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The pressure field distribution of a ballistic shock wave (BSW) therapy device is a crucial factor for clarifying its treatment mechanism. We developed a lattice Boltzmann model (LBM) to describe the propagation of BSW. Based on the assumption that the propagation of BSW causes weak compressible flow, our simulaton was performed by coupling Tait equation of state. For a two-dimensional LBM, we used the density initial condition for initial turbulent region near the applicator. We first compared our simulation results with previous experimental measurements. Then we predicted the temporal and spatial distribution of pressure field. The pressure field of ballistic shock wave has a primary compressive region followed by a primary expansive region with the other disturbances. A secondary pressure pulse consists of a positive phase followed by a negative phase. Our results agree well with previous experimental data and provide additional data on the pressure field of BSW. Our model encourages further investigation to clear the biological mechanism of BSW therapy and to design more effective device. [ABSTRACT FROM AUTHOR]

High-intensity focused ultrasound (HIFU) is a therapy method to treat the tumors in prostate, liver, kidney, pancreas, bone, breast, and uterine fibroids. In the HIFU therapy process, the ultrasound generated in an ultrasonic transducer concentrates on a focal zone. At the zone, the temperature rises locally up to 56°C to provoke the necrosis of human tissue. Therefore, to control the therapy process, it is essential to perceive the main principle of heat generation in human tissue. We study FDTD-LBM (finite difference time domain—lattice Boltzmann method) as a method of predicting the temperature distribution in human tissue during HIFU therapy. The nonlinear Westervelt wave equation is employed for computing the pressure distribution in human tissue during ultrasound propagation, while the Pennes bio-heat transfer equation is used for calculating the temperature distribution in the tissue. Finite difference time domain (FDTD) is applied to solving the nonlinear Westervelt wave equation, and the lattice Boltzmann method can solve the Pennes bio-heat transfer equation. Simulation results have shown that the numerical simulation method proposed has improved the accuracy in analyzing the temperature field in human tissue. [ABSTRACT FROM AUTHOR]

Background: Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available. Objectives: The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS. Methods: We did a population-based study using data from the Hong Kong Hospital Authority's Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91–120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions. Results: 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42–18.69), 5.88 (2.46–14.04), and 4.77 (1.95–11.66). Conclusions: Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded. [ABSTRACT FROM AUTHOR]

Background: Haloperidol remains a frequently prescribed first-generation antipsychotic. However, haloperidol-associated mortality risk by all causes, cardiovascular disease (CVD), and pneumonia compared with other antipsychotics is unknown.Objective: This study investigated the mortality risk associated with long-term haloperidol treatment versus that with other antipsychotics.Methods: We identified incident antipsychotic users from 2004 to 2014 in the Clinical Data Analysis and Reporting System (CDARS), a population-based clinical database managed by the Hong Kong Hospital Authority. We included patients who were aged ≥ 18 and received antipsychotics for any indication apart from terminal illnesses or management of acute behavioural disturbance. Patients on haloperidol and other antipsychotic agents (risperidone, quetiapine, olanzapine, chlorpromazine, aripiprazole, sulpiride, amisulpride, or trifluoperazine) were matched by propensity score. Hazard ratios (HRs) for all-cause mortality and death due to CVD and pneumonia were estimated with 95% confidence intervals (CIs) using a Cox proportional hazards model.Results: In total, 136,593 users of antipsychotics were included. During a mean follow-up of 3.2 years, the incidence of all-cause mortality ranged from 186.8/1000 person-years for haloperidol to 10.4/1000 person-years for trifluoperazine. The risk of all-cause mortality was lower with non-haloperidol antipsychotics than with haloperidol, with HRs ranging from 0.68 (95% CI 0.64-0.72 [chlorpromazine]) to 0.43 (95% CI 0.36-0.53 [trifluoperazine]). Risperidone, quetiapine, sulpiride, chlorpromazine, aripiprazole, and trifluoperazine were associated with a significantly lower risk of pneumonia-related mortality. A significantly lower risk of CVD mortality was observed for risperidone, sulpiride, chlorpromazine, and quetiapine.Conclusion: Haloperidol was associated with increased overall mortality when compared with other antipsychotics in long-term follow-up. Treatment with haloperidol should be carefully considered, especially in older patients and patients at risk of CVD or pneumonia, since the risk of death appears to be lower with non-haloperidol agents. [ABSTRACT FROM AUTHOR]

Background: Melatonin is widely available either on prescription for the treatment of sleep disorders or as an over-the-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jetlag. Little is known about the potential for adverse events (AEs), in particular AEs resulting from long-term use. Concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma.Objectives: The aim of this systematic review was to assess the evidence for AEs associated with short-term and longer-term melatonin treatment for sleep disorders.Methods: A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of < 1 week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk-of-bias criteria.Results: 37 RCTs met criteria for inclusion. Daily melatonin doses ranged from 0.15 mg to 12 mg. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (4 weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%). Very few AEs considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. Most AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged 'good' overall with respect to the Cochrane risk-of-bias criteria. Of the remaining papers, 16 were considered 'fair' and 13 'poor' but publication of almost half of the papers preceded that of the earliest version of the guidelines.Conclusion: Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinically significant adverse effects in potentially at-risk populations. Future studies should be designed to comply with appropriate quality standards for RCTs, which most past studies have not. [ABSTRACT FROM AUTHOR]

