ZNF212 promotes genomic integrity through direct interaction with TRAIP.

TRAIP is a key factor involved in the DNA damage response (DDR), homologous recombination (HR) and DNA interstrand crosslink (ICL) repair. However, the exact functions of TRAIP in these processes in mammalian cells are not fully understood. Here we identify the zinc finger protein 212, ZNF212, as a novel binding partner for TRAIP and find that ZNF212 colocalizes with sites of DNA damage. The recruitment of TRAIP or ZNF212 to sites of DNA damage is mutually interdependent. We show that depletion of ZNF212 causes defects in the DDR and HR-mediated repair in a manner epistatic to TRAIP. In addition, an epistatic analysis of Zfp212, the mouse homolog of human ZNF212, in mouse embryonic stem cells (mESCs), shows that it appears to act upstream of both the Neil3 and Fanconi anemia (FA) pathways of ICLs repair. We find that human ZNF212 interacted directly with NEIL3 and promotes its recruitment to ICL lesions. Collectively, our findings identify ZNF212 as a new factor involved in the DDR, HR-mediated repair and ICL repair though direct interaction with TRAIP.

Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma.

Osteolytic bone lesion is a major cause of lower quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow (BM) and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306, and 52 patients with MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in BM-derived plasma and found to be significantly higher in MM than in AML or ALL, which rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa, and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling and nuclear translocation of ß-catenin. These results collectively show that the FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of the osteolytic process in MM with hyperdiploidy.

Efficacy and safety of a fixed-dose combination of dapagliflozin and linagliptin (AJU-A51) in patients with type 2 diabetes mellitus: A multicentre, randomized, double-blind, parallel-group, placebo-controlled phase III study.

AIMS: To evaluate the efficacy and safety of add-on dapagliflozin in patients with type 2 diabetes mellitus (T2D) who had inadequate glycaemic control with metformin and linagliptin. MATERIALS AND METHODS: A total of 235 patients with inadequate response to metformin (≥1000 mg/day) plus linagliptin (5 mg/day) were randomized to receive either dapagliflozin/linagliptin fixed-dose combination (FDC [AJU-A51]) 10/5 mg/day (n = 117) or linagliptin 5 mg plus placebo (n = 118) for 24 weeks. After the main treatment period, patients who received linagliptin plus placebo were treated with AJU-A51 for an additional 28 weeks. Change in glycated haemoglobin (HbA1c) from baseline to Week 24 was the primary endpoint. RESULTS: AJU-A51 significantly reduced HbA1c levels (from 7.93% ± 0.82% to 7.11% ± 0.61%) compared with linagliptin plus placebo (from 7.80% ± 0.71% to 7.87% ± 0.94%), with a least squares mean difference of -0.88% (95% confidence interval -1.07 to -0.68; p < 0.0001) at 24 weeks. The AJU-A51 group had a significantly higher proportion of patients who achieved HbA1c <7.0% at Week 24 than the control group (44.8% vs. 18.6%; p < 0.001). The AJU-A51 group maintained glycaemic efficacy up to 52 weeks, whereas the control group showed a substantial reduction in HbA1c after switching to AJU-A51 in the extension study period. Both groups had similar incidence of treatment-emergent and serious adverse events, and no cases of symptomatic hypoglycaemia were reported. CONCLUSIONS: Dapagliflozin and linagliptin FDC (AJU-A51) showed potent glucose-lowering effects, with good tolerability, in patients with T2D who had poor glycaemic control on metformin and linagliptin (ClinicalTrials.gov [NCT06329674]).

Association between estimated glucose disposal rate and subclinical coronary atherosclerosis.

