Showing papers by "Kanazawa Medical University published in 2019"

Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function.

Abstract: The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health concern, and novel therapeutic strategies to prevent T2DM are urgently needed worldwide. Aging is recognized as one of the risk factors for metabolic impairments, including insulin resistance and T2DM. Inflammation, oxidative stress, and mitochondrial dysfunction are closely related to both aging and metabolic disease. Calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related disorders, such as insulin resistance and diabetes. Therefore, metabolic CR mimetics may represent new therapeutic targets for insulin resistance and T2DM. Sirtuin 1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The activation of SIRT1 is closely associated with longevity under CR, and it is recognized as a CR mimetic. Currently, seven sirtuins have been identified in mammals. Among these sirtuins, SIRT1 and SIRT2 are located in the nucleus and cytoplasm, SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. These sirtuins regulate metabolism through their regulation of inflammation, oxidative stress and mitochondrial function via multiple mechanisms, resulting in the improvement of insulin resistance and T2DM. In this review, we describe the current understanding of the biological functions of sirtuins, especially SIRT1, SIRT2, SIRT3, and SIRT6, focusing on oxidative stress, inflammation, and mitochondrial function, which are closely associated with aging.

Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice.

Abstract: Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (Oxt−/−, Cd38−/−) or its receptor (Oxtr−/−) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt−/− and Cd38−/−, but not Oxtr−/− mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager−/− male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager−/− mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.

Equalization of four cardiovascular risk algorithms after systematic recalibration: Individual-participant meta-analysis of 86 prospective studies

Abstract: AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. (Less)

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial-Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis.

Abstract: Dipeptidyl peptidase (DPP)-4 is a multifunctional glycoprotein involved in various biological and pathologic processes. DPP-4 has been widely recognized as a therapeutic target for type 2 diabetes mellitus but is also implicated in the development of human malignancies. Here, we show that inhibition of DPP-4 accelerates breast cancer metastasis via induction of CXCL12/CXCR4, which activates mTOR to promote epithelial-mesenchymal transition (EMT). In cultured cells, DPP-4 knockdown induced EMT and cell migration. Treatment with the DPP-4 inhibitor KR62436 (KR) promoted primary tumor growth and lung metastasis in a 4T1 tumor allograft mouse model; DPP-4 knockdown in 4T1 cells displayed similar phenotypes in vivo and in vitro. KR treatment enhanced the levels of CXCL12/CXCR4 and phosphorylated mTOR, which were associated with the induction of EMT in metastatic cancer cells. KR-induced EMT in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 or the mTOR inhibitor rapamycin, and AMD3100 suppressed KR-induced metastasis in vivo. Our findings suggest that DPP-4 plays a significant role in cancer biology and that inhibition of DPP-4 promotes cancer metastasis via induction of the CXCL12/CXCR4/mTOR/EMT axis. SIGNIFICANCE: These findings reveal that inhibition of DPP-4 increases the metastatic potential of breast cancer. This is especially important given the potential use of DPP-4 inhibition as a therapeutic strategy for type 2 diabetes.

MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER-mitochondria contact sites.

Abstract: Unresolved endoplasmic reticulum (ER) stress shifts the unfolded protein response signaling from cell survival to cell death, although the switching mechanism remains unclear. Here, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) inhibits ER stress-induced apoptosis through ubiquitylation of IRE1α at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination of IRE1α at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1α mutant (K481R) allows for IRE1α hyper-oligomerization and enhances RIDD activity, resulting in apoptosis. Similarly, in the spinal cord of MITOL-deficient mice, ER stress enhances RIDD activity and subsequent apoptosis. Notably, unresolved ER stress attenuates IRE1α ubiquitylation, suggesting that this directs the apoptotic switch of IRE1α signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1α ubiquitylation by MITOL at the MAM.

Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease

Abstract: Castleman disease (CD) is a rare lymphoproliferative disorder that can be unicentric or multicentric. Multicentric CD (MCD) is further subdivided into human herpesvirus type-8-associated, POEMS syndrome-associated, and idiopathic (iMCD). TAFRO syndrome is a newly identified disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The TAFRO syndrome is sometimes regarded as a subtype of iMCD (TAFRO-iMCD), whereas iMCD without TAFRO syndrome is considered "not otherwise specified" (iMCD-NOS). However, a proportion of patients with TAFRO syndrome have been diagnosed without lymph node biopsies (TAFRO syndrome without proven iMCD; TAFRO-w/op-iMCD). To clarify the clinical features of iMCD-NOS, TAFRO-iMCD, and TAFRO-w/op-iMCD, we retrospectively analyzed 220 patients extracted from the database of the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome. The patients included 87 with iMCD-NOS, 63 with TAFRO-iMCD, and 19 with TAFRO-w/op-iMCD. Patients in all three groups exhibited anemia, hypoalbuminemia, and elevated serum C-reactive protein and interleukin-6 levels. No significant differences in clinical, laboratory, and prognostic features were noted between the TAFRO-iMCD, and TAFRO-w/op-iMCD groups. However, the iMCD-NOS group exhibited polyclonal hyper-γ-globulinemia. The five-year survival rates of patients in the iMCD-NOS and TAFRO-involved groups were 100% and 66.5%, respectively (dropping markedly during the first few months in the latter). The iMCD-NOS and the TAFRO-iMCD samples typically showed plasma cell and mixed-type histologies, respectively. Thus, iMCD can be classified into two distinct subtypes, iMCD-NOS and TAFRO-iMCD. As such, TAFRO-iMCD and TAFRO-w/op-iMCD may be considered the same entity, requiring prompt diagnosis and intensive care.

Induced 2C Expression and Implantation-Competent Blastocyst-like Cysts from Primed Pluripotent Stem Cells.

Abstract: Summary Soon after fertilization, the few totipotent cells of mammalian embryos diverge to form a structure called the blastocyst (BC). Although numerous cell types, including germ cells and extended-pluripotency stem cells, have been developed from pluripotent stem cells (PSCs) in vitro, generating functional BCs only from PSCs remains elusive. Here, we describe induced self-organizing 3D BC-like cysts (iBLCs) generated from mouse PSC culture. Resembling natural BCs, iBLCs have a blastocoel-like cavity and were formed with outer cells expressing trophectoderm lineage markers and with inner cells expressing pluripotency markers. iBLCs transplanted to pseudopregnant mice uteruses implanted, induced decidualization, and exhibited growth and development before resorption, demonstrating that iBLCs are implantation competent. iBLC precursor intermediates required the transcription factor Prdm14 and concomitantly activated the totipotency-related cleavage-stage MERVL reporter and 2C genes. Thus, our system may contribute to the understanding of molecular mechanisms underpinning totipotency, embryogenesis, and implantation.

Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells

Abstract: Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established. Here, we report that the adaptive signalling of the unfolded protein response, IRE1α-XBP1, protects HSCs from endoplasmic reticulum stress-induced apoptosis. IRE1α knockout leads to reduced reconstitution of HSCs. Furthermore, we show that oncogenic N-RasG12D activates IRE1α-XBP1, through MEK-GSK3β, to promote HSC survival under endoplasmic reticulum stress. Inhibiting IRE1α-XBP1 abolished N-RasG12D-mediated survival under endoplasmic reticulum stress and diminished the competitive advantage of NrasG12D HSCs in transplant recipients. Our studies illuminate how the adaptive endoplasmic reticulum stress response is advantageous in sustaining self-renewal of HSCs and promoting pre-leukaemic clonal dominance.

