Osteoporosis and depression in perimenopausal women: From clinical association to genetic causality.

BACKGROUND: Osteoporosis and major depressive disorder (MDD) represent two significant health challenges globally, particularly among perimenopausal women. This study utilizes NHANES data and Mendelian randomization (MR) analysis to explore the link between them, aiming to provide a basis for intervention strategies for this group. METHODS: The study analyzed NHANES 2007-2018 data using weighted logistic regression in R software to evaluate the link between MDD and osteoporosis risk. Then, a two-sample MR analysis with GWAS summary statistics was performed, mainly using the IVW method. Additional validation included MR Egger, Weighted Median, Mode, and MR-PRESSO methods. RESULTS: The research analysis indicated a significant link between MDD and the risk of osteopenia/osteoporosis. Our analysis revealed a significant positive relationship between MDD and both femoral neck osteoporosis (OR = 6.942 [95 % CI, 1.692-28.485]) and trochanteric osteoporosis (OR = 4.140 [95 % CI, 1.699-10.089]). In analyses related to osteopenia, a significant positive correlation was observed between MDD and both total femoral osteopenia (OR = 3.309 [95 % CI, 1.577-6.942]) and trochanteric osteopenia (OR = 2.467 [95 % CI, 1.004-6.062]). Furthermore, in the MR analysis, genetically predicted MDD was causally associated with an increased risk of osteoporosis via the IVW method (P = 0.013). LIMITATIONS: Our study was limited by potential selection bias due to excluding subjects with missing data, and its applicability was primarily to European and American populations. CONCLUSION: Integrating NHANES and MR analyses, a robust correlation between MDD and osteoporosis was identified, emphasizing the significance of addressing this comorbidity within clinical practice and meriting further investigation.

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice.

Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca2+) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca2+ leakiness. Chemotherapy was furthermore associated with abnormalities in brain glucose metabolism and neurocognitive dysfunction in breast cancer mice. RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107. Genetic ablation of the RyR2 PKA phosphorylation site (RyR2-S2808A) also prevented the development of chemobrain. Chemotherapy increased brain concentrations of the tumor necrosis factor-α and transforming growth factor-ß signaling, suggesting that increased inflammatory signaling might contribute to oxidation-driven biochemical remodeling of RyR2. Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure-associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca2+ dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies.

Zoledronic acid improves bone quality and muscle function in a high bone turnover state.

SUMMARY: Zoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGFß release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease. Context and significance: TGFß is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGFß causes several bone disorders and skeletal muscle weakness. Reducing excess TGFß release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acid's benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.

11-epi-Sinulariolide Acetate-induced Apoptosis in Oral Cancer Cells Is Regulated by FOXO Through Inhibition of PI3K/AKT Pathway.

BACKGROUND/AIM: Oral cancer is a general term for carcinomas that occur around the oral tissues, and most are squamous cell carcinoma. Oral cancer is a common disease among Taiwanese males and poses a great threat to national health owing to its high mortality rate. In this study, we used the CAL-27 oral cancer cell lines as in vitro models to investigate the pathways involved in 11-epi-sinulariolide acetate (11-epi-SA)-induced apoptosis. MATERIALS AND METHODS: There have been no previous studies of the anticancer activity of 11-epi-SA isolated from Sinularia flexibilis against oral cancer. We used MTT assay, cell morphologic analysis, DNA fragmentation, TUNEL/DAPI assay, and JC-1 fluorescence staining to analyze the inhibitory effect of 11-epi-SA against the CAL-27 oral cancer cell line and assessed the potential molecular mechanism of apoptosis using western blot. RESULTS: Our results showed that 11-epi-SA inhibited CAL-27 cell proliferation, and its effect on cell growth was mediated through an apoptotic pathway mechanism. 11-epi-SA inhibited the PI3K/AKT pathway, allowing downstream FOXO to separate from 14-3-3 and return to the nucleus. We also observed that 11-epi-SA disrupted mitochondrial Bcl family protein homeostasis and activated caspase-3 and caspase-9, which led to apoptosis. CONCLUSION: A low concentration of 11-epi-SA can effectively induce apoptosis in oral cancer cells through the PI3K/AKT/FOXO pathway. 11-epi-SA has great potential as a new drug for the treatment of oral cancer.

