Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long-term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus.

No abstract available

Little is known about whether sodium intake is associated with the clinical effects of SGLT2 inhibitors (SGLT2is); however, SGLT2is may increase urinary sodium excretion. Thus, we investigated the impact of daily sodium intake on the estimated glomerular filtration rate (eGFR) via an SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D).

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

Aggregatibacter actinomycetemcomitans is the etiological agent of periodontitis, and there is a strong association between clone JP2 and aggressive periodontitis in adolescents of African descent. The JP2 clone has an approximately 530-bp deletion (∆530) in the promoter region of the lkt/ltx gene, which encodes leukotoxin, and this clone has high leukotoxic activity. Therefore, this clone is very important in aggressive periodontitis. To diagnose this disease, culture methods and conventional PCR techniques are used. However, quantitative detection based on qPCR for the JP2 clone has not been developed due to genetic difficulties. In this study, we developed a qPCR-based quantification method specific to the JP2 clone.

Aims/Introduction:  We compared the safety and efficacy of liraglutide vs glibenclamide in patients with poorly controlled (HbA1c, 7.4-10.4%) type 2 diabetes.

To evaluate the efficacy and safety of alogliptin added to treatment with glimepiride.

Little is known about the association between total cholesterol (TC) and all-cause mortality in the elderly (especially the very elderly). Here we examined the association between TC and all-cause mortality in 207 very elderly (85-year-old) participants. In 2003, we performed a baseline laboratory blood examination, and blood pressure (BP) and body mass index (BMI) measurements, and lifestyle questionnaires were completed by the participants. The participants were followed for the subsequent 10 years. As of 2013, of the 207 participants in 2003, 70 participants had survived, 120 individuals had died, and 17 were lost to follow up. The TC values were divided into high-TC (≥209 mg/dL), intermediate-TC (176-208 mg/dL), and low-TC (≤175 mg/dL) categories. With the Kaplan-Meier method, we found that both the high-TC and intermediate-TC participants survived longer than the low-TC participants. The men with high TC survived longer than those with low TC, but no corresponding difference was found for the women. A multivariate Cox proportional hazards regression model, with adjustment for gender, smoking, alcohol intake, history of stroke or heart disease, serum albumin concentration, BMI, and systolic BP, revealed that the total mortality in the low-TC group was 1.7-fold higher than that in the high-TC group. Mortality, adjusted for the same factors, decreased 0.9% with each 1 mg/dL increase in the serum TC concentration and decreased 0.8% with each 1 mg/dL increase in the serum (low-density lipoprotein) LDL-cholesterol (LDL-C) concentration. Our results indicate an association between lower serum TC concentrations and increased all-cause mortality in a community-dwelling, very elderly population. Mortality decreased with the increases in both TC and LDL-C concentrations, after adjustment for various confounding factors. These findings suggest that low TC and low LDL-C may be independent predictors of high mortality in the very elderly.

The fifth component (CSN5) of the mammalian COP9 signalosome complex plays an essential role in cell proliferation and senescence, but its molecular mediator remains to be determined. Here, we searched for interactors among various cell cycle regulators, and found that CSN5, but not the CSN holo-complex, bound to CDK2 in vivo and in vitro. Depletion of CSN5 enhanced phosphorylation of CDK2 by Akt, resulting in cytoplasmic accumulation of CDK2 together with cyclin E in a leptomycin B-resistant manner, and impaired phosphorylation of the retinoblastoma protein. Additional knockdown of CDK2, which reduced the expression of cyclin E to the normal level, did not restore cell proliferation, but significantly suppressed senescence in CSN5-depleted cells. Enforced expression of cytoplasmic cyclin E induced premature senescence in immortalized cell lines. These results show that CSN5 functions through CDK2 to control premature senescence in a novel way, depending on cyclin E in the cytoplasm.

In this study, we investigated the effect of the dynamic changes in brain activation during neurofeedback training in the classification of the different brain states associated with the target tasks. We hypothesized that ongoing activation patterns could change during neurofeedback session due to learning effects and, in the process, could affect the performance of brain state classifiers trained using data obtained prior to the session. Using a motor imagery paradigm, we then examined the application of an incremental training approach where classifiers were continuously updated in order to account for these activation changes. Our results confirmed our hypothesis that neurofeedback training could be associated with dynamic changes in brain activation characterized by an initially more widespread brain activation followed by a more focused and localized activation pattern. By continuously updating the trained classifiers after each feedback run, significant improvement in accurately classifying the different brain states associated with the target motor imagery tasks was achieved. These findings suggest the importance of taking into account brain activation changes during neurofeedback in order to provide more reliable and accurate feedback information to the participants, which is critical for an effective neurofeedback application.

Overexpression of D-type cyclins in human cancer frequently occurs as a result of protein stabilization, emphasizing the importance of identification of the machinery that regulates their ubiqutin-dependent degradation. Cyclin D3 is overexpressed in ~50% of Burkitt's lymphoma correlating with a mutation of Thr-283. However, the E3 ligase that regulates phosphorylated cyclin D3 and whether a stabilized, phosphorylation deficient mutant of cyclin D3, has oncogenic activity are undefined. We describe the identification of SCF-Fbxl8 as the E3 ligase for Thr-283 phosphorylated cyclin D3. SCF-Fbxl8 poly-ubiquitylates p-Thr-283 cyclin D3 targeting it to the proteasome. Functional investigation demonstrates that Fbxl8 antagonizes cell cycle progression, hematopoietic cell proliferation, and oncogene-induced transformation through degradation of cyclin D3, which is abolished by expression of cyclin D3T283A, a non-phosphorylatable mutant. Clinically, the expression of cyclin D3 is inversely correlated with the expression of Fbxl8 in lymphomas from human patients implicating Fbxl8 functions as a tumor suppressor.

Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.

The sodium-glucose co-transporter 2 inhibitor empagliflozin reduced the total burden of cardiovascular, mortality, and all-cause hospitalization events, including first and recurrent events, in EMPA-REG OUTCOME participants with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD). We investigated the effect of empagliflozin on the total burden of cardiovascular and hospitalization events in Asian participants.

Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre-clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant.

Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).

Sodium-glucose co-transporter 2 inhibitors are a promising treatment for type 2 diabetes mellitus, but are associated with concerns about specific adverse drug reactions. We carried out a 1-year post-marketing surveillance of tofogliflozin, a novel agent in this class, in Japanese elderly patients with type 2 diabetes mellitus and here report the results of a 12-week interim analysis, focusing on adverse drug reactions of special interest.

Aims/Introduction:  Repaglinide is a short-acting insulin secretagogue. We assessed the efficacy and safety of repaglinide in comparison with nateglinide in Japanese patients with type 2 diabetes previously treated with diet and exercise.

Genetic risk variants for type 2 diabetes; rs391300-G in SRR and rs17584499-T in PTPRD, have been identified by a genome-wide association study using Han Chinese individuals living in Taiwan. In an attempt to know the effects of these two variants in conferring susceptibility to type 2 diabetes in the Japanese, we carried out a replication study for the association of the two single nucleotide polymorphisms (SNPs) with type 2 diabetes in a Japanese population.

The DUSP9 locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population.

To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) compared with its individual components in Japanese people with type 2 diabetes (T2D) uncontrolled on an oral antidiabetic drug (OAD).