Molecular mechanisms in the pathogenesis of N -nitrosodimethylamine induced hepatic fibrosis

Abstract: Hepatic fibrosis is marked by excessive synthesis and deposition of connective tissue proteins, especially interstitial collagens in the extracellular matrix of the liver. It is a result of an abnormal wound healing in response to chronic liver injury from various causes such as ethanol, viruses, toxins, drugs, or cholestasis. The chronic stimuli involved in the initiation of fibrosis leads to oxidative stress and generation of reactive oxygen species that serve as mediators of molecular events involved in the pathogenesis of hepatic fibrosis. These processes lead to cellular injury and initiate inflammatory responses releasing a variety of cytokines and growth factors that trigger activation and transformation of resting hepatic stellate cells into myofibroblast like cells, which in turn start excessive synthesis of connective tissue proteins, especially collagens. Uncontrolled and extensive fibrosis results in distortion of lobular architecture of the liver leading to nodular formation and cirrhosis. The perpetual injury and regeneration process could also results in genomic aberrations and mutations that lead to the development of hepatocellular carcinoma. This review covers most aspects of the molecular mechanisms involved in the pathogenesis of hepatic fibrosis with special emphasize on N-Nitrosodimethylamine (NDMA; Dimethylnitorsmaine, DMN) as the inducing agent.

Comparing different definitions of prediabetes with subsequent risk of diabetes: an individual participant data meta-analysis involving 76 513 individuals and 8208 cases of incident diabetes

Abstract: Objective There are currently five widely used definition of prediabetes. We compared the ability of these to predict 5-year conversion to diabetes and investigated whether there were other cut-points identifying risk of progression to diabetes that may be more useful. Research design and methods We conducted an individual participant meta-analysis using longitudinal data included in the Obesity, Diabetes and Cardiovascular Disease Collaboration. Cox regression models were used to obtain study-specific HRs for incident diabetes associated with each prediabetes definition. Harrell’s C-statistics were used to estimate how well each prediabetes definition discriminated 5-year risk of diabetes. Spline and receiver operating characteristic curve (ROC) analyses were used to identify alternative cut-points. Results Sixteen studies, with 76 513 participants and 8208 incident diabetes cases, were available. Compared with normoglycemia, current prediabetes definitions were associated with four to eight times higher diabetes risk (HRs (95% CIs): 3.78 (3.11 to 4.60) to 8.36 (4.88 to 14.33)) and all definitions discriminated 5-year diabetes risk with good accuracy (C-statistics 0.79–0.81). Cut-points identified through spline analysis were fasting plasma glucose (FPG) 5.1 mmol/L and glycated hemoglobin (HbA1c) 5.0% (31 mmol/mol) and cut-points identified through ROC analysis were FPG 5.6 mmol/L, 2-hour postload glucose 7.0 mmol/L and HbA1c 5.6% (38 mmol/mol). Conclusions In terms of identifying individuals at greatest risk of developing diabetes within 5 years, using prediabetes definitions that have lower values produced non-significant gain. Therefore, deciding which definition to use will ultimately depend on the goal for identifying individuals at risk of diabetes.

Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.

Abstract: Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material.

Abstract: Background Hepcidin concentrations measured by various methods differ considerably, complicating interpretation. Here, a previously identified plasma-based candidate secondary reference material (csRM) was modified into a serum-based two-leveled sRM. We validated its functionality to increase the equivalence between methods for international standardization. Methods We applied technical procedures developed by the International Consortium for Harmonization of Clinical Laboratory Results. The sRM, consisting of lyophilized serum with cryolyoprotectant, appeared commutable among nine different measurement procedures using 16 native human serum samples in a first round robin (RR1). Harmonization potential of the sRM was simulated in RR1 and evaluated in practice in RR2 among 11 measurement procedures using three native human plasma samples. Comprehensive purity analysis of a candidate primary RM (cpRM) was performed by state of the art procedures. The sRM was value assigned with an isotope dilution mass spectrometry-based candidate reference method calibrated using the certified pRM. Results The inter-assay CV without harmonization was 42.1% and 52.8% in RR1 and RR2, respectively. In RR1, simulation of harmonization with sRM resulted in an inter-assay CV of 11.0%, whereas in RR2 calibration with the material resulted in an inter-assay CV of 19.1%. Both the sRM and pRM passed international homogeneity criteria and showed long-term stability. We assigned values to the low (0.95±0.11 nmol/L) and middle concentration (3.75±0.17 nmol/L) calibrators of the sRM. Conclusions Standardization of hepcidin is possible with our sRM, which value is assigned by a pRM. We propose the implementation of this material as an international calibrator for hepcidin.

