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Background: Most materials used clinically for filling severe bone defects either cannot induce bone re-generation or exhibit low bone conversion, therefore, their therapeutic effects are limited. Human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit good osteoinduction. However, the mechanism by which combining a heterogeneous bone collagen matrix with hUC-MSCs to repair the bone defects of alveolar process clefts remains unclear.Methods: A rabbit alveolar process cleft model was established by removing the bone tissue from the left maxillary bone. 48 young Japanese white rabbits (JWRs) were divided into normal, control, material and MSCs groups. An equal volume of a bone collagen matrix alone or combined with hUC-MSCs was implanted in the defect. X-ray, micro-focus computed tomography (micro-CT), blood analysis, histochemical staining and TUNEL were used to detect the newly formed bone in the defect area at 3 and 6 months after the surgery. Results: The bone formation rate obtained from the skull tissue in MSCs group was significantly higher than that in control group at 3 months (PPPPConclusions: Combining bone collagen matrix with hUC-MSCs promoted the new bone regeneration in the rabbit alveolar process cleft model through promoting osteoblasts formations and chondrocyte growth, and inducing type 1 collagen formation and BMP-2 generation.

Objective: A model of alveolar cleft phenotype was established in rabbits to evaluate the effect of active bone particles containing modified rhecombinant human BMP-2 on the repair of the alveolar cleft. Methods: 2-month-old Japanese white rabbits were selected and randomly divided into four groups: normal, control, material and BMP groups. Blood biochemical analysis, skull tomography (microfocus computerized tomography), and histological and immunohistochemical staining analysis of paraffin sections were performed 3 and 6 months after operation. Results: Both types of collagen particles showed good biocompatibility and promoted bone regeneration. The effect of active bone particles on bone repair and regeneration was better than that of bone collagen particles. Conclusions: Active bone particles containing modified rhecombinant human BMP-2 can be used for incisors regeneration.

Background The clinical application of most materials used to fill severe bone defects is limited owing to the insufficient ability of such materials to induce bone regeneration or the long repair period. The purpose of this study was to establish a model for the alveolar process cleft in rabbits to evaluate the effect of active bone material in bone defect repair. The active bone material used in this study is a new bone repair material composed of a heterogeneous collagen membrane implanted with modified recombinant human bone morphogenetic protein 2 (rhBMP-2). This proposed active bone material can specifically bind to collagen. Methods Twenty-four young Japanese white rabbits (JWRs) were selected and randomly divided into four groups (normal, control, material and BMP groups). The alveolar process cleft model was established by removing an equal-volume bone at the left maxillary position. Blood samples were collected from the JWRs 3 and 6 months after the surgery to evaluate the biocompatibility of the active bone materials. Subsequently, the skull model was established, and the appearance was observed. Imaging methods (including X-ray examination and Micro-computerized tomography (CT) scanning), tissue engineering staining and immunohistochemistry were employed for the evaluation. Results The bone collagen material and active bone material exhibited high biocompatibility. In addition, the ability of the active bone material to induce bone repair and regeneration was higher than that of the bone collagen material. Conclusions The active bone material exhibited satisfactory bone regeneration performance in rabbits, indicating its potential as an active material for repairing congenital alveolar process clefts in humans.

Background Alveolar cleft is a type of cleft lip and palate that seriously affects the physical and mental health of patients. In this study, a model of the alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (HUC-MSCs) on the repair of alveolar cleft bone defects. Methods A model of alveolar clefts in rabbits was established by removing the incisors on the left side of the upper jaw bone collagen particles combined with HUC-MSCs that were then implanted in the defect area. Blood biochemical analysis was performed 3 months after surgery. Skull tissues were harvested for gross observation, and micro-focus computerised tomography (micro-CT) analysis. Tissues were harvested for histological and immunohistochemical staining. The experiments were repeated 6 months after surgery. Results Bone collagen particles and HUC-MSCs showed good biocompatibility. Bone collagen particles combined with HUC-MSCs were markedly better at inducing bone repair and regeneration than bone collagen particles alone. Conclusions Combining HUC-MSCs with bone collagen particles provides a simple, rapid and suitable method to fill a bone defect site and treat of alveolar cleft bone defects.

