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Objective: This study examined the effect of Sirtuin 4 (Sirt4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC)., Methods: Data from The Cancer Genome Atlas (TCGA) were analyzed to identify Sirt4 expression in thyroid cancer. Subsequently, the correlation between Sirt4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated Sirt4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model., Results: GEO and TCGA data indicated that Sirt4 expression is lower in thyroid cancer and Sirt4 downregulation is associated with poor overall survival. In our PTC tissues, positive Sirt4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of Sirt4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. Sirt4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial-mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model., Conclusion: This study provides novel insight into the potential contribution of Sirt4 to regulation of the pathological progression of PTC. The data suggest that Sirt4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of Sirt4.

Purpose: Finasteride and dutasteride are used to treat benign prostatic hyperplasia (BPH) and reduce the risk of developing prostate cancer. Finasteride blocks only the type 2 form of 5-alpha-reductase, whereas dutasteride blocks both type 1 and 2 forms of the enzyme. Previous studies suggest the possibility that dutasteride may be superior to finasteride in preventing prostate cancer. We directly compared the effects of finasteride and dutasteride on the risk of prostate cancer in patients with BPH using a pooled analysis of 15 real-world databases., Materials and Methods: We conducted a multicenter, cohort study of new-users of finasteride and dutasteride. We include patients who were prescribed 5 mg finasteride or dutasteride for the first time to treat BPH and had at least 180 days of prescription. We excluded patients with a history of prostate cancer or a prostate-specific antigen level ≥ 4 ng/mL before the study drug prescription. Cox regression analysis was performed to examine the hazard ratio (HR) for prostate cancer after propensity score (PS) matching., Results: A total of 8,284 patients of new-users of finasteride and 8,670 patients of new-users of dutasteride were included across the 15 databases. In the overall population, compared to dutasteride, finasteride was associated with a lower risk of prostate cancer in both on-treatment and intent-to-treat time-at-risk periods. After 1:1 PS matching, 4,897 patients using finasteride and 4,897 patients using dutasteride were enrolled in the present study. No significant differences were observed for risk of prostate cancer between finasteride and dutasteride both on-treatment (HR=0.66, 95% confidence interval [CI]: 0.44-1.00; p=0.051) and intent-to-treat time-at-risk periods (HR=0.87, 95% CI: 0.67-1.14; p=0.310)., Conclusions: Using real-world databases, the present study demonstrated that dutasteride was not associated with a lower risk of prostate cancer than finasteride in patients with BPH., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Background: Gastric cancer, one of the leading causes of cancer-related death, is strongly associated with H. pylori infection, although other risk factors have been identified. The sirtuin (Sirt) family is involved in the tumorigenesis of gastric cancer, and sirtuins can have pro- or anti-tumorigenic effects., Methods: After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression, the effect of Sirt6 upregulation was also tested using a xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of mouse double minute 2 homolog (MDM2) and reactive oxygen species (ROS), was mainly analyzed using Western blotting and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins was measured using flow cytometric analysis., Results: Sirt6 overexpression led to Sirt1 suppression in gastric cancer cells, resulting in a higher level of gastric cancer cell death in vitro and a reduced tumor volume. ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression according to Western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death as determined via Western blot and flow cytometric analysis., Conclusion: We found that the upregulation of Sirt6 suppressed Sirt1, and Sirt6- and Sirt1-induced gastric cancer cell death was mediated by ROS production. These findings highlight the potential of Sirt6 and Sirt1 as therapeutic targets for treating gastric cancer.

Purpose: This study aimed to investigate the potential role of copine-1 (CPNE1), a calcium-dependent membrane-binding protein encoded by the CPNE1 gene, in colorectal cancer (CRC). Despite previous research on the involvement of copine family members in various solid tumors, the specific role of CPNE1 in CRC remains poorly understood., Methods: We conducted clinicopathological analysis and functional studies to explore the impact of CPNE1 in human CRC. We examined the expression levels of CPNE1 in CRC patients and correlated it with invasive depth, lymph node metastasis, distant metastasis, lymphatic invasion, and TNM stage. Additionally, we performed experiments to assess the functional consequences of CPNE1 knockdown in CRC cells, including proliferation, colony formation, migration, invasion, and the expression of key regulators involved in the cell cycle and epithelial-mesenchymal transition (EMT). Furthermore, we evaluated the effects of CPNE1 knockdown on tumor growth using a xenograft mouse model., Results: High expression of CPNE1 was significantly associated with advanced tumor features in CRC patients. CPNE1 knockdown in CRC cells led to impaired abilities in proliferation, colony formation, migration, and invasion. Furthermore, CPNE1 silencing resulted in the suppression of protein expression related to the cell cycle and EMT. In the xenograft mouse model, CPNE1 knockdown inhibited tumor growth., Conclusion: CPNE1 plays a crucial role in promoting tumorigenesis and metastasis in human CRC. By regulating the cell cycle and EMT, CPNE1 influences critical cellular processes at the membrane-cytoplasm interface. These results provide valuable insights into the potential development of novel therapeutic strategies for CRC targeting CPNE1., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2023, the Korean Surgical Society.)

One of the causes of sarcopenia is that homeostasis between anabolism and catabolism breaks down due to muscle metabolism changes. Rutin has shown antioxidant and anti-inflammatory effects in various diseases, but there are few studies on the effect on muscle loss with aging. The effect of rutin on muscle loss was evaluated using dexamethasone-induced muscle loss C2C12 myoblast and mouse model. In the group treated with dexamethasone, the muscle weight of gastrocnemius (GA), tibialis anterior (TA), and extensor digitorum longus (EDL) in the mouse model were significantly decreased ( p < 0.0001 in GA, p < 0.0001 in TA, and p < 0.001 in EDL) but recovered ( p < 0.01 in GA, p < 0.0001 in TA, and p < 0.01 in EDL) when treated with rutin. MAFbx, MuRF1, and FOXO3 protein expression of C2C12 myoblast were significantly increased ( p < 0.01 in MAFbx, p < 0.01 in MuRF1, and p < 0.01 in FOXO3) when treated with dexamethasone, but it was recovered ( p < 0.01 in MAFbx, p < 0.01 in MuRF1, and p < 0.01 in FOXO3) when rutin was treated. In addition, MAFbx and FOXO3 protein expression in GA of mouse model was significantly increased ( p < 0.0001 in MAFbx and p < 0.001 in FOXO3) when treated with dexamethasone, but it was also recovered ( p < 0.01 in MAFbx and p < 0.001 in FOXO3) when rutin was treated. The present study shows that rutin blocks the FOXO3/MAFbx and FOXO3/MuRf1 pathways to prevent protein catabolism. Therefore, rutin could be a potential agent for muscle loss such as sarcopenia through the blocking ubiquitin-proteasome pathway associated with catabolic protein degradation.