Current status of imaging biomarkers predicting the biological nature of hepatocellular carcinoma

Abstract: Hepatocellular carcinoma (HCC) is heterogeneous in terms of its biological nature. Various factors related to its biological nature, including size, multifocality, macroscopic morphology, grade of differentiation, macro/microvascular invasion, bile duct invasion, intra-tumoral fat and molecular factors, and their value as prognostic imaging biomarkers have been reported. And recently, genome-based molecular HCC classification correlated with clinical outcome has been elucidated. The imaging biomarkers suggesting a less aggressive nature of HCC are smaller size, solitary tumor, smooth margin suggesting small nodular type with indistinct margin and simple nodular type with distinct margin, capsule, imaging biomarkers predicting early or well-differentiated grade, intra-tumoral fat detection, and low fluorodeoxyglucose (FDG) accumulation. The imaging biomarkers suggesting an aggressive HCC nature are larger size, multifocality, non-smooth margin suggesting simple nodular type with extranodular growth, confluent multinodular, and infiltrative type, imaging biomarkers predicting poor differentiation, macrovascular tumor thrombus, predicting microvascular invasion imaging biomarkers, bile duct dilatation or tumor thrombus, and high FDG accumulation. In the genome-based molecular classification, CTNNB-1 mutated HCC shows a less aggressive nature, while CK19/EpCAM positive HCC and macrotrabecular massive HCC show an aggressive one. Better understanding of these imaging biomarkers can contribute to devising more appropriate treatment plans for HCC.

Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication

Abstract: Objective Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B*27:05, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B*27:05 expression and the UPR affect the Salmonella life-cycle within epithelial cells. Methods Isogenic epithelial cell lines expressing two copies of either HLA-B*27:05 and a control HLA-B*35:01 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B*27:05.HC physically linked to the light chain beta-2-microglobulin and a specific peptide (referred to as a single chain trimer, SCT) was also generated to determine the effects of HLA-B27 folding status on S. enterica life-cycle. XBP-1 venus and AMP dependent Transcription Factor (ATF6)-FLAG reporters were used to monitor UPR activation in infected cells. Triacin C was used to inhibit de novo lipid synthesis during UPR, and confocal imaging of ER tracker stained membrane allowed quantification of glibenclamide-associated membrane. Results S. enterica demonstrated enhanced replication with an altered cellular localisation in the presence of HLA-B*27:05.HC but not in the presence of HLA-B*27:05.SCT or HLA-B*35:01. HLA-B*27:05.HC altered the threshold for UPR induction. Salmonella activated the UPR and required XBP-1 for replication, which was associated with endoreticular membrane expansion and lipid metabolism. Conclusions HLA-B27 misfolding and a UPR cellular environment are associated with enhanced Salmonella replication, while Salmonella itself can activate XBP-1 and ATF6. These data provide a potential mechanism linking the life-cycle of Salmonella with the physicochemical properties of HLA-B27 and cellular events that may contribute to ReA pathogenesis. Our observations suggest that the UPR pathway maybe targeted for future therapeutic intervention.

Secular changes in clinical manifestations of kidney disease among Japanese adults with type 2 diabetes from 1996 to 2014

Abstract: AIMS/INTRODUCTION Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. MATERIALS AND METHODS Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross-sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. RESULTS The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30-60 mL/min/1.73 m2 ) and severely reduced eGFR (<30 mL/min/1.73 m2 ) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age-dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. CONCLUSIONS During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity- and high age-related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively.

Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder.

Abstract: Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies. We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder.

Improvement of psychiatrists’ clinical knowledge of the treatment guidelines for schizophrenia and major depressive disorders using the ‘Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)’ project: A nationwide dissemination, education, and evaluation study

Abstract: Aim Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the ‘Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)’ integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs.

