Lactobacillus-fermented milk products attenuate bone loss in an experimental rat model of ovariectomy-induced post-menopausal primary osteoporosis.

AIM: In this study, we investigated the anti-osteoporotic effect of two fermented milk products (FMPs) fermented by Lactobacillus plantarum A41 and Lactobacillus fermentum SRK414 on a rat model of ovariectomy-induced post-menopausal primary osteoporosis. METHODS AND RESULTS: The two Lactobacillus FMPs increased the bone volume and bone mineral density (BMD) in ovariectomized (OVX) rats, and normalized the bone biomarkers in the serum. Additionally, they altered the gene expression levels of bone-metabolism-related markers. Furthermore, the two Lactobacillus FMPs downregulated bone-apoptosis-related genes stimulated by ovariectomy. Interestingly, the Lactobacillus FMPs decreased the levels of inflammation markers in the serum, bone, ileum and colon of the rats. Gut bacterial populations were also affected upon FMP treatment due to increase in the abundance of the genus Lactobacillus and Faecalibacterium prausnitzii. CONCLUSIONS: Milk products fermented by L. plantarum A41 and L. fermentum SRK414 can exhibit anti-osteoporotic effects on post-menopausal osteoporosis via regulating the expression of bone-metabolism-related markers. SIGNIFICANCE AND IMPACT OF THE STUDY: The two Lactobacillus FMPs used in the study can be an ideal method that has its potential of treating post-menopausal osteoporosis instead of drug treatments.

Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2.

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis (Pg)-induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides (Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, ß-proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

Human Papillomavirus 16 E6 Induces FoxM1B in Oral Keratinocytes through GRHL2.

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

Effects of Bioactive Compounds on Odontogenic Differentiation and Mineralization.

Direct pulp capping involves the placement of dental materials directly onto vital pulp tissues after deep caries removal to stimulate the regeneration of reparative dentin. This physical barrier will serve as a "biological seal" between these materials and the pulp tissue. Although numerous direct pulp capping materials are available, the use of small bioactive compounds that can potently stimulate and expedite reparative dentin formation is still underexplored. Here, the authors compared and evaluated the pro-osteogenic and pro-odontogenic effects of 4 small bioactive compounds- phenamil (Phen), purmorphamine (Pur), genistein (Gen), and metformin (Met). The authors found that these compounds at noncytotoxic concentrations induced differentiation and mineralization of preosteoblastic MC3T3-E1 cells and preodontoblastic dental pulp stem cells (DPSCs) in a dose-dependent manner. Among them, Phen consistently and potently induced differentiation and mineralization in vitro. A single treatment with Phen was sufficient to enhance the mineralization potential of DPSCs in vitro. More importantly, Phen-treated DPSCs showed enhanced odontogenic differentiation and mineralization in vivo. Our study suggests that these small bioactive compounds merit further study for their potential clinical use as pulp capping materials.

Epigenetic gene regulation by histone demethylases: emerging role in oncogenesis and inflammation.

Histone N-terminal tails of nucleosomes are the sites of complex regulation of gene expression through post-translational modifications. Among these modifications, histone methylation had long been associated with permanent gene inactivation until the discovery of Lys-specific demethylase (LSD1), which is responsible for dynamic gene regulation. There are more than 30 members of the Lys demethylase (KDM) family, and with exception of LSD1 and LSD2, all other KDMs possess the Jumonji C (JmjC) domain exhibiting demethylase activity and require unique cofactors, for example, Fe(II) and α-ketoglutarate. These cofactors have been targeted when devising KDM inhibitors, which may yield therapeutic benefit. KDMs and their counterpart Lys methyltransferases (KMTs) regulate multiple biological processes, including oncogenesis and inflammation. KDMs' functional interactions with retinoblastoma (Rb) and E2 factor (E2F) target promoters illustrate their regulatory role in cell cycle progression and oncogenesis. Recent findings also demonstrate the control of inflammation and immune functions by KDMs, such as KDM6B that regulates the pro-inflammatory gene expression and CD4+ T helper (Th) cell lineage determination. This review will highlight the mechanisms by which KDMs and KMTs regulate the target gene expression and how epigenetic mechanisms may be applied to our understanding of oral inflammation.

