surgical procedures and intraoperative parameters and postoperative adjuvent treatments were studied. Patients' demographic characteristics and medical conditions including paralysis statues, quality of life and pain levels and postoperative survival time were identified. RESULTS: 50 patients were identified with mean age at the time of surgery of 57.68 years old (range 27-78 years). The mean Tokuhashi score was 8.48 and the spinal instability neoplastic score (SINS) averaged at 10.52 points. 48 patients (96%) encountered epidural spinal cord compression. Kaplan-Meier method determined median postoperative survival time was 12.00 months (95% CI: 7.05-16.95 months). The mean score of visual analogue scale (VAS) decreased from 7.66 preoperatively to 1.96 postoperatively. The Frankel scale was improved by at least one grade in 47 patients. Patient's quality of life showed significant improvements. CONCLUSION: Multidisciplinary treatment including palliative spinal surgery was associated with alleviating pain, improving neurologic function and quality of life in patients with Tomita type 7 spinal metastases.

SIAH1/ZEB1/IL-6 axis is involved in doxorubicin (Dox) resistance of osteosarcoma cells.

Osteosarcoma (OS) patients often exhibit pulmonary metastasis, which results in high patient mortality. Our present study established the doxorubicin (Dox) resistant human OS MG-63 and HOS cells and named them MG-63/Dox and HOS/Dox, respectively. The Dox resistant OS cells had greater invasion ability than that of parental cells. The expression of ZEB1, while not FOXM1, Snail, HIF-1α, or Sp1, was significantly increased in Dox resistant OS cells. Silencing of ZEB1 can attenuate the metastasis and increase Dox sensitivity of MG-63/Dox and HOS/Dox cells. The upregulation of ZEB1 can increase of the expression of interlukin-6 (IL-6). Anti-IL-6 inhibited the invasion and increase the Dox sensitivity of MG-63/Dox and HOS/Dox cells. There was no significant difference of ZEB1 mRNA between Dox resistant and control cells. The upregulation of ZEB1 in Dox resistant OS cells can be attributed to the increase of protein half-life. This was confirmed by results that the inhibitor of proteasomal degradation can increase ZEB1 in Dox resistant OS cells. Over expression of SIAH1 can inhibit the expression of ZEB1 and increase the Dox sensitivity of MG-63/Dox and HOS/Dox cells. Collectively, we confirmed that SIAH1 induced ZEB1 is involved in the Dox resistance of OS cells.

Incidence of bone metastasis and factors contributing to its development and prognosis in newly diagnosed renal cell carcinoma: a population-based study.

PURPOSE: The purpose of this study was to assess the incidence of and the risk factors and prognostic factors for bone metastasis (BM) in initial metastatic renal cell carcinoma (RCC) based on a large population analysis. PATIENTS AND METHODS: Data were obtained for a total of 45,824 RCC patients recorded in the database of the Surveillance, Epidemiology, and End Results program of the National Cancer Institute between 2010 and 2014. Multivariate logistic and Cox regression analyses were used to identify the risk factors and prognostic factors associated with BM in RCC patients. Kaplan-Meier analysis was used to estimate the overall survival of RCC patients, and the difference between the survival curves was tested by log-rank tests. RESULTS: A total of 1,509 (3.29%) patients were diagnosed with bone metastases at initial diagnosis. Male gender, higher T stage, lymph node involvement, poor tumor grade, presence of lung, liver, and brain metastases, and the collecting duct type of RCC were positively associated with BM occurrence. The median survival time for RCC patients with bone metastases was 12.0 (95% confidence interval [CI]: 10.69-13.31) months, and the survival time for those with collecting duct, clear-cell, papillary, and chromophobe subtypes of RCC were 3 (95% CI: 0.23-5.77), 13 (95% CI: 11.60-14.40), 8 (95% CI: 5.09-10.91), and 11 (95% CI: 5.02-16.98) months; these differences were significantly different (P<0.01). Older age, higher T stage, lymph node involvement, poor tumor grade, the presence of lung, liver, and brain metastases, collecting duct RCC, and the absence of surgical treatments were the factors associated with worse prognoses. CONCLUSION: BM was highly prevalent and significantly decreased the survival rate of RCC patients. A number of factors associated with the development and prognosis of BM were identified, and these insights provide preventive guidelines for screening and treatment of BM in RCC patients.

Recombined humanized endostatin (Endostar) combined with chemotherapy for advanced bone and soft tissue sarcomas in stage IV.