BACKGROUND AND AIMS: The estimated glucose disposal rate (eGDR) is an easily accessible clinical parameter for assessing insulin resistance in patients with diabetes mellitus. In this study, we aimed to investigate the link between eGDR and subclinical coronary atherosclerosis in an asymptomatic middle-aged Korean population. METHODS AND RESULTS: This study involved 4004 subjects who underwent routine health checkups with coronary multidetector computed tomography (MDCT) at Asan Medical Center from 2007 to 2011, among whom 913 had a follow-up analysis through 2014. The eGDR was calculated using: 21.16 - (0.09 ∗ waist circumference [cm]) - (3.41 ∗ hypertension) - (0.55 ∗ glycated hemoglobin [%]). Patients were categorized into three groups according to the tertiles of eGDR. Subclinical coronary atherosclerosis was defined by significant coronary stenosis (≥50%), presence of plaques, coronary artery calcification (CAC) score, and its progression. As a result, a lower eGDR level was associated with higher prevalence of significant coronary stenosis, plaques, moderate to severe CAC, and CAC progression. Compared to other markers or risk scores, eGDR was superior to other biomarkers of insulin resistance but did not provide additional information beyond classic cardiovascular risk models like the Framingham Risk Score and Pooled Cohort Equations. CONCLUSION: Decreased eGDR values were significantly associated with higher subclinical coronary atherosclerosis burdens in an asymptomatic middle-aged Korean population. However, its clinical implications remain uncertain due to its weaker performance compared to established cardiovascular risk models.

Classification of Skeletal Phenotypes of Adult Patients With Cleft Skeletal Class III Malocclusion Using Principal Component Analysis and Cluster Analysis.

The purpose of this study was to classify the skeletal phenotypes of adult patients with skeletal class III (C-III) malocclusion and unilateral or bilateral cleft lip and palate using principal component analysis and cluster analysis. The samples consisted of 81 adult C-III patients with cleft lip and palate (CLP) who underwent orthognathic surgery (OGS) or distraction osteogenesis (59 males and 22 females; 50 unilateral cleft lip and palate and 31 bilateral cleft lip and palate; mean age when lateral cephalograms were taken, 22.2±4.6 y). Thirteen angular and one ratio cephalometric variables were measured. Using 4 representative variables obtained from principal component analysis (SNA, SNB, Gonial angle, and Bjork sum), K-means cluster analysis was performed to classify the phenotypes. Then, statistical analysis was conducted to characterize the differences in the variables among the clusters. Five clusters were obtained from 3 groups: severely retrusive maxilla and moderately retrusive mandible group: cluster-1 (23.5%, severely hyperdivergent pattern), cluster-4 (27.2%, moderately hyperdivergent pattern), and cluster-5 (11.1%, normodivergent pattern); moderately retrusive maxilla and normal mandible group: cluster-2 (30.9%, normodivergent pattern); normal maxilla and moderately protrusive mandible group: cluster-3 (7.4%, normodivergent pattern). Although skeletal phenotypes were diverse, distribution of sex and cleft type did not differ among 5 clusters ( P >0.05). Sixty-two percent of cleft patients showed a severely retrusive maxilla and moderately retrusive mandible (cluster-1, cluster-4, and cluster-5), which indicated that these are the main cause of skeletal C-III malocclusion in CLP patients who were treated with OGS. Therefore, it is necessary to consider presurgical orthodontic treatment and surgical planning based on the skeletal phenotypes of CLP patients.

Facial Asymmetry Phenotypes in Adult Patients With Unilateral Cleft Lip and Palate and Skeletal Class III Malocclusion Using Principal Component Analysis and Cluster Analysis.

The purpose of this study was to classify and characterize facial asymmetry (FA) phenotypes in adult patients with unilateral cleft lip and palate (UCLP) and skeletal class III malocclusion. The samples comprised 52 adult UCLP patients (36 men and 16 women; mean age, 22.43 y) who had undergone orthognathic surgery for correction of class III malocclusion. After measurement of 22 cephalometric parameters in posteroanterior cephalograms taken 1 month before orthognathic surgery, principal component analysis was performed to obtain 5 representative parameters [deviation (mm) of ANS (ANS-dev), maxillary central incisor contact point (Mx1-dev), and menton (Me-dev); cant (degree) of the maxillary anterior occlusal plane (MxAntOP-cant) and mandibular border (MnBorder-cant)]. K-means cluster analysis was conducted using these representative parameters. The differences in cephalometric parameters among the clusters were statistically analyzed. The FA phenotypes were classified into 4 types: No-cant-and-No-deviation type (cluster-4, n=16, 30.8%); MxMn-cant-MxMn-dev to the cleft-side type (cluster-3, n=4, 7.7%); Mx-cant-Mn-shift to the cleft-side type (cluster-2, n=15, 28.8%); and Mn-cant-Mn-dev to the noncleft-side type (cluster-1, n=17, 32.7%). Asymmetry in the maxilla and/or mandible were observed in 70% of patients. One third of patients (cluster-2 and cluster-3; sum, 36.5%) exhibited significant cant of MxAntOP induced by cleft and cant or shift of the mandible to the cleft side. Another one third of patients (cluster-1, 32.7%) demonstrated significant deviation and cant of the mandible to the noncleft-side despite cleft in the maxilla. This FA phenotype classification might be a basic guideline for diagnosis and treatment planning for UCLP patients.