Summary: The plasma n-3 fatty acid level was 26.2% lower in patients with osteoporotic hip fracture than in those with osteoarthritis. In all patients, n-3 fatty acid was positively associated with bone mineral density and inversely associated with tartrate-resistant acid phosphatase-5b level in bone marrow aspirates, reflecting the bone microenvironment. Introduction: Despite the potential beneficial role of n-3 fatty acid (FA) on bone metabolism, the specific mechanisms underlying these effects in humans remain unclear. Here, we assessed whether the plasma n-3 level, as an objective indicator of its status, is associated with osteoporosis-related phenotypes and bone-related markers in human bone marrow (BM) samples. Methods: This was a case-control and cross-sectional study conducted in a clinical unit. n-3 FA in the blood and bone biochemical markers in the BM aspirates were measured by gas chromatography/mass spectrometry and immunoassay, respectively. BM fluids were collected from 72 patients who underwent hip surgery because of either osteoporotic hip fracture (HF; n = 28) or osteoarthritis (n = 44). Results: After adjusting for confounders, patients with HF had 26.2% lower plasma n-3 levels than those with osteoarthritis (P = 0.006), and each standard deviation increment in plasma n-3 was associated with a multivariate-adjusted odds ratio of 0.40 for osteoporotic HF (P = 0.010). In multivariate analyses including all patients, a higher plasma n-3 level was associated with higher bone mass at the lumbar spine (β = 0.615, P = 0.002) and total femur (β = 0.244, P = 0.045). Interestingly, the plasma n-3 level was inversely associated with the tartrate-resistant acid phosphatase-5b level (β = − 0.633, P = 0.023), but not with the bone-specific alkaline phosphatase level, in BM aspirates. Conclusions: These findings provide clinical evidence that n-3 FA is a potential inhibitor of osteoclastogenesis that favors human bone health. [ABSTRACT FROM AUTHOR]

Summary: The use of calcium phosphate bone cement has been described to allow for retention of reduction. Therefore, we evaluated whether augmentation with resorbable calcium phosphate could improve fracture stability in osteoporotic hip fractures. The results showed that augmentation with calcium phosphate cement significantly improved the stability of intertrochanteric fractures.Introduction: The aim with this study was to measure whether augmentation with resorbable calcium phosphate cement could improve fracture stability in osteoporotic hip fractures.Methods: We retrospectively reviewed 82 patients who underwent closed reduction and internal fixation with proximal femoral nail (PFN) for unstable intertrochanteric fractures between 2014 and 2017. In 42 of 82 patients, patients were treated with a PFN alone (group I). These patients were compared with 40 patients for whom the same device combined with calcium phosphate cement for augmentation was used (group II). Questionnaire surveys or telephone interviews were conducted and patients completed a self-report Harris hip score (HHS) and visual analog scale (VAS) scores. Radiographic outcomes including mean sliding distance of screw, femoral shortening, and varus collapse were compared. Postoperative complications were compared.Results: Clinical outcomes at 6 months after surgery were equivalent in both groups. Screw sliding, femoral shortening, and varus collapse were all significantly reduced in the cemented group at the last follow-up (p < 0.001, p = 0.005, p < 0.001, respectively). A total of 9 (21%) complications occurred in group I. In contrast, 2 (5%) complications were seen in group II (p = 0.029).Conclusions: Augmentation with calcium phosphate cement significantly improved the stability of intertrochanteric fractures fixed with a PFN and reduced overall failure rates. We believe augmentation with resorbable calcium phosphate cement for osteoporotic hip fractures is a reasonable option in selected patients. [ABSTRACT FROM AUTHOR]

Extended Hall-Petch relationships for yield (σy), cleavage (σcl) and intergranular fracture (σig) strengths of pure iron have been established through the direct calculation of the proportional constant (k) and the estimation of the friction stress (σ0). The magnitude orders of k and σ0 are generally ky and σy0<σcl0<σig0, respectively. Based on the Hall-Petch relationships, micro-yielding in a bcc steel occurs at the instance that the pile-up dislocations within a specific grain showing the Schmid factor of 0.5 propagate into the neighboring grain. The initial brittle crack is formed at the instance that the flow strength exceeds the brittle fracture strength. Once the brittle crack is formed, it grows catastrophically. Due to the smallest and ky and σy0, the cleavage and the intergranular fracture occur always after micro-yielding. The {100} cleavage fracture of the steel is due to the lowest theoretical {100} cleavage strength. Due to the thermal components included in cleavage and intergranular fracture strengths, they show also the temperature and strain rate dependence observed in yield strength. The increase in susceptibility to brittle fracture with decreasing temperature and increasing strain rate is due to the increase in dislocation density which causes the high work hardening rate. [ABSTRACT FROM AUTHOR]