Meta-analysis of physical activity and effects of social function and quality of life on the physical activity in patients with schizophrenia

Abstract: Schizophrenia patients have increased mortality and morbidity, mainly due to premature cardiovascular disease resulting from decreased physical activity (PA). However, which PA intensity is impaired in the patients and how factors such as social function and quality of life (QoL) are related to decreased PA is unknown. To assess PA, social function and QoL, the International Physical Activity Questionnaire (IPAQ), Social Functioning Scale (SFS) and Schizophrenia Quality of Life Scale (SQLS), respectively, were used in 109 schizophrenia patients and 69 healthy subjects. A meta-analysis comparing PA intensities (vigorous, moderate and light) assessed by the single PA measurement between schizophrenia patients and healthy subjects after including our case–control sample was performed. Furthermore, the effects of social function and QoL on each level of PA intensity were investigated in patients and controls. The meta-analysis in 212 schizophrenia patients and 132 healthy subjects revealed that patients showed lower total PA, particularly vigorous PA, than controls (I2 = 0, Hedges’ g = − 0.41, P = 2.80 × 10−4). The decreased total PA was correlated with impaired total SFS scores (β = 0.24, P = 2.86 × 10−3), withdrawal (β = 0.23, P = 3.74 × 10−3) and recreation (β = 0.23, P = 3.49 × 10−3) without significant heterogeneity between patients and controls. In contrast, the decreased total PA was affected by low independence–performance (β = 0.22, P = 0.034), employment/occupation (β = 0.27, P = 8.74 × 10−3), psychosocial (β = − 0.24, P = 0.021) and motivation/energy (β = − 0.26, P = 0.013), but only in patients. Similar findings were obtained for vigorous PA but not moderate or light PA. Our findings suggest that the impaired vigorous PA in schizophrenia patients may be mediated by schizophrenia-specific factors of social functioning and QoL. Understanding these factors has important implications for increasing PA participation in schizophrenia patients.

IgG4-related disease in the Japanese population: a genome-wide association study

Abstract: Summary Background IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of IgG4-related disease, we did a genome-wide association study. Methods We did a genome-wide association study of Japanese individuals, initially screening 857 patients with IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms. The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations identified in these two genes were examined. Findings We identified the HLA-DRB1 (p=1·1×10−11) and FCGR2B (p=2·0×10−8) regions as susceptibility loci for IgG4-related disease. We also identified crucial aminoacid residues in the β domain of the peptide-binding groove of HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease (p=1·7×10−14), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association with increased FCGR2B expression (p=2·7×10−10) and was in weak linkage disequilibrium with rs1050501, a missense variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035). Interpretation Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related disease and other immune-related disorders Funding The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, and Kyoto University Grant for Top Global University Japan Project.

Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells.

Abstract: Sulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like Peroxiredoxin 6 (Prdx6) and affects cellular homeostasis. We previously observed that dose levels of SFN are crucial in determining life or death of lens epithelial cells (LECs). Herein, we demonstrated that higher doses of SFN (>6 μM) activated death signaling by overstimulation of Nrf2/ARE (antioxidant response element)-mediated Kruppel-like factor (Klf9) repression of Prdx6 expression, which increased reactive oxygen species (ROS) load and cell death. Mechanistically, Klf9 bound to its repressive Klf9 binding elements (RKBE; 5-CA/GCCC-3) in the Prdx6 promoter, and repressed Prdx6 transcription. Under the condition of higher dose of SFN, excessive Nrf2 abundance caused death signaling by enforcing Klf9 activation through ARE (5-RTGAYnnnGC-3) in Klf9 promoter that suppress antioxidant genes such as Prdx6 via a Klf9-dependent fashion. Klf9-depletion showed that Klf9 independently caused ROS reduction and subsequent cell survival, demonstrating that Klf9 upregulation caused cell death. Our work revealed the molecular mechanism of dose-dependent altered activity of SFN in LECs, and demonstrated that SFN activity was linked to levels of Nrf2/Klf9/Prdx6 axis. We proposed that in the development of therapeutic interventions for aging/oxidative disorders, combinations of Klf9-ShRNA and Nrf2 inducers may prove to be a promising strategy.

