Circulating microRNA Profiles Identify a Patient Subgroup with High Inflammation and Severe Symptoms in Schizophrenia Experiencing Acute Psychosis.

Schizophrenia is a complex and heterogenous psychiatric disorder. This study aimed to demonstrate the potential of circulating microRNAs (miRNAs) as a clinical biomarker to stratify schizophrenia patients and to enhance understandings of their heterogenous pathophysiology. We measured levels of 179 miRNA and 378 proteins in plasma samples of schizophrenia patients experiencing acute psychosis and obtained their Positive and Negative Syndrome Scale (PANSS) scores. The plasma miRNA profile revealed three subgroups of schizophrenia patients, where one subgroup tended to have higher scores of all the PANSS subscales compared to the other subgroups. The subgroup with high PANSS scores had four distinctively downregulated miRNAs, which enriched 'Immune Response' according to miRNA set enrichment analysis and were reported to negatively regulate IL-1ß, IL-6, and TNFα. The same subgroup had 22 distinctively upregulated proteins, which enriched 'Cytokine-cytokine receptor interaction' according to protein set enrichment analysis, and all the mapped proteins were pro-inflammatory cytokines. Hence, the subgroup is inferred to have comparatively high inflammation within schizophrenia. In conclusion, miRNAs are a potential biomarker that reflects both disease symptoms and molecular pathophysiology, and identify a patient subgroup with high inflammation. These findings provide insights for the precision medicinal strategies for anti-inflammatory treatments in the high-inflammation subgroup of schizophrenia.

Efficacy and safety of the sodium-glucose co-transporter-2 inhibitor empagliflozin in elderly Japanese adults (≥65 years) with type 2 diabetes: A randomized, double-blind, placebo-controlled, 52-week clinical trial (EMPA-ELDERLY).

AIM: Use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) for glycaemic control is increasing in individuals with type 2 diabetes (T2D) for their additional benefits on heart failure and chronic kidney disease. However, SGLT2is generally reduce body weight, which might promote sarcopenia in older individuals. We evaluated the effects of the SGLT2i empagliflozin on muscle mass and strength in addition to glucose control in elderly adults with T2D. MATERIALS AND METHODS: Individuals with T2D aged ≥65 years with body mass index ≥22 kg/m2 and glycated haemoglobin (HbA1c) 7.0%-10.0% were randomized 1:1 to once-daily empagliflozin 10 mg or placebo for 52 weeks. The primary endpoint was change from baseline in HbA1c at week 52. Secondary endpoints included changes from baseline in muscle mass and strength. RESULTS: Of the 129 individuals randomized, 72.4% were men, mean age 74.1 years, body mass index 25.6 kg/m2 and HbA1c 7.6%. The placebo-adjusted mean change from baseline in HbA1c at week 52 with empagliflozin was -0.57% [95% confidence interval (CI) -0.78, -0.36]. Change in body weight was -3.26 kg and -0.90 kg with empagliflozin and placebo, respectively (placebo-adjusted difference: -2.37 kg; 95% CI -3.07, -1.68). Placebo-adjusted change in muscle mass was -0.61 kg (95% CI -1.61, 0.39), fat mass -1.84 kg (95% CI -2.65, -1.04) and grip strength -0.3 kg (95% CI -1.1, 0.5). CONCLUSIONS: Empagliflozin improved glucose control and reduced body weight without compromising muscle mass or strength in elderly adults with T2D in this trial.