Background: Cariprazine is a novel antipsychotic agent recently approved for treating schizophrenia and bipolar mania in the USA. The sample sizes of published randomized controlled trials (RCTs) of the drug are small; previous meta-analyses included few RCTs and did not specifically investigate the tolerability/safety profile of cariprazine.Objective: Our objective was to conduct a meta-analysis of published RCTs to systematically review the tolerability and safety of cariprazine versus placebo.Methods: We searched the clinical trial registers (the metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) and electronic databases (PubMed, Embase, PsycINFO and Cochrane library) up to June 2016 to identify phase II/III RCTs of cariprazine in patients with schizophrenia, bipolar disorder or major depressive disorder. We conducted a meta-analysis to investigate outcomes, including risks of discontinuation due to adverse events (AEs), extrapyramidal side effects (EPS) or related events, metabolic syndrome and cardiovascular-related events.Results: We included nine RCTs, with a total of 4324 subjects. The risk of discontinuation due to AEs for cariprazine was similar to that for placebo (risk ratio [RR] 1.13, 95 % confidence interval [CI] 0.77-1.66). Cariprazine was associated with higher risks of EPS-related events than was placebo, including risk of akathisia (RR 3.92, 95 % CI 2.83-5.43), tremor (RR 2.41, 95 % CI 1.53-3.79) and restlessness (RR 2.17, 95 % CI 1.38-3.40). The cariprazine treatment group was more likely to have clinically significant weight gain (RR 1.68, 95 % CI 1.12-2.52). No statistically significant differences in results were found in other metabolic parameters or cardiovascular-related events.Conclusion: There was a statistically significant higher risk of EPS-related AEs and a slight increase in mean body weight with cariprazine. There were no statistically significant effects on prolactin level or cardiovascular parameters. EPSs were the main short-term adverse reactions reported in the limited number of patients studied. Further clinical and post-marketing pharmacovigilance studies are needed to investigate the long-term safety of cariprazine. [ABSTRACT FROM AUTHOR]

Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-β (TGF-β) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, PAI-I and CDK inhibitors such as p15INK4b and p21Cip1. Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity. [ABSTRACT FROM AUTHOR]

Observational studies have been recognised to be essential for investigating the safety profile of medications. Numerous observational studies have been conducted on the platform of large population databases, which provide adequate sample size and follow-up length to detect infrequent and/or delayed clinical outcomes. Cohort and case-control are well-accepted traditional methodologies for hypothesis testing, while within-individual study designs are developing and evolving, addressing previous known methodological limitations to reduce confounding and bias. Respective examples of observational studies of different study designs using medical databases are shown. Methodology characteristics, study assumptions, strengths and weaknesses of each method are discussed in this review. [ABSTRACT FROM AUTHOR]

A fibrinolytic metalloprotease-like enzyme named TFase, was purified from the fruiting bodies of the medicinal fungus Tremella fuciformis. Purification of TFase was performed by a chromatography on DEAE Sepharose CL-6B and Superdex-75. TFase showed a molecular weight of 38 kDa by SDS-PAGE and displayed a strong fibrin zymogram lysis band corresponding to a similar molecular mass. The enzyme demonstrated wide temperature optimum from 10 to 40°C and pH optimum at pH 8.0. The fibrinolytic activity of TFase was strongly inhibited by EDTA and EGTA, which are metalloprotease inhibitors. The K and V values for enzyme using the artificial substrate pyroGlu-Gly-Arg-pNA were 3.81 mM and 4.88 µmoles mg min, respectively. TFase of T. fuciformis partially dissolved a fibrin clot directly and specifically cleaved the Aα and Bβ chains of fibrinogen. In addition, the enzyme prolonged the coagulation time, and increased the activated partial thromboplastin time and prothrombin time. These results suggest that TFase of T. fuciformis exhibits properties of a metalloprotease-like enzyme, shows novel fibrin(ogen)olytic enzyme activity, and has the potential to be a therapeutic agent for thrombosis. [ABSTRACT FROM AUTHOR]

Despite optimal pharmacotherapy and cognitive-behavioral treatments, a proportion of patients with obsessive-compulsive disorder (OCD) remain refractory to treatment. Neurosurgical ablative or nondestructive stimulation procedures to treat these refractory patients have been investigated. However, despite the potential benefits of these surgical procedures, patients show significant surgery-related complications. This preliminary study investigated the use of bilateral thermal capsulotomy for patients with treatment-refractory OCD using magnetic resonance-guided focused ultrasound (MRgFUS) as a novel, minimally invasive, non-cranium-opening surgical technique. Between February and May 2013, four patients with medically refractory OCD were treated with MRgFUS to ablate the anterior limb of the internal capsule. Patients underwent comprehensive neuropsychological evaluations and imaging at baseline, 1 week, 1 month and 6 months following treatment. Outcomes were measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A), and treatment-related adverse events were evaluated. The results showed gradual improvements in Y-BOCS scores (a mean improvement of 33%) over the 6-month follow-up period, and all patients showed almost immediate and sustained improvements in depression (a mean reduction of 61.1%) and anxiety (a mean reduction of 69.4%). No patients demonstrated any side effects (physical or neuropsychological) in relation to the procedure. In addition, there were no significant differences found in the comprehensive neuropsychological test scores between the baseline and 6-month time points. This study demonstrates that bilateral thermal capsulotomy with MRgFUS can be used without inducing side effects to treat patients with medically refractory OCD. If larger trials validate the safety, effectiveness and long-term durability of this new approach, this procedure could considerably change the clinical management of treatment-refractory OCD. [ABSTRACT FROM AUTHOR]