Development of an experimental apparatus to observe ultrafast phenomena by tender X-ray absorption spectroscopy at PAL-XFEL.

Understanding the ultrafast dynamics of molecules is of fundamental importance. Time-resolved X-ray absorption spectroscopy (TR-XAS) is a powerful spectroscopic technique for unveiling the time-dependent structural and electronic information of molecules that has been widely applied in various fields. Herein, the design and technical achievement of a newly developed experimental apparatus for TR-XAS measurements in the tender X-ray range with X-ray free-electron lasers (XFELs) at the Pohang Accelerator Laboratory XFEL (PAL-XFEL) are described. Femtosecond TR-XAS measurements were conducted at the Ru L3-edge of well known photosensitizer tris(bipyridine)ruthenium(II) chloride ([Ru(bpy)3]2+) in water. The results indicate ultrafast photoinduced electron transfer from the Ru center to the ligand, which demonstrates that the newly designed setup is applicable for monitoring ultrafast reactions in the femtosecond domain.

Promyelocytic Leukemia Proteins Regulate Fanconi Anemia Gene Expression.

Promyelocytic leukemia (PML) protein is the core component of subnuclear structures called PML nuclear bodies that are known to play important roles in cell survival, DNA damage responses, and DNA repair. Fanconi anemia (FA) proteins are required for repairing interstrand DNA crosslinks (ICLs). Here we report a novel role of PML proteins, regulating the ICL repair pathway. We found that depletion of the PML protein led to the significant reduction of damage-induced FANCD2 mono-ubiquitination and FANCD2 foci formation. Consistently, the cells treated with siRNA against PML showed enhanced sensitivity to a crosslinking agent, mitomycin C. Further studies showed that depletion of PML reduced the protein expression of FANCA, FANCG, and FANCD2 via reduced transcriptional activity. Interestingly, we observed that damage-induced CHK1 phosphorylation was severely impaired in cells with depleted PML, and we demonstrated that CHK1 regulates FANCA, FANCG, and FANCD2 transcription. Finally, we showed that inhibition of CHK1 phosphorylation further sensitized cancer cells to mitomycin C. Taken together, these findings suggest that the PML is critical for damage-induced CHK1 phosphorylation, which is important for FA gene expression and for repairing ICLs.

The Anti-Inflammatory Effect of Sulforaphane in Mice with Experimental Autoimmune Encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an immune-associated inflammatory disorder of the central nervous system and results in serious disability. Although many disease-modifying therapy drugs have been developed, these drugs have shown limited clinical efficacy and some adverse effects in previous studies, therefore, there has been reasonable need for less harmful and cost-effective therapeutics. Herein, we tested the anti-inflammatory effect of sulforaphane (SFN) in a mouse model of experimental autoimmune encephalomyelitis (EAE). METHODS: The EAE mice were randomly assigned into two experimental groups: the phosphate-buffered saline (PBS)-treated EAE group and SFN-treated EAE group. After EAE mice induction by auto-immunization against the myelin oligodendrocyte glycoprotein peptide, we evaluated EAE symptom scores and biochemical analyses such as infiltration of inflammatory cells and demyelination of the spinal cord. Furthermore, western blotting was performed using the spinal cords of EAE mice. RESULTS: In the behavioral study, the SFN-treated EAE mice showed favorable clinical scores compared with PBS-treated EAE mice at the 13th day (1.30 ± 0.15 vs. 1.90 ± 0.18; P = 0.043) and 14th day (1.80 ± 0.13 vs. 2.75 ± 0.17; P = 0.003). Additionally, the biochemical studies revealed that SFN treatment inhibited the inflammatory infiltration, demyelinating injury of the spinal cords, and the up-regulation of inducible nitric oxide synthase in the EAE mice. CONCLUSION: The SFN treatment showed anti-inflammatory and anti-oxidative effects in the EAE mice. Conclusively, this study suggests that SFN has neuroprotective effects via anti-inflammatory processing, so it could be a new therapeutic or nutritional supplement for MS.