Purpose: To identify changes in prostate cancer (PCa) risk-stratification during the last two decades in Korea, where the social perception of PCa was limited due to a relatively low incidence but has recently been triggered by the rapidly increasing incidence of benign prostate hyperplasia., Materials and Methods: Retrospective data of patients who had received a diagnosis of PCa in a single Korean province (Daegu-Gyeongsangbuk) at all seven training hospitals in the years 2003, 2007, 2011, 2015, 2019, and 2021 were subjected to analysis. Changes in PCa risk-stratification were investigated with respect to serum prostate-specific antigen (PSA), Gleason score (GS), and clinical stage., Results: Of the 3,393 study subjects that received a diagnosis of PCa, 64.1% had high-risk disease, 23.0% intermediate, and 12.9% low-risk disease. The proportion diagnosed with high-risk disease was 54.8% in 2003, 30.6% in 2019, but then increased to 35.1% in 2021. The proportion of patients with high PSA (>20 ng/mL) steadily decreased from 59.4% in 2003 to 29.6% in 2021, whereas the proportion with a high GS (>8) increased from 32.8% in 2011 to 34.0% in 2021, and the proportion with advanced stage disease (over cT2c) increased from 26.5% in 2011 to 37.1% in 2021., Conclusions: In this retrospective study, conducted in a single Korean province, high-risk PCa accounted for the largest proportion of newly registered Korean PCa patients during the last two decades and increased in the early 2020s. This outcome supports the adoption of nationwide PSA screening, regardless of current Western guidelines., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia., Competing Interests: The authors have declared that no competing interests exist.

Sarcopenia refers to a decline in muscle mass and strength with age, causing significant impairment in the ability to carry out normal daily functions and increased risk of falls and fractures, eventually leading to loss of independence. Maintaining protein homeostasis is an important factor in preventing muscle loss, and the decrease in muscle mass is caused by an imbalance between anabolism and catabolism of muscle proteins. Although β-sitosterol has various effects such as anti-inflammatory, protective effect against nonalcoholic fatty liver disease (NAFLD), antioxidant, and antidiabetic activity, the mechanism of β-sitosterol effect on the catabolic pathway was not well known. β-sitosterol was assessed in vitro and in vivo using a dexamethasone-induced muscle atrophy mice model and C2C12 myoblasts. β-sitosterol protected mice from dexamethasone-induced muscle mass loss. The thickness of gastrocnemius muscle myofibers was increased in dexamethasone with the β-sitosterol treatment group (DS). Grip strength and creatine kinase (CK) activity were also recovered when β-sitosterol was treated. The muscle loss inhibitory efficacy of β-sitosterol in dexamethasone-induced muscle atrophy in C2C12 myotube was also verified in C2C12 myoblast. β-sitosterol also recovered the width of myotubes. The protein expression of muscle atrophy F-box (MAFbx) was increased in dexamethasone-treated animal models and C2C12 myoblast, but it was reduced when β-sitosterol was treated. MuRF1 also showed similar results to MAFbx in the mRNA level of C2C12 myotubes. In addition, in the gastrocnemius and tibialis anterior muscles of mouse models, Forkhead Box O1 (FoxO1) protein was increased in the dexamethasone-treated group (Dexa) compared with the control group and reduced in the DS group. Therefore, β-sitosterol would be a potential treatment agent for aging sarcopenia.

Background: Androgen deprivation therapy for prostate cancer is known to increase the risk of cardiovascular disease, but there is controversy regarding the cardiovascular risk in patients with preexisting cardiovascular disease. This study assessed the risk of cardiovascular intervention after androgen deprivation therapy in patients with a history of cardiovascular disease, cerebrovascular disease, and cardiovascular intervention., Materials and Methods: Between 2008 and 2017, 195,308 men with newly diagnosed prostate cancer were identified from the nationwide claims database in South Korea. Among them, 49,090 men with a history of ischemic cardiovascular and cerebrovascular diseases were analyzed. The patients were divided into the androgen deprivation therapy (n = 14,092) and non-androgen deprivation therapy (n = 34,988) groups. The primary outcome was cardiovascular interventions (percutaneous transluminal angioplasty and coronary bypass surgery). Cox proportional hazard regression models were used to estimate the adjusted hazard ratios and 95% confidence intervals of the events., Results: After balancing the covariates with 1:1 exact matching, the two groups had 10,514 subjects each. Multivariable analysis demonstrated that androgen deprivation therapy was not significantly associated with an increased risk of cardiovascular interventions (hazard ratio, 1.060; 95% confidence interval, 0.923-1.217; P = 0.4104), regardless of the duration of therapy. A history of cardiovascular intervention, diabetes mellitus, antithrombotic medication use, and cardiovascular events significantly increased the risk of cardiovascular intervention., Conclusions: Androgen deprivation therapy was not associated with cardiovascular intervention in patients with a previous history of cardiovascular disease, regardless of the duration of therapy. Therefore, the cardiovascular risk of androgen deprivation therapy should be reassessed in this population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Semisulcospira libertina, a species of freshwater snail, is widespread in East Asia. It is important as a food source. Additionally, it is a vector of clonorchiasis, paragonimiasis, metagonimiasis, and other parasites. Although S. libertina has ecological, commercial, and clinical importance, its whole-genome has not been reported yet. Here, we revealed the genome of S. libertina through de novo assembly. We assembled the whole-genome of S. libertina and determined its transcriptome for the first time using Illumina NovaSeq 6000 platform. According to the k-mer analysis, the genome size of S. libertina was estimated to be 3.04 Gb. Using RepeatMasker, a total of 53.68% of repeats were identified in the genome assembly. Genome data of S. libertina reported in this study will be useful for identification and conservation of S. libertina in East Asia.

Sarcopenia leads to loss of skeletal muscle mass, quality, and strength due to aging; it was recently given a disease code (International Classification of Diseases, Tenth Revision, Clinical Modification, M62.84). As a result, in recent years, sarcopenia-related research has increased. In addition, various studies seeking to prevent and treat sarcopenia by identifying the various mechanisms related to the reduction of skeletal muscle properties have been conducted. Previous studies have identified muscle synthesis and breakdown; investigating them has generated evidence for preventing and treating sarcopenia. Mouse models are still the most useful ones for determining mechanisms underlying sarcopenia through correlations and interventions involving specific genes and their phenotypes. Mouse models used to study sarcopenia often induce muscle atrophy by hindlimb unloading, denervation, or immobilization. Though it is less frequently used, the senescence-accelerated mouse can also be useful for sarcopenia research. Herein, we discuss cases where senescence-accelerated and genetically engineered mouse models were used in sarcopenia research and different perspectives to use them.