Summary: Sarcopenia is the age-related reduction of skeletal muscle mass in older individuals. Respiratory muscle strength may be related to skeletal muscle mass and, thus, the present study attempted to estimate the risk of sarcopenia relative to decreased pulmonary function. The present findings demonstrated that low pulmonary function was associated with low muscle mass in community-dwelling older adults. Introduction: Lean body mass is related to pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, the relationship between muscle mass and pulmonary function in healthy older adults has yet to be clarified. Thus, the present study investigated the association of pulmonary function with muscle mass in an older community-dwelling Korean population. Methods: This study included 463 disease-free subjects over 65 years of age who underwent anthropometric measurements, laboratory tests, spirometry, and the estimation of appendicular skeletal muscle (ASM) mass in the 2008-2011 Korea National Health and Nutrition Examination Survey (KNHANES). Low muscle mass was defined as the value of ASM divided by height squared (ASM/height) that was less than two standard deviations (SD) below the sex-specific mean of the young reference group. Results: Forced expiratory volume in 1 s (FEV1[L]) and forced vital capacity (FVC[L]) were positively correlated with ASM/height in males ( p < 0.001 and p = 0.001, respectively) but not in females ( p = 0.360 and p = 0.779, respectively). A univariate logistic regression analysis revealed that males with low FEV1 or FVC were more likely to have low muscle mass (odds ratio [OR] = 3.11, 95 % confidence interval [CI] 1.62-5.99 for FEV1; OR = 1.99, 95 % CI 1.13-3.53 for FVC); similar results were found for females, but the significance was lower (OR = 11.37, 95 % CI 0.97-132.91 for FEV1; OR = 7.31, 95 % CI 1.25-42.74 for FVC). After adjusting for age, smoking, and moderate physical activity, a low FEV1 value was associated with low muscle mass in both males (OR = 2.90, 95 % CI 1.50-5.63) and females (OR = 9.15, 95 % CI 1.53-54.77). Conclusions: Using nationally representative data from the 2008-2011 KNHANES, low pulmonary function was found to be associated with low muscle mass in community-dwelling older Korean adults. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive cancer with a poor prognosis and low patient survival. Because chemotherapy for advanced HNSCC is often ineffective, discovering new therapeutic targets that are important for HNSCC development and progression and elucidating their molecular mechanisms are required. In the present study, we describe the role of DRAK1 (death-associated protein kinase-related apoptosis-inducing kinase 1) as a novel negative regulator of the transforming growth factor-β (TGF-β) tumor suppressor signaling pathway for the first time in human HNSCC cells. DRAK1 was significantly overexpressed in primary human HNSCCs and in HNSCC cell lines. Through gain- and loss-of-function experiments, we demonstrated that the DRAK1 expression level regulated TGF-β1-induced transcriptional activity and expression of the tumor suppressor gene p21Waf1/Cip1. DRAK1 depletion enhanced TGF-β1-induced growth inhibition in vitro and suppressed tumorigenicity in xenograft models in vivo. Mechanistically, DRAK1 was predominantly localized in the cytoplasm and bound to Smad3, thereby interrupting Smad3/Smad4 complex formation, which is the core process for the induction of tumor suppressor genes by TGF-β1. Thus, our findings suggest that cytoplasmic DRAK1 increases tumorigenic potential through inhibition of TGF-β1-mediated tumor suppressor activity in HNSCC cells and may be a potential therapeutic target for HNSCCs. [ABSTRACT FROM AUTHOR]

Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-obesity effect of Rubi Fructus (RF) extract using brown adipose tissue (BAT) and primary brown preadipocytes in vivo and in vitro.Methods: Male C57BL/6 J mice (n=5 per group) were fed a high-fat diet (HFD) for 10 weeks with or without RF. Brown preadipocytes from the interscapular BAT of mice (age, post-natal days 1-3) were cultured with differentiation media (DM) including isobutylmethylxanthine, dexamethasone, T3, indomethacin and insulin with or without RF.Results: In HFD-induced obese C57BL/6 J mice, long-term RF treatment significantly reduced weight gain as well as the weights of the white adipose tissue, liver and spleen. Serum levels of total cholesterol and low-density lipoprotein cholesterol were also reduced in the HFD group which received RF treatment. Furthermore, RF induced thermogenic-, adipogenic- and mitochondria-related gene expressions in BAT. In primary brown adipocytes, RF effectively stimulated the expressions of thermogenic- and mitochondria-related genes. In addition, to examine whether LIPIN1, a regulator of adipocyte differentiation, is regulated by RF, Lipin1 small interfering RNA (siRNA) and RF were pretreated in primary brown adipocytes. Pretreatment with Lipin1 siRNA and RF downregulated the DM-induced expression levels of thermogenic- and mitochondria-related genes. Moreover, RF markedly upregulated AMP-activated protein kinase. Our study shows that RF is capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes.Conclusions: This study demonstrates that RF prevents the development of obesity in mice fed with a HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes, which suggests that RF has potential as a therapeutic application for the treatment or prevention of obesity. [ABSTRACT FROM AUTHOR]

Fusion genes act as potent oncogenes, resulting from chromosomal rearrangements or abnormal transcription in many human cancers. Although multiple gastric cancer genomes have been sequenced, the driving recurrent gene fusions have not been well characterized. Here, we used paired-end transcriptome sequencing to identify novel gene fusions in 18 human gastric cancer cell lines and 18 pairs of primary human gastric cancer tissues and their adjacent normal tissues. Multiple samples revealed expression of PPP1R1B-STARD3 fusion transcript. The presence of PPP1R1B-STARD3 correlated with elevated levels of PPP1R1B mRNA. PPP1R1B-STARD3 fusion transcript was detected in 21.3% of primary human gastric cancers but not in adjacent matched normal gastric tissues. Based on reverse transcription PCR analysis of DNA, unlike other fusions described in gastric cancer, the PPP1R1B-STARD3 appears to be generated by RNA processing without chromosomal rearrangement. Overexpression of PPP1R1B-STARD3 in MKN-28 significantly increased cell proliferation and colony formation. This increased proliferation was mediated by activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling. Furthermore, expression of PPP1R1B-STARD3 fusion transcript enhanced the tumor growth of MKN-28 cells in athymic nude mice. These findings show that PPP1R1B-STARD3 fusion transcript has a key role in subsets of gastric cancers through the activation of PI3K/AKT signaling. [ABSTRACT FROM AUTHOR]