Low-Magnitude Mechanical Signals Combined with Zoledronic Acid Reduce Musculoskeletal Weakness and Adiposity in Estrogen-Deprived Mice.

Combination treatment of Low-Intensity Vibration (LIV) with zoledronic acid (ZA) was hypothesized to preserve bone mass and muscle strength while reducing adipose tissue accrual associated with complete estrogen (E 2 )-deprivation in young and skeletally mature mice. Complete E 2 -deprivation (surgical-ovariectomy (OVX) and daily injection of aromatase inhibitor (AI) letrozole) were performed on 8-week-old C57BL/6 female mice for 4 weeks following commencement of LIV administration or control (no LIV), for 28 weeks. Additionally, 16-week-old C57BL/6 female E 2 -deprived mice were administered ±LIV twice daily and supplemented with ±ZA (2.5 ng/kg/week). By week 28, lean tissue mass quantified by dual-energy X-ray absorptiometry was increased in younger OVX/AI+LIV(y) mice, with increased myofiber cross-sectional area of quadratus femorii. Grip strength was greater in OVX/AI+LIV(y) mice than OVX/AI(y) mice. Fat mass remained lower in OVX/AI+LIV(y) mice throughout the experiment compared with OVX/AI(y) mice. OVX/AI+LIV(y) mice exhibited increased glucose tolerance and reduced leptin and free fatty acids than OVX/AI(y) mice. Trabecular bone volume fraction and connectivity density increased in the vertebrae of OVX/AI+LIV(y) mice compared to OVX/AI(y) mice; however, this effect was attenuated in the older cohort of E 2 -deprived mice, specifically in OVX/AI+ZA mice, requiring combined LIV with ZA to increase trabecular bone volume and strength. Similar improvements in cortical bone thickness and cross-sectional area of the femoral mid-diaphysis were observed in OVX/AI+LIV+ZA mice, resulting in greater fracture resistance. Our findings demonstrate that the combination of mechanical signals in the form of LIV and anti-resorptive therapy via ZA improve vertebral trabecular bone and femoral cortical bone, increase lean mass, and reduce adiposity in mice undergoing complete E 2 -deprivation. One Sentence Summary: Low-magnitude mechanical signals with zoledronic acid suppressed bone and muscle loss and adiposity in mice undergoing complete estrogen deprivation. Translational Relevance: Postmenopausal patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors to reduce tumor progression experience deleterious effects to bone and muscle subsequently develop muscle weakness, bone fragility, and adipose tissue accrual. Bisphosphonates (i.e., zoledronic acid) prescribed to inhibit osteoclast-mediated bone resorption are effective in preventing bone loss but may not address the non-skeletal effects of muscle weakness and fat accumulation that contribute to patient morbidity. Mechanical signals, typically delivered to the musculoskeletal system during exercise/physical activity, are integral for maintaining bone and muscle health; however, patients undergoing treatments for breast cancer often experience decreased physical activity which further accelerates musculoskeletal degeneration. Low-magnitude mechanical signals, in the form of low-intensity vibrations, generate dynamic loading forces similar to those derived from skeletal muscle contractility. As an adjuvant to existing treatment strategies, low-intensity vibrations may preserve or rescue diminished bone and muscle degraded by breast cancer treatment.

4-Carbomethoxyl-10-Epigyrosanoldie E Extracted from Cultured Soft Coral Sinularia sandensis Induced Apoptosis and Autophagy via ROS and Mitochondrial Dysfunction and ER Stress in Oral Cancer Cells.

