No abstract

The human fibroblast growth factor 23 (hFGF23) and its autosomal dominant hypophosphatemic rickets (ADHR) mutant genes were incorporated into animals by naked DNA injection to investigate the action on phosphate homeostasis in vivo. The hFGF23 mutants (R176Q, R179Q, and R179W) markedly reduced serum phosphorus (6.2-6.9 mg/dl) compared with the plasmid MOCK (8.5 mg/dl). However, native hFGF23 did not affect serum phosphorus (8.6 mg/dl). Both hFGF23 and hFGF23R179Q mRNAs were expressed more than 100-fold in the liver 4 days after injection, however, the C-terminal portion of hFGF23 was detected only in the serum from hFGF23R179Q-injected animals (1109 pg/ ml). hFGF23R179Q mutant was secreted as a 32-kDa protein, whereas, native hFGF23 was detected as a 20-kDa protein in the cell-conditioned media. These results suggest the hFGF23R179Q protein is resistant to intracellular proteolytic processing. The hFGF23R179Q suppressed Na/P i co-transport activities both in kidney and in small intestine by 45 and 30%, respectively, as well as serum 1␣,25-dihydroxyvitamin D 3 to less than 15 pg/ml. However, it had little effect on serum parathyroid hormone (PTH). Infusion of hFGF23R179Q protein normalized serum phosphorus in thyroparathyroidectomized rats without affecting serum calcium. Taken together, the FGF23 mutants reduce both phosphate uptake in intestine and phosphate reabsorption in kidney, independent of PTH action.The FGF23 protein is a novel, secreted protein that consists of 251 amino acids, including a putative N-terminal signal peptide (residues 1-24) (1). Patients with autosomal dominant hypophosphatemic rickets (ADHR), 1 a rare renal phosphatewasting disorder, have been found to have three missense mutations in two arginine residues, R176Q, R179Q, and R179W in the FGF23 gene (2, 3). Also, the FGF23 was identified as a causative factor of oncogenic osteomalacia (OHO) (4). It was highly expressed in the tumor isolated from OHO patients (5), whereas, it was expressed at a very low level in normal tissues. Patients with OHO share similar manifestations with ADHR such as hypophosphatemia, decreased or inappropriately normal 1␣,25-dihydroxyvitamin D concentrations, and osteomalacia. Recent studies indicated administration of the recombinant FGF23 protein reduced serum phosphate without affecting serum calcium, as well as increasing renal phosphate excretion in mice. Mice bearing FGF23-expressing CHO cells showed a suppressed 25-hydroxyvitamin D 1␣-hydroxylase mRNA expression in the kidney (4). These results suggested FGF23 might inhibit renal sodium-dependent phosphate (Na/Pi) co-transporter activity. However, according to the results from the in vitro studies using opossum kidney cells, the FGF23 effects on Na/P i co-transporter are still controversial (4, 6). Yamashita et al. reported that heparin was required to activate FGF23⅐FGFR3c complex and phosphate reabsorption in opossum kidney cells. Also, the mitogen-activating protein kinase signal pathway was a major pathway for the FGF23 signaling (7). Shimada et al. a...

Purpose: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC.Experimental Design: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis.Results: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCCspecific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non -small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P < 0.01) and adenocarcinomas (P < 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC.Conclusion: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.

We have searched for intermediate-scale anisotropy in the arrival directions of ultrahigh-energy cosmic rays with energies above 57 EeV in the northern sky using data collected over a 5 yr period by the surface detector of the Telescope Array experiment. We report on a cluster of events that we call the hotspot, found by oversampling using 20 • radius circles. The hotspot has a Li-Ma statistical significance of 5.1σ , and is centered at R.A. = 146. • 7, decl. = 43. • 2. The position of the hotspot is about 19 • off of the supergalactic plane. The probability of a cluster of events of 5.1σ significance, appearing by chance in an isotropic cosmic-ray sky, is estimated to be 3.7 × 10 −4 (3.4σ).

ObjectiveTo date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for Helicobacter pylori treatment. This study aimed to investigate the efficacy of the 7-day vonoprazan and low-dose amoxicillin dual therapy as a first-line H. pylori treatment, and compared this with vonoprazan-based triple therapy.DesignThis prospective, randomised clinical trial was performed at seven Japanese institutions. Patients with H. pylori–positive culture test and naive to treatment were randomly assigned in a 1:1 ratio to either VA-dual therapy (vonoprazan 20 mg+amoxicillin 750 mg twice/day) or VAC-triple therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day) for 7 days, with stratification by age, sex, H. pylori antimicrobial resistance and institution. Eradication success was evaluated by 13C-urea breath test at least 4 weeks after treatment.ResultsBetween October 2018 and June 2019, 629 subjects were screened and 335 were randomised. The eradication rates of VA-dual and VAC-triple therapies were 84.5% and 89.2% (p=0.203) by intention-to-treat analysis, respectively, and 87.1% and 90.2% (p=0.372) by per-protocol analysis, respectively. VA-dual was non-inferior to VAC-triple in the per-protocol analysis. The eradication rates in strains resistant to clarithromycin for VA-dual were significantly higher than those for VAC-triple (92.3% vs 76.2%; p=0.048). The incidence of adverse events was equal between groups.ConclusionThe 7-day vonoprazan and low-dose amoxicillin dual therapy provided acceptable H. pylori eradication rates and a similar effect to vonoprazan-based triple therapy in regions with high clarithromycin resistance.Trial registration numberUMIN000034140.