Endurance Exercise Training-Attenuated Diabetic Kidney Disease with Muscle Weakness in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: The aim of this study was to evaluate protective effects of endurance exercise training against diabetic kidney disease (DKD) with muscle weakness by using male spontaneously diabetic Torii (SDT) fatty rats as type 2 diabetic animal models with obesity, hypertension, and hyperlipidemia. METHODS: Eight-week-old SDT fatty rats (n = 12) and Sprague-Dawley (SD) rats (n = 10) were randomly divided into exercise (Ex; SDT-Ex: n = 6, SD-Ex: n = 5) and sedentary groups (SDT-Cont: n = 6, SD-Cont: n = 5), respectively. Each group underwent regular treadmill exercise 4 times a week from ages 8-16 weeks. RESULTS: The exercise attenuated hypertension and hyperlipidemia and prevented increases in renal parameter levels without affecting blood glucose levels. In the SDT fatty rats, it prevented induction of renal morphological abnormalities in the interstitium of the superficial and intermediate layers of the cortex. Downregulated expression of endothelial nitric oxide synthase in the glomerulus of the SDT fatty rats was significantly upregulated by the exercise. The exercise upregulated the renal expressions of both medium-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor γ coactivator-1α related to fatty acid metabolism. It increased muscle strength and both muscle weight and cross-sectional area of type IIb muscle fibers in the extensor digitorum longus muscle in the SDT fatty rats. CONCLUSION: Endurance exercise training in type 2 diabetes ameliorates DKD by improving endothelial abnormality and enhancing fatty acid metabolism in addition to attenuated hypertension, hyperlipidemia, and muscle weakness independently of blood glucose levels.

Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats.

BACKGROUND: The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. METHODS: Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle. RESULTS: The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. CONCLUSIONS: Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Age-related decrease in muscle satellite cells is accompanied with diminished expression of early growth response 3 in mice.

Skeletal muscle regeneration is mostly dependent on muscle satellite cells. Proper muscle regeneration requires enough number of satellite cells. Recent studies have suggested that the number of satellite cells in skeletal muscle declines as we age, leading to the impairment of muscle regeneration in older population. Our earlier study demonstrated that zinc finger transcription factor early growth response 3 (Egr3) plays an important role for maintaining the number of myoblasts, suggesting that age-related decrease in muscle satellite cell should be associated with the expression levels of Egr3. The aim of this study was to investigate whether aging would alter the Egr3 expression in satellite cells. A couple groups of male C57BL/6J mice were examined in this study: young (3 Mo) and old (17 Mo). Immunohistochemical staining showed that the satellite cell number decreased in normal and injured muscles of old mice. In fluorescence-activated cell sorting-isolated muscle satellite cells from normal and injured muscles, the mRNA expression of Egr3 was significantly decreased with age regardless of injury. In harmony with these results, Pax7 mRNA levels also decreased in the satellite cells from old mice. Alternatively, inhibition of Egr3 expression by shRNA decreased Pax7 protein expression in cultured myoblasts. These results suggest that Egr3 is associated with the age-related decline of muscle satellite cells in older population. Also, Egr3 might be implicated in the regulation of Pax7. Therefore, the loss of Egr3 expression may elucidate attenuated MSCs function and muscle regeneration in older age.

The Possibility of Urinary Liver-Type Fatty Acid-Binding Protein as a Biomarker of Renal Hypoxia in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. OBJECTIVE: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. RESULTS: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. CONCLUSIONS: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.

Epizootic Hemorrhagic Disease Virus Serotype 6 Infection in Cattle, Japan, 2015.

During October-December 2015, an epizootic hemorrhagic disease outbreak occurred in cattle in Japan. Forty-six animals displayed fever, anorexia, cessation of rumination, salivation, and dysphagia. Virologic, serologic, and pathologic investigations revealed the causative agent was epizootic hemorrhagic disease virus serotype 6. Further virus characterization is needed to determine virus pathogenicity.

A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines.

More than 30 years ago, a calcium-dependent enzyme activity was described that generates N-acyl phosphatidylethanolamines (NAPEs), which are precursors for N-acyl ethanolamine (NAE) lipid transmitters, including the endocannabinoid anandamide. The identity of this calcium-dependent N-acyltransferase (Ca-NAT) has remained mysterious. Here, we use activity-based protein profiling to identify the poorly characterized serine hydrolase PLA2G4E as a mouse brain Ca-NAT and show that this enzyme generates NAPEs and NAEs in mammalian cells.

Early Growth Response 3 (Egr3) Contributes a Maintenance of C2C12 Myoblast Proliferation.