Neuroprotective Effects of Sigesbeckia pubescens Extract on Glutamate-Induced Oxidative Stress in HT22 Cells via Downregulation of MAPK/caspase-3 Pathways.

Sigesbeckia pubescens (SP) is a traditional Chinese medicine, possessing antioxidant and anti-inflammatory activities. In this study, we evaluate the neuroprotective activities of SP extract on glutamate-induced oxidative stress in HT22 cells and the molecular mechanism underlying neuroprotection. We applied 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), crystal violet, reactive oxygen species (ROS), lactate dehydrogenase (LDH), quantitative real-time polymerase chain reaction (qPCR), and western blot analyses for assessing the neuroprotective effects of SP extract. The experimental study revealed that SP considerably increased the cell viability, and reduced the oxidative stress promoted ROS and LDH generation in HT22 cells in a dose-dependent manner. Additionally, the morphology of HT22 cells was effectively improved by SP. Upregulated gene expressions of mitogen-activated protein kinase (MAPK) were markedly attenuated by SP. Similarly, SP notably suppressed the ROS-mediated phosphorylation of MAPK (pERK1/2, pJNK, and pp38) cascades and activation of apoptotic factor caspase-3 signaling pathway that overall contributed to the neuroprotection. Taken together, SP may exert neuroprotective effects via alteration of MAPK and caspase-3 pathways under oxidative stress condition. Therefore, SP is a potential agent for preventing oxidative stress-mediated neuronal cell death.

Desalted Salicornia europaea powder and its active constituent, trans-ferulic acid, exert anti-obesity effects by suppressing adipogenic-related factors.

CONTEXT: Salicornia europaea (Amaranthaceae) (SE) has been shown to reduce obesity, but it remains a problem as a food supplement because of its high salt content (25-35% NaCl). OBJECTIVES: This study investigated the anti-obesity effects and mechanism of action of desalted SE powder (DSP). MATERIALS AND METHODS: Sprague-Dawley rats (n = 50) were divided into a normal control group (NC), a high-fat diet (HFD)-induced obesity control group (HFD), and HFD groups co-administered DSP (250 and 500 mg/kg) or Garcinia cambogia (Clusiaceae) extract (GE, 200 mg/kg, standard control) orally each day for 12 weeks. RESULTS: The body weight was significantly reduced by co-administration of DSP (596.51 ± 19.84 kg, 4.60% and 562.08 ± 9.74 kg, 10.10%, respectively) and GE (576.00 ± 11.29 kg, 7.88%) relative to the HFD group (625.25 ± 14.02 kg) and was accompanied by reduced abdominal fat mass, and serum lipid levels, with no effects on feed intake. To find the underlying mechanism of the anti-obesity effects, trans-ferulic acid (TFA) was identified as the main ingredient and investigated with regard to whether it attenuated adipogenesity in 3T3L-1 cells. DSP-derived TFA suppressed adipocyte differentiation and accumulation of intracellular lipids. TFA also down-regulated the adipogenesis-related gene expression of sterol regulatory element-binding protein 1, peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein-α and fatty acid synthase. CONCLUSIONS: These findings suggest that DSP may be considered for use as a food supplement intent of controlling obesity through its antiobesity and antiadipogenic properties.

Extensive Surgical Procedures Result in Better Treatment Outcomes for Bisphosphonate-Related Osteonecrosis of the Jaw in Patients With Osteoporosis.

PURPOSE: To identify the risk factors associated with relapse or treatment failure after surgery for bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients with osteoporosis. PATIENTS AND METHODS: We performed a retrospective cohort study of BRONJ in patients with osteoporosis who had undergone surgical procedures from 2004 to 2016 at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. The predictor variables were a set of heterogeneous variables, including demographic (age, gender), anatomic (maxilla or mandible, or both, affected location), clinical (disease stage, etiology, comorbidities, history of intravenous bisphosphonate intake), time (conservative treatment before surgery, bisphosphonate treatment before the development of BRONJ, discontinuation of the drug before surgery, interval to final follow-up, interval to reoperation in the case of relapse or treatment failure), and perioperative variables (type of anesthesia, type of surgical procedures). The primary outcome variable was relapse after surgery that required reoperation (yes vs no). The descriptive and bivariate statistics were computed to assess the relationships between the study variables and the outcome. To determine the risk factors, we conducted a survival analysis using the Cox model. RESULTS: The final sample included 325 subjects with a median age of 75 years, and 97% were women. After surgery, 30% of patients did not completely recuperate and underwent repeat surgery. The interval from the first surgery to reoperation ranged from 10 days to 5.6 years. Relapse or treatment failure most often occurred immediately after surgery. The type of surgical procedure and mode of anesthesia were the most important factors in the treatment outcome. A drug holiday did not appear to influence the likelihood of relapse after surgery. CONCLUSIONS: Treatment of BRONJ in patients with osteoporosis might benefit from more careful and extensive surgical procedures rather than curettage performed with the patient under local anesthesia.

