Lipid Nanoparticles Enable Efficient In Vivo DNA Knock-In via HITI-Mediated Genome Editing.

In vivo genome editing holds great therapeutic potential for treating monogenic diseases by enabling precise gene correction or addition. However, improving the efficiency of delivery systems remains a key challenge. In this study, we investigated the use of lipid nanoparticles (LNPs) for in vivo knock-in of ectopic DNA.

Region-specific DNA hydroxymethylation along the malignant progression of IDH-mutant gliomas.

The majority of low-grade isocitrate dehydrogenase-mutant (IDH) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDH gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation.

Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis.

Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production.

Multiancestry genomic and transcriptomic analysis of gastric cancer.

Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C.

Ten-year outcomes of cataract surgery for glaucoma management in patients with primary angle-closure disease.

Purpose: To investigate the long-term outcomes of cataract surgery for glaucoma management in patients with primary angle-closure disease (PACD).

Study Design: Retrospective case series.

Methods: We reviewed the medical records of 87 eyes of 87 patients with PACD who underwent uncomplicated cataract surgery alone at the Kobe City Medical Center General Hospital.

Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis.

Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated "primed" state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation.

Increase in brain l-lactate enhances fear memory in diabetic mice: Involvement of glutamate neurons.

Previous reports suggest that diabetes mellitus is associated with psychiatric disorders, including depression and anxiety, but the mechanisms involved are unknown. We have reported that streptozotocin (STZ)-induced diabetic mice show enhancement of conditioned fear memory. To clarify the mechanisms through which diabetes affects conditioned fear memory, the present study investigated the role of l-lactate and glutamatergic function in enhancement of conditioned fear memory in diabetes.

TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma.

Ten-eleven translocation 1 (TET1) is an essential methylcytosine dioxygenase of the DNA demethylation pathway. Despite its dysregulation being known to occur in human cancer, the role of TET1 remains poorly understood. In this study, we report that TET1 promotes cell growth in human liver cancer.

[Effect of Relative Electron Density and Physical Density Adjustment in Patient-specific Quality Assurance Using PMMA Phantom].

Purpose: The purpose of this study was to improve the accuracy of dose-distribution calculations by understanding how the calculated dose varies with the change in the relative electron density replacing polymethyl methacrylate (PMMA) in patient-specific quality assurance.

Method: We calculated the relative electron density at which dose attenuation in each dose calculation algorithm coincides with the measured value of the dose attenuation of single-field irradiation. Next, the dose change was calculated by changing the relative electron density or physical electron density for substituting PMMA for each X-ray energy and calculation algorithm.

Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression.

Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC.

Publisher Correction: Base editors for simultaneous introduction of C-to-T and A-to-G mutations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Base editors for simultaneous introduction of C-to-T and A-to-G mutations.

We describe base editors that combine both cytosine and adenine base-editing functions. A codon-optimized fusion of the cytosine deaminase PmCDA1, the adenosine deaminase TadA and a Cas9 nickase (Target-ACEmax) showed a high median simultaneous C-to-T and A-to-G editing activity at 47 genomic targets. On-target as well as DNA and RNA off-target activities of Target-ACEmax were similar to those of existing single-function base editors.

Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma.

Background: There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.

Methods: A total of 80 cases of HGSC were analyzed in this study.

Defined lifestyle and germline factors predispose Asian populations to gastric cancer.

Germline and environmental effects on the development of gastric cancers (GC) and their ethnic differences have been poorly understood. Here, we performed genomic-scale trans-ethnic analysis of 531 GCs (319 Asian and 212 non-Asians). There was one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, almost all of which were attributable to alcohol intake behavior, smoking habit, and Asian-specific defective allele.

Duodenal Stenosis Due to Carcinoma of the Lower Bile Duct: A Case Report.