Satellite cell proliferation is a crucially important process for adult myogenesis. However, its regulatory mechanisms remain unknown. Early growth response 3 (Egr3) is a zinc-finger transcription factor that regulates different cellular functions. Reportedly, Egr3 interacts with multiple signaling molecules that are also known to regulate satellite cell proliferation. Therefore, it is possible that Egr3 is involved in satellite cell proliferation. Results of this study have demonstrated that Egr3 transcript levels are upregulated in regenerating mouse skeletal muscle after cardiotoxin injury. Using C2C12 myoblast culture (a model of activated satellite cells), results show that inhibition of Egr3 by shRNA impairs the myoblast proliferation rate. Results also show reduction of NF-кB transcriptional activity in Egr3-inhibited cells. Inhibition of Egr3 is associated with an increase in annexin V+ cell fraction and apoptotic protein activity including caspase-3 and caspase-7, and Poly-ADP ribose polymerase. By contrast, the reduction of cellular proliferation by inhibition of Egr3 was partially recovered by treatment of pan-caspase inhibitor Z-VAD-FMK. Collectively, these results suggest that Egr3 is involved in myoblast proliferation by interaction with survival signaling. J. Cell. Physiol. 232: 1114-1122, 2017. © 2016 Wiley Periodicals, Inc.

Long Term Changes in Muscles around the Knee Joint after ACL Resection in Rats: Comparisons of ACL-Resected, Contralateral and Normal Limb.

The purpose of this study was to investigate the long-term effects of anterior cruciate ligament (ACL) resection on the morphological and contractile characteristics of rectus femoris (RF) and semimembranosus (SM) muscles in both injured and contralateral hindlimbs in rats. Wistar male rats (8-week old) were used. Rats were divided into two groups; ACL-resected and (sham-operated) control groups. Furthermore, right and left limbs of rats in the ACL-resected group were assigned as ACL-resected and contralateral groups, respectively, at 1 day, 1, 4, and 48 weeks after ACL resection. No ACL-resection-associated changes in the mass of both muscles were observed 1 week after ACL resection. On the other hand, ACL-resection-associated reduction on mean fiber cross-sectional area (fiber CSA) in RF muscle lasted 48 weeks after ACL resection. Furthermore, ACL-resection associated increase in fiber composition of type I fiber in RF muscle in contralateral limbs. In addition, long-term effects of ACL resection were observed in both ACL-resected and contralateral limbs. Evidences from this study suggested that ACL resection may cause to change in the morphological (fiber CSA) and contractile (distribution of fiber types) properties of skeletal muscles around the knee joint in not only injured but also contralateral limb. Rehabilitation for quantitative and qualitative muscle changes by ACL resection may be required a special care for a long-term period.

Involvement of Transient Receptor Potential Cation Channel Vanilloid 1 (TRPV1) in Myoblast Fusion.

The mechanisms that underlie the complex process of muscle regeneration after injury remain unknown. Transient receptor potential cation channel vanilloid 1 (TRPV1) is expressed in several cell types, including skeletal muscle, and is activated by high temperature and by certain molecules secreted during tissue inflammation. Severe inflammation and local temperature perturbations are induced during muscle regeneration, which suggests that TRPV1 might be activated and involved in the process. The aim of this study, was to clarify the role of TRPV1 in the myogenic potential of satellite cells responsible for muscle regeneration. We found that mRNA and protein levels of TRPV1 increased during regeneration after cardiotoxin (CTX)-induced muscle injury in mice. Using isolated mouse satellite cells (i.e., myoblasts), we observed that activation of TRPV1 by its agonist capsaicin (CAP) augmented myogenin protein levels. Whereas CAP did not alter myoblast proliferation, it facilitated myoblast fusion (evaluated using myonucleii number per myotube and fusion index). In contrast, suppression of TRPV1 by siRNA impaired myoblast fusion. Using mice, we also demonstrated that intramuscular injection of CAP facilitated muscle repair after CTX-induced muscle injury. Moreover, we showed that these roles of TRPV1 might be mediated by interleukin-4 and calcium signaling during myoblast fusion. Collectively, these results suggest that TRPV1 underlies normal myogenesis through promotion of myoblast fusion. J. Cell. Physiol. 231: 2275-2285, 2016. © 2016 Wiley Periodicals, Inc.