The Anti-Inflammatory Effects of Oral-Formulated Tacrolimus in Mice with Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a T-lymphocyte-mediated autoimmune disease that is characterized by inflammation in the central nervous system (CNS). Although many disease-modifying therapies (DMTs) are presumed effective in patients with MS, studies on the efficacy and safety of DMTs for preventing MS relapse are limited. Therefore, we tested the immunosuppressive anti-inflammatory effects of oral-formulated tacrolimus (FK506) on MS in a mouse model of experimental autoimmune encephalomyelitis (EAE). The mice were randomly divided into 3 experimental groups: an untreated EAE group, a low-dose tacrolimus-treated EAE group, and a high-dose tacrolimus-treated EAE group. After autoimmunization of the EAE mice with myelin oligodendrocyte glycoprotein, symptom severity scores, immunohistochemistry of the myelination of the spinal cord, and western blotting were used to evaluate the EAE mice. After the autoimmunization, the symptom scores of each EAE group significantly differed at times. The group treated with the larger tacrolimus dose had the lowest symptom scores. The tacrolimus-treated EAE groups exhibited less demyelination and inflammation and weak immunoreactivity for all of the immunization biomarkers. Our results revealed that oral-formulated tacrolimus inhibited the autoimmunization in MS pathogenesis by inactivating inflammatory cells.

What Are the Contributing Factors for Postsurgical Relapse After Two-Jaw Surgery in Patients With Cleft Lip and Palate.

The purpose of this study was to investigate the amount and pattern of postsurgical relapse after 2-jaw surgery in cleft lip and palate patients in terms of the sagittal and vertical aspects. The samples consisted of 21 adult patients who had the similar initial skeletodental pattern before surgery and underwent 2-jaw surgery. They were divided into high relapse (n = 11) and low relapse groups (n = 10) (criteria, 30% forward relapse of the B point). After the cephalometric variables of cephalograms taken at 1 month before surgery (T0), immediately after surgery (T1), and at least 1 year after surgery (T2) were measured, the Wilcoxon test, Mann-Whitney U test, and Pearson correlation test were performed for statistical analysis. When compared with the low relapse group, the high relapse group exhibited significant counterclockwise rotation of the distal segment of the mandible resulting in more forward movement of the mandible and significant labioversion of the maxillary incisors during T1-T2. The amount of postsurgical relapse of the mandible had a positive relationship with the amounts of setback and clockwise rotation of the mandible with surgery. In addition, the more decrease in overbite through surgery occurred, the more relapse (forward movement of the mandible) produced. Therefore, for the prevention of significant postsurgical relapse of the mandible in cleft patients, it is necessary to reduce unnecessary clockwise rotation of the mandible and to increase the vertical stability of maxilla during orthognathic surgery.

Three-dimensional virtual-surgery simulation-assisted asymmetric bilateral mandibular distraction osteogenesis for a patient with bilateral condylar fractures.

INTRODUCTION: Our objective was to report a patient treated with 3-dimensional virtual-surgery simulation-assisted asymmetric bilateral mandibular distraction osteogenesis. METHODS: A boy (age, 9.5 years) had mandibular hypoplasia and facial asymmetry, induced by bilateral condylar fractures at 4 years of age. The asymmetric bilateral mandibular distraction osteogenesis was planned to correct facial asymmetry and mandibular hypoplasia. The 3-dimensional virtual-surgery simulation results were 11 mm of horizontal distraction on the right side and 4.5 mm of horizontal and 18 mm of vertical distraction on the left side of the mandible. Bilateral ramus osteotomies were performed, and intraoral unidirectional distraction devices were inserted. After a 6-day latency period, distraction was performed at 1 mm per day, followed by a 5-month consolidation period. Transarch and interarch elastics and an acrylic plate were used during distraction and consolidation. Total treatment time was 30 months. RESULTS: Satisfactory outcomes were obtained (achievement ratios between postconsolidation results and simulated results: gonial angle, 106% and 103.9%; mandibular body length, 94.2% and 89.9%; ramus height, 104.1% and 94.5% [values of the right and left sides, respectively]). The chin-point deviation and the transverse cant of the maxillary occlusal plane were significantly improved (10.1 mm to 3.3 mm; -6.8° to -4.4°). At 53 months of follow-up, the Class I molar relationship was well maintained. The transverse cant of the maxillary occlusal plane was slightly improved to -3.7° during pubertal growth. CONCLUSIONS: Three-dimensional virtual-surgery simulation can help clinicians to determine the optimal vector and amount of distraction with high accuracy in complex cases requiring simultaneous correction of a hypoplastic mandible and facial asymmetry.

