A ¹⁵N GC/MS Study of in Vivo Glutamine Synthesis in Liver Failure Rats

To clarify the nature of nitrogen metabolism between branched chain amino acid (BCAA) and glutamine (GIn) in liver failure, we measured arterial plasma concentrations of GIn and 15N uptake to amino-N and amide-N of GIn in normal and D-galactosamine-induced fulminant hepatic failure (FHF) rats after 15N-leucine (Leu) injection. Fifteen, 30 and 60 min after Leu injection, the arterial plasma concentrations of GIn were significantly higher in FHF rats than in controls. The concentrations of amino-15N GIn were also significantly higher in FHF rats than in controls at 5, 15, 30 and 60 min after injection. The concentrations of amide-15N GIn did not significantly differ between FHF and controls at 5, 15 and 30 min. However, at 60 min, the concentration was significantly higher in the FHF rats. The higher uptake of 15N to amino-N of GIn in FHF rats suggests the presence of an enhanced ability to synthesize GIn from Leu in FHF rats. The higher uptake of 15N to amide-N of GIn in FHF rats at 60 min after injection suggests that excessive administration of BCAA to patients with severely impaired urea-cycle capacity suffering with hepatic failure may lead to greater levels of hyperammonemia.</p

Analysis of Differentially Expressed Genes in Neuroendocrine Carcinomas of the Lung

IntroductionLarge cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) show considerable differences in their histology but share neuroendocrine (NE) characteristics and also genetic and/or expression patterns.MethodsWe used the subtractive expression method to identify differences in gene expression that would allow discrimination between these two types of NE lung carcinoma.ResultsEight cDNA fragments were transcribed at a higher level in LCNEC compared with SCLC, and these corresponded to five mitochondrial genes, two ribosomal genes, and one fetal regulation factor, neuronatin (NNAT). Immunohistochemically, NNAT protein was detected in 43% (6/14) of LCNECs but in only 8% (1/13) of SCLCs (p < 0.05). Positive staining for NNAT was observed in areas that did not show the NE morphology, such as palisading and rosettes.ConclusionsThe present results suggest that NNAT has the potential to be used as a differential maker between LCNEC and SCLC

A proto-cluster of massive quiescent galaxies at z=4

We report on discovery of a concentration of massive quiescent galaxies located at z=4. The concentration is first identified using high-quality photometric redshifts based on deep, mutli-band data in Subaru/XMM-Newton Deep Field. Follow-up near-infrared spectroscopic observations with MOSFIRE on Keck confirm a massive (~10^{11} Msun) quiescent galaxy at z=3.99. Our spectral energy distribution (SED) analyses reveal that the galaxy experienced an episode of starburst about 500 Myr prior to the observed epoch, followed by rapid quenching. As its spectrum is sufficiently good to measure the stellar velocity dispersion, we infer its dynamical mass and find that it is consistent with its stellar mass. The galaxy is surrounded by 4 massive (>10^{10} Msun) quiescent galaxies on a ~1 physical Mpc scale, all of which are consistent with being located at the same redshift based on high-accuracy spectro-photometric redshifts. This is likely a (proto-)cluster dominated by quiescent galaxies, the first of the kind reported at such a high redshift as z=4. Interestingly, it is in a large-scale structure revealed by spectroscopic redshifts from VANDELS. Furthermore, it exhibits the red sequence, adding further support to the physical concentration of the galaxies. We find no such concentration in the Illustris-TNG300 simulation; it may be that the cluster is such a rare system that the simulation box is not sufficiently large to reproduce it. The total halo mass of the quiescent galaxies is ~10^{13} Msun, suggesting that they form a group-sized halo once they collapse together. We discuss implications of our findings for the quenching physics and conclude with future prospects.Comment: 16 pages, 12 figures, submitted to Ap

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

Clinical Outcome of Patients with Pelvic and Retroperitoneal Bone and Soft Tissue Sarcoma : A Retrospective Multicenter Study in Japan

This study aimed to retrospectively analyze the clinical outcomes of patients with pelvic and retroperitoneal bone and soft tissue sarcoma (BSTS). Overall, 187 patients with BSTS in the pelvis and retroperitoneal region treated at 19 specialized sarcoma centers in Japan were included. The prognostic factors related to overall survival (OS), local control (LC), and progression-free survival (PFS) were evaluated. The 3-year OS and LC rates in the 187 patients were 71.7% and 79.1%, respectively. The 3-year PFS in 166 patients without any distant metastases at the time of primary tumor diagnosis was 48.6%. Osteosarcoma showed significantly worse OS and PFS than other sarcomas of the pelvis and retroperitoneum. In the univariate analyses, larger primary tumor size, soft tissue tumor, distant metastasis at the time of primary tumor diagnosis, P2 location, chemotherapy, and osteosarcoma were poor prognostic factors correlated with OS. Larger primary tumor size, higher age, soft tissue tumor, chemotherapy, and osteosarcoma were poor prognostic factors correlated with PFS in patients without any metastasis at the initial presentation. Larger primary tumor size was the only poor prognostic factor correlation with LC. This study has clarified the epidemiology and prognosis of patients with pelvic and retroperitoneal BSTS in Japan

A major quantitative trait locus for increasing cadmium-specific concentration in rice grain is located on the short arm of chromosome 7

Large phenotypic variations in the cadmium (Cd) concentration of rice grains and shoots have been observed. However, the genetic control of Cd accumulation remains poorly understood. Quantitative trait loci (QTLs) determining the grain Cd concentration of rice grown in a Cd-polluted paddy field were identified. Using a mapping population consisting of 85 backcross inbred lines derived from a cross between the low-Cd-accumulating cultivar Sasanishiki (japonica) and high-Cd-accumulating cultivar Habataki (indica), two QTLs for increasing grain Cd concentration were found on chromosomes 2 and 7. A major-effect QTL, qGCd7 (QTL for grain Cd on chromosome 7), was detected on the short arm of chromosome 7. It accounted for 35.5% of all phenotypic variance in backcross inbred lines. qGCd7 was not genetically related to any QTLs for concentrations of essential trace metals (Cu, Fe, Mn, and Zn) or those for agronomic traits such as heading date, suggesting that this QTL is specific to Cd. Furthermore, the existence of qGCd7 was confirmed using chromosome segment substitution lines (CSSLs) and an F2 population from a cross between the target CSSL and Sasanishiki grown in a Cd-polluted paddy soil. To our knowledge, qGCd7 is a novel QTL with major effects for increasing grain Cd concentrations