Background: Serum biomarkers associated with the severity of non-cystic fibrosis (CF) bronchiectasis are insufficient. This study determined the association of serum hepatocyte growth factor (HGF), osteopontin, and pentraxin-3 levels with disease severity and exacerbation in patients with non-CF bronchiectasis., Methods: Serum levels of HGF, osteopontin, and pentraxin-3 were measured in patients with clinically stable non-CF bronchiectasis (n = 61). The correlation between the biomarkers and bronchiectasis severity index (BSI) and FACED score was assessed using univariate and multivariate linear regression analyses. Predictive variables associated with exacerbation were analyzed using a Cox proportional hazards model and the time to first exacerbation in high and low HGF groups during the observation period was compared using Kaplan-Meier survival curves., Results: The BSI showed significant correlation with HGF (r = 0.423; p = 0.001) and pentraxin-3 (r = 0.316; p = 0.013). The FACED score was significantly correlated with HGF (r = 0.406; p = 0.001). Univariate and multivariate linear regression analysis revealed that serum level of HGF was independently associated with both scoring systems. The high HGF group showed a significantly shorter time to first exacerbation (Log-rank test, p = 0.014). Multivariate Cox proportional hazards regression analysis revealed that high serum HGF level and colonization with non-pseudomonas organisms were independent predictors of future exacerbations (HR 2.364; p = 0.024 and HR 2.438; p = 0.020, respectively)., Conclusion: Serum level of HGF is a potential biomarker that is closely associated with disease severity and future risk of exacerbations in patients with non-CF bronchiectasis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies.

Sirt6 is involved in multiple biological processes, including aging, metabolism, and tumor suppression. Sirt1, another member of the sirtuin family, functionally overlaps with Sirt6, but its role in tumorigenesis is controversial. In this study, we focused on cell death in association with Sirt6/Sirt1 and reactive oxygen species (ROS) in head and neck squamous cell carcinomas (HNSCCs). Sirt6 induced cell death, as widely reported, but Sirt1 contributed to cell death only when it was suppressed by Sirt6 via regulation of MDM2. Sirt6 and Sirt6-mediated suppression of Sirt1 upregulated ROS, which further led to HNSCC cell death. These results provide insight into the molecular roles of Sirt6 and Sirt1 in tumorigenesis and could therefore contribute to the development of novel strategies to treat HNSCC.

TWIK (tandem-pore domain weak inward rectifying K + )-related spinal cord K + channel (TRESK), a member of the two-pore domain K + channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TG TRESK ). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI ( p < 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TG TRESK SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TG TRESK mice showed lower TNF-α concentrations in the blood than WT mice. In addition, IL-1β concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TG TRESK SCI mice compared to WT-SCI mice ( p < 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes.

Background: The enhancer of rudimentary homolog (ERH) protein is implicated in transcriptional regulation, cell cycle progression, and malignancy. We previously conducted a proteomics analysis using gastric cancer (GC) tissues and identified ERH as a biomarker candidate. The aim of this study was to investigate whether ERH may be useful as a prognostic marker for GC., Methods: Surgically resected GC tissue specimens were obtained from 327 patients who underwent gastrectomy at Gyeongsang National University Hospital. Immunohistochemistry (IHC) was used to validate ERH as a prognostic marker in these tissues. SNU601 and MKN74 cells with siRNA-mediated knockdown of ERH expression and ERH-overexpressing SNU601 and MKN74 knock-in cells were used for analysis of ERH function., Results: ERH was overexpressed in stomach cancer tissues compared with normal tissues according to proteomics analysis (n=29, P<0.01) of patient samples. Based on IHC, patients with tumors overexpressing ERH had lower T stage and lower TNM stage classifications, lower cancer recurrence rates and longer survival times than did patients with tumors showing low expression of ERH (P=0.04). In vitro , forced expression of ERH significantly decreased GC cell migration and invasion, and depletion of ERH triggered GC cell migration and invasion but had no effect on proliferation in vitro ., Conclusions: The findings from the present study show that ERH is associated with decreased cancer cell migration and invasion, suggesting that overexpression of ERH may serve as a marker of good prognosis for patients with GC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-1498). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Purpose : To investigate the protective effects of nerve growth factor (NGF) against steroid-induced cataract formation in dexamethasone (Dex)-treated human lens epithelial B-3 (HLE-B3) cells and the possible molecular mechanisms underlying this protection. Materials and Methods : HLE-B3 cells were treated with Dex, and cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. The levels of expression of NGF, fibronectin, α-smooth muscle actin (α-SMA), and E-cadherin mRNAs were measured by real-time quantitative polymerase chain reaction (qPCR), and the levels of NGF, fibronectin, α-SMA, E-cadherin, tropomyosin receptor kinase A (TrkA), and Akt proteins were measured by Western blot analysis. Gene expression profiles of growth factors in Dex-treated HLE-B3 cells were determined by PCR arrays. In addition, anterior capsule tissue was obtained during cataract surgery, and the specimens were also examined expressions of NGF. Results : NGF was expressed in HLE-B3 cells and also in lens epithelial cells of anterior lens capsules. Dex treatment of HLE-B3 cells increased their expression of epithelial-mesenchymal transition (EMT) markers and migration activity, while markedly downregulating the expression of NGF. NGF treatment significantly reduced the expression of α-SMA and fibronectin, as well as cell proliferation. The decreased phosphorylation of p38 MAPK and Akt induced by Dex treatment was significantly reversed by treatment with NGF. Conclusion : NGF/TrkA may repress EMT by targeting the p38 MAPK and pAkt pathways in Dex-treated HLE-B3 cells. NGF may be a novel therapeutic target for patients with steroid-induced cataract.

The hallmark symptom of sarcopenia is the loss of muscle mass and strength without the loss of overall body weight. Sarcopenia patients are likely to have worse clinical outcomes and higher mortality than do healthy individuals. The sarcopenia population shows an annual increase of ~0.8% in the population after age 50, and the prevalence rate is rapidly increasing with the recent worldwide aging trend. Based on International Classification of Diseases, Tenth Revision, a global classification of disease published by the World Health Organization, issued the disease code (M62.84) given to sarcopenia in 2016. Therefore, it is expected that the study of sarcopenia will be further activated based on the classification of disease codes in the aging society. Several epidemiological studies and meta-analyses have looked at the correlation between the prevalence of sarcopenia and several environmental factors. In addition, studies using cell lines and rodents have been done to understand the biological mechanism of sarcopenia. Laboratory rodent models are widely applicable in sarcopenia studies because of the advantages of time savings, cost saving, and various analytical applications that could not be used for human subjects. The rodent models that can be applied to the sarcopenia research are diverse, but a simple and fast method that can cause atrophy or aging is preferred. Therefore, we will introduce various methods of inducing muscular atrophy in rodent models to be applied to the study of sarcopenia., Competing Interests: Conflict of interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 The Korean Society for Bone and Mineral Research.)