PURPOSE: This retrospective case-series study evaluated efficacy and safety of Endostar combined with chemotherapy in the treatment of advanced bone and soft tissue sarcomas in stage IV. MATERIALS AND METHODS: Forty-seven patients diagnosed with stage IV bone and soft tissue sarcomas and treated with chemotherapy in Tianjin Medical University Cancer Institute & Hospital were reviewed. Of these patients, 23 patients were treated with Endostar plus chemotherapy (designated as combined group), and 24 patients received only chemotherapy (designated as control group). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and clinical benefit response (CBR) were analyzed to find the difference between these two groups with the purpose to investigate the role of Endostar in metastatic sarcomas. RESULTS: Endostar combined with chemotherapy had significantly increased PFS. In the combined group and control groups, the median PFS (8.6 months versus 4.4 months) and the CBR (47.8% versus 16.7%) showed significant difference (P = 0.032), while the median overall survival (11.7 months versus 10.6 months, P = 0.658) and the ORR (17.4% versus 8.3%, P = 0.167) showed no significant difference. The common grade 3-4 side effects for both groups were myelosuppression and transient elevation of transaminases. CONCLUSION: Endostar combined with chemotherapy had significant activity to increase the PFS and improve CBR in patients with advanced sarcomas, with tolerable side effects.

Comparison of the therapeutic effects of surgery combined with postoperative radiotherapy and standalone radiotherapy in treating spinal metastases of lung cancer.

OBJECT: There are few studies comparing the therapeutic efficacy between surgery combined with postoperative radiotherapy and standalone radiotherapy in treating spinal metastases of lung cancer. The aim of this clinical study was to compare the clinical and functional efficacy, quality of life, and survival outcomes between surgery combined with postoperative radiotherapy and standalone radiotherapy in treating spinal metastases of lung cancer. METHODS: A retrospective analysis of clinical data from June 2008 to December 2013 was performed with 46 patients suffering spinal metastases of lung cancer. Among the studied patients, 25 patients received standalone radiotherapy (radiotherapy group), and the other 21 patients received surgery combined with postoperative radiotherapy (surgery group). Follow-up and survival time were analyzed. Pain levels of the patients were assessed by visual analogue scale (VAS) from pre-treatment to one month and three months after starting treatment. 3 months after surgery, Neurologic deficit of the patients was evaluated using Frankel Grade, and functional impairment were classified by Karnofsky Score. The quality of life (QOL) was assessed by EORTC QLQ-C30 questionnaire. RESULTS: The follow-up period of the patients ranged from 2 to 25 months with the average of 8.8 months. In radiotherapy group, the mean survival was 8.5 months with median survival time of 7.8 months. In surgery group, the mean survival was 10.6 months with median survival of 8.4 months. The difference in survival times between the two groups was not statistically significant (P=0.24>0.05). From pre-treatment to one month and three months after treatment initiation, the VAS in both groups showed statistical significant improvement (One month: P<0.01 Three months: P=0.001, p<<0.01). In the surgery group, 85.7% of all patients had functionally useful Frankel Grade D or E after surgery, compared with 71.4% pre-operatively. The percentage was 72.0% in the radiotherapy group post-treatment, compared with 68.0% pre-treatment. The relief of Frankel Grade in surgical group was superior to that of the radiotherapy group (p=0.025, p<0.01). KPS score (80-100) percentages in surgery group and in radiotherapy group were increased by 19% and 13.3%, respectively. The improvement of KPS was more in the surgery group (p=0.013, P<0.01). In radiotherapy group, the EORTC QLQ-C30 score was 86.13 ± 12.11 before treatment and 68.39 ± 14.96 after treatment. In surgery group, the EORTC QLQ-C30 score was 84.09 ± 9.48 before treatment and 54.64 ± 15.17 after treatment. The improvement of patient QOL was more in the surgery group (p=0.004, p<0.01). CONCLUSION: Compared with standalone radiotherapy, surgery combined with postoperative radiotherapy did not significantly prolong the survival time. However, surgery can improve pain, function and QOL of patients with spinal metastases of lung cancer.

Roles of low-density lipoprotein receptor-related protein 1 in tumors.

Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), a multifunctional endocytic and cell signaling receptor, is widely expressed on the surface of multiple cell types such as hepatocytes, fibroblasts, neurons, astrocytes, macrophages, smooth muscle cells, and malignant cells. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression. For example, LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase (MMP)-2 and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor, the serine/threonine protein kinase signaling pathway, and the expression of Caspase-3. LRP1-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion. In addition, LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1 CpG islands. Furthermore, a novel fusion gene, LRP1-SNRNP25, promotes osteosarcoma cell invasion and migration. Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma.