An 83-year-old man was referred to our hospital for a detailed evaluation for vomiting. Esophagogastroduodenoscopy and abdominal computed tomography showed duodenal stenosis with wall thickness. Biopsy including endoscopic ultrasound-guided fine-needle aspiration of the thickened wall showed inflammation without malignancy.

Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content.

Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM).

Endoscopic ultrasound-guided coil deployment with sclerotherapy for isolated gastric varices: Case series of feasibility, safety, and long-term follow-up.

The purpose of the present study is to report our experience of endoscopic ultrasound-guided coil deployment with sclerotherapy (EUS-CS) for isolated gastric varices (IGV) through a case series. Eight consecutive patients who had risky IGV were prospectively enrolled. EUS-CS was performed according to the following procedures: (i) several coils were first deployed in the IGV under EUS guidance; (ii) contrast medium was subsequently injected without removing the needle; (iii) if the infused contrast medium stayed in the IGV and feeding vein, sclerosant was then injected to obliterate the IGV and feeders.

Serum Endocrine Fibroblast Growth Factors as Potential Biomarkers for Chronic Kidney Disease and Various Metabolic Dysfunctions in Aged Patients.

Objective To prolong the health expectancy, it is important to prevent age-related diseases, such as osteoporosis and cerebrovascular disease, which are major causes of a bedridden state. Early predictable biomarkers for these diseases are urgently required in the clinical setting. Three members of the fibroblast growth factor (FGF) family - FGF19, FGF21, and FGF23 - are designated as endocrine FGFs and play crucial roles in various metabolic processes.

Spatial and temporal expansion of intrahepatic metastasis by molecularly-defined clonality in multiple liver cancers.

Multiple hepatocellular carcinoma (HCC) is divided into two categories: intrahepatic metastasis (IM), which is a true relapse of HCC, and multicentric origin (MO), which is a second primary tumor. Clinical diagnosis of multiple HCC is usually made based on tumor location and/or time to recurrence; however, it is often difficult to distinguish the two types of multiple HCC. Using 41 matched pairs of multiple HCC specimens, we confirmed the accuracy of clinical diagnoses using exome sequence data and investigated the importance of discriminating the type of multiple HCC.

Validity of Endoscopic Ultrasound Findings of Chronic Pancreatitis: Evaluation from the Viewpoint of Disease Risk Factors.

Background: The diagnosis of chronic pancreatitis (CP) using endoscopic ultrasound (EUS) criteria, referred to as the Rosemont classification (RC), has been widely performed. However, the validity of the RC, which was based on expert opinion, is still controversial. If EUS findings are associated with CP, then they should be associated with risk factors for CP.

The Feasibility and Histological Diagnostic Accuracy of Novel Menghini Needle (EUS Sonopsy CY™) for Endoscopic Ultrasound-Guided Fine-Needle Aspiration Biopsy of Solid Pancreatic Masses: A Prospective Crossover Study Comparing Standard Biopsy Needles.

Background And Objectives: Recently, a 21G Menghini-type needle for EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been developed. The stylet of the EUS Sonopsy CY™ remains inside the needle during aspiration. Therefore, it is expected to obtain higher-quality histological core specimens without crushing the material or blood contamination.

Dopaminergic mechanisms in the lateral hypothalamus regulate feeding behavior in association with neuropeptides.

This study investigated dopaminergic function in the lateral hypothalamus (LH) in the regulation of feeding behavior. Refeeding increased dopamine levels in the LH. Glucose injection also increased dopamine levels in the LH.

Monomeric structure of an active form of bovine cytochrome oxidase.

Cytochrome oxidase (CcO), a membrane enzyme in the respiratory chain, catalyzes oxygen reduction by coupling electron and proton transfer through the enzyme with a proton pump across the membrane. In all crystals reported to date, bovine CcO exists as a dimer with the same intermonomer contacts, whereas CcOs and related enzymes from prokaryotes exist as monomers. Recent structural analyses of the mitochondrial respiratory supercomplex revealed that CcO monomer associates with complex I and complex III, indicating that the monomeric state is functionally important.