Background/aim: Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC., Materials and Methods: The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells., Results: POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells., Conclusion: POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Bone mineral density of the humeral head is an independent determining factor for postoperative rotator cuff tendon healing. Bisphosphonates, which are commonly used to treat osteoporosis, have raised concerns regarding their relationships to osteonecrosis of the jaw and to atypical fracture of the femur. In view of the prevalence of rotator cuff tear in osteoporotic elderly people, it is important to determine whether bisphosphonates affect rotator cuff tendon healing. However, no studies have investigated bisphosphonates' cytotoxicity to human rotator cuff tendon fibroblasts (HRFs) or bisphosphonates' effects on rotator cuff tendon healing. The purpose of this study was to evaluate the cytotoxicity of alendronate (Ald), a bisphosphonate, and its effects on HRF wound healing., Methods: HRFs were obtained from human supraspinatus tendons, using primary cell cultures. The experimental groups were control, 0.1 μM Ald, 1 μM Ald, 10 μM Ald, and 100 μM Ald. Alendronate exposure was for 48 h, except during a cell viability analysis with durations from 1 day to 6 days. The experimental groups were evaluated for cell viability, cell cycle and cell proliferation, type of cell death, caspase activity, and wound-healing ability., Results: The following findings regarding the 100 μM Ald group contrasted with those for all the other experimental groups: a significantly lower rate of live cells (p < 0.01), a higher rate of subG1 population, a lower rate of Ki-67 positive cells, higher rates of apoptosis and necrosis, a higher number of cells with DNA fragmentation, higher caspase-3/7 activity (p < 0.001), and a higher number of caspase-3 positive staining cells. In scratch-wound healing analyses of all the experimental groups, all the wounds healed within 48 h, except in the 100 μM Ald group (p < 0.001)., Conclusions: Low concentrations of alendronate appear to have little effect on HRF viability, proliferation, migration, and wound healing. However, high concentrations are significantly cytotoxic, impairing cellular proliferation, cellular migration, and wound healing in vitro.

Due to a rapidly expanding aging population, the incidence of age-related or degenerative diseases has increased, and efforts to handle the issue with regenerative medicine via adult stem cells have become more important. And it is now clear that the mitochondrial energy metabolism is important for stem cell differentiation. When stem cells commit to differentiate, glycolytic metabolism is being shifted to mitochondrial oxidative phosphorylation (OXPHOS) to meet an increased cellular energy demand required for differentiated cells. However, the nature of cellular metabolisms during the differentiation process of periosteum-derived mesenchymal stem cells (POMSC) is still unclear. In the present study, we investigated mitochondrial biogenesis during the adipogenic, chondrogenic, and osteogenic differentiation of POMSCs. Both mitochondrial DNA (mtDNA) contents and mitochondrial proteins (VDAC and mitochondrial OXPHOS complex subunits) were increased during all of these mesenchymal lineage differentiations of POMSCs. Interestingly, glycolytic metabolism is reduced as POMSCs undergo osteogenic differentiation. Furthermore, reducing mtDNA contents by ethidium bromide treatments prevents osteogenic differentiation of POMSCs. In conclusion, these results indicate that mitochondrial biogenesis and OXPHOS metabolism play important roles in the differentiation of POMCS and suggest that pharmaceutical modulation of mitochondrial biogenesis and/or function can be a novel regulation for POMSC differentiation and regenerative medicine.

Purpose: To investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) for the selection of the optimal sequencing strategy using docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with M0 or M1 castration-resistant prostate cancer (CRPC). Currently, there is a need to identify biomarkers to guide optimal sequential treatment in CRPC., Methods: This multicenter, retrospective analysis included 303 consecutive patients initially diagnosed with M0 or M1 CRPC between September 2009 and March 2017. Of these, 52 (17.2%) patients received pre-docetaxel ARAT agents and 189 (62.4%) patients received post-docetaxel ARAT agents. The prognostic ability of NLR at CRPC diagnosis regarding radiographic progression-free survival (rPFS) and cancer-specific survival (CSS) were investigated. For the analysis, the NLR level was dichotomized at 2.5, and evaluated according to sequencing strategy., Results: Multivariate analysis revealed NLR ≥ 2.5 as an independent predictor of a lower risk for CSS. During the median follow-up of 18.5 months, patients with NLR ≥ 2.5 exhibited significantly lower 1-year rPFS (p = 0.011) and 2-year CSS rates (p = 0.005) compared to patients with NLR < 2.5. Among patients with NLR < 2.5, the post-docetaxel ARAT agent sequencing group exhibited higher 1-year rPFS (p = 0.031) and 2-year CSS (p = 0.026) rates compared to the pre-docetaxel ARAT agent sequencing group. Among patients with NLR ≥ 2.5, rPFS and CSS rates were comparable regardless of ARAT agent sequencing., Conclusion: NLR ≥ 2.5 at CRPC diagnosis is associated with a lower risk for CSS. Patients with NLR < 2.5 should primarily be offered docetaxel considering the survival benefit of docetaxel-to-ARAT agent sequencing.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy initiated by keratinocytes of the epidermis, which are able to invade the dermis and its periphery. Although most patients with cSCC present with curable localized tumors, recurrence, metastasis and mortality occasionally occur. In the present study, nicotinamide N‑methyltransferase (NNMT) was identified as an upregulated protein in the SCC12 cell line, which has high invasive potential compared with the SCC13 cell line. The effects of NNMT knockdown on proliferation, migration and invasion were investigated using SCC cells. shRNA‑mediated downregulation of NNMT expression levels inhibited the proliferation and density‑dependent growth of SCC12 cells. In addition, the results of a cell motility assay showed that the migration and invasion of SCC cells were markedly decreased in NNMT‑knockdown cells. The assessment of epithelial‑mesenchymal transition (EMT)‑associated gene expression using PCR array analysis revealed that high NNMT expression levels were accompanied by high expression levels of EMT‑associated genes, and that NNMT knockdown effectively suppressed the expression of matrix metalloproteinase 9, osteopontin, versican core protein and zinc finger protein SNAI2 in SCC12 cells. These results revealed that the upregulation of NNMT induced cellular invasion via EMT‑related gene expression in SCC cells.