Background: Alveolar cleft is a kind of cleft lip and palate, which seriously affects the physical and mental health of patients. In this study, a similar model of human alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (hUC-MSCs) on the repair of alveolar cleft bone defects. Methods: In this study, 24 adult Japanese white rabbits (JWRs) were selected and randomly divided into 4 groups. Including normal group, control group, materials group and MSCs group. The model of alveolar clefts was established by removing the incisors on the left side of the upper jaw. The normal group did nothing. In the control group, the incisors were removed and sutured directly. In the material group, the incisor were removed, then filled with bone collagen particles, and finally sutured. In the MSCs group, the incisors were first removed, then filled with bone collagen particles incubated by hUC-MSCs, and then stitched. Blood biochemical analysis was performed 3 months after the operation. Skull tissues were collected for gross observation, and micro-focus computerized tomography (micro-CT) analysis. Paraffin sections were prepared for histological and immunohistochemical staining. Results: The bone collagen particles and hUC-MSCs are not biotoxic and can promote alvenlus regeneration. Bone collagen particles combined with hUC-MSCs were much better than those used alone in inducing bone repair and regeneration. Conclusions: HUC-MSCs can be used as a bone generation inducer combined with bone collagen materials for bone regeneration and repair.

BACKGROUND Inflammation is considered as one of the main pathogeneses in OA-induced pain. Macrophage migration inhibitory factor (MIF) is a well known pro-inflammatory cytokine. We aimed to determine whether MIF levels in serum and synovial fluid (SF) are associated with severity of OA-induced pain. MATERIAL AND METHODS We recruited 226 patients with knee OA and 106 controls. Self-reported pain severity of OA patients was evaluated using the Western Ontario McMaster University Osteoarthritis (WOMAC) pain scores. MIF levels were detected using enzyme-linked immunosorbent assay (ELISA). RESULTS OA patients had similar serum MIF levels compared to controls (11.93 [5.68-18.10] vs. 10.06 [6.60-14.61] ng/ml, P>0.05). In OA patients, MIF levels in SF were dramatically lower compared to paired serum samples (3.39 [1.87-5.89] vs. 11.93 [5.68-18.10] ng/ml, P

BACKGROUND/AIMS To investigate the efficacy and safety of endoscopic biliary stenting for difficult common bile duct (CBD) stones in elderly patients. MATERIALS AND METHODS Elderly patients (≥65 years) with large (≥20 mm) or multiple (≥3) CBD stones were studied. The patients underwent placement of single (n=34, group A) or double (n=30, group B) plastic stents at the time of initial endoscopic retrograde cholangiopancreatography (ERCP). Approximately 3 months later, stone removal was attempted at the second ERCP. The reduction of stone size and number before and after biliary stenting, complete stone removal, 3-month stent patency rate, and complications were compared. RESULTS The mean size (longitudinal/transverse diameter) of the CBD stones was significantly reduced after biliary stenting in both groups (p

Background/Aims: A growing body of evidence has suggested that thiazolidinediones (TZDs) potentially reduce the risk of colorectal cancer (CRC). This study aimed to evaluate the effect of TZDs on CRC risk in patients with diabetes mellitus (DM). Patients and Methods: A systematic search of electronic databases was performed for studies evaluating the exposure to TZDs and reporting CRC risk in diabetic patients. Pooled estimates with 95% confidence intervals (CIs) were estimated using fixed or random effects models. Results: A total of 10 observational studies reporting more than 18,972 CRC cases in 2,470,768 DM patients were included. Meta-analysis showed a 9% reduction in CRC risk associated with TZDs use in all studies [relative risk (RR) =0.91, 95% CI = 0.84–0.99, P = 0.03] and cohort studies (RR = 0.89, 95% CI = 0.80–0.99, P = 0.04), respectively. However, such effect was not shown in case–control studies. In subgroup analyses, lower CRC risk was found in Asian population (RR = 0.40, 95% CI = 0.29–0.53, P = 0.00), and a trend toward lower CRC risk was observed in US population (RR = 0.94, 95% CI = 0.88–1.01, P = 0.08). CRC risk was significantly modified with non-pioglitazone TZD use (RR = 0.88, 95% CI = 0.82–0.95, P = 0.00), but not with pioglitazone use (RR = 0.95, 95% CI = 0.89–1.01, P = 0.11). No significant difference was observed with cancer site (colon or rectum). There was considerable inherent heterogeneity across studies, partly explained by study location. Conclusions: This meta-analysis supports a protective association between TZDs use and CRC risk in patients with DM. Future well-designed prospective studies with larger cohorts would be needed to understand this association better.