Oral cancer is a malignant neoplasia that is more common in Asian than other regions, and men are at higher risk than women. Currently, clinical treatment for oral cancer consists of radiation therapy combined with chemotherapy. Therefore, it is important to find a drug that can inhibit the growth of cancer cells more effectively and safely. In this study, we examined the cytotoxicity of 4-carbomethoxyl-10-epigyrosanoldie E extracted from cultured soft coral Sinularia sandensis towards oral cancer cells. MTT cell proliferation and colony formation assays were used to evaluate cell survival, and immunofluorescence staining and Western blotting were employed to analyze the effects of 4-carbomethoxyl-10-epigyrosanoldie E on apoptosis and autophagy. 4-Carbomethoxyl-10-epigyrosanoldie E treatment also induced the formation of reactive oxygen species (ROS), which are associated with 4-carbomethoxyl-10-epigyrosanoldie E-induced cell death. In addition, the 4-carbomethoxyl-10-epigyrosanoldie E-induced antiproliferation effects on Ca9-22 and Cal-27 cells were associated with the release of cytochrome c from mitochondria, activation of proapoptotic proteins (such as caspase-3/-9, Bax, and Bad), and inhibition of antiapoptotic proteins (Bcl-2, Bcl-xl, and Mcl-1). 4-Carbomethoxyl-10-epigyrosanoldie E treatment also triggered endoplasmic reticulum (ER) stress, leading to activation of the PERK/elF2α/ATF4/CHOP apoptotic pathway. Moreover, increased expressions of Beclin-1, Atg3, Atg5, Atg7, Atg12, Atg 16, LC3-I, and LC3-II proteins indicated that 4-carbomethoxyl-10-epigyrosanoldie E triggered autophagy in oral cancer cells. In conclusion, our findings demonstrated that 4-carbomethoxyl-10-epigyrosanoldie E suppressed human oral cancer cell proliferation and should be further investigated with regard to its potential use as a chemotherapy drug for the treatment of human oral cancer.

Relationships Between Metabolic Body Composition Status and Rapid Kidney Function Decline in a Community-Based Population: A Prospective Observational Study.

Obesity and metabolic syndrome are strong risk factors for incident chronic kidney disease (CKD). However, the predictive accuracy of metabolic body composition status (MBCS), which combines the status of obesity and metabolic syndrome, for rapid kidney function decline (RKFD) is unclear. The aim of this study was to investigate the relationship between MBCS and RKFD in a healthy population in a prospective community-based cohort study. In the current study, we followed changes in renal function in 731 people residing in northern Taiwan for 5 years. The participants were divided into four groups according to their MBCS, including metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy overweight (MUOW). We evaluated traditional risk factors for CKD and metabolic profiles. The primary outcome was RKFD, which was defined as a 15% decline in estimated glomerular filtration rate (eGFR) within the first 4 years, and a reduction in eGFR which did not improve in the 5th year. During the study period, a total of 731 participants were enrolled. The incidence of RKFD was 17.1% (125/731). Multiple Cox logistic regression hazard analysis revealed that age, cerebrovascular accident, eGFR, urine albumin-to-creatinine ratio, use of painkillers, depressive mood, MUNW and MUOW were independent predictors of RKFD. After adjusting for age, sex, eGFR and total cholesterol, the participants with MUNW and MUOW had higher hazard ratios (HRs) for RKFD [HR: 2.19, 95% confidence interval (CI): 1.22-3.95 for MUNW; HR: 1.86, 95% CI: 1.21-2.87 for MUOW] than those with MHNW. Similar results were also observed in subgroup analysis of those aged above 65 years. On the basis of the results of this study, we conclude that MBCS was independently associated with RKFD, especially in the older adults. On the basis of our results, we suggest that MUNW and MUOW should be considered as risk factors for RKFD.

Deep learning for predicting immunotherapeutic efficacy in advanced non-small cell lung cancer patients: a retrospective study combining progression-free survival risk and overall survival risk.