Purpose : Neuronal theory regarding rotator cuff degeneration has developed from the findings that glutamate, an amino acid and an excitatory neurotransmitter, is present in increased concentrations in tendon tissues with tendinopathy and that glutamate induces cell death in fibroblasts of origin in rat supraspinatus tendon. The purpose of the current study was to determine whether N-acetylcysteine (NAC) has cytoprotective effects against glutamate-induced fibroblast death. Materials and Methods : Primary cultured fibroblasts were obtained from rat supraspinatus tendons. Varying concentrations of glutamate (0.5, 1, 5, and 10 mM) and of NAC (0.5, 1, 2, and 5 mM) were used for evaluation of cytotoxicity. Cell viability, cell cycles, types of cell death, intracellular ROS production, expressions of caspase-3/7, and Ca 2+ influx were evaluated. Results : Glutamate significantly induced cell death, apoptosis, and Ca 2+ influx and significantly increased caspase-3/7 activity and intracellular ROS production ( p < 0.001). NAC significantly reduced the glutamate-induced cell death, apoptosis, Ca 2+ influx, caspase-3/7 activity, and intracellular ROS production ( p < 0.001). Conclusions : The glutamate-induced cytotoxic effects can be reduced by NAC, an antioxidant, through the reduction of intracellular oxidative stress and/or Ca 2+ influx.

Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. SIGNIFICANCE: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer., (©2019 American Association for Cancer Research.)

Prostate-specific antigen (PSA) kinetics predicts survival in castration-resistant prostate cancer (CRPC); however, the influence of prior treatment on this relationship is unclear. Patients with CRPC were stratified according to time to PSA nadir and time to CRPC progression to investigate their prognostic significance on prostate cancer-specific survival (PCSS) and whether PSA kinetics may serve as prognosticators regardless of prior local treatment. This multicenter retrospective study included 295 patients diagnosed with CRPC between September 2009 and November 2017. PSA kinetics during androgen-deprivation therapy (ADT) including %PSA decline, PSA nadir level, time to PSA nadir, and time to CRPC progression was investigated. Subgroup analysis was performed according to the prior history of local curative treatment. Patients who did not receive prior local treatment with ≥6 months to PSA nadir and <12 months to CRPC, showed lower PCSS rates than those with <6 months to PSA nadir (23.3% vs. 45.3%; p = 0.031) and ≥12 months to CRPC (20.0% vs. 47.8%; p = 0.001). In patients who had received local treatment, PSA kinetic parameters did not influence PCSS. Our results indicate that time to PSA nadir and time to CRPC progression are prognosticators of PCSS in patients with CRPC who did not previously receive curative local treatment.

We evaluated whether pelvic plexus block (PPB) is superior to periprostatic nerve block (PNB) for pain control during transrectal ultrasonography (TRUS)-guided prostate biopsy (PBx). A prospective, double-blind, randomized, controlled study was performed at a single center; 46 patients were enrolled and randomly allocated into two groups: PPB (n = 23) and PNB (n = 23). The visual analogue scale (VAS) was used; pain scores were measured four times: during local anesthesia, probe insertion, sampling procedures, and at 15 min post procedures. No significant differences were observed in VAS scores during local anesthesia (2.30 for PPB vs. 2.65 for PNB, p = 0.537) or during probe insertion (2.83 for PPB vs. 2.39 for PNB, p = 0.569). Similarly, no differences in VAS scores were detected during the sampling procedures (2.83 for PPB vs. 2.87 for PNB, p = 0.867) and at 15 min post procedures (1.39 for PPB vs. 1.26 for PNB, p = 0.631). No major complications were noted in either group. Both PPB and PNB are comparably effective and safe methods for PBx related pain relief, and PPB is not superior to PNB. Local anesthetic method could be selected based on the preference and skill of the operator., Competing Interests: The authors declare no conflict of interest.

We aimed to compare the effectiveness of various local anesthetic methods for controlling prostate biopsy (PBx) related pain using network meta-analysis. Literature searches were performed on PubMed/Medline, Embase, and Cochrane Library up to March 2018. Forty-seven randomized controlled trials, in which the effectiveness of PBx-related pain was investigated using a visual analogue scale after various local anesthetic methods, were included. The local anesthetic methods included intraprostatic local anesthesia (IPLA), intrarectal local anesthesia (IRLA), intravenous sedation (IVS), periprostatic nerve block (PNB), pelvic plexus block (PPB), and spinal anesthesia (SPA). Eight pairwise meta-analyses and network meta-analyses with 21 comparisons were performed. All modalities, except single use of IPLA and IRLA, were more effective than placebo. Our results demonstrate that PNB + IVS (rank 1) and SPA (rank 2) were the most effective methods for pain control. The followings are in order of PPB + IRLA, PNB + IPLA, PPB, PNB + IRLA, IVS, and PNB. In conclusion, the most effective way to alleviate PBx-related pain appears to be PNB + IVS and SPA. However, a potential increase in medical cost and additional risk of morbidities should be considered. In the current outpatient setting, PPB + IRLA, PNB + IPLA, PPB, PNB + IRLA, and PNB methods are potentially more acceptable options.

Purpose: To assess the effectiveness of alpha-1 adrenergic receptor blockers (α1-blockers) in the treatment of female lower urinary tract symptoms (LUTS)., Methods: A literature search was conducted using the PubMed/MEDLINE, Embase, and Cochrane Library databases. Fourteen studies with 1,319 patients were ultimately included. The study comprised 2 analyses: a comparison of urinary symptom scores, maximal flow rate (Qmax), and postvoid residual (PVR) urine volume before and after α1-blocker administration in 8 prospective, open-label studies and 5 randomized clinical trials (RCTs); and an evaluation of the same variables in α1-blocker and placebo groups in 4 RCTs., Results: The first meta-analysis showed that, following treatment, patients exhibited statistically significant symptom relief (mean difference [MD], -5.85; 95% confidence interval [CI], -7.71 to -3.99; P<0.00001), increased Qmax (MD, 3.67 mL/sec; 95% CI, 2.76-4.59 mL/sec; P<0.00001), and decreased PVR volume (MD, -28.46 mL; 95% CI, -34.99 to -21.93 mL; P<0.00001). In the second meta-analysis, α1-blockers demonstrated significant symptom relief relative to placebo (MD, -1.60; 95% CI, -2.68 to -0.51; P=0.004). However, no significant differences were observed in Qmax (MD, 0.05 mL/sec; 95% CI, -0.74 to 0.83 mL/sec, P=0.91) and PVR (MD, -8.10 mL; 95% CI, -32.32 to 16.12 mL, P=0.51) between the α1-blocker and placebo groups., Conclusion: These analyses suggest that α1-blockers are effective in the treatment of female LUTS patients. However, the effect of α1-blockers on female LUTS should be assessed according to the underlying cause, and the role of α1-blockers in combination therapy with other drugs should also be investigated.