To investigate the efficiency and safety profile of the addition of S-1 to gemcitabine (GEM)-based chemotherapy for advanced pancreatic cancer (APC).Computerized search was undertaken to identify randomized controlled trials of S-1 plus GEM versus GEM monotherapy in APC patients. The outcomes included overall survival (OS), progression-free survival (PFS), response rate, and toxicities.Five studies with 917 patients were included. Overall, there was a significant difference between the two regimens in terms of OS (HR=0.83, 95%CI=0.72-0.96, P=0.01), PFS (HR=0.64, 95%CI=0.56-0.74, P0.0001), and overall response rate (ORR; RR=2.36, 95%CI=1.73-3.22, P0.00001). Occurrence of grade 3/4 hematological toxicities (neutropenia, thrombocytopenia) and non-hematological toxicities (diarrhea, nausea/vomit, rush, stomatitis/mucositis) were significantly higher with GEM/S-1 treatment.This meta-analysis indicated a significant survival benefit with increased toxicity when S-1 was combined with GEM. GEM/S-1 might be an option of first-line chemotherapy for APC patients, at least in Asia.

AIM: To assess the association between smoking and alcohol consumption and extrahepatic cholangiocarcinoma (ECC) through a meta-analysis of clinical observational studies. METHODS: A literature search was conducted using Embase and MEDLINE databases from inception to 31 May 2013 without language limitations, and by manually searching the references of retrieved articles. Case-control and cohort studies that investigated the association between smoking or alcohol consumption and ECC were included. The quality of these studies was assessed using the Newcastle-Ottawa quality assessment scale. Summary relative risks and corresponding 95%CI were calculated using a random-effects model. Publication bias was assessed by Begg’s funnel plot and Egger’s test. RESULTS: A total of 12 eligible articles (11 case-control studies and one cohort study) were included in this meta-analysis. Eleven studies reported the association between smoking and ECC. Pooled analysis indicated that smokers had an increased risk of ECC development as compared with non-smokers (summary RR = 1.23; 95%CI: 1.01-1.50). This correlation was present in population-based studies (n = 5; summary RR = 1.47; 95%CI: 1.06-2.05) but not in hospital-based studies (n = 6; summary RR = 1.10; 95%CI: 0.88-1.37) and in non-Asian regions (n = 7; summary RR = 1.39; 95%CI: 1.03-1.87) but not in Asia (n = 4; summary RR = 1.08; 95%CI: 0.85-1.38). Seven studies reported an association between consuming alcohol and ECC. Pooled analysis indicated that alcohol drinkers had a similar risk of ECC development as did individuals who did not drink alcohol (summary RR = 1.09; 95%CI: 0.87-1.37). There was moderate heterogeneity among the studies and no evidence of publication bias. CONCLUSION: Smoking is associated with an increased risk of ECC, but alcohol consumption is not. Further population-based studies, particularly cohort studies, are warranted to enable definitive conclusions.

Summary Aims To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer. Methods An electronic search was undertaken to identify randomized controlled trials comparing raltitrexed-based regimen to 5-fluorouracil-based regimen in patients with advanced colorectal cancer. The outcomes included overall survival, overall response rate and toxicities. Results This meta-analysis included 11 studies with 4622 patients. Overall, there were no significant differences between the two regimens in terms of overall survival (HR = 1.06, 95% CI: 0.96–1.17, P = 0.23) or overall response rate (RR = 1.09, 95% CI: 0.86–1.38, P = 0.47). In subgroup analysis, patients in raltitrexed/oxaliplatin group had significantly higher partial response (RR = 1.53, 95% CI: 1.17–2.00, P = 0.002), overall response rate (RR = 1.42, 95% CI: 1.10–1.82, P = 0.006), disease control rate (RR = 1.16, 95% CI: 1.04–1.29, P = 0.009) and lower progressive disease (RR = 0.61, 95% CI: 0.45–0.84, P = 0.002) when compared to 5-fluorouracil/leucovorin/oxaliplatin group. Occurrence of severe anemia (RR = 2.23, 95% CI: 1.38–3.59, P = 0.0001), asthenia (RR = 2.29, 95% CI: 1.36–3.84, P = 0.002), hepatic disorders (RR = 7.51, 95% CI: 1.30–43.56, P = 0.02), and nausea/vomit (RR = 1.70, 95% CI: 1.03–2.81, P = 0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of grade 3/4 alopecia (RR = 0.36, 95% CI: 0.26–0.50, P P Conclusions Raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-fluorouracil-based regimen in patients with advanced colorectal cancer. Raltitrexed can be a treatment option for these patients when 5-fluorouracil-based regimens are not tolerated or inappropriate.