Three-dimensional isotropic T2-weighted fast spin-echo (VISTA) ankle MRI versus two-dimensional fast spin-echo T2-weighted sequences for the evaluation of anterior talofibular ligament injury.

AIM: To compare the performance of axial images of the ankle joint on three-dimensional (3D) volume isotropic turbo spin echo acquisition (VISTA) with that of two-dimensional (2D) fast spin echo (FSE) T2-weighted images for the diagnosis of anterior talofibular ligament (ATFL) injury. MATERIALS AND METHODS: This retrospective study included 101 patients who underwent both 2D FSE T2-weighted and 3D VISTA magnetic resonance imaging (MRI) of the ankle. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of both sequences were measured. The anatomical identification score and diagnostic performances of both sequences were evaluated by two radiologists. The diagnostic performances of 3D VISTA and 2D FSE images were analysed in terms of sensitivity, specificity, and accuracy for diagnosing ATFL injury. Surgically or clinically confirmed diagnoses were used as reference standards. RESULTS: The margin sharpness scores on 3D VISTA were significantly inferior to those of 2D FSE (p<0.001). Other scores (entire length, entire width) were not significantly different between the two imaging methods. The SNRs and CNRs of 3D VISTA were significantly higher than those of 2D FSE (p<0.001). When diagnoses were classified as normal and abnormal, the specificity of the 3D VISTA images for the diagnosis of ATFL injury was 95.7%, significantly superior to 2D FSE (84.3-85.7%). There were no significant differences between 3D VISTA and 2D FSE images in sensitivity or accuracy for diagnosis (p=0.227-1.000), with the exception of accuracy by reader 1 (p=0.039). CONCLUSION: 3D VISTA imaging has a diagnostic performance comparable to that of 2D FSE for the diagnosis of ATFL injury, although 3D VISTA is inferior to 2D FSE for the evaluation of margin sharpness. Replacing axial and coronal images with 3D VISTA can save imaging time without negatively impacting the diagnostic ability for ATFL injury.

The Role of ORAI1 in the Odontogenic Differentiation of Human Dental Pulp Stem Cells.

Pulp capping, or placing dental materials directly onto the vital pulp tissues of affected teeth, is a dental procedure that aims to regenerate reparative dentin. Several pulp capping materials are clinically being used, and calcium ion (Ca(2+)) released from these materials is known to mediate reparative dentin formation. ORAI1 is an essential pore subunit of store-operated Ca(2+) entry (SOCE), which is a major Ca(2+) influx pathway in most nonexcitable cells. Here, we evaluated the role of ORAI1 in mediating the odontogenic differentiation and mineralization of dental pulp stem cells (DPSCs). During the odontogenic differentiation of DPSCs, the expression of ORAI1 increased in a time-dependent manner. DPSCs knocked down with ORAI1 shRNA (DPSC/ORAI1sh) or overexpressed with dominant negative mutant ORAI1(E106Q) (DPSC/E106Q) exhibited the inhibition of Ca(2+) influx and suppression of odontogenic differentiation and mineralization as demonstrated by alkaline phosphatase (ALP) activity/staining as well as alizarin red S staining when compared with DPSCs of their respective control groups (DPSC/CTLsh and DPSC/CTL). The gene expression for odontogenic differentiation markers such as osteocalcin, bone sialoprotein, and dentin matrix protein 1 (DMP1) was also suppressed. When DPSC/CTL or DPSC/E106Q cells were subcutaneously transplanted into nude mice, DPSC/CTL cells induced mineralized tissue formation with significant increases in ALP and DMP1 staining in vivo, whereas DPSC/E106Q cells did not. Collectively, our data showed that ORAI1 plays critical roles in the odontogenic differentiation and mineralization of DPSCs by regulating Ca(2+) influx and that ORAI1 may be a therapeutic target to enhance reparative dentin formation.

Pulp-dentin Regeneration: Current State and Future Prospects.

