Induction of Skin Allograft Chimerism by Pharmacological Mobilization of Endogenous Bone Marrow-Derived Stem Cells.

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine.

Expression profile and prognostic values of SMC family members in HCC.

OBJECTIVE: The structural maintenance of chromosome (SMC) gene family, including 6 proteins, is involved in a wide range of biological functions in different human cancers. Nevertheless, there is little research on the expression patterns, potential functions and prognostic value of SMC genes in hepatocellular carcinoma (HCC). Based on publicly available databases and integrative bioinformatics analysis, we tried to determine the value of SMC gene expression in predicting the risk of developing HCC. METHODS: The expression and copy number variations data of SMC family members were obtained from TCGA (The Cancer Genome Atlas). We identified the prognostic values of SMC family members and their clinical features. GSEA (Gene Set Enrichment Analysis) was conducted to detect the mechanism underlying the involvement of SMC family members in liver cancer. We used Tumor Immune Estimation Resource database to explore the associations between TIICs (Tumor Immune Infiltrating Cells) and the SMC family members. RESULTS: Our analysis proved that downregulation of SMC family members was common modification in HCC patients. In HCC, the expression of SMC1A, SMC2, SMC3, SMC4, SMC6 were upregulated. Upregulation of SMC2, SMC3, and SMC4, along with the clinical stage of HCC, were associated with a poor prognosis according to the results of univariate and multivariate Cox proportional hazards regression analysis. SMC2, SMC3, and SMC4 are also related to tumor purity and immune infiltration levels of HCC. The GSEA results proved that SMC family members take part in numerous biological processes underlying tumorigenesis. CONCLUSION: In this study, we comprehensively analyzed the expression of SMC family members in patients with HCC. This can provide insights for further investigation of the SMC members as potential therapeutic targets in HCC and suggest that the use of SMC inhibitor targeting SMC2, SMC3, and SMC4 can be a practical strategy for the therapy of HCC.

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function.

Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.

Role of Metastasis Suppressor KAI1/CD82 in Different Cancers.

Metastasis is one of the characteristics of malignant tumors and the main cause of death worldwide. The process of metastasis is mainly affected by tumor metastasis genes, tumor metastasis suppressor genes, tumor microenvironment, extracellular matrix degradation, and other factors. Thus, it is essential to elucidate the mechanism of metastasis and find the therapeutic targets in order to prevent the development of malignant tumors. KAI1/CD82, a member of tetraspanin superfamily of glycoproteins, has been reported as a tumor metastasis suppressor gene in various types of cancers without affecting the tumor formation. Many studies have demonstrated that low expression of KAI1/CD82 might lead to poor prognosis due to its interactions with other tetraspanins and integrins, resulting in the regulation of cell motility and invasion, cell-cell adhesion, and apoptosis. Considering its pathological and physiological significance, KAI1/CD82 could be a potential strategy for clinical predicting and preventing tumor progression and metastasis. The present review aims to discuss the role of KAI1/CD82 in metastasis for different cancers and examine its prospects as a metastasis biomarker and a therapeutic target.

Preresidency Publication Productivity of U.S. Neurosurgery Interns.

BACKGROUND: Research experience is believed to be an important component of the neurosurgery residency application process. One measure of research productivity is publication volume. The preresidency publication volume of U.S. neurosurgery interns and any potential association between applicant publication volume and the match results of top-ranked residency programs have not been well characterized. OBJECTIVE: In this study, we sought to characterize the preresidency publication volume of U.S. neurosurgery residents in the 2018-2019 intern class using the Scopus database. METHODS: For each intern, we recorded the total number of publications, total number of first or last author publications, total number of neuroscience-related publications, mean number of citations per publication, and mean impact factor of the journal per publication. Preresidency publication volumes of interns at the top-25 programs (based on a composite ranking score according to 4 different ranking metrics) were compared with those at all other programs. RESULTS: We found that 82% of neurosurgery interns included in the analysis (190 interns from 95 programs) had at least 1 publication. The average number of publications per intern among all programs was 6 ± 0.63 (mean ± standard error of the mean). We also found that interns at top-25 neurosurgery residency programs tended to have a higher number of publications (8.3 ± 1.2 vs. 4.8 ± 0.7, P = 0.0137), number of neuroscience-related publications (6.8 ± 1.1 vs. 4.1 ± 0.7, P = 0.0419), and mean number of citations per publication (9.8 ± 1.7 vs. 5.7 ± 0.8, P = 0.0267) compared with interns at all other programs. CONCLUSIONS: Our results provide a general estimate of the preresidency publication volume of U.S. neurosurgery interns and suggest a potential association between publication volume and matching in the top-25 neurosurgery residency programs.

Major Improvement in Wound Healing Through Pharmacologic Mobilization of Stem Cells in Severely Diabetic Rats.

Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow-derived CD133+ and CD34+ endothelial progenitor cells and Ym1/2+ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.

Surgical management of hand deformities in patients with recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a congenital disease caused by a mutation in the COL7A1 gene and frequently results in hand contractures and pseudosyndactyly. Although multiple treatments exist that can improve the hand malformations, there are currently still no radical cures for this disease because of its high recurrence rate. The present study reports our experiences on how to improve hand deformities in 11 RDEB patients with surgical management and postoperative skin dressings. Hand function was substantially improved after complete release of pseudosyndactyly and achievement of favorable digital web spaces. Patients were followed up for two years, and nine of which showed slight decrease in hand function characterized by re-narrowed web spaces, digit adhesion and flexed metacarpophalangeal (MP) and interphalangeal (IP) joints, while the last two patients underwent hand reoperation one year after their initial surgery because of recurrence. In conclusion, our results show that surgical correction followed by skin dressing changes is an effective approach to improving mitten-hand malformations in RDEB patients.

Melanocyte Chitosan/Gelatin Composite Fabrication with Human Outer Root Sheath-Derived Cells to Produce Pigment.

The hair follicle serves as a melanocyte reservoir for both hair and skin pigmentation. Melanocyte stem cells (MelSCs) and melanocyte progenitors reside in the bulge/sub-bulge region of the lower permanent portion of the hair follicle and play a vital role for repigmentation in vitiligo. It would be beneficial to isolate MelSCs in order to further study their function in pigmentary disorders; however, due to the lack of specific molecular surface markers, this has not yet been successfully accomplished in human hair follicles (HuHF). One potential method for MelSCs isolation is the "side population" technique, which is frequently used to isolate hematopoietic and tumor stem cells. In the present study, we decided to isolate HuHF MelSCs using "side population" to investigate their melanotic function. By analyzing mRNA expression of TYR, SOX10, and MITF, melanosome structure, and immunofluorescence with melanocyte-specific markers, we revealed that the SP-fraction contained MelSCs with an admixture of differentiated melanocytes. Furthermore, our in vivo studies indicated that differentiated SP-fraction cells, when fabricated into a cell-chitosan/gelatin composite, could transiently repopulate immunologically compromised mice skin to regain pigmentation. In summary, the SP technique is capable of isolating HuHF MelSCs that can potentially be used to repopulate skin for pigmentation.

Stem cells in burn wound healing: A systematic review of the literature.

INTRODUCTION: Severe burns are often associated with high morbidity and unsatisfactory functional and esthetic outcomes. Over the last two decades, stem cells have generated great hopes for the treatment of numerous conditions including burns. The aim of this systematic review is to evaluate the role of stem cell therapy as a means to promote burn wound healing. METHODS: Comprehensive searches in major databases were carried out in March 2017 for articles on stem cell therapy in burn wound healing. In total 2103 articles were identified and screened on the basis of pre-determined inclusion and exclusion criteria. RESULTS: Fifteen experimental and two clinical studies were included in the review. The majority of studies reported significant improvement in macroscopic burn wound appearance as well as a trend toward improved microscopic appearance, after stem cell therapy. Other parameters evaluated, such as re-vascularization, collagen formation, level of pro- and anti-inflammatory mediators, apoptosis and cellular infiltrates, yielded heterogeneous results across studies. CONCLUSION: Stem cell therapy appears to exert a positive effect in burn wound healing. There is, therefore, justification for continued efforts to evaluate the use of stem cells as an adjunct to first-line therapies in burns.