Premature senescence induced by oncogenic stimuli or tumor suppressor activation plays opposing roles in tumorigenesis. Here, we propose that galectin-3, a β-galactoside-binding lectin, regulates premature senescence without oncogenic stress. We detected premature senescence, decreased Skp2, and increased p27KIP1 expression in galectin-3 knockout MEFs and galectin-3-depleted gastric cancer cells. Interestingly, galectin-3 depletion did not affect other senescence inducers such as p14ARF, p16INK4A, and p21WAF1/CIP1, suggesting that galectin-3-regulated senescence is p27KIP1 dependent. We demonstrate that galectin-3 depletion decreases retinoblastoma protein (Rb) phosphorylation (Ser780, Ser807/811), cyclin D1 and CDK4 expression, and E2F1 transcriptional activation. Galectin-3 directly interacts with the cyclin D1/CDK4 complex and promotes hyperphosphorylation of Rb. It also blocks the inhibition of E2F1 transcription, thereby increasing the expression of Skp2 and reducing the stability of p27KIP1 to promote the proliferation of gastric cancer cells. Xenograft mice with galectin-3-depleted gastric cancer cells display tumor growth retardation that is reversed by Skp2 overexpression. Increased expression of galectin-3 is also associated with the advanced TNM (tumor, lymph node, metastasis) system, clinicopathological stage, and lymph node metastases. The probability of survival was significantly decreased in gastric cancer patients with galectin-3high p27KIP1-lowcells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence. [ABSTRACT FROM AUTHOR]

BackgroundTo investigate the changes in inner foveal contour after surgery for macular hole (MH) and its clinical implications.MethodsThis retrospective observational case series included 66 eyes from 66 patients who underwent surgery for MH. Notching of tissue was defined as an abrupt alteration in the inner contour of the parafoveal tissue based on postoperative optical coherence tomography (OCT) image. The distance between the parafoveal edges of the outer plexiform layer (OPL) was defined as the inter-OPL distance. The inter-OPL distance was divided into nasal, temporal, superior, and inferior lengths. The difference in the lengths of each direction between the early and late postoperative period was compared between directions with and without notching.ResultsThe early and late postoperative examination was performed at 4.6±2.9 weeks and 6.2±0.6 months, respectively. Notching of tissue was noted in 54 eyes (81.8%). In 53 eyes with a measurable inter-OPL distance, the notching of tissue was noted in 45 eyes (84.9%) regardless of preoperative MH size. The mean amount of foveal tissue elongation that occurred during the designated period was 104.6±68.8 and 78.4±72.9 μm in the directions with and without the notching of tissue (P<0.001), respectively.ConclusionsThe changes in the inner foveal contour, including notching of tissue and elongation of foveal tissue, were noted in the majority of eyes after MH surgery. Notching of tissue on OCT image could be a clinical marker for the development of foveal tissue elongation after MH surgery. [ABSTRACT FROM AUTHOR]

In low alloy steels containing Nb, the poor hot ductility is basically due to the austenite grain boundary segregation of sulfur and the additional matrix strengthening of Nb(C,N) precipitates, both of which decrease the equicohesive temperature. The recovery of hot ductility is therefore attributed to not only the clean grain boundaries that the segregated sulfur is scavenged through the MnS reaction but also the matrix softening by the coarse Nb(C,N) precipitates. [ABSTRACT FROM AUTHOR]

Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3′-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which examines the relationship of JAK2V617F mutation and acquired uniparental disomy (UPD) at 9p chromosome in patients with polycythemia vera (PV).

Despite strong possibility that endothelial cells (ECs) of tumors and normal tissues may differ in various aspects, most previous studies on ECs have used normal cells. Here, we purified ECs from tumorous and normal human breast tissues, and studied the effect of radiation on angiogenesis and relevant molecular mechanisms in these cells. We found that in normal tissue-derived ECs (NECs), 4 Gy irradiation increased tube formation, matrix metalloproteinase 2 (MMP-2) expression and extracellular signal-regulated kinase (ERK) pathway activation. In cancer-derived ECs (CECs), however, 4 Gy irradiation significantly reduced tube formation, increased the production of angiostatin and interleukin-6 (IL-6), and upregulated AKT and c-Jun N-terminal kinase (JNK) pathway activation. Knockdown experiments showed that siMMP-2 efficiently inhibited tube formation by irradiated NECs, whereas siPlasminogen effectively attenuated the radiation-induced suppression of tube formation and the upregulation of angiostatin in CECs. Moreover, siIL-6 clearly inhibited the radiation-induced generation of angiostatin in CECs. Inhibition of ERK with a pharmacological inhibitor or small interfering RNAs (siRNAs) markedly suppressed the radiation-induced tube formation and MMP-2 upregulation in NECs, whereas the inhibition of either AKT or JNK with pharmacological inhibitor or siRNA treatment of CECs markedly attenuated the inhibition of tube formation and the upregulation of angiostatin and IL-6 caused by 4 Gy irradiation. These observations collectively demonstrate that there are distinct differences in the radiation responses of NECs and CECs, and might provide important clues for improving the efficacy of radiation therapy. [ABSTRACT FROM AUTHOR]