Background: Radiomics based on computed tomography (CT) images is potential in promoting individualized treatment of non-small cell lung cancer (NSCLC), however, its role in immunotherapy needs further exploration. The aim of this study was to develop a CT-based radiomics score to predict the efficacy of immune checkpoint inhibitor (ICI) monotherapy in patients with advanced NSCLC. Methods: Two hundred and thirty-six ICI-treated patients were retrospectively included and divided into a training cohort (n=188) and testing cohort (n=48) at a ratio of 8 to 2. The efficacy outcomes of ICI were evaluated based on overall survival (OS) and progression-free survival (PFS). We designed a survival network and combined it with a Cox regression model to obtain patients' OS risk score (OSRS) and PFS risk score (PFSRS). Results: Based on OSRS and PFSRS, patients were divided into high- and low-risk groups in the training cohort and the test cohort with distinctly different [training cohort, log-rank P<0.001, hazard ratio (HR): 4.14; test cohort, log-rank P=0.014, HR: 4.54] and PFS (training cohort, log-rank P<0.001, HR: 4.52; test cohort, log-rank P<0.001, HR: 6.64). Further joint evaluation of OSRS and PFSRS showed that both were significant in the Cox regression model (P<0.001), and multi-overall survival risk score (MOSRS) displayed more outstanding stratification capabilities than OSRS in both the training (P<0.001) and test cohorts (P=0.002). None of the clinical characteristics were significant in the Cox regression model, and the score that predicted the best immune response was not as good as the risk score from follow-up information in the performance of prognostic stratification. Conclusions: We developed a CT imaging-based score with the potential to become an independent prognostic factor to screen patients who would benefit from ICI treatment, which suggested that CT radiomics could be applied for individualized immunotherapy of NSCLC. Our findings should be further validated by future larger multicenter study.

Temperature sensor based on fiber Bragg grating combined with a microwave photonic-assisted fiber loop ring down.

A temperature sensor based on fiber Bragg grating (FBG) combined with a microwave photonic-assisted fiber loop ring down (FLRD) is proposed and experimentally investigated. An optical edge filter (OEF) is inserted in the FLRD to provide a wavelength dependent loss; thanks to the linear response of the OEF, the wavelength shift of the FBG caused by the applied temperature is linearly converted to the additional loss of the FLRD. The frequency response of the FLRD is measured by a vector network analyzer (VNA), the time domain ring-down curves are calculated by applying invert faster Fourier transform (IFFT) to the frequency response. Subsequently, the relationship between the ring-down time and the temperature applied to the FBG is obtained. Results show a good linearity between the ring-down time and the temperature. Limited by the VNA used in our experiment, the sensitivity of the proposed sensor is 6.30 ns/°C in the temperature range of 40-45 °C with a resolution of ±0.14 °C.

Learning Curve of Upper Aerodigestive Tract Foreign Body Management for Otorhinolaryngology Residents.

INTRODUCTION: Foreign body ingestion is the most common reason for otolaryngology specialist consultations in emergency departments. Among the different types of foreign bodies, fish bones are the most common, particularly in Asian populations. In Taiwan, upper aerodigestive tract foreign bodies (UADT-FBs) are mostly managed by residents in the otorhinolaryngology (ORL) department. Considering the learning curve required for all procedures, different management types between residents, and possible resulting safety issues, this study explored the outcomes of UADT-FB management by residents in different years of ORL training. MATERIALS AND METHODS: The medical records of 2,283 patients who visited Kaohsiung Veterans General Hospital's Emergency Department for UADT-FB during June 2013-August 2019 were retrospectively reviewed. The reviewed data included the demographic data of enrolled patients, outcomes of foreign body management, and follow-up chart records of the patients. RESULTS: Among the 2,283 patients, 1,324 (58%) were found to be negative for foreign bodies, and foreign bodies in 951 (41.7%) were removed immediately. In the negative finding (NF) group, 2 (4.9%) patients were later found to be positive for foreign bodies during follow-up in the outpatient department. One (2.4%) patient developed a deep neck infection and esophageal perforation. The percentage of NFs decreased from 62.58% in residents in the first half of their first year (R1a) to 54% for third-year residents (R3). Comparing R1a with R3, the number needed to harm for retained UADT-FBs after patients visited the emergency department was 12.2. DISCUSSION/CONCLUSION: This study provides data from 1 referral center regarding the management of UADT-FBs. With increasing resident training, the percentage of NFs declined from 62.58 to 54%. Young residents, especially those in the first 6 months of their training, should have senior residents perform a second examination if UADT-FBs are not found in suspected cases.