Purpose: We purposed to assess the effects of adjuvant chemotherapy (ACH) on survival outcomes in patients with locally advanced muscle-invasive bladder cancer (MIBC) who are treated with radical cystectomy (RC)., Materials and Methods: Literature search was conducted in PubMed, Embase, and Cochrane library databases for all articles that were published until February 2018. Systematic review and meta-analysis were performed by pooling the randomized controlled trials (RCTs) that compared patients with locally advanced MIBC who received ACH after RC to those who underwent cystectomy alone. Endpoints were progression free survival (PFS) and overall survival (OS)., Results: Four RCTs with a total of 490 patients were selected for the analysis. These four trials included patients with locally advanced MIBC. Pooled HRs for PFS and OS across the studies were 0.48 (95% confidence interval [CI], 0.39-0.60; p<0.00001) and 0.63 (95% CI, 0.48-0.83; p=0.0009), respectively. Absolute increases in PFS and OS for locally advanced MIBC were 17% and 10%, respectively (i.e., equivalent to numbers needed to treat of 5.9 and 10)., Conclusions: ACH following RC may improve the survival outcomes of locally advanced MIBC patients. Beneficial effect of ACH might be more marked in patients with locally advanced MIBC when comparing the previously reported meta-analysis with all MIBC patients., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Background: The role of neoadjuvant chemotherapy (NAC) for the management of upper tract urothelial carcinoma (UTUC) remains controversial. The aim of present study was to evaluate the contemporary role of NAC for patients with locally advanced UTUC through systematic review and meta-analysis of the literature., Methods: Systematic literature searches were conducted in PubMed/Medline and Embase for all studies that examined the role of chemotherapy for UTUC. We performed this study according to the Preferred Reported Items for Systematic Reviews and Meta-analysis guidelines. Endpoints were overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS)., Results: A total of four trials on 318 patients were included in this study. Each of the included studies was retrospective. Compared to controls, NAC improved OS, CSS, and PFS by 57% (95% confidence interval [CI], 0.25-0.73; p = 0.002), 59% (95% CI, 0.27-0.57; p < 0.00001), and 45% (95% CI, 0.50-0.60; p < 0.00001), respectively. The absolute increases in OS, CSS, and PFS were 11%, 18%, and 13%, respectively, and these increases are equivalent to numbers-needed-to-treat of 9, 5.5, and 7.6, respectively. Pooled odds ratio for the effect of NAC on downstaging was 0.21 (95% CI, 0.09-0.60; p = 0.004), which indicates that NAC group had a 4.76-fold higher probability of having pathologic N stage 0 than control group., Conclusions: NAC treatment before radical nephroureterectomy might provide better survival outcomes in patients with locally advanced UTUC. Prospective randomized studies are needed to confirm the benefits of NAC in locally advanced UTUC patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We aimed to evaluate the change in bone mineral density (BMD) in patients with prostate cancer (PCa) receiving androgen deprivation therapy (ADT) compared to those with PCa or other urologic conditions not receiving ADT. Literature searches were conducted throughout October 2018. The eligibility of each study was assessed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the Participant, Intervention, Comparator, Outcome, and Study design method. The outcomes analyzed were the mean difference (MD) of percent changes in BMD of lumbar spine, femur neck, and total hip. Five prospective cohort studies with a total of 533 patients were included in the present study. Statistically significant decreases of BMD change relative to the control group were observed in the ADT treatment group in the lumbar spine (MD -3.60, 95% CI -6.72 to -0.47, P = 0.02), femoral neck (MD -3.11, 95% CI -4.73 to -1.48, P = 0.0002), and total hip (MD -1.59, 95% CI -2.99 to -0.19, P = 0.03). There is a significant relationship between ADT and BMD reduction in patients with PCa. Regular BMD testing and the optimal treatment for BMD loss should, therefore, be considered in patients with PCa undergoing ADT.

Background: The aim of this study is to determine whether there is correlation between endothelial function and skeletal muscle function measured by hand grip strength in elderly women., Methods: This cross-sectional study used data of NAMGARAM-2 cohort. The NAMGARAM-2 cohort consisted of a group of people living in three rural communities. They were enrolled for studies on activity limitation due to age-related musculoskeletal disorders including knee osteoarthritis, osteoporosis, and sarcopenia. They were residents aged 40 years or older. They agreed to participate in this cohort from March 2016 to May 2017. Peripheral endothelial function was assessed by reactive hyperaemia-peripheral arterial tonometry using EndoPAT2000 system. Hand grip strength was measured using a digital hand dynamometer., Results: Endothelial function index assessed by EndoPAT was worse in the low grip strength group than that in the normal group of elderly women (1.54 ± 0.51 in the low grip strength group vs. 1.77 ± 0.67 in the normal group, P = 0.003). There was a positive correlation between hand grip strength and endothelial function (r = 0.176, P = 0.007). On stepwise multivariate analysis, endothelial dysfunction (reactive hyperaemia-peripheral arterial tonometry index < 1.67) significantly increased the risk of low hand grip strength (odds ratio = 2.019; 95% confidence interval = 1.107-3.682; P = 0.022)., Conclusions: Endothelial function and skeletal muscle strength had a significant correlation in elderly women, providing additional support for the relevant role of vascular system in sarcopenia., (© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Robot-assisted radical prostatectomy (RARP) is a feasible treatment option for high-risk prostate cancer (PCa). While patients may achieve undetectable prostate-specific antigen (PSA) levels after RARP, the risk of disease progression is relatively high. We investigated metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS) outcomes and prognosticators in such patients., Methods: In a single-center cohort of 342 patients with high-risk PCa (clinical stage ≥ T3, biopsy Gleason score ≥ 8, and/or PSA levels ≥ 20 ng/mL) treated with RARP and pelvic lymph node dissection between August 2005 and June 2011, we identified 251 (73.4%) patients (median age, 66.5 years; interquartile range [IQR], 63.0-71.0 years) who achieved undetectable PSA levels (< 0.01 ng/mL) postoperatively. Survival outcomes were evaluated for the entire study sample and in groups stratified according to the time to biochemical recurrence dichotomized at 60 months., Results: During the median follow-up of 75.9 months (IQR, 59.4-85.8 months), metastasis occurred in 38 (15.1%) patients, most often to the bones, followed by the lymph nodes, lungs, and liver. The 5-year metastasis-free, cancer-specific, and OS rates were 87.1%, 94.8%, and 94.3%, respectively. Multivariate Cox-regression analysis revealed time to recurrence as an independent predictor of metastasis ( P < 0.001). Time to metastasis was an independent predictor of OS ( P = 0.003). Metastasis-free and CSS rates were significantly lower among patients with recurrence within 60 months of RARP (log-rank P < 0.001)., Conclusion: RARP confers acceptable oncological outcomes for high-risk PCa. Close monitoring beyond 5 years is warranted for early detection of disease progression and for timely adjuvant therapy., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

