Conserved metabolic enzymes as vaccine antigens for giardiasis.

Giardia lamblia is a leading protozoal cause of diarrheal disease worldwide. Infection is associated with abdominal pain, malabsorption and weight loss, and protracted post-infectious syndromes. A human vaccine is not available against G.

MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages.

Background & Aims: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers.

Oxidative stress-responsive apoptosis-inducing protein in patients with heterozygous familial hypercholesterolemia.

Oxidative stress, an inducer of apoptosis, plays a critical role in ischemia/reperfusion injury and atherosclerosis. We previously identified an apoptosis-inducing ligand, the post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A), 'oxidative stress-responsive apoptosis-inducing protein' (ORAIP). In this study, we investigated the role of ORAIP in patients with heterozygous familial hypercholesterolemia (HeFH), a leading cause of premature cardiovascular disease.

Quantitative sonographic assessment of quadriceps muscle thickness for fall injury prediction in patients undergoing maintenance hemodialysis: an observational cohort study.

Background: Accidental fall risk is high in patients undergoing maintenance hemodialysis. Falls are associated with fatal injury, comorbidities, and mortality. Risk assessment should be a primary component of fall prevention.

Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during Infection.

The mechanism of -induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach.

Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis.

While the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9a) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN).

Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan.

Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates.

Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls.

AdipoR agonist increases insulin sensitivity and exercise endurance in AdipoR-humanized mice.

Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects. Although muscle-specific disruption of AdipoR1 has been shown to result in decreased insulin sensitivity and decreased exercise endurance, it remains to be determined whether upregulation of AdipoR1 could reverse them in obese diabetic mice. Here, we show that muscle-specific expression of human AdipoR1 increased expression levels of genes involved in mitochondrial biogenesis and oxidative stress-detoxification to almost the same extents as treadmill exercise, and concomitantly increased insulin sensitivity and exercise endurance in obese diabetic mice.

5-Aminolevulinic acid-mediated photodynamic activity in patient-derived cholangiocarcinoma organoids.

Background: Accurate diagnosis of the disease extension of cholangiocarcinoma (CCA) is often difficult in clinical practice. The diagnostic yield of conventional pre-operative imaging or endoscopic procedures is sometimes insufficient for the evaluation of longitudinal spreading of CCA. Here we investigated the usefulness of 5-aminolevulinic acid (5-ALA) for the pre- or intra-operative diagnosis of CCA, using patient-derived organoids.

Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis.

Background/aim: The entire mechanisms by which epigenetic modifiers contribute to the development of pancreatic cancer remain unknown. Although the histone methyltransferase G9a is a promising target in human cancers, its role in pancreatic carcinogenesis has been under-studied. The aim of the study was to examine the role of G9a in pancreatic carcinogenesis by a gene-targeting mouse model.

Comparison of twenty indices of insulin sensitivity in predicting type 2 diabetes in Japanese Americans: The Japanese American Community Diabetes Study.

Aims: We compared 20 previously reported indices of insulin sensitivity derived from samples during an oral glucose tolerance test (OGTT) to determine which was best in predicting incident type 2 diabetes.

Methods: We prospectively followed 418 Japanese Americans without diabetes for 10-11 years. We compared ability to predict incident diabetes of 20 insulin sensitivity indices-9 based on fasting samples, 7 based on 2-h and/or fasting samples, and 4 based on multiple samples (0, 30, 60, 120 min) during an OGTT-by integrated discrimination improvement, category free net reclassification improvement, and area under the receiver operator characteristic curve.

Thresholds for postprandial hyperglycemia and hypertriglyceridemia associated with increased mortality risk in type 2 diabetes patients: A real-world longitudinal study.

Aims/introduction: To identify thresholds for postprandial hyperglycemia and hypertriglyceridemia predictive of all-cause mortality in patients with type 2 diabetes.

Materials And Methods: A total of 1,928 patients with type 2 diabetes visited our clinic for the first time from 1995 to 1999 and were followed up for ≥1 year. During the first year, 2-h post-breakfast blood glucose (2h-BG) levels were measured in 1,122 patients (BG cohort) and postprandial serum triglyceride (ppTG) levels were measured in 1,826 patients (TG cohort).

Association between Low Protein Intake and Mortality in Patients with Type 2 Diabetes.