Effective Preventive Strategies to Prevent Secondary Transmission of COVID-19 in Hemodialysis Unit: The First Month of Community Outbreak in Taiwan.

BACKGROUND: Dialyzed patients are vulnerable to coronavirus infection disease 2019 (COVID-19). The incidence and outcome of COVID-19 in hemodialysis (HD) patients in Taiwan remain unclear. A series of preventive measures were executed to combat COVID-19 transmission among HD patients. METHODS: We carried out a series of forward-looking and practical preventive strategies of COVID-19 control in our HD center. Incidences of COVID-19 of our HD unit were compared with those of national and local estimates from a community outbreak from 15 May to 30 June 2021. Prognostic factors associated with mortality were analyzed. RESULTS: The national incidence of COVID-19 was 0.062%; being highest in Taipei City (0.173%), followed by New Taipei City (0.161%) and Keelung (0.083%). The overall incidence in Keelung HD patients was 0.666%. One patient of our HD center contracted COVID-19 from the household; however, we have contained secondary transmission in our HD center by implementing strict preventive measures. The mortality rate of HD patients in Keelung was 66.6%. The median Ct value of HD patients was 17.53 (11.75-27.90) upon diagnosis. The deceased patients had a higher cardiac/thoracic ratio than alive (0.61 vs. 0.55, p = 0.036). CONCLUSIONS: Taking aggressive and proactive infection preventive measures impedes the secondary transmission of COVID-19 in HD facilities. COVID-19-associated mortality was high in HD patients, being the high cardiac-thoracic ratio, an important prognostic factor for clinical outcome of infected HD patients.

Radiomics nomogram for prediction disease-free survival and adjuvant chemotherapy benefits in patients with resected stage I lung adenocarcinoma.

BACKGROUND: Robust imaging biomarkers are needed for risk stratification in stage I lung adenocarcinoma patients in order to select optimal treatment regimen. We aimed to construct and validate a radiomics nomogram for predicting the disease-free survival (DFS) of patients with resected stage I lung adenocarcinoma, and further identifying candidates benefit from adjuvant chemotherapy (ACT). METHODS: Using radiomics approach, we analyzed 554 patients' computed tomography (CT) images from three multicenter cohorts. Prognostic radiomics features were extracted from computed tomography (CT) images and selected using least absolute shrinkage and selection operator (LASSO) Cox regression model to build a radiomics signature for DFS stratification. The biological basis of radiomics was explored in the Radiogenomics dataset (n=79) by gene set enrichment analysis (GSEA). Then a nomogram that integrated the signature with these significant clinicopathologic factors in the multivariate analysis were constructed in the training cohort (n=238), and its prognostic accuracy was evaluated in the validation cohort (n=237). Finally, the predictive value of nomogram for ACT benefits was assessed. RESULTS: The radiomics signature with higher score was significantly associated with worse DFS in both the training and validation cohorts (P<0.001). The GSEA presented that the signature was highly correlated to characteristic metabolic process and immune system during cancer progression. Multivariable analysis revealed that age (P=0.031), pathologic TNM stage (P=0.043), histologic subtype (P=0.010) and the signature (P<0.001) were independently associated with patients' DFS. The integrated radiomics nomogram showed good discrimination performance, as well as good calibration and clinical utility, for DFS prediction in the validation cohort. We further found that the patients with high points (point ≥8.788) defined by the radiomics nomogram obtained a significant favorable response to ACT (P=0.04) while patients with low points (point <8.788) showed no survival difference (P=0.7). CONCLUSIONS: The radiomics nomogram could be used for prognostic prediction and ACT benefits identification for patient with resected stage I lung adenocarcinoma.

Sarcopenia results in poor survival rates in oral cavity cancer patients.