The goal of regenerative endodontics is to reinstate normal pulp function in necrotic and infected teeth that would result in reestablishment of protective functions, including innate pulp immunity, pulp repair through mineralization, and pulp sensibility. In the unique microenvironment of the dental pulp, the triad of tissue engineering would require infection control, biomaterials, and stem cells. Although revascularization is successful in resolving apical periodontitis, multiple studies suggest that it alone does not support pulp-dentin regeneration. More recently, cell-based approaches in endodontic regeneration based on pulpal mesenchymal stem cells (MSCs) have demonstrated promising results in terms of pulp-dentin regeneration in vivo through autologous transplantation. Although pulpal regeneration requires the cell-based approach, several challenges in clinical translation must be overcome-including aging-associated phenotypic changes in pulpal MSCs, availability of tissue sources, and safety and regulation involved with expansion of MSCs in laboratories. Allotransplantation of MSCs may alleviate some of these obstacles, although the long-term stability of MSCs and efficacy in pulp-dentin regeneration demand further investigation. For an alternative source of MSCs, our laboratory developed induced MSCs (iMSCs) from primary human keratinocytes through epithelial-mesenchymal transition by modulating the epithelial plasticity genes. Initially, we showed that overexpression of ΔNp63α, a major isoform of the p63 gene, led to epithelial-mesenchymal transition and acquisition of stem characteristics. More recently, iMSCs were generated by transient knockdown of all p63 isoforms through siRNA, further simplifying the protocol and resolving the potential safety issues of viral vectors. These cells may be useful for patients who lack tissue sources for endogenous MSCs. Further research will elucidate the level of potency of these iMSCs and assess their transdifferentiation capacities into functional odontoblasts when transplanted into the root canal microenvironment.

Usefulness of the oblique coronal plane in ankle MRI of the calcaneofibular ligament.

AIM: To evaluate the usefulness and diagnostic accuracy of oblique coronal MRI of the calcaneofibular ligament (CFL) view for diagnosis of CFL injury. MATERIAL AND METHODS: This retrospective study included 91 patients who were suspected to have CFL injury who underwent CFL view imaging. Anatomical identification of the CFL on orthogonal MRI sequences and CFL views was evaluated. Two radiologists evaluated the CFL based on an entire length view, an entire width view, and margin sharpness using a four-point scale. Diagnostic accuracy using orthogonal and CFL views was evaluated by calculating sensitivity, specificity, and accuracy. Arthroscopic or clinical findings were used as the reference standard. RESULTS: Both readers found identification of lesions using the entire length, entire width, and sharp margin from CFL view images to be superior to that based on orthogonal images. The sensitivity and accuracy of diagnosing CFL injury were significantly higher when using the CFL view compared to the orthogonal view, although specificity was not significantly different between the CFL view and orthogonal view images. CONCLUSIONS: CFL view imaging enables better anatomical evaluation and improved sensitivity and accuracy of diagnosis of CFL injury. CFL view images should therefore be used to evaluate potential CFL injuries.

Impact of guideline adherence on patient outcomes in early-stage epithelial ovarian cancer.

AIM: The aim of this study was to evaluate the effects of adherence to National Comprehensive Cancer Network (NCCN) guidelines on survival outcomes in patients with early-stage epithelial ovarian cancer. METHODS: Our institutional cancer registry data on 266 patients with Stage I epithelial ovarian cancer was reviewed retrospectively and compliance with treatment guidelines for surgery and adjuvant treatment was determined. Patients were categorized according to adherence or non-adherence. The primary endpoints were recurrence-free survival and disease-specific survival. Hazard ratios (HRs) for survival were estimated with a Cox proportional hazards model. RESULTS: Of the 266 patients, 71 (26.7%) underwent adequate surgical staging in accordance with the guidelines. The guidelines for adjuvant chemotherapy were followed adequately in all 71 patients that were adherent to surgical staging and in 163 of the 195 patients with non-adherence to surgical staging (83.6%). Multivariate analysis, adjusted for prognostic factors, identified higher recurrence-free survival (HR, 0.36; 95% CI, 0.15-0.88) and disease-specific survival (HR, 0.42; 95% CI, 0.16-1.12) among patients whose treatment adhered to both surgical and chemotherapy guidelines, although disease-specific survival was not statistically significant. When excluding clear cell histology from the cohort, the guideline-adherent group had significantly better disease-specific survival than the non-adherent group (HR, 0.13; 95% CI, 0.02-0.94). CONCLUSION: The results of this study suggest that adherence to NCCN guidelines may improve survival outcomes in patients with early-stage epithelial ovarian cancer, particularly in cases other than clear cell histology.