The aim of this study was to investigate the association between protein intake and mortality risk in patients with type 2 diabetes. We analyzed a pooled data of 2494 diabetic patients from two prospective longitudinal studies. Nutritional intake was assessed using a Food Frequency Questionnaire at baseline.

How self-stigma affects patient activation in persons with type 2 diabetes: a cross-sectional study.

Objectives: Self-stigma is associated with lower patient activation levels for self-care in persons with type 2 diabetes mellitus (T2DM). However, the causal pathway linking self-stigma with patient activation for self-care has not been shown. In order to determine how self-stigma affects patient activation for self-care, we tested a two-path hypothetical model both directly and as mediated by self-esteem and self-efficacy.

The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B axis.

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass.

Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB).

Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31).

Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis.

Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value.

Combined effect of diabetic retinopathy and diabetic kidney disease on all-cause, cancer, vascular and non-cancer non-vascular mortality in patients with type 2 diabetes: A real-world longitudinal study.

Aims/introduction: We assessed the relationship between diabetic retinopathy (DR) and/or diabetic kidney disease (DKD) according to their severity and all-cause, cancer, vascular and non-cancer non-vascular mortality in real-world patients with type 2 diabetes.

Materials And Methods: A total of 1,902 patients with type 2 diabetes were enrolled from 1995 to 1999 and followed to 2017. At baseline, DR was diagnosed in 374 patients, DKD in 529, vision-threatening DR in 123 and advanced DKD in 287.

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.

Objective: Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic variant in the lysophosphatidylinositol acyltransferase 1 (, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.

GPR30-Expressing Gastric Chief Cells Do Not Dedifferentiate But Are Eliminated via PDK-Dependent Cell Competition During Development of Metaplasia.

Background & Aims: Gastric chief cells, a mature cell type that secretes digestive enzymes, have been proposed to be the origin of metaplasia and cancer through dedifferentiation or transdifferentiation. However, studies supporting this claim have had technical limitations, including issues with the specificity of chief cell markers and the toxicity of drugs used. We therefore sought to identify genes expressed specifically in chief cells and establish a model to trace these cells.

Efficacy and Safety of Once-Weekly Dulaglutide in Type 2 Diabetes Patients Using Insulin: Exploratory Subgroup Analysis by Insulin Regimen.

Purpose: In East Asian patients, type 2 diabetes mellitus (T2DM) is characterized primarily by β-cell dysfunction, with lower insulin secretion than in Caucasian individuals. Therefore, bolus insulin and premixed insulin containing a bolus insulin component are important therapeutic tools in Japan, in addition to basal insulin. This subgroup analysis is stratified by insulin regimen and uses data from a phase 4, randomized, placebo-controlled, double-blind and subsequent open-label study in Japan to assess the efficacy and safety of once-weekly dulaglutide combined with various insulin therapies.

Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation.

Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC).

Effect of postprandial hyperglycemia at clinic visits on the incidence of retinopathy in patients with type 2 diabetes: An analysis using real-world long-term follow-up data.

Aims/introduction: There is little evidence on the role of postprandial glycemia in the incidence of diabetic retinopathy (DR) in a real-world setting. We aimed to assess the effect of postprandial hyperglycemia at clinic visits on the incidence of DR in patients with type 2 diabetes, and whether its effect differs depending on glycated hemoglobin (HbA1c) values and age.

Materials And Methods: Intrapersonal mean blood glucose levels at 1-2 h post-breakfast (1-2h-PBBG), post-lunch (1-2 h-PLBG) and both (1-2h-PBLBG) during 2 years from the first visit were used as baseline data.

Once-Weekly Dulaglutide with Insulin Therapy for Type 2 Diabetes: Efficacy and Safety Results from a Phase 4, Randomized, Placebo-Controlled Study.

Introduction: Although global studies have investigated the combination of dulaglutide with insulin in patients with type 2 diabetes mellitus (T2DM), differences in lean body mass and dulaglutide dosing can complicate the extrapolation of global study results to Japanese patients. This phase 4, randomized, placebo-controlled, double-blind, and subsequent open-label study aimed to assess the efficacy and safety of once-weekly dulaglutide 0.75 mg in combination with insulin therapy in patients with T2DM.