OBJECTIVE: This study aimed to determine the impact or survival of low skeletal muscle mass (SMM) among patients with oral squamous cell carcinoma (OSCC) undergoing primary surgery. DESIGN: This study was a retrospective cohort study. SETTING: Oral squamous cell carcinoma patients treated at our referral centre from April 2005 to March 2014 were examined. PARTICIPANTS: The cohort comprised 276 patients with OSCC undergoing primary surgery. MAIN OUTCOME MEASURES: Estimated SMM was measured by calculating the cervical skeletal muscle mass from a CT scan of the head and neck. The 5-year overall survival (OS) and disease-specific survival (DSS) were analysed using a multivariable Cox regression model. RESULTS: There were 276 patients with a male-to-female ratio of 12:1. A low SMM (<47.5 cm2 /m2 ) was associated with worse survival. After adjustment for other factors, the result remained robust for OS (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.14-2.67) and disease-specific survival (HR 1.67, 95% CI 1.04-2.67). In the subgroup analysis, worse OS and DSS were particularly noted in male patients (HR = 1.90, 95% CI 1.22-2.97; HR = 1.91, 95% CI 1.27-3.19) and in those younger than 60 years of age (HR = 1.91, 95% CI 1.14-3.22; HR = 2.12, 95% CI 1.23-3.64) with low SMM. CONCLUSIONS: Low SMM was a significant independent factor that was associated with lower survival in patients who have oral cavity cancers and are undergoing primary surgery. Preoperative CT scans of the head and neck could be utilised to evaluate SMM, predict treatment outcomes and facilitate nutrition management.

Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.

Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.

Primary tumour resection showed survival benefits for non-small-cell lung cancers with unexpected malignant pleural dissemination.

OBJECTIVES: Although non-small-cell lung cancer (NSCLC) with malignant pleural nodules is generally contraindicated for surgery, there is no consensus concerning on-site operative decisions for unexpected, intraoperatively encountered malignant pleural disseminations. The rationale underlying the primary tumour removal and other aggressive interventions remains controversial. METHODS: All surgical NSCLC cases (9576) of Shanghai Pulmonary Hospital between January 2005 and December 2013 were reviewed. Among them, 83 cases (0.9%) met the definition of 'unexpected' macroscopic malignant pleural nodules, despite routine preoperative evaluations for tumour metastasis. No pleural effusion was visualized in 52 cases during operations, and 31 had pleural effusion in minimal volume (<300 ml). Survivals were calculated with the Kaplan-Meier method and risk factors were evaluated by the log-rank test. RESULTS: The overall 3- and 5-year survival rates were 36.1 and 16.8%, respectively. The median survival time (MST) after surgery was significantly longer in the group without pleural effusion (37 months) compared with the group with pleural effusion (22 months, P = 0.005). Twenty-one cases had only biopsy, whereas 62 cases had primary tumour resection. Primary tumour resection had significantly better outcome compared with biopsy (MST: respectively, 35 vs 17 months, 3-year survival rate 45.8 vs 11.8%, P = 0.001). No baseline differences emerged in characteristics between biopsy and primary tumour resection groups including targeted therapy. Multivariate analysis showed that primary tumour resection (HR: 3.678, P = 0.014), no pleural effusion (HR: 3.409, P = 0.001) and adenocarcinoma (HR: 5.481, P = 0.002) were favourable prognostic factors in patients with malignant pleural nodules. CONCLUSIONS: Patients with malignant pleural nodules but without pleural effusion had better survival compared with those with effusions. Primary tumour resection had survival benefits for patients with unexpected intraoperatively proven malignant pleural nodules.

Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model.

Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well-characterized in clinically relevant animal models. Using 20-week-old male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One week postirradiation, trabecular bone volume declined in irradiated tibias (-22%; p < 0.0001) and femurs (-14%; p = 0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibias (-17%; p = 0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number, and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, whereas osteoblast number was unchanged. Despite no change in osteoblast number 1 week postirradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose-dependent and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, whereas calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48 hours postirradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation, and coculture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multifaceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses; they have important implications for bone health in patients treated with radiation therapy.