Eckols reduce dental pulp inflammation through the ERK1/2 pathway independent of COX-2 inhibition.

OBJECTIVES: The aim of this study was to elucidate the role of 6-6 bieckol (EB1) and pholorofucofuroeckol-A (EB5) from brown seaweed marine algae (Eisenia bicyclis) on lipopolysaccharide (LPS)-induced inflammation in human dental pulp cells (HDPCs). METHODS: The cytotoxicity of EB1 and EB5 was examined by MTT assay on LPS-induced human dental pulp cells. Their role on expression of inflammatory, odontogenic, and osteogenic molecules was determined by Western blot analysis. The dentin mineralization was checked by alkaline phosphatase activity. RESULTS: The five compounds from E. bicyclis have different structure with non-cytotoxic in HDPCs. EB1 and EB5 showed anti-inflammatory properties and inhibited phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) and phosphorylated-c-jun N-terminal kinases (p-JNK) without any cytotoxicity. In particular, EB1 inhibited cyclooxygenase-2 (COX-2) and p-ERK1/2 signaling, and EB5 inhibited only p-ERK1/2 signaling but not COX-2. Both compounds inhibited nuclear factor kappa-B (NF-κB) translocation. Furthermore, EB1 and EB5 increased dentinogenic and osteogenic molecules, and dentin mineralized via alkaline phosphatase activity (ALP) in LPS-induced HDPCs. CONCLUSIONS: This study elucidates that EB1 and EB5 have different types of anti-inflammatory property and help in dentin formation. Therefore, these compounds derived from marine algae of E. bicyclis may be used as selective therapeutic strategies for pulpitis and oral diseases.

Relationship between polymorphisms near the IL28B gene and spontaneous HBsAg seroclearance: a systematic review and meta-analysis.

Polymorphisms near the interleukin (IL) 28B gene have been proposed to be associated with spontaneous clearance of the hepatitis C virus. The purpose of this study was to assess the relationship between IL28B polymorphisms and the rate of spontaneous hepatitis B surface antigen (HBsAg) seroclearance by means of meta-analysis. MEDLINE/PubMed and EMBASE were utilized to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were analysed together to assess the strength of the association. Subgroup analyses were mainly performed according to ethnicity. A total of 4028 cases with persistent chronic hepatitis B and 2327 spontaneously recovered controls were included from 11 studies. The single nucleotide polymorphism (SNP), rs12979860, had no significant association with HBsAg seroclearance (OR = 0.98, 95% CI: 0.84-1.14 in the dominant model; OR = 1.00, 95% CI: 0.68-1.46 in the recessive model; and OR = 0.95, 95% CI: 0.82-1.09 in the allelic model). The SNP, rs12980275, had no significant association either (OR = 1.03, 95% CI: 0.84-1.26 in the dominant model; OR = 1.17, 95% CI: 0.46-2.96 in the recessive model; and OR = 1.04, 95% CI: 0.86-1.26 in the allelic model), nor did the SNP, rs8099917 (OR = 0.94, 95% CI: 0.77-1.15 in the dominant model; OR = 0.74, 95% CI: 0.34-1.62 in the recessive model; and OR = 0.93, 95% CI: 0.77-1.13 in the allelic model). Similarly, the results of subgroup analyses by ethnicity also showed no association in either the Asian group or non-Asian group. We concluded that there was no significant association between common IL28B polymorphisms and the rate of spontaneous HBsAg seroclearance.

Usefulness of meniscal width to transverse diameter ratio on coronal MRI in the diagnosis of incomplete discoid lateral meniscus.