Human Intestinal Raf Kinase Inhibitor Protein (RKIP) Catalyzes Prasugrel as a Bioactivation Hydrolase.

Prasugrel is a thienopyridine antiplatelet prodrug that undergoes rapid hydrolysis in vivo to a thiolactone metabolite by human carboxylesterase-2 (hCE2) during gastrointestinal absorption. The thiolactone metabolite is further converted to a pharmacologically active metabolite by cytochrome P450 isoforms. The aim of the current study was to elucidate hydrolases other than hCE2 involved in the bioactivation step of prasugrel in human intestine. Using size-exclusion column chromatography of a human small intestinal S9 fraction, another peak besides the hCE2 peak was observed to have prasugrel hydrolyzing activity, and this protein was found to have a molecular weight of about 20 kDa. This prasugrel hydrolyzing protein was successfully purified from a monkey small intestinal cytosolic fraction by successive four-step column chromatography and identified as Raf-1 kinase inhibitor protein (RKIP) by liquid chromatography-tandem mass spectrometry. Second, we evaluated the enzymatic kinetic parameters for prasugrel hydrolysis using recombinant human RKIP and hCE2 and estimated the contributions of these two hydrolyzing enzymes to the prasugrel hydrolysis reaction in human intestine, which were approximately 40% for hRKIP and 60% for hCE2. Moreover, prasugrel hydrolysis was inhibited by anti-hRKIP antibody and carboxylesterase-specific chemical inhibitor (bis p-nitrophenyl phosphate) by 30% and 60%, respectively. In conclusion, another protein capable of hydrolyzing prasugrel to its thiolactone metabolite was identified as RKIP, and this protein may play a significant role with hCE2 in prasugrel bioactivation in human intestine. RKIP is known to have diverse functions in many intracellular signaling cascades, but this is the first report describing RKIP as a hydrolase involved in drug metabolism.

Elevated levels of TWEAK in skeletal muscle promote visceral obesity, insulin resistance, and metabolic dysfunction.

Skeletal muscle is responsible for the majority of glucose disposal in body. Impairment in skeletal muscle glucose handling capacity leads to the state of insulin resistance. The TNF-like weak inducer of apoptosis (TWEAK) cytokine has now emerged as a major regulator of skeletal muscle mass and function. However, the role of TWEAK in skeletal muscle metabolic function remains less understood. Here, we demonstrate that with progressive age, skeletal muscle-specific TWEAK-transgenic (TWEAK-Tg) mice gain increased body weight (∼16%) and fat mass (∼64%) and show glucose intolerance and insulin insensitivity. TWEAK-Tg mice also exhibit adipocyte hypertrophy in the epididymal fat. Oxygen uptake, voluntary physical activity, and exercise capacity were significantly reduced in TWEAK-Tg mice compared with controls. Overexpression of TWEAK inhibited (∼31%) 5' AMP-activated protein kinase (AMPK) and reduced (∼31%) the levels of glucose transporter type 4 (GLUT4) without affecting the Akt pathway. TWEAK also inhibited insulin-stimulated glucose uptake (∼32%) and repressed the levels of GLUT4 (∼50%) in cultured myotubes from C57BL6 mice. TWEAK represses the levels of Krüppel-like factor 15; myocyte enhancer factor 2, and peroxisome proliferator-activated receptor-γ coactivator-1α, which are required for the activation of the GLUT4 locus. Collectively our study demonstrates that elevated levels of TWEAK in skeletal muscle cause metabolic abnormalities. Inhibition of TWEAK could be a potential approach to prevent weight gain and type 2 diabetes.

Clinical characteristics and intravascular ultrasound findings of culprit lesions in elderly patients with acute coronary syndrome.