Osteosarcoma is a highly aggressive bone disease with a tendency to metastasize to the lung. The 5-year survival of patients with metastatic osteosarcoma is only 20 %. Many studies have demonstrated SDF-1/CXCR4 and MMP9 play important roles in the metastasis of malignant tumors, including osteosarcoma. The aim of this study was to investigate the association of CXCR4 and MMP9 expression with clinicopathological features and pulmonary metastasis in osteosarcoma. Using tumor tissue microarrays, we analyzed the expression of CXCR4 and MMP9 among 34 primary osteosarcomas with pulmonary metastasis and 62 primary osteosarcomas without metastasis. A median time of 57.5 months (range: 6 to 171 months) follow-up was performed to evaluate tumor metastasis and the patient survival. The prognostic values were determined by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics (ROC) curves (AUC). The expression of CXCR4 and MMP9 was significantly correlated in tumor tissues (P = 0.026). Both CXCR4 and MMP9 were independent predictors for overall survival and metastasis-free survival by Cox multivariate analysis, and high expression for both CXCR4 and MMP9 were even more significant and better biomarkers for osteosarcoma metastasis and survival. The combination of CXCR4 and MMP9 high expression is very likely to be a valuable independent predictor of lung metastasis and survival in osteosarcoma patients.

PLA2G16 Expression in Human Osteosarcoma Is Associated with Pulmonary Metastasis and Poor Prognosis.

BACKGROUND: Osteosarcoma is the most frequent type of malignant bone tumor in children and adolescents and is associated with a high propensity for lung metastasis. Recent experiments have indicated that PLA2G16 contributes to osteosarcoma progression and metastasis in both mouse and human osteosarcoma cell lines. The aim of this study was to compare the expression of PLA2G16 in non-metastatic and metastatic osteosarcomas to determine whether PLA2G16 expression can serve as a biomarker of osteosarcoma prognosis and metastasis. METHODS: Quantitative real-time PCR was used to examine PLA2G16 mRNA in primary osteosarcoma patients (18 patients without metastases and 17 patients with metastases), and immunohistochemistry (IHC) staining of PLA2G16 was performed on tissue microarrays from 119 osteosarcoma patients. Tumor metastatic behavior and survival of the patients were followed up for a minimum of 36 months and a maximum of 171 months. The prognostic value of PLA2G16 expression was evaluated by the Kaplan-Meier method and a log-rank test. Multivariate Cox regression analysis was used to identify significant independent prognostic factors. RESULTS: Osteosarcoma patients with metastasis showed a higher expression of PLA2G16 at both the mRNA and protein levels (both at P values< 0.05) than did patients without metastasis. Osteosarcoma patients with positive IHC staining of PLA2G16 expression at primary sites had shorter overall survival and metastasis-free survival (both at P values <0.02). Moreover, multivariate Cox analysis identified PLA2G16 expression as an independent prognostic factor to predict poor overall survival and metastasis-free survival (both P values < 0.03). CONCLUSIONS: This study indicated that PLA2G16 expression is a significant prognostic factor in primary osteosarcoma patients for predicting the development of metastases and poor survival.

Improvement in nerve regeneration through a decellularized nerve graft by supplementation with bone marrow stromal cells in fibrin.

Acellular nerve grafting is often inferior as well as an inadequate alternative to autografting for the repair of long gaps in peripheral nerves. Moreover, the injection method is not perfect. During the injection of cells, the syringe can destroy the acellular nerve structure and the limited accumulation of seed cells. To resolve this problem, we constructed a nerve graft by acellular nerve grafting. Bone marrow-mesenchymal stromal cells (BM-MSCs) were affixed with fibrin glue and injected inside or around the graft, which was then used to repair a 15-mm nerve defect in rats. The acellular nerve graft maintained its structure and composition, and its tensile strength was decreased, as determined by two-photon microscopy and a tensile testing device. In vitro, MSCs embedded in fibrin glue survived and secreted growth factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). We repaired 15-mm Sprague-Dawley rat sciatic nerve defects using this nerve graft construction, and MSCs injected around the graft helped improve nerve regeneration and functional recovery of peripheral nerve lesions as determined by functional analysis and histology. Therefore, we conclude that supplying MSCs in fibrin glue around acellular nerves is successful in maintaining the nerve structure and can support nerve regeneration similar to the direct injection of MSCs into the acellular nerve for long nerve defects but may avoid destroying the nerve graft. The technique is simple and is another option for stem cell transplantation.

The role of mesenchymal stem/progenitor cells in sarcoma: update and dispute.

Sarcoma is the collective name for a relatively rare, yet heterogeneous group of cancers, most probably derived from mesenchymal tissues. There are currently over 50 sarcoma subtypes described underscoring the clinical and biologic diversity of this group of malignant cancers. This wide lineage range might suggest that sarcomas originate from either many committed different cell types or from a multipotent cell. Mesenchymal stem/progenitor cells (MSCs) are able to differentiate into many cell types and these multipotent cells have been isolated from several adult human tumors, making them available for research as well as potential beneficial therapeutical agents. Recent accomplishments in the field have broadened our knowledge of MSCs in relation to sarcoma origin and sarcoma treatment in therapeutic settings. However, numerous concerns and disputes have been raised about whether they are the putative originating cells of sarcoma and their questionable role in sarcomagenesis and progression. We summarize the update and dispute about MSC investigations in sarcomas including the definition, cell origin hypothesis, functional and descriptive assays, roles in sarcomagenesis and targeted therapy, with the purpose to give a comprehensive view of the role of MSCs in sarcomas.