AIM: To evaluate the clinical utility of the meniscal width to transverse diameter ratio (L/M ratio) of the lateral meniscus in the diagnosis of incomplete discoid lateral meniscus (IDLM) as compared with the arthroscopic diagnosis, meniscal width to tibial diameter ratio (L/T ratio) and conventional lateral meniscus width criteria. MATERIALS AND METHODS: This retrospective study sample included 41 patients with IDLM who underwent knee magnetic resonance imaging (MRI) and arthroscopy, as well as 50 controls with normal lateral menisci. MRI examinations were interpreted independently by two radiologists, both of whom were blinded to clinical information and radiological reports. Assessment of meniscal width (L), maximal transverse diameter of the lateral meniscus (M), and transverse diameter of the tibia (T) was carried out on central coronal sections that were observed to pass through the medial collateral ligament. L/M and L/T ratios were calculated. These results were correlated with arthroscopic findings and analysed statistically using categorical regression analysis and non-parametric correlation analysis. Using arthroscopic findings as the standard of reference, sensitivity and specificity were calculated for: (1) 12, 13, 14, and 15 mm meniscal width thresholds; (2) 40%, 50%, 60%, and 70% L/M ratio thresholds; and (3) 15%, 18%, 20%, and 25% L/T ratio thresholds. RESULTS: The mean L/M ratio of the IDLM was approximately 67% and was statistically significantly higher than the control (44%). The best diagnostic discrimination was achieved using a threshold of 50%. The mean L/T ratio of the IDLM was approximately 23% and was statistically significant. The best diagnostic discrimination was achieved using a threshold of 18%. The threshold of 13 mm of meniscal width also showed high sensitivity and high specificity. CONCLUSION: The use of the L/M ratio or L/T ratio in combination with meniscal width criteria may be a useful method for evaluating IDLM.

Clinical correlation of a new practical MRI method for assessing central lumbar spinal stenosis.

OBJECTIVE: To evaluate interobserver agreement and determine whether a new MRI grading system agrees with symptoms and neurological signs. METHODS: We examined 160 patients (72 males and 88 females; mean age 57 years) who underwent MRI of the lumbar spine at our institution and were evaluated by two musculoskeletal radiologists. The presence and grade of central lumbar spinal stenosis (CLSS) at L3-4, L4-5 and L5-S1 were assessed according to a new grading system, the Lee system. The results were correlated with clinical manifestations and neurological examinations [positive neurological manifestation (PNM) and negative neurological manifestation (NNM)]. Statistical analyses were performed using kappa statistics and non-parametric correlation analysis (Spearman's correlation). RESULTS: Interobserver agreement in the grading of CLSS between the two readers was substantial (κ=0.780). Interobserver agreement of the L4-5 level and older age group was high (0.789, 0.814). The correlation coefficient (R) of Reader 1 between MRI Grades 0, 1, 2 or 3 and neurological manifestations (negative or positive) was 0.654; the R of Reader 2 was 0.591. In the younger age group (<57 years), the R of Reader 1 was 0.634 and the R of Reader 2 was 0.500. In the older age group (≥57 years), the R of Reader 1 was 0.650 and the R of Reader 2 was 0.645. Correlation coefficients were higher at the L3-4 level (0.612-0.678) than at other levels but did not show statistical significance (p>0.05). CONCLUSION: Interobserver agreement for the new CLSS grading system was substantial. Grade 0 was associated with NNMs and Grade 3 with PNMs in this cohort. Grade 2 demonstrates more cases of PNM than NNM but requires further evaluation. Correlations between MRI grades and clinical manifestations were moderate and slightly higher in older patients. ADVANCES IN KNOWLEDGE: The new practical MRI grading method can be useful in the categorisation of CLSS and shows strong clinical correlation.

A practical MRI grading system for cervical foraminal stenosis based on oblique sagittal images.