Acute coronary syndrome (ACS) is one of the main causes of cardiovascular death. According to rapid aging of society, the peak age of ACS onset has grown older globally. Despite growing recognition of the necessity to build the ACS prevention strategy in the elderly, patients background and culprit lesion morphology of these elderly ACS patients have not been well studied. We sought to assess the clinical characteristics and intravascular ultrasound (IVUS) findings of the culprit lesions in elderly ACS patients. One-hundred and fifty-eight consecutive ACS patients whose culprit lesions imaged by pre-intervention IVUS were divided into two groups based on the age of onset: elderly [E] group (≥75 years, n = 65) and non-elderly [NE] group (<75 years, n = 93). As compared with NE group, hemoglobin (12.7 ± 2.0 g/dL vs. 13.7 ± 1.6 g/dL, p = 0.001), estimated glomerular filtration rate (62.5 ± 22.5 mL/min/1.73 m(2) vs. 75.5 ± 20.5 mL/min/1.73 m(2), p = 0.0001), and body mass index (22.9 ± 3.4 kg/m(2) vs. 24.5 ± 3.4 kg/m(2), p = 0.003) were significantly lower, and comorbid malignancy was more common (20.0 vs 6.5 %, p = 0.01) in E group. Although whole culprit segment was not positively remodeled (mean vessel area was 15.2 ± 5.6 mm(3)/mm vs. 16.2 ± 5.1 mm(3)/mm, p = 0.16) in E group, at maximum external elastic membrane site of the culprit lesion, lumen area was smaller (5.5 ± 3.2 mm(2) vs. 6.7 ± 3.5 mm(2), p = 0.04), and plaque burden tended to be more abundant (70 ± 13 vs. 66 ± 13 %, p = 0.08). Interestingly, echo attenuation arc of culprit attenuated plaque was significantly greater in E group than in NE group (157 ± 83° vs. 118 ± 60°, p = 0.01). In conclusion, extracardiac comorbidity was more common in elderly ACS patients, and their culprit coronary lesions were still rupture prone, and "vulnerable."

[A Case of Intrascrotal Liposarcoma].

A 69-year-old man was referred to our hospital with the chief complaint of a painless right scrotal swelling gradually increasing in size during the past 10 years. Testicular tumor markers were within the normal range. Ultrasonography showed an intrascrotal homogeneous mass. Computed tomography and magnetic resonance imaging revealed an inguinal mass, which mainly consisted of fat signal area and partially well enhanced in vascular density. Pre-surgical diagnosis was liposarcoma of spermatic cord estimated by radiographic examination and resection of the right intrascrotal tumor with high inguinal orchitectomy was performed. Histopathological diagnosis revealed well-differentiated liposarcoma. No recurrence phenomenon has been observed after 12 months without any adjuvant therapy. This case is the 129th report of intrascrotal liposarcoma in the Japanese literature.

Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program.

Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.

Review of Bioptic Gleason Scores by Central Pathologist Modifies the Risk Classification in Prostate Cancer.

OBJECTIVES: The Gleason score (GS) is the primary classification of clinical risk in prostate cancer (PCa). Here, we estimated the factors predictive of accordance of local and central pathologist-dependent GS and clinical risk classification in an increased number of cases. METHODS: Between January 2009 and December 2013, 388 patients were diagnosed with PCa by 80 independent pathologists from local communities and were referred to our hospital. Validation of the GS with needle-core biopsy specimens was carried out by a single central pathologist, and clinical risk, according to the D'Amico risk classification, was determined. Discrepancies between the GS and risk classification, based on the GS estimated by the local or central pathologist, were reviewed, and predictive factors for accordance of clinical risk classification were estimated. RESULTS: When pathological results were compared, 59.5% of cases were given concordant GSs by local and central pathologists. A significant discrepancy existed in the classification of intermediate risk (p < 0.0001). Multivariate analysis indicated that local pathologist-dependent GS7, lower prostate-specific antigen (≤ 10 ng/ml), and lower T stage (T1 or T2a) were significant predictive factors for discordance with the central pathologist-dependent risk classification. CONCLUSION: Review of bioptic GSs by central pathologists affected discrepancies in risk classification in patients with PCa.