Transnasal endoscopic orbital decompression: 15-year clinical experience in Southern Taiwan.

BACKGROUND/PURPOSE: To present the results and evaluate the efficacy of endoscopic transnasal orbital decompression for dysthyroid orbitopathy. METHODS: Retrospective chart review of patients who underwent endoscopic transnasal orbital decompression from 1996 to 2010 in one institution. We included 42 orbits of 25 patients. Preoperative and postoperative examinations included visual acuity, Hertel exophthalmometry, tonometry, exposure keratitis, and diplopia. The measurements of outcome depend on proptosis reduction, intraocular pressure reduction, and visual acuity improvement of 42 orbits of 25 patients. RESULTS: There were no surgical complications for the 42 orbital decompressions except one patient experienced cerebrospinal fluid leak during the operation. Mean proptosis reduction in all orbits was 1.93 ± 0.25 (mean ± standard deviation, p < 0.01) after 1 month postoperatively and 2.07 ± 0.29 (p < 0.01) after 3 months postoperatively. An average reduction of intraocular pressure was 4.40 ± 0.72 (p < 0.01) and 4.38 ± 0.80 (p < 0.01) respectively after 1 and 3 months postoperatively. Visual acuity increased from a preoperative average of 0.45 ± 0.34 to 0.66 ± 0.36 and 0.70 ± 0.35 after 1 and 3 months postoperatively. In addition, postoperative relief of exposure keratitis is also noted. CONCLUSION: The transnasal orbital decompression procedure has statistically significant improvements in proptosis, intraocular pressure, and visual acuity. The procedure has obvious benefit in relieving exposure keratitis. Furthermore, there are favorable cosmetic results and rare complications.

Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats.

Our previous study shows that conventional protein kinases C (cPKCs) are key signaling mediators that are activated by extracellular inhibitory molecules. Inhibition of cPKC by intrathecal infusion of a cPKC inhibitor, GÖ6976, into the site of dorsal hemisection (DH) induces regeneration of lesioned dorsal column sensory, but not corticospinal tract (CST), axons. Here, we investigated whether a direct cortical delivery of GÖ6976 into the soma of corticospinal neurons promotes regeneration of CST and the recovery of forelimb function in rats with cervical spinal cord injuries. We report that cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKCα and PKCß1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GÖ6976 promoted even greater CST axonal regeneration and recovery of forelimb function. Thus, this study has demonstrated a novel strategy that can promote anatomical regeneration of damaged CST axons and partial recovery of forelimb function. Importantly, such an effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons.

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB.

The ubiquitous inducible transcription factor NF-κB plays central roles in immune and inflammatory responses and in tumorigenesis. Complex posttranslational modifications of the p65 subunit (RelA) are a major aspect of the extremely flexible regulation of NF-κB activity. Although phosphorylation, acetylation, ubiquitination, and lysine methylation of NF-κB have been well described, arginine methylation has not yet been found. We now report that, in response to IL-1ß, the p65 subunit of NF-κB is dimethylated on arginine 30 (R30) by protein-arginine methyltransferase 5 (PRMT5). Expression of the R30A and R30K mutants of p65 substantially decreased the ability of NF-κB to bind to κB elements and to drive gene expression. A model in which dimethyl R30 is placed into the crystal structure of p65 predicts new van der Waals contacts that stabilize intraprotein interactions and indirectly increase the affinity of p65 for DNA. PRMT5 was the only arginine methyltransferase that coprecipitated with p65, and its overexpression increased NF-κB activity, whereas PRMT5 knockdown had the opposite effect. Microarray analysis revealed that ∼85% of the NF-κB-inducible genes that are down-regulated by the R30A mutation are similarly down-regulated by knocking PRMT5 down. Many cytokine and chemokine genes are among these, and conditioned media from cells expressing the R30A mutant of p65 had much less NF-κB-inducing activity than media from cells expressing the wild-type protein. PRMT5 is overexpressed in many types of cancer, often to a striking degree, indicating that high levels of this enzyme may promote tumorigenesis, at least in part by facilitating NF-κB-induced gene expression.