The regulation of CCAAT/enhancer-binding protein-homologous protein (CHOP), an endoplasmic reticulum (ER) stress-response factor, is key to cellular survival. Hypoxia is a physiologically important stress that induces cell death in the context of the ER, especially in solid tumors. Although our previous studies have suggested that Cyclophilin B (CypB), a molecular chaperone, has a role in ER stress, currently, there is no direct information supporting its mechanism under hypoxia. Here, we demonstrate for the first time that CypB is associated with p300 E4 ligase, induces ubiquitination and regulates the proteasomal turnover of CHOP, one of the well-known pro-apoptotic molecules under hypoxia. Our findings show that CypB physically interacts with the N-terminal α-helix domain of CHOP under hypoxia and cooperates with p300 to modulate the ubiquitination of CHOP. We also show that CypB is transcriptionally induced through ATF6 under hypoxia. Collectively, these findings demonstrate that CypB prevents hypoxia-induced cell death through modulation of ubiquitin-mediated CHOP protein degradation, suggesting that CypB may have an important role in the tight regulation of CHOP under hypoxia. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma upregulated factor (PAUF) was recently reported to be a metastasis factor for pancreatic cancer cells. Here, we demonstrate a novel role for PAUF as a potent endothelial activator, promoting both angiogenesis and vascular permeability. Overexpression of PAUF in a mouse pancreatic cancer model resulted in increased tumor vascularity. Recombinant PAUF (rPAUF) enhanced proliferation, migration and capillary-like tube formation of human endothelial cells (ECs), consistently with increased neovascularization in vivo. rPAUF also increased endothelial permeability through the disruption of vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects were attenuated upon treatment with an antibody against PAUF. Moreover, PAUF evoked a time- and dose-dependent activation of extracellular signal-regulated kinase (ERK)1/2, AKT and endothelial NO synthase (eNOS) in ECs, which are closely linked to rPAUF-induced angiogenesis. Finally, rPAUF upregulated the expression of C-X-C chemokine receptor 4 (CXCR4) in ECs and potentiated the in vitro and in vivo EC angiogenic responses to stromal cell-derived factor-1 (SDF-1), a ligand for CXCR4. Taken together, these data demonstrate that PAUF has a novel function in promoting angiogenesis and vascular permeability. Our findings suggest new possibilities for PAUF's role in the pathogenesis of angiogenesis-dependent diseases. [ABSTRACT FROM AUTHOR]

This research investigates mixing phenomena in bottom gas-stirred ladles using water modeling, which incorporates hexane as the top layer. The effects of slag thickness, nozzle position, number of nozzles, and gas flow rate on mixing time have been investigated. Conditions to improve mixing time have been identified. A single nozzle located at two-thirds of the ladle radius was found to produce the shortest mixing time. Under extremely low gas flow rates, an unusual behavior was observed, where the top layer promoted a decrease in mixing time. [ABSTRACT FROM AUTHOR]

PurposeTo evaluate the effect of partial posterior hyaloidectomy (PPH) in preventing iatrogenic retinal breaks related to the induction of a posterior vitreous detachment (IPVD)MethodsFifty-nine patients who necessitated IPVD for an epiretinal membrane or macular hole were included in this prospective, interventional case series. Extensive removal of vitreous gel, close to the retina, was conducted before IPVD under 23 G (gauge)-vitrectomy system. The PPH involved the limited extent of IPVD and limited removal of the outermost vitreous cortex to an area slightly beyond the margin of the temporal major vascular arcade. The incidence of retinal breaks related to the surgery was compared with 57 eyes that had undergone conventional 23-G total vitrectomy accompanied by extensive IPVD using χ2-test.ResultsPatients were followed-up for a mean of 14.3 months (6-30 months) after the surgery. The incidence of peripheral retinal breaks after the PPH was 3.4% (2/59 eyes), which was significantly lower than that in the eyes that underwent conventional 23 G vitrectomy (15.8%, 9/57 eyes, P=0.023) for the same disorders that required an IPVD. No patient complained of postoperative floaters, postoperatively.ConclusionsPPH would be an efficient procedure to prevent iatrogenic peripheral retinal breaks related to an IPVD. [ABSTRACT FROM AUTHOR]

We have developed a technique to observe the intrinsic Josephson effect in BiSrCaCuO (Bi-2212) single crystal whiskers. In this technique, a raw Bi-2212 single crystal whisker used as intrinsic Josephson junctions (IJJs) along the c-axis. The technique is simple, quick, and less-cost processing. First, a whisker made to stand on ac-plane and then two electrodes were made in ab-planes on either side. The standing whisker with this configuration worked as IJJs. The standing whisker (1.6 mm×40 μm×3 μm) showed the transition temperature of about 84 K. The critical current was about 15 mA at 8 K (critical current density ∼23 A/cm). We observed voltage gap of about 500 mV in current-voltage ( I- V) characteristics. This corresponds to a few hundred of IJJs out of ∼2,000 IJJs in the whisker thickness. Observations reflect that the technique can be further improved with the single crystal quality, shape of single crystal whisker, and annealing conditions. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate the clinical characteristics and surgical outcomes of early-onset exotropia and to compare differences between constant and intermittent exotropia at presentation.MethodsThe medical records of 45 exotropia patients with a reported onset before 1 year of age who were operated on between 2008 and 2011 were reviewed, and the clinical characteristics and surgical outcomes of these patients were analyzed retrospectively. Patients were then divided into two groups according to type of exotropia at presentation: a constant (XT) group and an intermittent (X(T)) group. Clinical features and surgical results of exotropia were then compared between these two groups.ResultsThe mean age of onset of exodeviation in 45 patients was 9.3±3.8 months. Mean age at surgery was 4.5±2.4 years, and the mean postoperative follow-up period was 17.3 months (range, 6-37 months). Of the 45 patients, 67% showed alignment of less than±10 prism diopters (PD) at final visit. Gross stereopsis was achieved in all 34 testable patients, and bifixation developed in 10 patients (29%). Eleven patients were included in XT group and 34 patients in X(T) group. No significant intergroup difference was found between surgical success rates and binocularities.ConclusionSurgical outcomes, both motor and sensory, were not poor in early-onset exotropia patients, even in patients with constant deviation. Good binocular results following surgery can be achieved in children presenting with apparently constant early-onset exotropia. [ABSTRACT FROM AUTHOR]