A multicenter Korean Prostate Cancer Database (K-CaP) has been established to provide information regarding Korean patients with prostate cancer (PCa). We used the K-CaP registry to investigate the value of age and comorbidity for predicting cancer-specific mortality (CSM) and other-cause mortality (OCM) according to risk grouping.The K-CaP registry includes 2253 patients who underwent radical prostatectomy (RP) between May 2001 and April 2013 at 5 institutions. Preoperative clinicopathologic data were collected and stratified according to the National Comprehensive Cancer Network risk criteria. Survival was evaluated using Gray's modified log-rank test according to risk category, age (<70 years vs ≥70 years), and Charlson comorbidity index (CCI) (0 vs ≥1).The median follow-up was 55.0 months (interquartile range: 42.0-70.0 months). Competing-risk regression analysis revealed that, independent of CCI, ≥70-year-old high-risk patients had significantly greater CSM than <70-year-old high-risk patients (P = .019). However, <70-year-old high-risk patients with a CCI of ≥1 had similar CSM relative to ≥70-year-old patients. Survival was not affected by age or CCI among low-risk or intermediate-risk patients. Multivariate analysis revealed that a CCI of ≥1 was independently associated with a higher risk of CSM (P = .003), while an age of ≥70 years was independently associated with a higher risk of OCM (P = .005).Age and comorbidity were associated with survival after RP among patients with high-risk PCa, although these associations were not observed among low-risk or intermediate-risk patients. Therefore, older patients with high-risk diseases and greater comorbidity may require alternative multidisciplinary treatment.

The purpose of this study is to investigate the effect of TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-α (TNF-α)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-α-induced interleukin (IL)-6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) by regulating phosphorylated-IκB-α (p-IκB-α) and IκB-α in TNF-α-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-α-induced RA-FLS activities via NF-κB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA.

Purpose: Enolase is a cytoplasmic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the glycolytic pathway. The aim of this study was to investigate whether the overexpression of neuron-specific enolase (NSE) can serve as a prognostic factor in patients with gastric cancer (GC)., Materials and Methods: To assess its prognostic value in GC, NSE expression was measured by immunohistochemistry in a clinically annotated tissue microarray comprising of 327 human GC specimens. Cytoplasmic NSE expression was scored from 0 to 4, reflecting the percentage of NSE-positive cells., Results: In terms of histology as per the World Health Organization criteria (P=0.340), there were no differences between the NSE overexpression (NSE-OE) and NSE underexpression (NSE-UE) groups. The NSE-OE group showed a significantly lower rate of advanced GC (P<0.010), lymph node metastasis (P=0.010), advanced stage group (P<0.010), cancer-related death (P<0.010), and cancer recurrence (P<0.010). Additionally, a Kaplan-Meier survival analysis revealed that the NSE-OE group had longer cumulative survival times than the NSE-UE group (log-rank test, P<0.010). However, there were no significant differences in the serum levels of NSE expression in patients with GC and healthy volunteers (P=0.280)., Conclusions: Patients with NSE overexpressing GC tissues showed better prognostic results, implying that NSE could be a candidate biomarker of GC., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Procyanidins can inhibit cell proliferation and tumorigenesis and induce apoptosis in human skin, breast and prostate carcinoma cell lines. Squamous cell carcinoma (SCC) of the skin is a common form of keratinocytic or non-melanoma skin cancer and is a deadly disease with a poor prognosis due to the ineffectiveness of therapy. The present study aimed to determine whether grape seed proanthocyanidin (GSP) may regulate different modes of cell death in the human SCC12 cell line. The present study found that the treatment of SCC12 cells with GSP inhibited proliferation in a dose-dependent manner and reduced the motility and invasiveness of SCC12 cells through suppression of matrix metalloproteinase-2/9 expression. GSP treatment also resulted in induction of apoptosis and autophagy via generation of reactive oxygen species. The inhibition of autophagy by 3-methyladenine decreased GSP-induced cell death, which suggested that GSP-induced autophagy can promote cell death. The results of the present study suggested that autophagy functions as a death mechanism in SCC and provided a rationale for the use of GSP in combination with autophagy activators for treating cancers such as SCC.

Background: To measure ascorbic acid concentration in aqueous humor of patients with cataract after oral or intravenous vitamin C supplementation., Methods: Forty-two eyes of 42 patients with senile cataract who underwent uncomplicated cataract surgery were enrolled. Patients (n = 14 each) were administered oral vitamin C (2 g), intravenous vitamin C (20 g) or no treatment (control group) on the day before surgery. Samples of aqueous humor (0.1 cm 3 ) were obtained by anterior chamber aspiration at the beginning of surgery and stored at -80 °C. Ascorbic acid concentration in aqueous humor was measured by high-pressure liquid chromatography., Results: The mean age at surgery was 62.5 years, with no difference among the three groups. The mean ± standard deviation concentrations of ascorbic acid in aqueous humor in the control and oral and intravenous vitamin C groups were 1347 ± 331 μmol/L, 1859 ± 408 μmol/L and 2387 ± 445 μmol/L, respectively. Ascorbic acid concentration was significantly lower in the control than in the oral (P < 0.01) and intravenous (P < 0.001) vitamin C groups and was significantly higher in the intravenous than in the oral vitamin C group (P < 0.05)., Conclusions: Ascorbic acid concentration in aqueous humor is increased by systemic vitamin C supplementation, with intravenous administration being more effective than oral administration.