Enrichment of hematopoietic stem/progenitor cells in the zebrafish kidney

Abstract: Hematopoietic stem cells (HSCs) maintain the entire blood system throughout life and are utilized in therapeutic approaches for blood diseases. Prospective isolation of highly purified HSCs is crucial to understand the molecular mechanisms underlying regulation of HSCs. The zebrafish is an elegant genetic model for the study of hematopoiesis due to its many unique advantages. It has not yet been possible, however, to purify HSCs in adult zebrafish due to a lack of specific HSC markers. Here we show the enrichment of zebrafish HSCs by a combination of two HSC-related transgenes, gata2a:GFP and runx1:mCherry. The double-positive fraction of gata2a:GFP and runx1:mCherry (gata2a+ runx1+) was detected at approximately 0.16% in the kidney, the main hematopoietic organ in teleosts. Transcriptome analysis revealed that gata2a+ runx1+ cells showed typical molecular signatures of HSCs, including upregulation of gata2b, gfi1aa, runx1t1, pbx1b, and meis1b. Transplantation assays demonstrated that long-term repopulating HSCs were highly enriched within the gata2a+ runx1+ fraction. In contrast, colony-forming assays showed that gata2a- runx1+ cells abundantly contain erythroid- and/or myeloid-primed progenitors. Thus, our purification method of HSCs in the zebrafish kidney is useful to identify molecular cues needed to regulate self-renewal and differentiation of HSCs.

Efficacy of Scalp Cooling in Preventing and Recovering From Chemotherapy-Induced Alopecia in Breast Cancer Patients: The HOPE Study.

Abstract: Purpose: This study aimed to assess the efficacy of scalp-cooling devices in preventing chemotherapy-induced alopecia in Japanese breast cancer patients and investigate whether a scalp-cooling device improves hair volume recovery over a 12 weeks period after completing chemotherapy. Methods: This multicenter controlled trial included women with breast cancer undergoing chemotherapy in Japan between February 2016 and March 2018. The primary endpoint was the proportion of patients with no alopecia at the end of chemotherapy. The secondary endpoint included hair volume at 12 weeks after completing chemotherapy. Results: A total of 48 patients were enrolled; of them, 34 and 14 were sequentially allocated to the scalp-cooling group using the Paxman Hair Loss Prevention System and the control group, respectively. There was no significant difference in average age between the scalp-cooling and the control groups (50.0 ± 9.6 vs. 49.0 ± 9.0 years). More than 50% of patients in each group had stage II breast cancer (scalp-cooling group: 53.1%; control group: 64.3%), more than 90% received adjuvant chemotherapy (scalp-cooling group: 96.9%; control group: 92.9%), and more than 60% were treated with a docetaxel/cyclophosphamide regimen (scalp-cooling group: 75.0%; control group: 64.3%). There were more patients judged to have no alopecia at the end of chemotherapy in the scalp-cooling group than in the control group (26.7% [8/30] vs. 0% [0/13]; P = 0.011). The proportion of patients with alopecia who experienced an increase in hair volume of ≥50% within 12 weeks duration after chemotherapy was 85.7% (24/28) in the scalp-cooling group and 50.0% (6/12) in the control group. No patient developed serious adverse events related to the scalp-cooling device. Conclusions: The use of a scalp-cooling device prevented alopecia with acceptable safety for Japanese patients. In addition, scalp cooling resulted in faster recovery of hair volume after chemotherapy, even in patients for whom scalp cooling failed to prevent chemotherapy-induced alopecia.

Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Abstract: Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative-minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative-MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive-MRD with complete remission [CR] and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative-MRD or positive-MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new-generation TKI for high-risk patients are warranted to improve the outcomes after allogeneic HSCT.