Objective Inflammation is implicated to be involved in the pathogenesis of osteoarthritis (OA). CXCL12, also known as stromal cell-derived factor, is the unique identified natural ligand of the G-protein-coupled receptor CXCR4 and exhibits both homeostatic and proinflammatory functions. This study aims to determine whether CXCL12 levels in serum and synovial fluid (SF) of patients with knee OA are correlated with the disease severity. Methods This study consisted of 252 patients with knee OA and 144 healthy controls. The radiological grading of OA in the knee was performed according to the Kellgren-Lawrence grading system. CXCL12 levels in serum and SF were measured by enzyme-linked immunosorbent assay. Results Higher levels of serum CXCL12 were found in knee OA patients compared with healthy controls. The CXCL12 levels in SF of knee OA patients with KL grade 4 were significantly elevated compared with those with KL grades 2 and 3. Furthermore, knee OA patients with KL grade 3 had significantly higher SF levels of CXCL12 compared with those with KL grade 2. CXCL12 levels in SF of knee OA patients were significantly correlated with disease severity evaluated by KL grading criteria. However, there were no significant differences in the serum CXCL12 levels between patients with different KL grades. Conclusion CXCL12 levels in SF were closely related to the radiographic severity of OA. CXCL12 levels in SF may be an alternative biomarker for the progression of OA.

To investigate whether therapeutic treatment with melatonin could protect rats against acute pancreatitis and its associated lung injury.Seventy-two male Sprague-Dawley rats were randomly divided into three groups: the sham operation (SO), severe acute pancreatitis (SAP), and melatonin treatment (MT) groups. Acute pancreatitis was induced by infusion of 1 mL/kg of sodium taurocholate (4% solution) into the biliopancreatic duct. Melatonin (50 mg/kg) was administered 30 min before pancreatitis was induced, and the severity of pancreatic and pulmonary injuries was evaluated 1, 4 and 8 h after induction. Serum samples were collected to measure amylase activities, and lung tissues were removed to measure levels of mRNAs encoding interleukin 22 (IL-22) and T helper cell 22 (Th22), as well as levels of IL-22.At each time point, levels of mRNAs encoding IL-22 and Th22 were significantly higher (P0.001) in the MT group than in the SAP group (0.526 ± 0.143 vs 0.156 ± 0.027, respectively, here and throughout, after 1 h; 0.489 ± 0.150 vs 0.113 ± 0.014 after 4 h; 0.524 ± 0.168 vs 0.069 ± 0.013 after 8 h, 0.378 ± 0.134 vs 0.122 ± 0.015 after 1 h; 0.205 ± 0.041 vs 0.076 ± 0.019 after 4 h; 0.302 ± 0.108 vs 0.045 ± 0.013 after 8 h, respectively) and significantly lower (P0.001) in the SAP group than in the SO group (0.156 ± 0.027 vs 1.000 ± 0.010 after 1 h; 0.113 ± 0.014 vs 1.041 ± 0.235 after 4 h; 0.069 ± 0.013 vs 1.110 ± 0.213 after 8 h, 0.122 ± 0.015 vs 1.000 ± 0.188 after 1 h; 0.076 ± 0.019 vs 0.899 ± 0.125 after 4 h; 0.045 ± 0.013 vs 0.991 ± 0.222 after 8 h, respectively). The mean pathological scores for pancreatic tissues in the MT group were significantly higher (P0.01) than those for samples in the SO group (1.088 ± 0.187 vs 0.488 ± 0.183 after 1 h; 2.450 ± 0.212 vs 0.469 ± 0.242 after 4 h; 4.994 ± 0.184 vs 0.513 ± 0.210 after 8 h), but were significantly lower (P0.01) than those for samples in the SAP group at each time point (1.088 ± 0.187 vs 1.969 ± 0.290 after 1 h; 2.450 ± 0.212 vs 3.344 ± 0.386 after 4 h; 4.994 ± 0.184 vs 6.981 ± 0.301 after 8 h). The severity of SAP increased significantly (P0.01) over time in the SAP group (1.088 ± 0.187 vs 2.450 ± 0.212 between 1 h and 4 h after inducing pancreatitis; and 2.450 ± 0.212 vs 4.994 ± 0.184 between 4 and 8 h after inducing pancreatitis).Melatonin protects rats against acute pancreatitis-associated lung injury, probably through the upregulation of IL-22 and Th22, which increases the innate immunity of tissue cells and enhances their regeneration.