PurposeTo evaluate the variability in subfoveal choroidal thickness measurements in patients with age-related macular degeneration (AMD) and central serous chorioretinopathy using enhanced depth imaging optical coherence tomography (EDI-OCT).MethodsOne hundred and sixty eyes of 160 patients who were diagnosed with early AMD (N=40), exudative AMD (N=40), polypoidal choroidal vasculopathy (PCV, N=40), or central serous chorioretinopathy (CSC, N=40) were included in this retrospective observational study. In addition, we included 40 normal eyes of 40 subjects. Subfoveal choroidal thickness was measured manually by two masked observers based on EDI-OCT images. The correlation of choroidal thickness with the absolute value of the difference in the choroidal thickness measurement was estimated for all 200 eyes. Intraobserver and interobserver coefficients of repeatability (CRs) were calculated.ResultsThere was a significant positive correlation between subfoveal choroidal thickness and both intraobserver (P<0.001) and interobserver (P<0.001) difference in choroidal thickness measurements. The mean intraobserver CRs in nonexudative AMD, exudative AMD, PCV, CSC, and normal eyes were ∼15-21, 23-29, 24-35, 32-38, and 19-25 μm, respectively. The mean interobserver CRs were ∼24-28, 30-36, 39-45, 46-57, and 26-35 μm, respectively.ConclusionsRelatively great measurement variability should be considered when investigating eyes with pathologic conditions related to a thick choroid, including PCV or CSC. [ABSTRACT FROM AUTHOR]

PurposeTo investigate the long-term clinical course and visual outcomes of Peters' anomaly cases treated with various treatment modalities.Patients and MethodsAll patients with Peters' anomaly treated at Seoul National University Children's Hospital from 1985 to 2005 were reviewed retrospectively. Patients who were followed for more than 5 years after the first visit were enrolled for analysis of the visual outcome. Final visual outcomes were presented with respect to disease severity and treatment modalities. Disease severity was determined according to the corneal status and accompanied eye anomalies in mild or severe form. Treatment plans were classified into the following groups: (1) a medical treatment group; (2) a surgical treatment group; and (3) a no-treatment group.ResultsA total of 106 eyes in 76 patients were diagnosed as Peters' anomaly, and 90 eyes in 65 patients were analysed regarding the visual outcome. Overall, 60 eyes (67%) had severe disease, and 30 eyes (33%) had mild disease. Twenty-six eyes (29%) received medical treatment, 44 eyes (49%) received surgical treatment, and 20 eyes (22%) received no treatment. The mean final visual acuity was 1.415 logMAR, 2.344 logMAR, and 2.282 logMAR, respectively. The visual outcomes of the eyes with mild disease in each group were significantly better than the eyes with severe disease.ConclusionsThe long-term visual outcomes of Peters' anomaly differed according to the disease severity in each treatment group. Therefore, before making treatment plans for Peters' anomaly, it is important to investigate the corneal status and accompanying eye disease to determine disease severity. [ABSTRACT FROM AUTHOR]

Background:In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin.Methods:We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification.Results:Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m−2 of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio.Conclusion:We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretin hormones that exert insulinotropic and anti-apoptotic actions on pancreatic β-cells. Insulinotropic actions of the incretins involve modulation of voltage-gated potassium (Kv) channels. In multiple cell types, Kv channel activity has been implicated in cell volume changes accompanying initiation of the apoptotic program. Focusing on Kv2.1, we examined whether regulation of Kv channels in β-cells contributes to the prosurvival effects of incretins. Overexpression of Kv2.1 in INS-1 β-cells potentiated apoptosis in response to mitochondrial and ER stress and, conversely, co-stimulation with GIP/GLP-1 uncoupled this potentiation, suppressing apoptosis. In parallel, incretins promoted phosphorylation and acetylation of Kv2.1 via pathways involving protein kinase A (PKA)/mitogen- and stress-activated kinase-1 (MSK-1) and histone acetyltransferase (HAT)/histone deacetylase (HDAC). Further studies demonstrated that acetylation of Kv2.1 was mediated by incretin actions on nuclear/cytoplasmic shuttling of CREB binding protein (CBP) and its interaction with Kv2.1. Regulation of β-cell survival by GIP and GLP-1 therefore involves post-translational modifications (PTMs) of Kv channels by PKA/MSK-1 and HAT/HDAC. This appears to be the first demonstration of modulation of delayed rectifier Kv channels contributing to the β-cell prosurvival effects of incretins and of 7-transmembrane G protein-coupled receptor (GPCR)-stimulated export of a nuclear lysine acetyltransferase that regulates cell surface ion channel function. [ABSTRACT FROM AUTHOR]