Role of stem cells in the regeneration and repair of peripheral nerves.

Peripheral nerve regeneration is a complex process, with Wallerian degeneration the most elementary reaction and Schwann cells playing an important role. In recent years, stem cells have been widely used to repair injured peripheral nerves. The sources of these stem cells are widespread and their effectiveness in the treatment of peripheral nerve injury may lie in their ability to differentiate into Schwann cells, secrete neurotrophic factors, and assist in myelin formation. Stem cells have been used as seed cells in tissue-engineered nerve grafts. The understanding of stem cell homing, novel repair material, and the ability to mobilize endogenous stem cells to assist peripheral nerve regeneration constitute a research direction of great interest.

Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration.

Chemical-extracted acellular nerve allografting, containing the natural nerve structure and elementary nerve extracellular matrix (ECM), has been used for peripheral nerve-defect treatment experimentally and clinically. However, functional outcome with acellular nerve allografting decreases with increased size of gap in nerve defects. Cell-based therapy is a good strategy for repairing long nerve defects. Bone-marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) can be induced to differentiate into cells with Schwann cell-like properties (BMSC-SCs or ADSC-SCs), which have myelin-forming ability in vitro and secrete trophic nerve growth factors. Here, we aimed to determine whether BMSC-SCs or ADSC-SCs are a promising cell type for enriching acellular grafts in nerve repair. We evaluated axonal regeneration distance by immunofluorescence staining after 2-week implantation. We used functional and histomorphometric analysis to evaluate 3-month regeneration of the novel cell-supplemented tissue-engineered nerve graft used to bridge a 15-mm-long sciatic nerve gap in rats. Introducing BMSC-SCs or ADSC-SCs to the acellular nerve graft promoted sciatic nerve regeneration and functional recovery. Nerve regeneration with BMSC-SCs or ADSC-SCs was comparable to that with autografting and Schwann cells alone and better than that with acellular nerve allografting alone. Differentiated bone-marrow-or adipose-derived MSCs may be a promising cell source for tissue-engineered nerve grafts and promote functional recovery after peripheral nerve injury.

Protein expression of sensory and motor nerves: Two-dimensional gel electrophoresis and mass spectrometry.

The present study utilized samples from bilateral motor branches of the femoral nerve, as well as saphenous nerves, ventral roots, and dorsal roots of the spinal cord, to detect differential protein expression using two-dimensional gel electrophoresis and nano ultra-high performance liquid chromatography electrospray ionization mass spectrometry tandem mass spectrometry techniques. A mass spectrum was identified using the Mascot search. Results revealed differential expression of 11 proteins, including transgelin, Ig kappa chain precursor, plasma glutathione peroxidase precursor, an unnamed protein product (gi|55628), glyceraldehyde-3-phosphate dehydrogenase-like protein, lactoylglutathione lyase, adenylate kinase isozyme 1, two unnamed proteins products (gi|55628 and gi|1334163), and poly(rC)-binding protein 1 in motor and sensory nerves. Results suggested that these proteins played roles in specific nerve regeneration following peripheral nerve injury and served as specific markers for motor and sensory nerves.

Repair of nerve defect with acellular nerve graft supplemented by bone marrow stromal cells in mice.

The acellular nerve graft that can provide internal structure and extracellular matrix components of the nerve is an alternative for repair of peripheral nerve defects. However, results of the acellular nerve grafting for nerve repair still remain inconsistent. This study aimed to investigate if supplementing bone marrow mesenchymal stromal cells (MSCs) could improve the results of nerve repair with the acellular nerve graft in a 10-mm sciatic nerve defect model in mice. Eighteen mice were divided into three groups (n = 6 for each group) for nerve repairs with the nerve autograft, the acellular nerve graft, and the acellular nerve graft by supplemented with MSCs (5 × 10(5)) fibrin glue around the graft. The mouse static sciatic index was evaluated by walking-track testing every 2 weeks. The weight preservation of the triceps surae muscles and histomorphometric assessment of triceps surae muscles and repaired nerves were examined at week 8. The results showed that the nerve repair by the nerve autografting obtained the best functional recovery of limb. The nerve repair with the acellular nerve graft supplemented with MSCs achieved better functional recovery and higher axon number than that with the acellular nerve graft alone at week 8 postoperatively. The results indicated that supplementing MSCs might help to improve nerve regeneration and functional recovery in repair of the nerve defect with the acellular nerve graft.