International prostate symptom score (IPSS) change and changing factor in intensity-modulated radiotherapy combined with androgen deprivation therapy for prostate cancer.

The purposes of this study on prostate cancer are to demonstrate the time course of International Prostate Symptom Score (IPSS) after intensity-modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT) and to examine the factor associated with the IPSS change. This study included 216 patients treated with IMRT between 2006 and 2010. Patients were evaluated in three groups according to baseline IPSS as defined by the American Urological Association classification, where IPSSs of 0 to 7, 8 to 19, and 20 to 35 represent mild (n = 124), moderate (n = 70), and severe (n = 22) symptom groups, respectively. The average IPSSs ± standard deviation at baseline vs. those at 24 months after IMRT were 3.5 ± 2.1 vs. 5.1 ± 3.6 in the mild group (P < 0.001), 12.6 ± 3.4 vs. 10.0 ± 6.0 in the moderate group (P = 0.0015), and 23.8 ± 2.9 vs. 14.4 ± 9.1 in the severe group (P < 0.001). Among factors of patient and treatment characteristics, age, IPSS classification, pretreatment GU medications, and positive biopsy rates were associated with the IPSS difference between baseline and 24 months (P = 0.023, < 0.001, 0.044, and 0.028, respectively). In conclusion, patients with moderate to severe urinary symptoms can exhibit improvement in urinary function after IMRT, whereas patients with mild symptoms may have slightly worsened functions. Age, baseline IPSS, GU medications, and tumor burden in the prostate can have an effect on the IPSS changes.

Microcurrent electrical neuromuscular stimulation facilitates regeneration of injured skeletal muscle in mice.

Conservative therapies, mainly resting care for the damaged muscle, are generally used as a treatment for skeletal muscle injuries (such as muscle fragmentation). Several past studies reported that microcurrent electrical neuromuscular stimulation (MENS) facilitates a repair of injured soft tissues and shortens the recovery period. However, the effects of MENS on the regeneration in injured skeletal muscle are still unclear. The purpose of this study was to investigate the effect of MENS on the regenerative process of injured skeletal muscle and to elucidate whether satellite cells in injured skeletal muscle are activated by MENS by using animal models. Male C57BL/6J mice, aged 7 weeks old, were used (n = 30). Mice were randomly divided into two groups: (1) cardiotoxin (CTX)-injected (CX, n = 15) and (2) CTX-injected with MENS treatment (MX, n=15) groups. CTX was injected into tibialis anterior muscle (TA) of mice in CX and MX groups to initiate the necrosis-regeneration cycle of the muscle. TA was dissected 1, 2, and 3 weeks after the injection. Muscle weight, muscle protein content, the mean cross-sectional areas of muscle fibers, the relative percentage of fibers having central nuclei, and the number of muscle satellite cells were evaluated. MENS facilitated the recovery of the muscle dry weight and protein content relative to body weight, and the mean cross-sectional areas of muscle fibers in CTX-induced injured TA muscle. The number of Pax7-positive muscle satellite cells was increased by MENS during the regenerating period. Decrease in the percentages of fibers with central nuclei after CTX-injection was facilitated by MENS. MENS may facilitate the regeneration of injured skeletal muscles by activating the regenerative potential of skeletal muscles. Key pointsMicrocurrent electrical neuromuscular stimulation (MENS) facilitated the recovery of the relative muscle dry weight, the relative muscle protein content, and the mean cross-sectional areas of muscle fibers of injured TA muscle in mice.The number of satellite cells was increased by MENS during the regenerating phase of injured skeletal muscle.Decrease in the percentages of fibers with central nuclei was facilitated by MENS.MENS may facilitate the regeneration of injured skeletal muscles.

Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) suppresses satellite cell self-renewal through inversely modulating Notch and NF-κB signaling pathways.

Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7(+)/MyoD(-) cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7(+) cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-κB transcription factor in satellite cells and inhibition of NF-κB significantly improved the number of Pax7(+) cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-κB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self-renewal through activating NF-κB and repressing Notch signaling.