Neuroprotective Effect of Human Adipose Stem Cell-Derived Extract in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The precise pathogenic mechanisms of the disease remain uncertain, and as of yet, there is no effective cure. Human adipose stem cells (hASC) can be easily obtained during operative procedures. hASC have a clinically feasible potential to treat neurodegenerative disorders, since cytosolic extract of hASC contain a number of essential neurotrophic factors. In this study, we investigated effects of hASC extract on the SOD1 G93A mouse model of ALS and in vitro test. Administration of hASC extract improved motor function and prolonged the time until symptom onset, rotarod failure, and death in ALS mice. In the hASC extracts group, choline acetyltransferase immunostaining in the ventral horn of the lumbar spinal cord showed a large number of motor neurons, suggesting normal morphology. The neuroprotective effect of hASC extract in ALS mice was also suggested by western blot analysis of spinal cord extract from ALS mice and in vitro test. hASC extract treatment significantly increased expression of p-Akt, p-CREB, and PGC-1α in SOD1 G93A mouse model and in vitro test. Our results indicated that hASC extract reduced apoptotic cell death and recovered mutant SOD1-induced mitochondrial dysfunction. Moreover, hASC extract reduced mitochondrial membrane potential. In conclusion, we have demonstrated, for the first time, that hASC extract exert a potential therapeutic action in the SOD1 G93A mouse model of ALS and in vitro test. These findings suggest that hASC hold promise as a novel therapeutic strategy for treating ALS.

CLINICAL COURSE OF DIABETIC RETINOPATHY IN KOREAN TYPE 2 DIABETES AFTER BARIATRIC SURGERY: A Pilot Study.

PURPOSE: To assess the changes in diabetic retinopathy (DR) in Type 2 diabetes (T2DM) patients after bariatric surgery. METHODS: Consecutive 20 patients with T2DM who underwent bariatric surgery and were followed for at least 12 months were enrolled. The case history was reviewed retrospectively, and laboratory data were assessed at baseline and every 3 months postoperatively. Two retinal specialists evaluated the severity of DR with dilated fundus examination preoperatively and postoperatively. Factors associated with DR progression were assessed. RESULTS: During the follow-up period, 2 of 12 patients without DR and 2 of 3 patients with mild nonproliferative DR before surgery developed moderate nonproliferative DR. All five patients with moderate nonproliferative DR or worse preoperatively had progression requiring intervention. Preexisting DR (P = 0.005) and albuminuria (P = 0.01) were identified as associated with DR progression. Six patients (30%) entered remission of T2DM, but remission of T2DM could not halt the DR progression. CONCLUSION: Diabetic retinopathy progression can occur in patients with or without before DR after bariatric surgery, regardless of remission of T2DM. All patients with T2DM should be examined regularly by an ophthalmologist postoperatively, and more carefully patients with previous DR or albuminuria.

Simultaneous inferior alveolar nerve regeneration and osseointegration with a nerve growth factor-supplying implant: a preliminary study.