c-Jun N-terminal kinase (JNK) is activated by dual phosphorylation of both threonine and tyrosine residues in the phosphorylation loop of the protein in response to several stress factors. However, the precise molecular mechanisms for activation after phosphorylation remain elusive. Here we show that Pin1, a peptidyl-prolyl isomerase, has a key role in the JNK1 activation process by modulating a phospho-Thr-Pro motif in the phosphorylation loop. Pin1 overexpression in human breast cancer cell lines correlates with increased JNK activity. In addition, small interfering RNA (siRNA) analyses showed that knockdown of Pin1 in a human breast cancer cell line decreased JNK1 activity. Pin1 associates with JNK1, and then catalyzes prolyl isomerization of the phospho-Thr-Pro motif in JNK1 from trans- to cis-conformation. Furthermore, Pin1 enhances the association of JNK1 with its substrates. As a result, Pin1−/− cells are defective in JNK activation and resistant to oxidative stress. These results provide novel insights that, following stress-induced phosphorylation of Thr in the Thr-Pro motif of JNK1, JNK1 associates with Pin1 and undergoes conformational changes to promote the binding of JNK1 to its substrates, resulting in cellular responses from extracellular signals. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the efficacy and safety of combination treatment using anticholinergics with α-blocker for initial treatment of both overactive bladder (OAB) and other lower urinary tract symptoms (LUTS), secondary to BPH. A 12-week, randomized, double-blind, placebo-controlled trial was conducted at four urology clinics in Korea, involving men, aged 50 years or older, with LUTS related to BPH and OAB. A total of 176 patients were randomly assigned to receive doxazosin (4 mg) plus placebo or doxazosin (4 mg) plus tolterodine SR (4 mg), once a day for 12 weeks. Changes from baseline in total International Prostate Symptom Score (IPSS), bladder diary variables, patient perception of bladder condition (PPBC), uroflowmetry, postvoid residual volume and IPSS subscores (voiding and storage) were analyzed. Of the 176 enrolled patients, 91 had doxazosin gastrointestinal therapeutic system (GITS) and placebo, and 85 had combined medication with doxazosin GITS and tolterodine SR. Compared with the doxazosin plus placebo group, the doxazosin plus tolterodine group showed significant reductions in IPSS storage subscore and improvement in the quality of life item, urgency episodes, as well as in micturition frequency at weeks 4 and 12. However, it failed to improve PPBC at week 4 as well as at week 12. Earlier intervention with anticholinergics plus α-blocker was tolerated well, including the questions about urinary retention (n=1) and dry mouth (n=2). Initial combination treatment of anticholinergics plus α-blocker showed positive results for men with LUTS related to BPH and OAB symptoms and did not increase the risk of urinary retention. [ABSTRACT FROM AUTHOR]

PurposeTo determine whether horizontal macular contraction caused by epiretinal membranes (ERMs) improves after surgical removal.MethodsIn this prospective, single-center, observational study, 63 consecutive patients with unilateral idiopathic ERM in one eye and no retinal disease in the fellow eye underwent pars plana vitrectomy. Fundus photography and optical coherence tomography (OCT) were performed preoperatively and at 3 months postoperatively. The area enclosed by superior and inferior major vessels from the optic disc to the fovea (area under major vessel (AUV)) and the macroscopic diverging angle (MDA) between superior and inferior major vessels were calculated using digital image analysis of fundus photographs and compared pre- and postoperatively.ResultsAUV was significantly smaller in the eyes with ERM compared with the normal fellow eyes (P<0.001). Significant postoperative change in AUV and MDA was demonstrated after ERM removal (P<0.001). However, postoperative AUV of grade 2 and 3 ERM eyes was still significantly smaller than that of normal fellow eyes. Macular thickness differences measured with stratus OCT were positively correlated with AUV differences.ConclusionsRetinal topographic changes caused by ERM improved in part after ERM removal. The improvement of topographic changes were correlated with tomographic changes detected with OCT. [ABSTRACT FROM AUTHOR]

Owing to its tumor tropism and prolonged transgene expression, mesenchymal stem cell (MSC) has been considered as an ideal delivery vehicle for cancer gene therapies or therapeutic vaccines. In this study, we demonstrated that intratumoral (i.t.) injection of MSCs expressing modified interleukin-12 (MSCs/IL-12M) exhibited stronger tumor-specific T-cell responses and antitumor effects as well as more sustained expressions of IL-12 and interferon (IFN)-γ in both sera and tumor sites than did IL-12M-expressing adenovirus (rAd/IL-12M) in mice bearing both solid and metastatic tumors. Subcutaneous (s.c.) injection of MSCs/IL-12M at contralateral site of tumor exhibited similar levels of serum IL-12 and IFN-γ as i.t. injection, but much weaker antitumor effects in both B16F10 melanoma and TC-1 cervical cancer models than i.t. injection. Although intravenous (i.v.) injection elicited earlier peak serum levels of cytokines, it induced weaker tumor-specific T-cell responses and antitumor effects than i.t. injection, indicating that serum cytokine levels are not surrogate indicators of antitumor effects. Taken together, these results indicated that MSC is more efficient than adenovirus as a cytokine gene delivery vehicle and that i.t. injection of MSCs/IL-12M is the best approach to induce strong tumor-specific T-cell responses that correlate with anti-metastatic effects as well as inhibition of solid tumor growth, although MSCs themselves have an ability to migrate into the tumor site. In addition, MSCs/IL-12M embedded in Matrigel (MSCs/IL-12M/Matrigel) exhibited significant antitumor effects even in immunodeficient mice such as SCID and BNX mice lacking T, B and natural killer (NK) cells, but not in IFN-γ knockout mice. Our findings provide an optimal approach for designing an efficient clinical protocol of MSC-based cytokine gene therapy to induce strong tumor-specific T-cell responses and therapeutic anticancer efficacy. [ABSTRACT FROM AUTHOR]