Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety

<p>Abstract</p> <p>Background</p> <p>Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule.</p> <p>Methods</p> <p>Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m²/day) intravenously for 12 to 14 days.</p> <p>Results</p> <p>We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF.</p> <p>Conclusions</p> <p>Intravenous rh-HGF at a dose of 0.6 mg/m²was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.</p

Invasive behavior of ulcerative colitis-associated carcinoma is related to reduced expression of CD44 extracellular domain: comparison with sporadic colon carcinoma

<p>Abstract</p> <p>Background</p> <p>To elucidate relations of invasion of ulcerative colitis (UC)-associated carcinoma with its prognosis, the characteristics of invasive fronts were analyzed in comparison with sporadic colonic carcinomas.</p> <p>Methods</p> <p>Prognoses of 15 cases of UC-associated colonic carcinoma were compared with those of sporadic colon carcinoma cases, after which 75 cases of sporadic invasive adenocarcinoma were collected. Tumor budding was examined histologically at invasive fronts using immunohistochemistry (IHC) of pancytokeratin. Expressions of beta-catenin with mutation analysis, CD44 extracellular domain, Zo-1, occludin, matrix matalloproteinase-7, laminin-5γ2, and sialyl Lewis X (Le^X) were immunohistochemically evaluated.</p> <p>Results</p> <p>UC-associated carcinoma showed worse prognosis than sporadic colon carcinoma in all the cases, and exhibited a tendency to become more poorly differentiated when carcinoma invaded the submucosa or deeper layers than sporadic carcinoma. When the lesions were compared with sporadic carcinomas considering differentiation grade, reduced expression of CD44 extracellular domain in UC-associated carcinoma was apparent. Laminin-5γ2 and sialyl-Le^Xexpression showed a lower tendency in UC-associated carcinomas than in their sporadic counterparts. There were no differences in the numbers of tumor budding foci between the two lesion types, with no apparent relation to nuclear beta-catenin levels in IHC.</p> <p>Conclusions</p> <p>UC-associated carcinoma showed poorer differentiation when the carcinoma invaded submucosa or deeper parts, which may influence the poorer prognosis. The invasive behavior of UC-associated carcinoma is more associated with CD44 cleavage than with basement membrane disruption or sialyl-Lewis-antigen alteration.</p

The RNA acetyltransferase driven by ATP hydrolysis synthesizes N4-acetylcytidine of tRNA anticodon

The wobble base of Escherichia coli elongator tRNAMet is modified to N4-acetylcytidine (ac4C), which is thought to ensure the precise recognition of the AUG codon by preventing misreading of near-cognate AUA codon. By employing genome-wide screen of uncharacterized genes in Escherichia coli (‘ribonucleome analysis'), we found the ypfI gene, which we named tmcA (tRNAMet cytidine acetyltransferase), to be responsible for ac4C formation. TmcA is an enzyme that contains a Walker-type ATPase domain in its N-terminal region and an N-acetyltransferase domain in its C-terminal region. Recombinant TmcA specifically acetylated the wobble base of E. coli elongator tRNAMet by utilizing acetyl-coenzyme A (CoA) and ATP (or GTP). ATP/GTP hydrolysis by TmcA is stimulated in the presence of acetyl-CoA and tRNAMet. A mutation study revealed that E. coli TmcA strictly discriminates elongator tRNAMet from the structurally similar tRNAIle by mainly recognizing the C27–G43 pair in the anticodon stem. Our findings reveal an elaborate mechanism embedded in tRNAMet and tRNAIle for the accurate decoding of AUA/AUG codons on the basis of the recognition of wobble bases by the respective RNA-modifying enzymes

The Ganymede Laser Altimeter (GALA) for the Jupiter Icy Moons Explorer (JUICE): Mission, science, and instrumentation of its receiver modules

The Jupiter Icy Moons Explorer (JUICE) is a science mission led by the European Space Agency, being developed for launch in 2023. The Ganymede Laser Altimeter (GALA) is an instrument onboard JUICE, whose main scientific goals are to understand ice tectonics based on topographic data, the subsurface structure by measuring tidal response, and small-scale roughness and albedo of the surface. In addition, from the perspective of astrobiology, it is imperative to study the subsurface ocean scientifically. The development of GALA has proceeded through an international collaboration between Germany (the lead), Japan, Switzerland, and Spain. Within this framework, the Japanese team (GALA-J) is responsible for developing three receiver modules: the Backend Optics (BEO), the Focal Plane Assembly (FPA), and the Analog Electronics Module (AEM). Like the German team, GALA-J also developed software to simulate the performance of the entire GALA system (performance model). In July 2020, the Proto-Flight Models of BEO, FPA, and AEM were delivered from Japan to Germany. This paper presents an overview of JUICE/GALA and its scientific objectives and describes the instrumentation, mainly focusing on Japan’s contribution

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

Impacts of Heterogeneous TiO₂ and Al₂O₃ Composite Mesoporous Scaffold on Formamidinium Lead Trihalide Perovskite Solar Cells

Heterogeneous TiO₂ and Al₂O₃ composites were employed as a mesoporous scaffold in formamidinium lead trihalide (FAPbI_3–<i>x</i>Cl_<i>x</i>)-based perovskite solar cells to modify surface properties of a mesoporous layer. It was found that the quality and morphology of the perovskite film were strongly affected by the TiO₂/Al₂O₃ ratio in the mesoporous film. The conversion efficiency of the perovskite solar cell was improved by using a composite of TiO₂ and Al₂O₃ in comparison with TiO₂- and Al₂O₃-based cells, yielding 11.0% for a cell with a 7:3 TiO₂/Al₂O₃ composite. Our investigation shows a change of electron transport path depending on a composition ratio of insulating Al₂O₃ to n-type semiconducting TiO₂ in a mesoporous layer