PURPOSE: Although nerve growth factor (NGF) has been proved to enhance inferior alveolar nerve (IAN) regeneration, its clinical application remains a challenging issue. This study investigated the functional regeneration of IAN injury by supplying NGF using an NGF-supplying implant and its effect on the osseointegration. MATERIALS AND METHODS: In canine IAN transection-and-repair models (n = 9), NGF-supplying implants connected to osmotic pumps were installed just above the transection site. In the right IAN, NGF 300 µg in phosphate buffered saline (PBS) 2 mL was loaded in the pump and pure PBS 2 mL was loaded in the left IAN. The gross clinical finding was evaluated by wound healing, inflammation, implant exposure, and loss of fixture. To evaluate IAN regeneration, electrophysiologic (amplitude, latency, conduction velocity, and peak voltage) and histomorphometric (axon count and density, myelin thickness, and ratio of axon diameter to fiber diameter) analyses were performed. Implant stability quotient, bone-to-implant contact ratio, and new bone area were measured to assess the osseointegration of the NGF-supplying implant. RESULTS: The conduction velocity (2.675 m/second) and peak voltage (1.940 µV) of the NGF group at 6 weeks were considerably higher than those of the PBS group (1.892 m/second and 1.300 µV, respectively). The same results were observed for axon count (NGF vs PBS, 4,576.107 ± 270.413 vs 3,606.972 ± 242.876), axon density (10,707.458 ± 638.835 vs 7,899.781 ± 1,063.625/mm(2)), and myelin thickness (1.670 ± 0.555 vs 1.173 ± 0.388 µm). There were no meaningful differences for the other parameters. CONCLUSIONS: Supplying NGF with specially designed dental implants can be a new therapeutic approach to enable IAN regeneration and osseointegration simultaneously.

Postsurgical Relapse in Class III Patients Treated With Two-Jaw Surgery: Conventional Three-Stage Method Versus Surgery-First Approach.

The aim of this study was to investigate the pattern, amount, and distribution of postsurgical relapse in skeletal Class III patients treated with two-jaw surgery (TJS) using conventional three-stage method (CTM) and surgery-first approach (SFA). A total of 38 patients who underwent the nonextraction approach and TJS (LeFort I posterior impaction and mandibular setback) were divided into CTM and SFA groups (all n = 19/group). Lateral cephalograms were taken before treatment (T0), at 1 month before surgery (T1), immediately after surgery (T2), and at debonding (T3) for CTM patients and at T0, T2, and T3 stages for SFA patients. Cephalometric measurements and statistical analyses were performed. There were no significant differences in the cephalometric variables at all stages except maxillary incisor inclination (U1-UOP) and overbite at T0 between 2 groups. They also did not exhibit significant differences in the amounts of surgical movement except for advancement of the maxilla. The mandible in both groups was rotated slightly clockwise by surgery and counterclockwise during T2-T3 without a significant difference. Distribution of cases with "high relapse" (>30%) and "low relapse" (<30%) of the mandible differed for 2 groups (P < 0.05). SFA group had more "high relapse" cases than CTM group (57.9% versus 26.3%). Postsurgical relapse of the mandible had a positive relationship with the amount of mandibular setback in SFA group (P < 0.01) and clockwise rotation of the proximal segment of the mandible in both groups (P < 0.05 and P < 0.01). The results suggest that SFA might be an effective alternative to CTM if the cause of "high relapse" including amounts of mandibular setback and clockwise rotation of the proximal segment of the mandible during surgery can be controlled.

A novel FGFR2 mutation in tyrosine kinase II domain, L617F, in Crouzon syndrome.

The purposes of this study were to find a novel mutation of FGFR2 in Korean Crouzon syndrome patients and to identify the functional consequences of this mutation. The samples consisted of 16 Crouzon patients. Peripheral venous blood was collected from the patients. FGFR2 mutation screening was performed by direct PCR sequencing of all exons and part of the introns. Restriction fragment length polymorphism (RFLP) analysis was performed to confirm the novel mutation. For functional studies, we performed luciferase assay for Runx2 transcriptional activity, real-time PCR for the bone markers (osteocalcin and alkaline phosphatase), and Western blot for phosphorylated FGFR2 and ERK1/2-MAPK protein. Among 16 patients, 10 showed FGFR2 mutations that had already been reported elsewhere. A novel FGFR2 mutation associated with tyrosine kinase II (TK-II) domain, L617F, was found in one Crouzon syndrome patient by direct PCR sequencing. Presence of this mutation was confirmed using RFLP analysis. Runx2 transcriptional activity and expression of osteocalcin and alkaline phosphatase significantly increased in L617F-transfected cells compared to wild-type cells. FGFR2 autophosphorylation in L617F-transfected cells increased in 1% serum, but ERK1/2-MAPK protein was not activated. The FGFR2-L617F mutation associated with the TK domain is potentially related to premature suture closure in Crouzon syndrome patient.