Today, autogenous bone graft (ABG) is still considered as the gold standard for joint fusion. Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) which is of chemotactic and mitogenic to mesenchymal stem cells and possesses outstanding osteogenetic potentials has been used for ankle and foot fusion in recent years. The goal of this article is to evaluate the safety and efficacy of rhPDGF-BB versus ABG in foot and ankle fusion. The PubMed MEDLINE, EMBASE, Web of Science, and Cochrane Library were systematic searched. Finally, three randomized controlled trials (RCTs) with 634 patients were enrolled in this study. Results of radiologic effectiveness which included CT and radiographic union rates revealed that there was no significant difference between rhPDGF-BB approach and ABG approach. Analysis of clinical results held the same outcomes expect that ABG group was superior in long-term Short Form-12 physical component scores. The pooled results also demonstrated that rhPDGF-BB was as safe as ABG in foot and ankle surgery. However, autograft harvesting procedure has some drawbacks such as donor-site pain and morbidity, additional operation time, blood loss, and scarring, which can be overcome by rhPDGF-BB. Thus, rhPDGF-BB is a viable alternative to autograft in foot and ankle fusion surgery. Yet, more high-quality RCTs with long-term follow-up are still required to make the final conclusion.

A promising approach to the treatment of chronic ischaemic heart disease and congestive heart failure is the use of stem cells. The last decade has seen a plethora of randomised controlled trials developed worldwide, which have generated conflicting results.

Esophageal cancer was a vital cause of cancer-related mortality worldwide, and the insulin-like growth factor-binding proteins (IGFBPs) has been proved to be an important factor of multiple types of tumors. There is a controversy that whether the IGFBP-3 level is associated with the clinical pathological characteristics and overall survival of esophageal cancer patients. Herein, we aimed to comprehensively assess the association between the low IGFBP-3 level and the risk, overall survival and clinical pathological characteristics of esophageal cancer.

To assess the safety and efficacy of cell therapies for chronic stroke.

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies.

This study was aimed to investigate the efficacy and safety of the combination treatment of dendritic cells co-cultured with cytokine-induced killer cells and chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC). Literatures were searched from the Cochrane Library Central, PubMed, Web of Science and EMBASE. The primary endpoint of interest was overall survival (OS), and secondary endpoints were disease control rate (DCR) and progression free survival (PFS). Finally 7 trials published between January 2005 and March 2016 met inclusion criteria and totally 610 patients were enrolled. The combination group showed advance in DCR (RR = 1.31, 95% CI = 1.13-1.52, p = 0.0004), 1-year OS (RR = 1.18, 95% CI = 1.05-1.33, p = 0.007), and 2-year OS (RR = 1.37, 95% CI = 1.10-1.70, p = 0.005), with statistical significance. The proportions of CD3+ T cells (p = 0.002), NK cells (p = 0.02) and NKT cells (p = 0.001) were significantly higher in the peripheral blood of combination group, compared with those of the control group. Moreover, adverse reactions were obviously decreased in the combination group. However, no significant difference was identified in ORR and PFS between two groups (p > 0.05). In conclusion, the combination therapy was safe and applicable for patients with advanced NSCLC.

Craniofacial bone defects are challenging problems for maxillofacial surgeons over the years. With the development of cell and molecular biology, gene therapy is a breaking new technology with the aim of regenerating tissues by acting as a delivery system for therapeutic genes in the craniofacial region rather than treating genetic disorders. A systematic review was conducted summarizing the articles reporting gene therapy in maxillofacial surgery to answer the question: Was gene therapy successfully applied to regenerate bone in the maxillofacial region? Electronic searching of online databases was performed in addition to hand searching of the references of included articles. No language or time restrictions were enforced. Meta-analysis was done to assess significant bone formation after delivery of gene material in the surgically induced maxillofacial defects. The search identified 2081 articles, of which 57 were included with 1726 animals. Bone morphogenetic proteins were commonly used proteins for gene therapy. Viral vectors were the universally used vectors. Sprague-Dawley rats were the frequently used animal model in experimental studies. The quality of the articles ranged from excellent to average. Meta-analysis results performed on 21 articles showed that defects favored bone formation by gene therapy. Funnel plot showed symmetry with the absence of publication bias. Gene therapy is on the top list of innovative strategies that developed in the last 10 years with the hope of developing a simple chair-side protocol in the near future, combining improvement of gene delivery as well as knowledge of the molecular basis of oral and maxillofacial structures.

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

The regenerative potential of tissue-engineered bone constructs may be enhanced by in vitro coculture and in vivo cotransplantation of vasculogenic and osteogenic (progenitor) cells. The objective of this study was to systematically review the literature to answer the focused question: In animal models, does cotransplantation of osteogenic and vasculogenic cells enhance bone regeneration in craniofacial defects, compared with solely osteogenic cell-seeded constructs? Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, electronic databases were searched for controlled animal studies reporting cotransplantation of endothelial cells (ECs) with mesenchymal stem cells (MSCs) or osteoblasts in craniofacial critical size defect (CSD) models. Twenty-two studies were included comparing outcomes of MSC/scaffold versus MSC+EC/scaffold (co)transplantation in calvarial (n = 15) or alveolar (n = 7) CSDs of small (rodents, rabbits) and large animal (minipigs, dogs) models. On average, studies presented with an unclear to high risk of bias. MSCs were derived from autologous, allogeneic, xenogeneic, or human (bone marrow, adipose tissue, periosteum) sources; in six studies, ECs were derived from MSCs by endothelial differentiation. In most studies, MSCs and ECs were cocultured in vitro (2-17 days) before implantation. Coculture enhanced MSC osteogenic differentiation and an optimal MSC:EC seeding ratio of 1:1 was identified. Alloplastic copolymer or composite scaffolds were most often used for in vivo implantation. Random effects meta-analyses were performed for histomorphometric and radiographic new bone formation (%NBF) and vessel formation in rodents' calvarial CSDs. A statistically significant benefit in favor of cotransplantation versus MSC-only transplantation for radiographic %NBF was observed in rat calvarial CSDs (weighted mean difference 7.80% [95% confidence interval: 1.39-14.21]); results for histomorphometric %NBF and vessel formation were inconclusive. Overall, heterogeneity in the meta-analyses was high (I2 > 80%). In summary, craniofacial bone regeneration is enhanced by cotransplantation of vasculogenic and osteogenic cells. Although the direction of treatment outcome is in favor of cotransplantation strategies, the magnitude of treatment effect does not seem to be of relevance, unless proven otherwise in clinical studies.

In recent years, CD44 and CD133 have been identified as 2 common used cancer stem cell (CSC) markers in gastric cancer. However, the clinicopathological and prognostic value of these markers in gastric cancer remains controversial; moreover, there is lack of comparison of these 2 markers' roles in clinical applications. A systematic review and meta-analysis was conducted to elucidate these markers' clinicopathological features and association with prognosis in patients with gastric cancer.

Isolated hormone deficiency might be caused by loss of a specific type of endocrine cells, and regenerating these missing cells may provide a new option for future treatment. It is known that POU1F1 lineage cells can differentiate into thyrotroph, somatotroph, and lactotroph. However, there is no effective way of controlling pituitary stem/progenitor cells to differentiate into a specific type of endocrine cell. We thereby analyzed multiple genomic publications related to POU1F1 and pituitary development in this study to identify genes and agents regulating POU1F1 lineage cell differentiation. ANOVA analyses were performed to obtain differentially expressed genes. Ingenuity pathway analyses were performed to obtain signaling pathways, interaction networks, and upstream regulators. Venn diagram was used to determine the overlapping information between studies. Summary statistics was performed to rank genes according to their frequency of occurrence in these studies. The results from upstream analyses indicated that 326 agents may regulate pituitary cell differentiation. These agents can be categorized into 12 groups, including hormones and related pathways, PKA-cAMP pathways, p53/DNA damaging/cell cycle pathways, immune/inflammation regulators, growth factor and downstream pathways, retinoic/RAR pathways, ROS pathways, histone modifications, CCAAT/enhancer binding protein family, neuron development/degeneration pathways, calcium related and fat acid, and glucose pathways. Additional experiments demonstrated that H2O2 and catalase differentially regulate growth hormone and prolactin expression in somatolactotroph cells, confirming potential roles of ROS pathway on regulating somatotroph and lactotroph functions.

Chinese herbal medicine (CHM) has been used to treat stroke for thousands of years. The objective of the study is to assess the current evidence for bioactive components of CHM as neurogenesis agent in animal models of ischemic stroke.

<strong>Objective</strong> To investigate the short- and long-term therapeutic efficacies of intravenous trans- plantation of bone marrow stem cells (MSCs) in rats with experimental myocardial infarction by meta- analysis. <strong>Methods</strong> Randomized controlled trials were systematically searched from PubMed, Science Citation Index (SCI), Chinese journal full-text database (CJFD) up to December 2014. While the experimental groups (MSCs groups) were injected MSCs intravenously, the control groups were injected Delubecco's minimum essential medium (DMEM) or phosphate buffered saline (PBS). Subgroup analysis for each outcome measure was performed for the observing time point after the transplantation of MSCs. Weighted mean differences (WMD) and 95% confidence intervals (CI) were calculated for outcome parameters including ejection fraction (EF) and fractional shortening (FS), which were measured by echocardiogram after intravenous injection and analyzed by RevMan 5.2 and STATA 12.0. <strong>Results</strong> Data from 9 studies (190 rats) were included in the meta-analysis. As compared to the control groups, the cardiac function of the experimental groups were not improved at day 7 (EF: WMD=0.08, 95%CI -1.32 to 1.16, P>0.01; FS: WMD=-0.12, 95%CI -0.90 to 0.65, P>0.01) until at day 14 after MSCs' transplantation (EF: WMD=10.79, 95%CI 9.16 to 12.42, P<0.01; FS: WMD=11.34, 95%CI 10.44 to 12.23, P<0.01), and it lasted 4 weeks or more after transplantation of MSCs (EF: WMD=13.94, 95%CI 12.24 to 15.64, P<0.01; FS: WMD=9.64, 95%CI 7.98 to 11.31, P<0.01). <strong>Conclusion</strong> The therapeutic efficacies of MSCs in rats with myocardid infarction become increasing apparent as time advances since 2 weeks after injection.

Combined cell implantation has been widely applied in tissue engineering in recent years. In this meta-analysis, we aimed to establish whether the combined transplantation of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) promotes angiogenesis and tissue repair, compared with transplantation of a single cell type, following tissue injury or during tissue regeneration.

Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs.

Macrolide antibiotics, erythromycin, in particular, have been linked to the development of infantile hypertrophic pyloric stenosis (IHPS). Our aim was to conduct a systematic review of the evidence of whether post-natal erythromycin exposure is associated with subsequent development of IHPS.

Many transcription factors and signaling molecules involved in the guidance of myogenic differentiation have been investigated in previous studies. However, the precise molecular mechanisms of myogenic differentiation remain largely unknown. In the present study, by performing a meta-analysis of C2C12 myogenic differentiation microarray data, we found that leucine-rich repeat-containing 75B (Lrrc75b), also known as AI646023, a molecule of unknown biological function, was downregulated during C2C12 myogenic differentiation. The knockdown of Lrrc75b using specific siRNA in C2C12 myoblasts markedly enhanced the expression of muscle-specific myogenin and increased myoblast fusion and the myotube diameter. By contrast, the adenovirus-mediated overexpression of Lrrc75b in C2C12 cells markedly inhibited myoblast differentiation accompanied by a decrease in myogenin expression. In addition, the phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) was suppressed in the cells in which Lrrc75b was silenced. Taken together, our results demonstrate that Lrrc75b is a novel suppressor of C2C12 myogenic differentiation by modulating myogenin and Erk1/2 signaling.

Relevant markers of CSCs may serve as prognostic biomarkers of RCC. However, their actual prognostic significance remains inconclusive. Thus, a meta-analysis was performed to reevaluate the association of CSCs-relevant markers (CXCR4, CD133, CD44, CD105) expression with RCC prognosis more precisely.

To evaluate the safety and efficacy of cell therapies administered acutely/sub-acutely after stroke.