OBJECTIVE: To propose a new and practical MRI grading method for cervical neural foraminal stenosis and to evaluate its reproducibility. METHODS: We evaluated 50 patients (37 males and 13 females, mean age 49 years) who visited our institution and underwent oblique sagittal MRI of the cervical spine. A total of 300 foramina and corresponding nerve roots in 50 patients were qualitatively analysed from C4-5 to C6-7. We assessed the grade of cervical foraminal stenosis at the maximal narrowing point according to the new grading system based on T2 weighted oblique sagittal images. The incidence of each of the neural foraminal stenosis grades according to the cervical level was analysed by χ(2) tests. Intra- and interobserver agreements between two radiologists were analysed using kappa statistics. Kappa value interpretations were poor (κ<0.1), slight (0.1≤κ≤0.2), fair (0.2<κ≤0.4), moderate (0.4<κ≤0.6), substantial (0.6<κ≤0.8) and almost perfect (0.8<κ≤1.0). RESULTS: Significant stenoses (Grades 2 and 3) were rarely found at the C4-5 level. The incidence of Grade 3 at the C5-6 level was higher than that at other levels, a difference that was statistically significant. The overall intra-observer agreement according to the cervical level was almost perfect. The agreement at each level was almost perfect, except for only substantial agreement at the right C6-7 by Reader 2. No statistically significant differences were seen according to the cervical level. Overall kappa values of interobserver agreement according to the cervical level were almost perfect. In addition, the agreement of each level was almost perfect. Overall intra- and interobserver agreement for the presence of foraminal stenosis (Grade 0 vs Grades 1, 2 and 3) and for significant stenosis (Grades 0 and 1 vs Grades 2 and 3) showed similar results and were almost perfect. However, only substantial agreement was seen in the right C6-7. CONCLUSION: A new grading system for cervical foraminal stenosis based on oblique sagittal MRI provides reliable assessment and good reproducibility. This new grading system is a useful and easy method for the objective evaluation of cervical neural foraminal stenosis by radiologists and clinicians. ADVANCES IN KNOWLEDGE: The use of the new grading system for cervical foraminal stenosis based on oblique sagittal MRI can be a useful method for evaluating cervical neural foraminal stenosis.

Impact of intraoperative rupture of the ovarian capsule on prognosis in patients with early-stage epithelial ovarian cancer: a meta-analysis.

BACKGROUND: The impact of intraoperative rupture on prognosis is controversial in early-stage epithelial ovarian cancer (EOC). Thus, we performed a meta-analysis to determine its impact and to evaluate factors to increase its risk. METHODS: We searched PubMed, Embase, and the Cochrane Library till May 2011, and 9 eligible studies including 2382 patients were evaluated. All patients were classified into three groups: no rupture; intraoperative rupture; preoperative involvement. RESULTS: Preoperative involvement decreased progression-free survival when compared with intraoperative rupture (PFS; HR, 1.47; 95% CI, 1.01-2.14), which also showed poorer PFS than no rupture (HR, 2.41; 95% CI, 1.74-3.33). Although preoperative involvement reduced PFS when compared with intraoperative rupture (HR, 2.63; 95% CI, 1.11-6.20), there was no difference in it between intraoperative rupture and no rupture in patients who underwent complete surgical staging operation and adjuvant platinum-based chemotherapy if needed (HR, 1.49; 95% CI, 0.45-4.95). Furthermore, adhesion to adjacent tissues, grade 2 or 3 disease were more common (ORs, 2.01 and 2.47; 95% CIs, 1.20-3.37 and 1.12-5.46), whereas mucinous tumor was less frequent (OR, 0.51; 95% CI, 0.37-0.72) in intraoperative rupture than in no rupture. CONCLUSIONS: Intraoperative rupture may not decrease PFS when compared with no rupture in patients with early-stage EOC who underwent complete surgical staging operation and adjuvant platinum-based chemotherapy. Furthermore, more adhesion to adjacent tissues and grade 2 or 3 disease, and less mucinous tumor are expected to increase the risk of intraoperative rupture.

Soybean extract showed modulation of retinoic acid-related gene expression of skin and photo-protective effects in keratinocytes.