Purpose: Nuclear factor-kappa B (NF-κB) has been proposed as a therapeutic target for the treatment of cataracts. The authors investigated the relationship between nuclear factor of activated T cells 5 (NFAT5) and NF-κB in ultraviolet B (UVB)-irradiated human lens epithelial (HLE) cells., Methods: Human lens epithelial B-3 (HLE-B3) cells were exposed to UVB light at a dose of 10 mJ/cm 2 and then incubated for 24 h. Cell viability was assessed by using the Cell Counting Kit-8 (CCK-8) assay. Gene expression level of NFAT5 was determined using real-time quantitative polymerase chain reaction (qPCR). Protein expression levels of NFAT5, NF-κB p65, and α-smooth muscle actin (α-SMA) and the association of NFAT5 with the NF-κB p65 subunit were measured by Western blot analysis and a co-immunoprecipitation assay, respectively. The cellular distribution of NFAT5 and NF-κB p65 was examined by triple immunofluorescence staining., Results: At 24 h after UVB exposure, cell viability significantly decreased in a dose-dependent manner, and UVB light (15 and 20 mJ/cm 2 ) significantly increased the ROS generation. UVB irradiation increased NFAT5 mRNA and protein levels and increased phosphorylation of NF-κB in HLE-B3 cells. α-SMA protein levels were increased in the irradiated cells. In addition, NFAT5 and NF-κB translocated from the cytoplasm to the nucleus, and binding between the p65 subunit and NFAT5 was increased., Conclusions: Exposure to UVB radiation induces nuclear translocation and stimulates binding between NFAT5 and NF-κB proteins in HLE-B3 cells. These interactions may form part of the biochemical mechanism of cataractogenesis in UVB-irradiated HLECs.

Local anesthetics (LA) are among the drugs most frequently used for musculoskeletal problems, in procedures ranging from diagnosis to postoperative pain control. Chondrocyte toxicity induced by LA is an emerging area of concern. The purpose of this study was to determine whether N-acetyl cysteine (NAC), an antioxidant, will exert cytoprotective effects against chondrocyte death induced by LA. Primary cultured human chondrocytes were used for this study. This study used control, NAC, LA, and NAC-LA groups. Cytotoxicity was induced in the LA subgroups and their paired NAC-LA subgroups through exposure to ropivacaine (0.075%), bupivacaine (0.05%), or lidocaine (0.2%) for 24 h. The NAC-LA subgroups were exposed to 10 mM NAC for 1 h, before LA exposure. These study groups were evaluated for rates of cell viability, apoptosis, necrosis, intracellular ROS production, and caspase-3/7 activity. Cell viability in all LA subgroups was significantly lower than in the control group (p < 0.001). Cell viability in the NAC-LA subgroups was significantly higher than in their paired LA subgroups (p < 0.001). In the LA subgroups, rates of apoptosis and necrosis, intracellular ROS production, and caspase-3/7 activity were significantly higher than in the control group (p ≤ 0.029). In the NAC-LA subgroups, rates of apoptosis and necrosis, intracellular ROS production, and caspase-3/7 activity were significantly lower than in their paired LA subgroups (p ≤ 0.023). These results indicate that N-acetyl cysteine, an antioxidant, has cytoprotective effects against LA-induced toxicity to chondrocytes in vitro. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:297-303, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Autophagy plays a critical role in maintaining cell homeostasis in response to various stressors through protein conjugation and activation of lysosome-dependent degradation. MAP1LC3B/LC3B (microtubule- associated protein 1 light chain 3 β) is conjugated with phosphatidylethanolamine (PE) in the membranes and regulates initiation of autophagy through interaction with many autophagy-related proteins possessing an LC3-interacting region (LIR) motif, which is composed of 2 hydrophobic amino acids (tryptophan and leucine) separated by 2 non-conserved amino acids (WXXL). In this study, we identified a new putative LIR motif in PEBP1/RKIP (phosphatidylethanolamine binding protein 1) that was originally isolated as a PE-binding protein and also a cellular inhibitor of MAPK/ERK signaling. PEBP1 was specifically bound to PE-unconjugated LC3 in cells, and mutation (WXXL mutated to AXXA) of this LIR motif disrupted its interaction with LC3 proteins. Interestingly, overexpression of PEBP1 significantly inhibited starvation-induced autophagy by activating the AKT and MTORC1 (mechanistic target of rapamycin [serine/threonine kinase] complex 1) signaling pathway and consequently suppressing the ULK1 (unc-51 like autophagy activating kinase 1) activity. In contrast, ablation of PEBP1 expression dramatically promoted the autophagic process under starvation conditions. Furthermore, PEBP1 lacking the LIR motif highly stimulated starvation-induced autophagy through the AKT-MTORC1-dependent pathway. PEBP1 phosphorylation at Ser153 caused dissociation of LC3 from the PEBP1-LC3 complex for autophagy induction. PEBP1-dependent suppression of autophagy was not associated with the MAPK pathway. These findings suggest that PEBP1 can act as a negative mediator in autophagy through stimulation of the AKT-MTORC1 pathway and direct interaction with LC3.

Age-related rotator cuff tendon degeneration is related to tenofibroblast apoptosis. Anthocyanins reduce oxidative stress-induced apoptotic cell death in tenofibroblasts. The current study investigated the presence of cell protective effects in cyanidin and delphinidin, the most common aglycon forms of anthocyanins. We determined whether these anthocyanidins have antiapoptotic and antinecrotic effects in tenofibroblasts exposed to H2O2, and evaluated their biomolecular mechanisms. Both cyanidin and delphinidin inhibited H2O2-induced apoptosis in a dose-dependent manner. However, at concentrations of 100 μg/ml or greater, delphinidin showed cytotoxicity against tenofibroblasts and a decreased antinecrotic effect. Cyanidin and delphinidin both showed inhibitory effects on the H2O2-induced increase in intracellular ROS formation and the activation of ERK1/2 and JNK. In conclusion, both cyanidin and delphinidin have cytoprotective effects on cultured tenofibroblasts exposed to H2O2. These results suggest that cyanidin and delphinidin are both beneficial for the treatment of oxidative stress-mediated tenofibroblast cell death, but their working concentrations are different.

The deleterious role of cigarette smoke has long been documented in various human diseases including periodontal complications. In this report, we examined this adverse effect of cigarette smoke on human gingival fibroblasts (HGFs) which are critical not only in maintaining gingival tissue architecture but also in mediating immune responses. As well documented in other cell types, we also observed that cigarette smoke promoted cellular reactive oxygen species in HGFs. And we found that this cigarette smoke-induced oxidative stress reduced HGF viability through inducing apoptosis. Our results indicated that an increased Bax/Bcl-xL ratio and resulting caspase activation underlie the apoptotic death in HGFs exposed to cigarette smoke. Furthermore, we detected that cigarette smoke also triggered autophagy, an integrated cellular stress response. Interesting, a pharmacological suppression of the cigarette smoke-induced autophagy led to a further reduction in HGF viability while a pharmacological promotion of autophagy increased the viability of HGFs with cigarette smoke exposures. These findings suggest a protective role for autophagy in HGFs stressed with cigarette smoke, highlighting that modulation of autophagy can be a novel therapeutic target in periodontal complications with cigarette smoke.

The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-γT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co-cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA.