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Purpose: To compare health-related quality of life (QoL) in urinary, bowel, and sexual domains after combined external beam radiation therapy (EBRT) and either low-dose rate (LDR) or high-dose rate (HDR) prostate brachytherapy (BT)., Methods and Materials: Eligible men with intermediate or high-risk prostate cancer treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score, Index of Erectile Function, and Expanded Prostate Cancer Composite were collected at baseline, 1, 3, 6, and 12 months, every 6 months to 3 years and then annually along with prostate-specific antigen/testosterone. Fisher's exact test compared categorical variables and the Mann-Whitney U test Expanded Prostate Cancer Index Composite (EPIC) domain scores., Results: From January 2014 to December 2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89 and 88 respectively for Genito-urinary; 92 and 93 for Gastro-intestinal. EPIC urinary scores decreased at 1 month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained more than the minimum clinically important difference out to 5 years., Conclusions: The patient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The outer circulation of tropical cyclones (TCs) on the western North Pacific has been reported to substantially influence the atmospheric environment over the Guangdong-Hong Kong-Macau Greater Bay Area (GBA) of China, whereas dynamic evolution and redistribution of water vapor and aerosol in the atmospheric boundary layer (ABL) responding to moving TCs have yet to be understood. This study aims to answer three key research questions related to the influences of the approaching TCs: (1) how do water vapor and aerosol particles over the GBA change during the TC approaching stage? (2) how does the ABL in terms of vertical wind structure respond to the approaching TCs? and (3) how does turbulence influence the vertical profile of aerosol during the approaching stage? Based on an intensive analysis of three-year reanalysis and Doppler LiDAR data, this study identified a dry-polluted time over the GBA when a TC was located at ~1000 km away on South China Sea. Before that, horizontal wind has consistently come from the northeast, creating a favorable condition for weak transboundary air pollution to the GBA. During the dry-polluted time, the highest surface PM 2.5 concentration was resulted from the enhanced downdraft and early-stage wind shear, i.e., stronger wind started occurring at upper-level ABL, while the further turbulent mixing induced by wind shear enhancement and updrafts recovery pumped surface pollution upward to the upper level when TCs became closer. Our findings are expected to improve both weather and PM 2.5 forecasts under the impacts of approaching TCs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steve H.L. Yim reports financial support was provided by Dr. Stanley Ho Medical Development Foundation. Steve H.L. Yim reports financial support was provided by Government of Singapore Ministry of Education. Steve H.L. Yim reports financial support was provided by Earth Observatory of Singapore at NTU., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Bending Asymmetry Index (BAI) has been proposed to characterize the types of scoliotic curve in three-dimensional ultrasound imaging. Scolioscan has demonstrated its validity and reliability in scoliosis assessment with manual assessment-based X-ray imaging. The objective of this study is to investigate the ultrasound-derived BAI method to X-ray imaging of scoliosis, with supplementary information provided for the pre-surgery planning., Methods: About 30 pre-surgery scoliosis subjects (9 males and 21 females; Cobb: 50.9 ± 19.7°, range 18°-115°) were investigated retrospectively. Each subject underwent three-posture X-ray scanning supine on a plain mattress on the same day. BAI is an indicator to distinguish structural or non-structural curves through the spine flexibility information obtained from lateral bending spinal profiles. BAI was calculated semi-automatically with manual annotation of vertebral centroids and pelvis level inclination adjustment. BAI classification was validated with the scoliotic curve type and traditional Lenke classification using side-bending Cobb angle measurement (S-Cobb)., Results: 82 curves from 30 pre-surgery scoliosis patients were included. The correlation coefficient was R 2  = 0.730 (p < 0.05) between BAI and S-Cobb. In terms of scoliotic curve type classification, all curves were correctly classified; out of 30 subjects, 1 case was confirmed as misclassified when applying to Lenke classification earlier, thus has been adjusted., Conclusion: BAI method has demonstrated its inter-modality versatility in X-ray imaging application. The curve type classification and the pre-surgery Lenke classification both indicated promising performances upon the exploratory dataset. A fully-automated of BAI measurement is surely an interesting direction to continue our endeavor. Deep learning on the vertebral-level segmentation should be involved in further study., (© 2022. CARS.)

Aim: To use computed tomography (CT) to assess the validity and reliability of the posterior landmarks, spinous processes (SP), transverse processes (TP), and centre of lamina (COL), as compared to the Cobb angle to assess the curve severity and progression of adolescent idiopathic scoliosis (AIS)., Materials and Methods: A consecutive series of CT examinations of severe AIS patients were included retrospectively. SP, TP, and COL angles were measured for all curves and compared to the Cobb angle., Results: One hundred and five patients were included. The mean Cobb versus SP, TP, and COL angles were, 54° versus 37°, 49°, and 51° in the thoracic curves and 34° versus 26°, 31°, and 34° in the (thoraco)lumbar curves. Intraclass correlation coefficient values for intra-rater measurements of the SP, TP, and COL angles were 0.93, 0.97, and 0.95 and 0.70, 0.90, and 0.88 for inter-rater measurements. The correlations between the Cobb angle and SP, TP, and COL angles in thoracic and (thoraco)lumbar curves were 0.79 and 0.66, 0.87 and 0.84, and 0.80 and 0.70., Conclusions: The posterior spinal landmarks can be used for assessment of scoliosis severity in AIS; however, they show a systematic underestimation, but a strong correlation with the coronal Cobb angle. TP and COL angles had the highest validity., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Periodontitis is a chronic inflammatory disease caused by multiple potential contributing factors such as bacterial biofilm infection of the tissues surrounding the teeth and environmental determinants and a dysregulated host response for modifying and resolving the inflammation. Because periodontal disease is a major public health concern with substantial increases in the prevalence and severity in aging populations, previous studies of periodontitis tended to approach the disease as an age-associated outcome across the life span. However, few investigations have considered that, as a chronic noncommunicable disease, periodontitis may not simply be a disease that increases with age but may contribute to more rapid biologic aging., Objectives: Increasing population data supports the potential disconnect between chronological aging and biologic aging, which would contribute to the heterogeneity of aging phenotypes within chronologic ages across populations. Thus, our aim was to test whether periodontal disease affects biological aging across the life span., Methods: The prevalence of periodontitis in the adult US population is a portion of the assessment of the National Health and Nutrition Examination Survey (NHANES), which has been ongoing since 1971 through 2-y cycles sampling populations across the country. We used NHANES 2001-2002 to test the hypothesis that the presence/severity of periodontal disease as an exposure variable would negatively affect telomere length, a measure of biological aging, and that this relationship is modified by factors that also affect the progression of periodontitis, such as sex, race/ethnicity, and smoking., Results: The data demonstrated a significant impact of periodontitis on decreasing telomere lengths across the life span. These differences were modulated by age, sex, race/ethnicity, and smoking within the population., Conclusion: The findings lay the groundwork for future studies documenting broader effects on biological aging parameters as well as potential intervention strategies for periodontitis in driving unhealthy aging processes., Knowledge Transfer Statement: Periodontitis is a chronic inflammatory disease and dysregulated host response. Shortening of telomeres is a reflection of biologic aging. Decreased telomere lengths with periodontitis are seemingly related to chronic infection and persistent local and systemic inflammation. These findings suggest that periodontitis is not simply a disease of aging but may also transmit chronic systemic signals that could affect more rapid biological aging. Clinicians can use this outcome to recognize the role of periodontitis in driving unhealthy aging processes in patients.

Decreased cortical bone density and bone strength at peak height velocity (PHV) were noted in girls with adolescent idiopathic scoliosis (AIS). These findings could provide the link to the previously reported observation that low bone mineral density (BMD) could contribute as one of the prognostic factors for curve progression that mostly occurs during PHV in AIS., Introduction: As part of the studies related to aetiopathogenesis of AIS, we assessed bone qualities, bone mechanical strength and bone turnover markers (BTMs) focusing at the peri-pubertal period and PHV in AIS girls., Methods: 396 AIS girls in two separate cohorts were studied. Skeletal maturity was assessed using the validated thumb ossification composite index (TOCI). Bone qualities and strength were evaluated with high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA)., Results: Cohort-A included 179 girls (11.95 ± 0.95 years old). Girls at TOCI-4 had numerically the highest height velocity (0.71 ± 0.24 cm/month) corresponding to the PHV. Subjects at TOCI-4 had lower cortical volumetric BMD (672.36 ± 39.07 mg/mm 3 ), cortical thickness (0.68 ± 0.08 mm) and apparent modulus (1601.54 ± 243.75 N/mm 2 ) than: (a) those at TOCI-1-3 (724.99 ± 32.09 mg/mm 3 (p < 0.001), 0.79 ± 0.11 mm (p < 0.001) and 1910.88 ± 374.75 N/mm 2 (p < 0.001), respectively) and (b) those at TOCI-8 (732.28 ± 53.75 mg/mm 3 (p < 0.001), 0.84 ± 0.14 mm (p < 0.001), 1889.11 ± 419.37 N/mm 2 (p < 0.001), respectively). Cohort-B included 217 girls (12.22 ± 0.89 years old). Subjects at TOCI-4 had higher levels of C-terminal telopeptide of type 1 collagen (1524.70 ± 271.10 pg/L) and procollagen type 1 N-terminal propeptide (941.12 ± 161.39 µg/L) than those at TOCI-8 (845.71 ± 478.55 pg/L (p < 0.001) and 370.08 ± 197.04 µg/L (p < 0.001), respectively)., Conclusion: AIS girls had decreased cortical bone density and bone mechanical strength with elevated BTMs at PHV. Coupling of PHV with decreased cortical and FEA parameters could provide the link to the previously reported observation that low BMD could contribute as one of the prognostic factors for curve progression that mostly occurs during PHV in AIS., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Previous studies have reported abnormal muscle morphology and functions in patients with adolescent idiopathic scoliosis (AIS). To answer whether such abnormalities could be reflected in their circulation and their clinical implication for predicting curve progression to the surgical threshold, this preliminary study explored the presence of baseline muscle-related proteins and their association with curve progression. Plasma samples were collected at the first clinical visit for AIS, with patients divided into non-progressive or progressive groups ( N = four and four) according to their Cobb angle in six-year follow-ups, with age- and sex-matched healthy subjects ( N = 50). Then, the samples were subjected to isobaric tags for relative and absolute quantitation (iTRAQ) for global comparison of untargeted protein expression. Seventy-one differentially expressed proteins (DEPs) were found elevated in progressive AIS. Functional analysis showed that 18 of these are expressed in muscles and play an essential role in muscle activities. Among the muscle-related DEPs, α-actin had the highest fold change in progressive/non-progressive groups. This preliminary study firstly suggested higher circulating levels of muscle structural proteins in progressive AIS, indicating the likelihood of structural damage at the microscopic level and its association with progression to the surgical threshold. Further studies with larger sample sizes are warranted to validate these novel candidates for early diagnosis and predicting progression.

The association between the risk of fractures and suboptimal vitamin D (Vit-D) status remains controversial in children. This meta-analysis suggested that serum 25(OH)Vit-D levels were lower in pediatric cases with fractures. 25-hydroxyvitamin D (25(OH)Vit-D) levels less than 50 nmol/L were associated with increased fracture risk in children., Introduction: This study aimed to assess the association between serum 25(OH)Vit-D and the risk of fractures in children, and to explore the sources of heterogeneity and investigate their impact on results., Methods: Systematic review and meta-analysis were conducted for observational studies comparing serum 25(OH)Vit-D levels between fracture and non-fracture pediatric cases. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS)., Results: Analysis on 17 case-control and 6 cross-sectional studies (2929 fracture cases and 5000 controls) suggested that 25(OH)Vit-D was lower in fracture cases than in controls (pooled mean difference (MD) = - 3.51 nmol/L; 95% confidence interval (CI): - 5.60 to - 1.42) with a heterogeneity (I 2 ) of 73.9%. The sensitivity analysis which merged the case-control studies that had a NOS score ≥ 4 showed a pooled MD of - 4.35 nmol/L (95% CI: - 6.64 to - 2.06) with a heterogeneity (I 2 ) of 35.9%. Pooled odds ratio of fracture in subjects with 25(OH)Vit-D ≤ 50 nmol/L compared to subjects with 25(OH)Vit-D > 50 nmol/L was 1.29 (95% CI: 1.10 to 1.53; I 2 < 1%)., Conclusion: This study indicated that serum 25(OH)Vit-D levels were lower in pediatric patients with fractures. 25(OH)Vit-D ≤ 50 nmol/L was associated with increased fracture risk in children.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries., (Copyright © 2019 European Society for Medical Oncology. All rights reserved.)

Purpose: The EOS-imaging system is increasingly adopted for clinical follow-up in scoliosis with the advantages of simultaneous biplanar imaging of the spine in an erect position. Skeletal maturity assessment using a hand radiograph is an essential adjunct to spinal radiography in scoliosis follow-up. This study aims at testing the feasibility and validity of a newly proposed EOS workflow with sequential spine-hand radiography for skeletal maturity assessment and bracing recommendation., Methods: EOS spine-hand radiographs from patients with diagnosis of idiopathic scoliosis, including both sexes and an age range of ten to 14 years, were scored using the Thumb Ossification Composite Index (TOCI), Sanders and Risser methods. Intraclass correlation coefficients (ICCs) were calculated for inter/intraobserver agreement and were tested with Cronbach's alpha values., Results: In all, 60 EOS-spine hand radiographs selected from subjects with diagnosis of adolescent idiopathic scoliosis (AIS), including 32 male patients (mean age 11.53 years; 10 to 14) and 28 female patients (mean age 11.50 years; 10 to 13) who underwent sequential spine-hand low dose EOS imaging were generated for analysis. The overall interobserver (ICC = 0.997) and intraobserver agreement (α > 0.9) demonstrated excellent agreement for TOCI staging; ICC > 0.994 for both TOCI and Sanders staging comparing traditional digital versus EOS hand radiography; ICC ≥ 0.841 for agreement on bracing recommendation among TOCI versus the Risser and Sanders system., Conclusion: With the proposed new EOS workflow it was feasible to produce high image quality for skeletal maturity assessment with excellent reliability and validity to inform consistent bracing recommendation in AIS. The workflow is applicable for busy daily clinic settings in tertiary scoliosis centres with reduced time cost, improved efficiency and throughput of the radiology department., Level of Evidence: III.

Most osteoporotic fractures occur at metaphyseal regions of long bones. The present study proposed a clinically relevant animal model that satisfied: i) induction of osteoporosis, ii) unilateral complete osteotomy at metaphysis, iii) internal fixation. 6 months old female Sprague-Dawley rats (n = 64) were randomly divided into the ovariectomised-metaphyseal osteotomy (OVX, n = 32) and metaphyseal osteotomy (SHAM, n = 32) groups. The metaphyseal-osteotomy model was created with a plate-fixation of the osteotomy and assessed by X-ray, micro-computed tomography, histomorphometry and mechanical testing at weeks 1, 3 and 6. X-ray results showed complete healing of metaphyseal osteotomy at week 6. Histology showed 3 stages of metaphyseal healing. Stage 1 was characterised by fibrous tissue, consisting of disorganised orientation of collagen fibres, and infiltration of immune cells. At stage 2, a transitional zone consisting of maturing fibrous tissue and differentiating mesenchymal cells with early trabecular bone formation and disorganised woven bone were observed. During stage 3, cortical bone ends unified and woven bone underwent transformation to lamellar bone. OVX group healing was significantly delayed when compared to SHAM samples. The study demonstrated that healing of osteoporotic osteotomy at the metaphyseal region was delayed in terms of radiography, histomorphometry and mechanical strength. These quantitative evaluations, along with histological features, may provide key references for future studies. The animal model may provide additional clinical relevance as most osteoporotic fracture in humans occurs at metaphyseal regions.

Purpose: Prospective randomized controlled trials and long-term studies are essential future directions for building -evidence-based practices in developmental dysplasia of the hip (DDH), however, sufficient attrition in data (> 20%) can introduce bias deteriorating research quality. Pelvic radiography is synonymous with DDH assessment and so are -Gonadal Shield (GS) recommendations with pelvic radiography. -Nonetheless, losses to diagnostic information and inadequate protection have been increasingly implicated to GS usage, with significantly worse implications in female patients. Understandably for DDH, a disease with 80% female prevalence, the impact of GS usage on quality of radiographs and readability of radiological data may be drastic. This study aims to objectively define the implications of GS recommendations in DDH patients., Methods: Pelvis radiographs of all DDH patients under the hip surveillance programme at a tertiary care hospital with a written protocol for GS usage were evaluated. Images were reviewed for gender, GS presence, adequate gonadal protection and obstruction of essential anatomical landmarks for pelvic indices., Results: In all, 131 pelvis radiographs with DDH diagnoses (age: 1.25 to 6 years; 107 female, 24 male pelvises) were reviewed. Only 42.67% (56) of pelvis radiographs used GS despite the presence of a clear protocol. Useful anatomical landmarks were obstructed in 58.9% of radiographs with GS present. Lost diagnostic information was more common in female patients than male patients (68.1% versus 11.1%, p < 0.01). GS was ineffective at gonadal protection in 73.2% (41) of the pelvises with worse protection in female patients (78.7% vs 44.4%; p = 0.03)., Conclusions: Ironically, essential anatomy was obstructed in all the adequately protected female pelvises. Routine GS usage results in substantial attrition of radiographic data in DDH patients., Level of Evidence: III.

Background and Purpose: Neural system was one of the important contributors to the etiopathogenesis of adolescent idiopathic scoliosis; additionally, the morphology of corpus callosum interconnecting both hemispheres of the brain was found to be altered morphologically. Our aim was to evaluate and compare the microstructural changes of the corpus callosum and its interhemispheric white matter fiber tracts interconnecting both cerebral hemispheres in patients with adolescent idiopathic scoliosis and matched controls using diffusion tensor imaging., Materials and Methods: Brain DTI was performed in 69 patients with adolescent idiopathic scoliosis (female, right thoracic/thoracolumbar curve) and 40 age-matched controls without adolescent idiopathic scoliosis (female). 2D and 3D segmentation of the corpus callosum were performed using a region-growing method, and the corpus callosum was further divided into 6 regions, including the rostrum, genu, anterior and posterior midbodies, isthmus, and splenium. The laterality index was calculated to quantify the asymmetry of the corpus callosum. Interhemispheric fiber tractography were performed using the Brodmann atlas., Results: 2D ROI analysis revealed reduced fractional anisotropy in the genu and splenium ( P = .075 and P = .024, respectively). Consistently reduced fractional anisotropy on the left sides of the genu and splenium was also found in 3D ROI analysis ( P = .03 and P = .012, respectively). The laterality index analysis revealed a pseudo-right lateralization of the corpus callosum in adolescent idiopathic scoliosis. Interhemispheric fibers via the splenium interconnecting Brodmann 3, 1, and 2; Brodmann 17; and Brodmann 18 (corresponding to the primary somatosensory cortex and primary and secondary visual cortices) were also found to have reduced fractional anisotropy ( P ≤ .05)., Conclusions: Reduced fractional anisotropy was found in the genu and splenium of the corpus callosum and corresponding interhemispheric fiber tracts interconnecting the somatosensory and visual cortices via the splenium. Our results are suggestive of altered white matter microstructure within the brain of those with adolescent idiopathic scoliosis, which could be related to abnormal brain maturation during adolescence in adolescent idiopathic scoliosis and could possibly explain the previously documented somatosensory function impairment and visuo-oculomotor dysfunction in this condition., (© 2018 by American Journal of Neuroradiology.)

Salmonella spp. is a foodborne pathogen that causes zoonotic disease worldwide. The aim of this study was to investigate the prevalence of antimicrobial resistance of Salmonella isolated from turkey farms in Taiwan. During the past 2 yr, 243 strains of Salmonella were isolated from 2,040 samples (11.9%) from turkey farms, including 32.5% (52/160) from the intestines of 12-day-old turkey poults, 14.2% (119/840) from feces collected from the turkey growing periods, and 6.9% (72/1,040) from finishing periods. S. Albany (35.0%, 85/243), S. Schwarzengrund (23.0%, 56/243), and S. Hadar (19.3%, 47/243) were the most common serovars on turkey farms. For these strains, a high frequency of resistance was observed against florfenicol (97.5%), oxytetracycline (89.3%), doxycycline (78.6%), colistin (77.8%), ampicillin (75.7%), amoxicillin (75.3%), trimethoprim-sulfamethoxazole (73.7%), chloramphenicol (69.1%), and nalidixic acid (67.9%). floR (63.8%), tet (A) (60.5%), blaPSE (57.6%), blaTEM (42.0%), blaCTX-M (34.2%), cmlA (34.2%), and tet (D) (29.2%) were the most common resistance genes found in this study. The int1 gene was identified in 72.4% (176/243) of Salmonella isolates in which the conserved region 3' of class 1 integrons also was amplified, whereas none had the int2 gene. This study demonstrates that imported and fattening turkeys could be a reservoir for Salmonella isolates resistant to multiple antimicrobials. These results also reinforce the need to develop strategies and implement specific control procedures to reduce the development of antimicrobial resistance., (© Crown copyright 2017.)

Objectives: The treatment of osteoporotic fractures is a major challenge, and the enhancement of healing is critical as a major goal in modern fracture management. Most osteoporotic fractures occur at the metaphyseal bone region but few models exist and the healing is still poorly understood. A systematic review was conducted to identify and analyse the appropriateness of current osteoporotic metaphyseal fracture animal models., Materials and Methods: A literature search was performed on the Pubmed, Embase, and Web of Science databases, and relevant articles were selected. A total of 19 studies were included. Information on the animal, induction of osteoporosis, fracture technique, site and fixation, healing results, and utility of the model were extracted., Results: Fracture techniques included drill hole defects (3 of 19), bone defects (3 of 19), partial osteotomy (1 of 19), and complete osteotomies (12 of 19). Drill hole models and incomplete osteotomy models are easy to perform and allow the study of therapeutic agents but do not represent the usual clinical setting. Additionally, biomaterials can be filled into drill hole defects for analysis. Complete osteotomy models are most commonly used and are best suited for the investigation of therapeutic drugs or noninvasive interventions. The metaphyseal defect models allow the study of biomaterials, which are associated with complex and comminuted osteoporotic fractures., Conclusion: For a clinically relevant model, we propose that an animal model should satisfy the following criteria to study osteoporotic fracture healing: 1) induction of osteoporosis, 2) complete osteotomy or defect at the metaphysis unilaterally, and 3) internal fixation. Cite this article : R. M. Y. Wong, M. H. V. Choy, M. C. M. Li, K-S. Leung, S. K-H. Chow, W-H. Cheung, J. C. Y. Cheng. A systematic review of current osteoporotic metaphyseal fracture animal models. Bone Joint Res 2018;7:6-11. DOI: 10.1302/2046-3758.71.BJR-2016-0334.R2., Competing Interests: Conflicts of Interest Statement: The authors declare no conflict of interests., (© 2018 Wong et al.)

Essentials Disabled-2 (Dab2) phosphorylation status in thrombin signaling of human platelet was investigated. Ser723 was the major Dab2 phosphorylation site in human platelets stimulated by thrombin. Dab2 S723 phosphorylation (pS723) caused the dissociation of Dab2-CIN85 protein complex. Dab2-pS723 regulated ADP release and integrin αIIbβ3 activation in thrombin-treated platelets., Summary: Background Disabled-2 (Dab2) is a platelet protein that is functionally involved in thrombin signaling in mice. It is unknown whether or not Dab2 undergoes phosphorylation during human platelet activation. Objectives To investigate the phosphorylation status of Dab2 and its functional consequences in thrombin-stimulated human platelets. Methods Dab2 was immunoprecipitated from resting and thrombin-stimulated platelet lysates for differential isotopic labeling. After enrichment of the phosphopeptides, the phosphorylation sites were analyzed by mass spectrometry. The corresponding phospho-specific antibody was generated. The protein kinases responsible for and the functional significance of Dab2 phosphorylation were defined by the use of signaling pathway inhibitors/activators, protein kinase assays, and various molecular approaches. Results Dab2 was phosphorylated at Ser227, Ser394, Ser401 and Ser723 in thrombin-stimulated platelets, with Ser723 phosphorylation being the most significantly increased by thrombin. Dab2 was phosphorylated by protein kinase C at Ser723 in a G αq -dependent manner. ADP released from the stimulated platelets further activated the G βγ -dependent pathway to sustain Ser723 phosphorylation. The Cbl-interacting protein of 85 kDa (CIN85) bound to Dab2 at a motif adjacent to Ser723 in resting platelets. The consequence of Ser723 phosphorylation was the dissociation of CIN85 from the Dab2-CIN85 complex. These molecular events led to increases in fibrinogen binding and platelet aggregation in thrombin-stimulated platelets by regulating α II b β 3 activation and ADP release. Conclusions Dab2 Ser723 phosphorylation is a key molecular event in thrombin-stimulated inside-out signaling and platelet activation, contributing to a new function of Dab2 in thrombin signaling., (© 2017 International Society on Thrombosis and Haemostasis.)

Some individuals are more distracted by pain during a cognitive task than others, representing poor pain coping. We have characterized individuals as A-type (attention dominates) or P-type (pain dominates) based on how pain interferes with task speed. The ability to optimize behavior during pain may relate to the flexibility in communication at rest between the dorsolateral prefrontal cortex (DLPFC) of the executive control network, and the anterior mid-cingulate cortex (aMCC) of the salience network (SN) - regions involved in cognitive-interference. The aMCC and aIns (SN hub) also signify pain salience; flexible communication at rest between them possibly allowing prioritizing task performance during pain. We tested the hypotheses that pain-induced changes in task performance are related to resting-state dynamic functional connectivity (dFC) between these region pairs (DLPFC-aMCC; aMCC-aIns). We found that 1) pain reduces task consistency/speed in P-type individuals, but enhances performance in A-type individuals, 2) task consistency is related to the FC dynamics within DLPFC-aMCC and aMCC-aIns pairs, 3) brain-behavior relationships are driven by dFC within the slow-5 (0.01-0.027Hz) frequency band, and 4) dFC across the brain decreases at higher frequencies. Our findings point to neural communication dynamics at rest as being associated with prioritizing task performance over pain., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The objective of this study is to evaluate the effects of the Multi-disciplinary Orthopaedics Rehabilitation Empowerment (MORE) Program on reducing chronic disability among injured workers and improving efficiency of work rehabilitation process., Methods: A cohort of patients with workplace injuries in the lower back were recruited from orthopaedics clinics and assigned to either MORE group (n= 139) or control group (n= 106). Patients in MORE group received an early MRI screening and a coordinated multi-disciplinary management, while patients in the control group received conventional care. Outcome variables are time to return-to-work (RTW) from date of injury, waiting time for MRI screening and time to medical assessment board (MAB)., Results: Patients in the MORE Program had significantly shorter duration for RTW (MORE: 6.1 months,, Control: 12.8 months, p< 0.01), and more RTW cases (n= 64, 46.0%) compared to CONTROL group (n= 29, 27.4%). The MORE group also had much shorter waiting time for MRI scans (91.85 vs. 309.2 days, p< 0.001) and MAB referral after MRI scans (97.2 vs. 178.9 days, p= 0.001) compared to CONTROL group., Conclusions: The MORE Program which emphasizes early intervention and early MRI screening, is shown to be effective in shortening sick leave and improving RTW outcomes of injured workers.

Unlabelled: Vitamin D deficiency and insufficiency are highly prevalent among adolescents in Hong Kong, which is a sub-tropical city with ample sunshine. Vitamin D level is significantly correlated with key bone density and bone quality parameters. Further interventional studies are warranted to define the role of vitamin D supplementation for improvement of bone health among adolescents., Introduction: The relationship between bone quality parameters and vitamin D (Vit-D) status remains undefined among adolescents. The aims of this study were to evaluate Vit-D status and its association with both bone density and bone quality parameters among adolescents., Methods: Three hundred thirty-three girls and 230 boys (12-16 years old) with normal health were recruited in summer and winter separately from local schools. Serum 25(OH) Vit-D level, bone density and quality parameters by Dual Energy X-ray Absorptiometry (DXA) and High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT), dietary calcium intake, and physical activity level were assessed., Results: Sixty-four point seven percent and 11.4 % of subjects were insufficient [25 ≤ 25(OH)Vit-D ≤ 50 nmol/L] and deficient [25(OH)Vit-D < 25 nmol/L] in Vit-D, respectively. The mean level of serum 25(OH)Vit-D in summer was significantly higher than that in winter (44.7 ± 13.6 and 35.9 ± 12.6 nmol/L, respectively) without obvious gender difference. In girls, areal bone mineral density (aBMD) and bone mineral content (BMC) of bilateral femoral necks, cortical area, cortical thickness, total volumetric bone mineral density (vBMD), and trabecular thickness were significantly correlated with 25(OH)Vit-D levels. In boys, aBMD of bilateral femoral necks, BMC of the dominant femoral neck, cortical area, cortical thickness, total vBMD, trabecular vBMD, BV/TV, and trabecular separation were significantly correlated with 25(OH)Vit-D levels., Conclusion: Vit-D insufficiency was highly prevalent among adolescents in Hong Kong with significant correlation between Vit-D levels and key bone density and bone quality parameters being detected in this study. Given that this is a cross-sectional study and causality relationship cannot be inferred, further interventional studies investigating the role of Vit-D supplementation on improving bone health among adolescents are warranted.

Dysregulation of γ-synuclein (SNCG) has been reported in many cancers; however, its role in cancer development is still controversial. Here, we examined the potential involvement of DNA methylation in regulating SNCG and its role in oral squamous cell carcinoma (OSCC). We used 8 OSCC cell lines to investigate SNCG methylation and expression. SNCG methylation was examination by methylation-specific polymerase chain reaction and bisulfate sequencing. Cells showing a high degree of SNCG methylation were treated with 5-aza (methylation inhibitor), and changes in their methylation and expression profiles were analyzed. Functional effects of SNCG in OSCC were examined by its overexpression and knockdown. Additionally, methylation and expression of SNCG in OSCC tissues were investigated and correlated with clinicopathologic features. All OSCC cells showed detectable SNCG expression at the mRNA and protein levels. Methylation-specific polymerase chain reaction and bisulfate sequencing revealed high SNCG expression in SCC25 cells with the unmethylated allele, and their 15 CpG islands were unmethylated. The methylated allele was detected only in OEC-M1 cells exhibiting low SNCG expression, and their CpG islands were partially methylated. 5-aza treatment in OEC-M1 cells attenuated methylation and restored SNCG expression. SNCG overexpression increased colony forming, migration, and invasion abilities in OEC-M1 cells. Silencing SNCG in SCC25 cells suppressed these behaviors. All 25 tumor-adjacent normal tissues were negative for SNCG immunostaining. SNCG upregulation was frequently observed in dysplastic and OSCC tissues. Positive SNCG expression was found in 45% (37 of 82) OSCC tissues. Positive SNCG expression in OSCC significantly correlated with cancer staging and lymph node metastasis. However, SNCG methylation did not correlate with its expression and clinicopathologic variables in OSCC tissues. DNA methylation may participate in regulating SNCG expression in some OSCC cells. SNCG upregulation could be involved in OSCC progression., (© International & American Associations for Dental Research 2015.)

Membrane type 1 matrix metalloproteinase (MT1-MMP) binds to and regulates the function of tetraspanin-enriched microdomains. It also physically interacts with claudin-1 and acireductone dioxygenase 1 (ADI1), both associated with hepatitis C virus (HCV) cell entry. Here, we examined hepatic expression of MT1-MMP, ADI1 and claudin-1 as well as their physical interaction in relation to serum or intrahepatic HCV-RNA levels. A total of 104 liver biopsies obtained from chronic hepatitis C patients and 84 liver tissues obtained from noncancerous parts of surgically removed HCV-related hepatocellular carcinoma were analysed. Positive cytoplasmic ADI1 in liver biopsies was associated with higher serum HCV-RNA levels (P = 0.009). Positive MT1-MMP and ADI1 interaction assessed by co-immunoprecipitation was associated with lower tissue HCV-RNA levels (P = 0.009). Hepatic HCV-RNA levels were positively associated with ADI1 levels in the MT1-MMP and ADI1 co-immunoprecipitates (P = 0.030). Overexpression of MT1-MMP in Huh7.5 cells suppressed cell entry of HCV pseudoparticles as well as HCVcc infection. The suppression effect could be reversed by co-expression of ADI1 in a dose-dependent manner. In summary, clinical and cell-based experiments suggested that physical interaction between MT1-MMP and ADI1 led to suppression of HCV infection. This inhibitory effect could be reversed by ADI1 overexpression., (© 2015 John Wiley & Sons Ltd.)

Overlapping functional magnetic resonance imaging (fMRI) activity elicited by physical pain and social rejection has posited a common neural representation between the two experiences. However, Woo and colleagues (Nat Commun 5: 5380, 2014) recently used multivariate statistics to challenge the "shared representation" theory of pain. This study has implications in the way results from fMRI studies are interpreted and has the potential of broadening our understanding of different pain states and future development of personalized medicine., (Copyright © 2015 the American Physiological Society.)

Previous studies found adolescent idiopathic scoliosis (AIS) is associated with low bone mineral density (BMD) and abnormal bone quality, whilst the association between AIS and their bone strength is unknown. From high-resolution peripheral quantitative computed tomography-generated images, bone mechanical properties can be evaluated with finite element analysis (FEA), and trabecular rod-plate configuration related to trabecular bone strength can be quantified by structure model index (SMI). This study aimed to compare trabecular configuration and bone mechanical properties between AIS and the controls. 95 AIS girls aged 12-14 years and 97 age- and gender-matched normal controls were recruited. Bilateral femoral necks and non-dominant distal radius were scanned by dual-energy X-ray absorptiometry for areal BMD and HR-pQCT for SMI and FEA, respectively. Subjects were further classified into osteopenic and non-osteopenic group based on their areal BMD. Bone mechanical properties (stiffness, failure load and apparent modulus) were calculated using FEA. Linear regression model was used for controlling age, physical activity and calcium intake. AIS was associated with lower failure load and apparent modulus after adjusting for age, whereas AIS was associated with lower apparent modulus after adjusting for all confounders. Osteopenic AIS was associated with more rod-like trabeculae when compared with non-osteopenic AIS, whereas no difference was detected between osteopenic and non-osteopenic controls. This might be the result of abnormal regulation and modulation of bone metabolism and bone modelling and remodelling in AIS which will warrant future studies with a longitudinal design to determine the significance of micro-architectural abnormalities in AIS.

Ovarian high-grade serous carcinomas (HGSCs) and invasive low-grade serous carcinomas (LGSCs) are considered to be distinct entities. In particular, LGSCs are thought to arise from non-invasive serous borderline ovarian tumors (SBOTs) and show poor responsiveness to conventional chemotherapy. The pro-apoptotic effects of CD40 ligand (CD40L) have been demonstrated in HGSC, though the underlying mechanisms are not fully understood. Conversely, the therapeutic potential of the CD40L-CD40 system has yet to be evaluated in LGSC. We now show that CD40 protein is focally expressed on tumor cells in two of five primary LGSCs compared with no expression in eight primary SBOTs. Treatment with CD40L or agonistic CD40 antibody decreased the viability of LGSC-derived MPSC1 and VOA1312 cells, but not SBOT3.1 cells. Small interfering RNA (siRNA) targeting CD40 was used to show that it is required for these reductions in cell viability. CD40L treatment increased cleaved caspase-3 levels in MPSC1 cells though, surprisingly, neither pan-caspase inhibitor nor caspase-3 siRNA reversed or even attenuated CD40L-induced cell death. In addition, CD40-induced cell death was not affected by knockdown of the mitochondrial proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG). Interestingly, CD40L-induced cell death was blocked by necrostatin-1, an inhibitor of receptor-interacting protein 1 (RIP1), and attenuated by inhibitors of RIP3 (GSK'872) or MLKL (mixed lineage kinase domain-like; necrosulfonamide). Our results indicate that the upregulation of CD40 may be relatively common in LGSC and that CD40 activation induces RIP1-dependent, necroptosis-like cell death in LGSC cells.

Unlabelled: In a cohort of 393 Chinese women, by using high-resolution peripheral quantitative computed tomography (HR-pQCT), we found that significant cortical bone loss occurred after midlife. Prominent increase in cortical porosity began at the fifth decade but reached a plateau before the sixth decade. Trabecular bone loss was already evident in young adulthood and continued throughout life., Introduction: This study aimed to investigate age-related differences in volumetric bone mineral density (vBMD), microarchitecture, and estimated bone strength at peripheral skeleton in Chinese female population., Methods: In a cross-sectional cohort of 393 Chinese women aged 20-90 years, we obtained vBMD, microarchtecture, and micro-finite element-derived bone strength at distal radius and tibia using HR-pQCT., Results: The largest predictive age-related difference was found for cortical porosity (Ct.Po) which showed over four-fold and two-fold differences at distal radius and tibia, respectively, over the adulthood. At both sites, cortical bone area, vBMD, and thickness showed significant quadratic association with age with significant decrease beginning after midlife. Change of Ct.Po became more prominent between age of 50 and 57 (0.26 %/year at distal radius, 0.54 %/year at distal tibia, both p ≤ 0.001) but thereafter, reached a plateau (0.015 and 0.028 %/year, both p > 0.05). In contrast, trabecular vBMD and microarchitecture showed linear association with age with significant deterioration observed throughout adulthood. Estimated age of peak was around age of 20 for trabecular vBMD and microarchitecture and Ct.Po and age of 40 for cortical vBMD and microarchitecture. Estimated stiffness and failure load peaked at mid-30s at the distal radius and at age 20 at distal tibia., Conclusions: Age-related differences in vBMD and microarchitecture in Chinese women differed by bone compartments. Significant cortical bone loss occurred after midlife. Prominent increase in Ct.Po began at the fifth decade but appeared to be arrested before the sixth decade. Loss of trabecular bone was already evident in young adulthood and continued throughout life.

Objective: The phenomenon of foot binding, also known as 'lotus feet', has an enduring and influential history in China. To achieve a man-made smaller foot size, lifelong foot binding may have had adverse effects on the skeleton. We investigated bone properties in postmenopausal women with bound feet, which may provide new information for developing countermeasures for prevention of fragility fractures., Design: Population-based cohort study., Participants: This study involved 254 postmenopausal women aged 65-80, including 172 with bound feet and 82 age- and gender-matched control subjects, living in a remote region of China., Outcomes: Anthropometric, SF-36 Lifestyle Questionnaire and heel quantitative ultrasound (QUS) data were collected for the whole study population. A small subset of two cases was also invited for assessment of bone mineral density and microarchitecture at the distal tibia using high-resolution peripheral quantitative CT (HR-pQCT) and gait and balance tests., Results: Women with bound feet had significantly lower QUS values than age-matched women with normal feet; this was supported by HR-pQCT data. However, SF-36 Questionnaire results did not reveal any statistically significant differences in any categorical responses, including physical functioning, general health vitality and physical component summary score, and number of previous fractures. No impairment of body balance was found in the small subset., Conclusions: The man-made changes caused by foot binding led to reduced physical activity, making the subjects prone to osteoporosis. Women with bound feet and osteoporosis did not have a higher incidence of fragility fractures than controls. This might be explained by compensation in physical activity to improve body balance, implying the importance of improving or maintaining body balance in overall prevention strategies against fragility fractures., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Reelin is a large extracellular glycoprotein that is present in the peripheral blood. That Reelin interacts with the coagulation components and elicits a functional role in hemostasis has not yet been elucidated., Objectives: The hemostatic activity of Reelin is investigated and defined in this study., Methods: The interplay of Reelin with coagulation components was elucidated by far-Western and liposome/platelet binding assays. In vivo and ex vivo hemostasis-related analyses of Reelin-deficient mice and plasma were also performed., Results: Reelin interacted with the liposomes containing phosphatidylserine (PS) or phosphatidylcholine. Instead of interacting with known Reelin receptors (ApoE receptor 2, very low density lipoprotein receptor and integrin β1), Reelin interacted with PS of the activated platelets. The interaction between Reelin and the coagulation factors of thrombin and FXa was also demonstrated with the Kd of 11.7 and 21.2 nm, respectively. Reelin-deficient mice displayed a prolonged bleeding time and an increase in rebleeding rate. Despite the fact that Reelin deficiency had no significant effect on the clotting time of prothrombin and activated partial thromboplastin time, the fibrin clot formation was abnormal and the fibrin clot structure was relatively loosened with reduced clot strength. Abnormal fibrinogen expression did not account for the hemostatic defects associated with Reelin deficiency. Instead, thrombin generation was impaired concomitant with an altered prothrombin cleavage pattern., Conclusions: By interacting with platelet phospholipids and the coagulation factors, thrombin and FXa, Reelin plays a selective role in coagulation activation, leading to thrombin generation and formation of a normal fibrin clot., (© 2014 International Society on Thrombosis and Haemostasis.)

Background and Purpose: Disturbed somatosensory evoked potentials have been demonstrated in patients with adolescent idiopathic scoliosis (but this functional delay was found to originate above the C5-6 level, while the lower cord level was unaffected). Together with MR imaging observation of tonsillar ectopia and a relatively tethered cord, we hypothesized that there is disturbed mean diffusivity integrity along the spinal cord. In this study, advanced DTI was used to evaluate whether there was underlying decreased WM integrity within the brain stem and spinal cord in adolescent idiopathic scoliosis and any relationship to cerebellar tonsillar ectopia. Clinical impact on balance testing was also correlated., Materials and Methods: Thirteen girls with adolescent idiopathic scoliosis with right thoracic curves were compared with 13 age-matched healthy girls. DTI of the brain and whole spinal cord was performed. ROIs were manually defined for the medulla oblongata and along each intervertebral segment of the cord. Mean values of fractional anisotropy and mean diffusivity were computed at the defined regions. Between-group comparisons were performed by 1-way ANOVA., Results: Significantly decreased fractional anisotropy values and increased mean diffusivity values were found at the medulla oblongata and C1-2, C2-3, C3-4, and C4-5 segments in patients with adolescent idiopathic scoliosis compared with healthy subjects. No significant difference was found in the lower cord levels. Significant correlation was found between the tonsillar level and fractional anisotropy value at the C4-5 level in patients with adolescent idiopathic scoliosis only., Conclusions: The findings from this study are in agreement with previous findings showing abnormal somatosensory evoked potential readings occurring only above the C5-6 level in patients with adolescent idiopathic scoliosis; these findings might partially explain the pathophysiology of the neural pathway involved., (© 2014 by American Journal of Neuroradiology.)

Acid ceramidase (AC) is overexpressed in most prostate tumors and confers oncogenic phenotypes to prostate cancer cells. AC modulates the cellular balance between ceramide, sphingosine and sphingosine 1-phosphate (S1P). These bioactive sphingolipids have diverse, powerful and often oppositional impacts on cell signaling, including the activation status of the oncogenic kinase Akt. Our studies show that AC expression correlates with phosphorylation of Akt in human prostate tumors, and elevation of phosphorylated Akt in tumor versus patient-matched benign tissue is contingent upon AC elevation. Investigation of the mechanism for AC-induced Akt activation revealed that AC activates Akt through sphingosine kinase 1 (SphK1)-derived generation of S1P. This signaling pathway proceeds through S1P receptor 2 (S1PR2)-dependent stimulation of PI3K. Functionally, AC-overexpressing cells are insensitive to cytotoxic chemotherapy, however, these cells are more susceptible to targeted inhibition of Akt. AC-overexpressing cells proliferate more rapidly than control cells and form more colonies in soft agar; however, these effects are profoundly sensitive to Akt inhibition, demonstrating increased dependence on Akt signaling for the oncogenic phenotypes of AC-overexpressing cells. These observations may have clinical implications for targeted therapy as PI3K and Akt inhibitors emerge from clinical trials.

Unlabelled: The aim of this randomized controlled trial was to determine whether whole body vibration (WBV) therapy was effective for treating osteopenia in adolescent idiopathic scoliosis (AIS) patients. Results showed that WBV was effective for improving areal bone mineral density (aBMD) at the femoral neck of the dominant side and lumbar spine BMC in AIS subjects., Introduction: AIS is associated with osteopenia. Although WBV was shown to have skeletal anabolic effects in animal studies, its effect on AIS subjects remained unknown. The objective of this study was to determine whether WBV could improve bone mineral density (BMD) and bone quality for osteopenia in AIS subjects., Methods: This was a randomized, controlled trial recruiting 149 AIS girls between 15 and 25 years old and with bone mineral density (BMD) Z-scores <-1. They were randomly assigned to the Treatment or Control groups. The Treatment group (n = 61) stood on a low-magnitude high-frequency WBV platform 20 min/day, 5 days/week for 12 months. The Control group (n = 63) received observation alone. Bone measurement was done at baseline and at 12 months: (1) aBMD and BMC at femoral necks and lumbar spine using dual-energy X-ray absorptiometry (DXA) and (2) bone quality including bone morphometry, volumetric BMD (vBMD), and trabecular bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) for nondominant distal radius and bilateral distal tibiae., Results: The Treatment group had numerically greater increases in all DXA parameters with a statistically significant difference being detected for the absolute and percentage increases in femoral neck aBMD at the dominant leg (0.015 (SD = 0.031)g/cm(2), 2.15 (SD = 4.32)%) and the absolute increase in lumbar spine BMC (1.17 (SD = 2.05)g) in the Treatment group as compared with the Control group (0.00084 (SD = 0.026)g/cm(2), 0.13 (SD = 3.62)% and 0.47 (SD = 1.88)g, respectively). WBV had no significant effect for other bone quality parameters., Conclusions: WBV was effective for improving aBMD at the femoral neck of the dominant side and lumbar spine BMC in AIS subjects.

Loss of the cell adhesion protein E-cadherin increases the invasive capability of ovarian cancer cells. We have previously shown that epidermal growth factor (EGF) downregulates E-cadherin and induces ovarian cancer cell invasion through the H(2)O(2)/p38 MAPK-mediated upregulation of the E-cadherin transcriptional repressor Snail. However, the molecular mechanisms underlying the EGF-induced downregulation of E-cadherin are not fully understood. In the current study, we demonstrated that treatment of two ovarian cancer cell lines, SKOV3 and OVCAR5, with EGF induced the expression of the transcription factor Egr-1, and this induction was abolished by small interfering RNA (siRNA)-mediated depletion of the EGF receptor. EGF-induced Egr-1 expression required the activation of the ERK1/2 and PI3K/Akt signaling pathways and was unrelated to EGF-induced H(2)O(2) production and activation of the p38 MAPK pathway. Moreover, depletion of Egr-1 with siRNA abolished the EGF-induced downregulation of E-cadherin and increased cell invasion. Interestingly, siRNA depletion of Egr-1 attenuated the EGF-induced expression of Slug, but not that of Snail. Moreover, chromatin immunoprecipitation (ChIP) analysis showed that Slug is a target gene of Egr-1. These results provide evidence that Egr-1 is a mediator that is involved in the EGF-induced downregulation of E-cadherin and increased cell invasion. Our results also demonstrate that EGF activates two independent signaling pathways, which are the H(2)O(2)/p38 MAPK-mediated upregulation of Snail expression and the Egr-1-mediated upregulation of Slug expression. These two signaling pathways contribute to the EGF-induced downregulation of E-cadherin, which subsequently increases the invasive capability of ovarian cancer cells.

Background and Purpose: In this study, the clinical outcome and prognostic factors of adult medulloblastoma patients receiving multimodal treatment were investigated., Patients and Methods: The clinical manifestations, treatment variables, and outcome of adult patients with medulloblastoma at our institution between 1983 and 2009 were retrospectively reviewed., Results: A total of 20 adult patients were included (median age 22 years). Craniospinal irradiation (CSI) was given postoperatively. The craniospinal axis received a median of 30 Gy (range 23.4-39.6 Gy) in fractions of 1.6-2 Gy/day, and the tumor was boosted to a total median dose of 50 Gy (range 50-55.25 Gy). The 3-year disease-free survival (DFS) and overall survival (OS) rates for all patients were 45% and 50%, respectively. In univariate analysis, Karnofsky Performance Scale (KPS) > 70, neurologic symptoms duration > 30 days, lateral tumor location, standard risk patients, no hydrocephalus, radiotherapy (RT) treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were associated with better DFS. Standard-risk patients, RT treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were also significantly associated with better OS., Conclusion: The combined modality treatment results in a favorable outcome for adult medulloblastoma patients. Further investigation of the prognostic factors, radiation-related factors, and systemic chemotherapy is needed.

Unlabelled: Countermeasures are desirable to retard bone loss during long-term space flight. We evaluated the effect of an intervention protocol on bed rest-induced bone loss., Introduction: We developed a resistive vibration exercise (RVE) platform to test if an intervention RVE protocol would be effective to protect bed rest-induced bone loss., Methods: Fourteen male subjects were assigned randomly to either the RVE group (n = 7) that performed daily supervised resistive vibration exercise or to the no any exercise control (CON) group (n = 7). Both dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were used to monitor changes in bone mineral density., Results: RVE significantly prevented bone loss at multiple skeletal sites, including calcaneus, distal tibia, hip, and lumbar spine (L2-L4). The ratio of urinary calcium and creatinine was found higher after starting bed rest in CON group while no significant changes were observed in RVE group. No significant temporal change was found for osteocalcin-N during and after bed rest in CON group. However, a significant increase was shown after bed rest in RVE group. In both groups, the urinary concentration of bone resorption markers, such as C-telopeptide of type I collagen (CTX-I) and deoxypyridinoline (DPD), were significantly elevated after bed rest. In the CON group, no significant temporal effect was found for hydroxyproline (HOP), CTX-I, and DPD during bed rest and the serum concentration of HOP and TGF-β significantly increased about 52.04% and 24.03%, respectively only after bed rest. However, all these markers tended to decrease in the RVE group., Conclusions: Our results might imply that the intervention of RVE retarded bone loss induced by simulated microgravity in humans that was mainly attributed to its anabolic effects.

Antiviral effect of interferon is mediated by the expression of interferon-stimulated genes (ISGs). However, because of the difficulty in obtaining paired liver biopsies before and after interferon treatment, the key ISGs expressed in human hepatocytes and responsible for interferon-based antiviral activities in chronic hepatitis C remain illusive. Prior to a standard course of peginterferon plus ribavirin therapy, 104 patients underwent a liver biopsy. A small piece of the liver biopsy sample from each patient was submitted for ex vivo tissue culture in the presence or absence of interferon. Hepatic expression of 8 ISGs was detected by RT-PCR. The ISG expression patterns and clinicopathological variables were correlated with subsequent treatment outcomes. Multivariate logistic regression analysis showed that hepatic MxA expression (P = 0.008) and leucocyte count (P = 0.040) independently predicted the end of therapeutic virological response, while hepatic OAS1 expression (P = 0.003), genotype 1 (P = 0.002), HCV-RNA level (P = 0.007), AST/ALT ratio (P = 0.004) and leucocyte count (P = 0.034) independently predicted the sustained virological response. Immunohistochemistry analysis showed that interferon-induced OAS1 expression localized to the hepatocytes. In conclusion, hepatic MxA and OAS1 expression predicted, respectively, the end of therapeutic and sustained virological responses in interferon-based treatment of chronic hepatitis C., (© 2011 Blackwell Publishing Ltd.)

Matrix metalloproteinases (MMPs) associate with tumor progression and metastasis. We sought to investigate the role of MMP-9 from sublethally irradiated tumor in accelerated pulmonary metastasis of Lewis lung carcinoma (LLC-LM) and the corresponding anti-metastasis strategies in C57BL/6 mice. We used Matrigel-coated Boyden chamber assays and chicken chorioallantoic membrane assays to evaluate the invasion capability of irradiated LLC-LM cells (7.5 Gy), reverse transcription-polymerase chain reaction and the western blot assay to investigate the expression of MMPs by irradiated cells, and small interfering RNA duplexes to inhibit MMP-9 expression. LLC-LM cells differing in MMP-2 or -9 expression were subcutaneously injected into right thighs and the resulting tumors were irradiated (10 Gy × 5) to induce pulmonary metastasis. Radiation significantly enhanced MMP-9 at both the transcriptional and translational levels. MMP-9 siRNA significantly inhibited in vitro radiation-enhanced invasiveness. The number of radiation-accelerated pulmonary metastases was significantly reduced by MMP-9 knockdown and MMP-2/9 knockdown. Reverse transcription-polymerase chain reaction of LLC-LM cells in the blood and lung tissue revealed MMP-9 involvement in radiation-enhanced intravasation. Either higher-dose irradiation (30 Gy × 2) or pretreatment with prototypical MMP-9 inhibitor, zoledronic acid, significantly reduced the number of pulmonary metastases. The viability of irradiated tumor was seen on both positron emission tomography and magnetic resonance imaging, and tumor/serum MMP-9 levels suggested the association of local control of primary tumor and inhibition of time-dependent MMP-9 activities. Our results demonstrate that MMP-9 is crucially involved in radiation-enhanced LLC-LM cell invasiveness in vitro and in pulmonary metastasis from inadequately irradiated primary tumor in vivo.

Purpose: The accurate volumetric calculation of moving targets/organs is required to use cone-beam computed tomography (CBCT) for replanning purposes. This study was aimed to correct the reconstructed volume losses of moving phantoms by phase-specific CBCT., Materials and Methods: Planning fan-beam CT (FBCT) of five hepatobiliary/gastrointestinal/pancreatic cancer patients were acquired under active breathing control and compared with free-breathing CBCT for kidney volumes. Three different-sized ball phantoms were scanned by FBCT and CBCT. Images were imported to a planning system to compare the reconstructed volumes. The phantoms were moved longitudinally on an oscillator with different amplitudes/frequencies. The phase-specific projections of CBCT for moving phantoms were selected for volume reconstruction., Results: The differences in reconstructed volumes of static small, medium, large phantoms between FBCT and CBCT were - 6.7%, - 2.3%, and - 2.0%, respectively. With amplitudes of 7.5-20 mm and frequencies of 8-16 oscillations/min, volume losses on CBCT were comparable with FBCT in large moving phantoms (range 9.1-27.2%). Amplitudes were more subject to volume losses than frequencies. On phase-specific CBCT, volume losses were reduced to 2.3-6.5% by reconstruction using 2-3 projections at end/midoscillation phase., Conclusion: Amplitude had more impact than frequency on volume losses of moving phantoms on CBCT. Phase-specific CBCT reduced volume losses.

The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinoma-derived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibition-induced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.

A ferromagnetic resonance (FMR) spectrometer whose main components consist of an X-band resonator and a vector network analyzer (VNA) was developed. This spectrometer takes advantage of a high Q-factor (9600) cavity and state-of-the-art VNA. Accordingly, field modulation lock-in technique for signal to noise ratio (SNR) enhancement is no longer necessary, and FMR absorption can therefore be extracted directly. Its derivative for the ascertainment of full width at half maximum height of FMR peak can be found by taking the differentiation of original data. This system was characterized with different thicknesses of permalloy (Py) films and its multilayer, and found that the SNR of 5 nm Py on glass was better than 50, and did not have significant reduction even at low microwave excitation power (-20 dBm), and at low Q-factor (3000). The FMR other than X-band can also be examined in the same manner by using a suitable band cavity within the frequency range of VNA.

Serous borderline ovarian tumors (SBOTs) are slow-growing, non-invasive ovarian epithelial neoplasms. SBOTs are considered to be distinct entities that give rise to invasive low-grade serous carcinomas (LGCs), which have a relatively poor prognosis and are unrelated to high-grade serous carcinomas (HGCs). The mechanisms underlying the progression of non-invasive SBOTs to invasive epithelial ovarian carcinomas are not understood. We recently established short-term cultures of SBOT cells from tumor biopsies and showed that inactivation of p53, retinoblastoma (Rb) and/or PP2A by the simian virus 40 (SV40) large (LT) and small T antigens extends the life span of the cells and endows them with the ability to invade Matrigel-coated transwells. In this study, we show that concurrent inhibition of p53 and Rb by the SV40 LT produces cells (referred to as SBOT4-LT) with increased life span and cell invasion. To distinguish the roles of p53 and Rb in the progression from SBOTs to invasive ovarian carcinomas, we performed small interfering RNA-mediated knockdown of endogenous p53 in a spontaneously immortalized SBOT cell line, SBOT3.1, which increased cell invasion. This increased invasive activity was associated with the transcriptional downregulation of E-cadherin, correlated with an increase in PIK3CA levels and the increased activation of Akt. Conversely, in invasive LGC-derived MPSC1 cells, enhancing the levels of p53 decreased cell invasion and diminished the phosphatidylinositol 3-kinase (PI3K)/Akt-mediated downregulation of E-cadherin. Inhibition of Rb also enhanced invasiveness, but did not affect the levels of PIK3CA and E-cadherin in SBOT3.1 cells, suggesting that it functions by a different pathway. To our knowledge, this study is the first to show that p53 has an important role in the progression from SBOTs to invasive carcinomas. In addition, our findings suggest that downregulation of E-cadherin by the PI3K/Akt pathway contributes to this progression.

Acid ceramidase (AC) overexpression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC overexpression is the ability to convert ceramide, which is often produced as a proapoptotic response to stress, to sphingosine, which can then be converted to the prosurvival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines overexpressing AC also have increased lysosomal density and increased levels of autophagy. Furthermore, pretreatment with 3-methyladenine restores sensitivity of these cells to treatment with C(6) ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that AC overexpression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.

The severity of an influenza epidemic season may be influenced not only by variability in the surface glycoproteins, but also by differences in the internal proteins of circulating influenza viruses. To better understand viral antigenic evolution, all eight gene segments from 44 human H3N2 epidemic strains isolated during 2004-2008 in Taiwan were analyzed to provide a profile of protein variability. Comparison of the evolutionary profiles of the HA, NA and PB2 genes of influenza A (H3N2) viruses indicated that they were derived from a group of H3N2 isolates first seen in 2004. However, the PA, M and PB1 genes were derived from a different group of H3N2 isolates from 2004. Tree topology revealed the NP and NS genes could each be segregated into two groups similar to those for the polymerase genes. In addition, new genetic variants occurred during the non-epidemic period and become the dominant strain after one or two seasons. Comparison of evolutionary patterns in consecutive years is necessary to correlate viral genetic changes with antigenic changes as multiple lineages co-circulate., (© 2010 The Authors. Journal Compilation © 2010 European Society of Clinical Microbiology and Infectious Diseases.)

Background and Purpose: Adolescent idiopathic scoliosis (AIS) is a spinal deformity with unknown cause. Previous studies have suggested that subclinical neurologic abnormalities are associated with AIS. The objective of this prospective study was to characterize systematically neuroanatomic changes in patients with left thoracic AIS vs right thoracic AIS and healthy control subjects by using volume-based morphometry., Materials and Methods: Our current study involved 9 girls with left thoracic AIS and 20 girls with right thoracic AIS vs 11 and 17 matched female control subjects, respectively. Voxel-based morphometry (VBM), deformation-based morphometry (DBM), and tensor-based morphometry (TBM) were used to analyze the MR images aligned with a specific brain template of local adolescent girls. The statistical t test was used in VBM and TBM, and the Hotelling T(2) test was applied in DBM., Results: Using VBM, we found statistically significant differences (P < .05) in the white matter attenuation of the genu of the corpus callosum and left internal capsule (left thoracic AIS < control subjects). In contrast, no significant differences were observed between patients with right thoracic AIS and control subjects., Conclusions: White matter attenuation in the corpus callosum and left internal capsule, responsible for interhemispheric communication and conduit of the corticothalamic projectional fibers, respectively, were found to be significantly lower in left thoracic AIS compared with control subjects; however, this was not the case in right thoracic AIS. Confirmation of the findings is required in future research, which needs to evaluate the relationship of white matter abnormality to curve laterality, pathogenesis, and prognosis in patients with AIS, with biologic significance and possible therapeutic correction.

In this study, we evaluated the effectiveness of using swept-source optical coherence tomography (SS-OCT) to monitor the enhancement of hepatocellular carcinoma (HCC) cell invasiveness by radiation. SS-OCT images were acquired and recorded to obtain three-dimensional datasets at discrete time points of 12, 24 and 48 h after irradiating HepG2 cells with 7.5 Gy. The cell migration distance in three-dimensional tissue models was quantified from images of radiation-induced and sham-irradiated cells, and this method was compared with the conventional Boyden chamber assay conducted at the same time points. SS-OCT measurements show that most cells were found near the gel surface, but a few were much deeper. Among those HCC cells with a high degree of migration capability, the mean migration distances at 24 h and 48 h were significantly greater for irradiated cells than for sham-irradiated cells (0.7 +/- 0.23 mm versus 0.65 +/- 0.26 mm at 24 h, P = 0.019 and 0.84 +/- 0.30 mm versus 0.65 +/- 0.524 mm at 48 h, P = 0.009). The results of radiation-enhanced invasion in HCC cells obtained by the non-invasive, quantitative SS-OCT method were consistent with those obtained using the traditional assay for measuring biological invasion.

Background: It has been recognised that genetic or hereditary factors may contribute to the aetiology of adolescent idiopathic scoliosis (AIS). Recently, two linkage analyses have identified 19p13.3 as the candidate region for AIS. The dipeptidyl peptidase 9 (DPP9) gene is located on chromosome 19p13.3., Objective: To investigate whether DPP9 gene polymorphisms are associated with the occurrence or curve severity of AIS., Methods: 571 girls with AIS and 236 normal controls were recruited. Using the Chinese data from the HapMap project, a set of tagging single-nucleotide polymorphisms (tagSNPs) were defined for the DPP9 gene. Five SNPs were genotyped by PCR restriction fragment length polymorphism. Statistical analysis of genotype frequencies between cases and controls was performed by the chi2 test. One-way analysis of variance was used to compare mean maximum Cobb angles with different genotypes in case-only analysis., Results: Genotype frequencies were comparable between cases and controls for all five polymorphisms (p>0.05). The mean maximum Cobb angles of different genotypes were similar to each other for all five polymorphisms., Conclusions: The DPP9 gene is not associated with the occurrence or curve severity of AIS. It is neither a disease-predisposition nor a disease-modifying gene of AIS.

The aim of this study was to evaluate the outcome and prognosticators for patients with resectable head and neck cancer (RHNC) undergoing definitive concurrent chemotherapy and radiotherapy (CCRT). In total, 110 RHNC patients receiving definitive CCRT to defer radical surgery were enrolled. Radiotherapy was given as either 2 Gy once daily with 70 Gy, or 1.2 Gy twice daily with 74.4 Gy. Chemotherapy involved the administration of 5-fluorouracil and cisplatin in two concomitant and two post-radiotherapy adjuvant cycles. 3 months after CCRT, MRI was performed to evaluate the response and determine further treatment plans. Survival outcome was calculated by the Kaplan-Meier method. Log-rank test and Cox regression analyses were used to estimate the significance of prognosticators. 4-year local-regional control, distant metastasis-free survival, disease-free survival and overall survival rates were 76.1%, 85.6%, 67.5% and 53.2%, respectively. Local recurrence (odds ratio = 4.09; p < 0.0001) and T3/T4 stage (odds ratio = 2.34; p = 0.01) were the independent factors associated with poor survival. T stage (odds ratio = 3.29; p = 0.03) and/or remission status on post-CCRT MRI (odds ratio = 7.22; p < 0.0001) were significantly associated with local control, distant metastasis-free survival and disease-free survival. 13 of 20 patients with imaging residuum had local recurrence, compared with 12 of 89 with complete remission (4-year local control rate of 27% vs 86%; p < 0.0001). Post-CCRT MRI may thus be used to predict the chance of a successful non-surgical approach.

Purpose: To assess the length of the patellar tendon in Chinese and its correlation with patient age, gender, and operated side., Methods: 109 men and 11 women aged 15 to 45 (mean, 25) years underwent arthroscopic bone-tendon-bone reconstruction for anterior cruciate ligament (ACL) insufficiency. 55 (46%) injured the left side, and 65 (54%) the right side. Each patient's age, gender, and operated side were recorded. The length of the patellar tendon harvested was measured., Results: The mean length of the patellar tendon graft was 42.6 (standard deviation, 4.6; range, 30-54) mm. There was no correlation between the length of the patellar tendon and patient's age (p=0.147), gender (p=0.076), or operated side (p=0.466)., Conclusion: The length of the patellar tendon in the Chinese is comparable to that in Caucasians. Because of the shorter ACL but similar patellar tendon length, graft-tunnel mismatch may be more common in Chinese than Caucasian patients.

Background: The effect of traditional risk factors on the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and stroke was rarely studied previously. We investigated such effect in Taiwanese type 2 diabetic patients., Materials and Methods: A total of 872 (422 men and 450 women) patients aged 63.5 (SD: 11.6) years were recruited. Among them, 92 cases (48 men and 44 women) had stroke. Polymerase chain reaction was used to classify the genotypes as II, ID and DD. Analyses were performed in separate sexes., Results: The adjusted odds ratios for stroke for ID vs. II and DD vs. II were 0.837 (0.413-1.697) and 1.778 (0.596-5.300), respectively, for men; but were 1.700 (0.824-3.505) and 3.706 (1.375-9.985), respectively, for women. In models assuming recessive (DD vs. II + ID), dominant (DD + ID vs. II) and additive (II = 0, ID = 1 and DD = 2) transmission, none of the odds ratios was significant for men; but were all significant for women: 2.784 (1.137-6.818), 1.996 (1.006-3.962) and 1.877 (1.155-3.050), respectively. In models using patients without risk factors (hypertension, obesity, smoking or dyslipidaemia ) as a referent group and comparing them to patients with the risk factor and with ID/II, and with DD genotypes, all models (except for smoking) favoured an increasing trend of risk with patients having the risk factor and DD genotype at the highest risk in women. Similar trends for hypertension and dyslipidaemia were also observed in men., Conclusion: Traditional risk factors play an important role in the association between the ACE genotypes and stroke. Patients with DD genotype and having traditional risk factors are at the highest risk.