Soy extracts are well known as medicinal and nutritional ingredients, and exhibit benefits towards human skin including depigmenting or anti-ageing effects. Despite the wrinkle decreasing effects of retinoids on skin as an anti-ageing ingredient, retinoid application can causes photo-sensitive responses such as skin irritation. Thus, their daytime usage is not recommended. The aim of this study is the investigation into the activities of soybean extract as an anti-ageing ingredient and their comparison to retinoids in this respect. Soybean extract decreased the relative ratio of MMP-1/TIMP-1 mRNA to the same degree as retinoic acid in normal human fibroblasts. It also affected mRNA levels of HAS2 and CRABP2 in normal human keratinocytes. Furthermore, we investigated its effect on mRNA expression of histidase, an enzyme that converts histidine into urocanic acid, the main UV light absorption factor of the stratum corneum. Unlike the complete inhibition of histidase exhibited by the mRNA expression of retinoic acid, the effect of soybean extract on histidase gene expression was weaker in normal human keratinocytes. Also, soybean extract pretreatment inhibited UVB-induced cyclobutane pyrimidine dimer formation dose-dependently in normal human keratinocytes. In this study, we found that soybean extract modulated retinoic acid-related genes and showed photo-protective effects. Our findings suggest that soybean extract could be an anti-ageing ingredient that can be safely used under the sunlight.

Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis.

BACKGROUND: The efficacy of neoadjuvant chemotherapy before surgery (NCS) has not been well-established in FIGO stage IB1 to IIA cervical cancer when compared with primary surgical treatment (PST). Thus, we performed a meta-analysis to determine the efficacy of NCS in patients with FIGO stage IB1 to IIA cervical cancer when compared with PST. METHODS: We searched Pubmed, Embase and the Cochrane Library between January 1987 and September 2010. Since there was a relative lack of relevant randomized controlled trials (RCTs), we included 5 RCTs and 4 observational studies involving 1784 patients among 523 potentially relevant studies. RESULTS: NCS was related with lower rates of large tumor size (≥4 cm) (ORs, 0.22 and 0.10; 95% CI, 0.13-0.39 and 0.02-0.37) and lymph node metastasis (ORs, 0.61 and 0.38; 95% CI, 0.37-0.99 and 0.20-0.73) than PST in all studies and RCTs. Furthermore, NCS reduced the need of adjuvant radiotherapy (RT) in all studies (OR, 0.57; 95% CI, 0.33-0.98), and distant metastasis in all studies and RCTs (ORs, 0.61 and 0.61; 95% CI, 0.42-0.89 and 0.38-0.97). However, overall and loco-regional recurrences and progression-free survival were not different between the 2 treatments. On the other hand, NCS was associated with poorer overall survival in observational studies when compared with PST (HR, 1.68; 95% CI, 1.12-2.53). CONCLUSIONS: Although NCS reduced the need of adjuvant RT by decreasing tumor size and lymph node metastasis, and distant metastasis, it failed to improve survival when compared with PST in patients with FIGO stage IB1 to IIA cervical cancer.

Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism.

We recently identified Grainyhead-like 2 (GRHL2), a mammalian homolog of Grainyhead in Drosophila, to be a novel transcription factor that regulates hTERT gene expression and enhances proliferation of normal human epidermal keratinocytes (NHEK). In the current study, we show that GRHL2 impairs keratinocyte differentiation through transcriptional inhibition of the genes clustered at the epidermal differentiation complex (EDC), located at chromosome 1q21. Gene expression profiling and subsequent in vitro assays revealed consistent downregulation of EDC genes, for example, IVL, KRT1, FLG, LCEs, and SPRRs, in NHEK expressing exogenous GRHL2. In vivo binding assay by chromatin immunoprecipitation revealed GRHL2 association at the promoter regions of its target genes, many of which belong to EDC. Exogenous GRHL2 expression also inhibited recruitment of histone demethylase Jmjd3 to the EDC gene promoters and enhanced the level of histone 3 Lys 27 trimethylation enrichment at these promoters. Survey of GRHL2 expression in human skin tissues demonstrated enhanced protein and mRNA levels in chronic skin lesions with impaired keratinocyte differentiation, for example, atopic dermatitis and psoriasis, compared with normal epidermis. These data indicate that GRHL2 impairs epidermal differentiation by inhibiting EDC gene expression through epigenetic mechanisms and support its role in the hyperproliferative skin diseases.

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels.

Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on-treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty-two patients with HBeAg-positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on-treatment factors, on-treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log(10) IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940-1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On-treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut-off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log(10) PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on-treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg-positive CHB patients with entecavir treatment.