Fibroblast growth factor 23 enhances renal klotho abundance

Klotho constitutes the receptor for fibroblast growth factor 23 (FGF23). However, the effects of FGF23 on renal and circulating klotho are not well-known. In vivo experiments were performed to assess the effects of FGF23 (10 μg/kg), parathyroid hormone (PTH, 10 μg/kg), and 1,25-dihydroxy-vitamin D3 (1,25VD, 1 μg/kg) on renal expression and serum concentration of klotho in Wistar rats. Phosphate excretion was increased at 3 h after FGF23 administration (p?<?0.05). Renal klotho expressions and serum klotho levels were elevated at 3 h (p?<?0.01) by FGF23. At 24 h, phosphate excretion was still elevated (p?<?0.05), and serum phosphate, 1,25VD, and PTH were reduced (p?<?0.05). However, serum and renal klotho returned to the control level at 24 h. PTH markedly increased phosphate excretion after 24 h (p?<?0.01). There were increases in FGF23 at 3 and 24 h, and 1,25VD at 24 h after PTH administration (p?<?0.05). Serum klotho concentration and renal klotho expression were elevated by PTH at 3 or 24 h. After 24 h of exposure to 1,25VD, considerable increases in serum FGF23, calcium, and phosphate were seen (p?<?0.05), but PTH was decreased (p?<?0.01). 1,25 VD elevated renal klotho expression and serum klotho (p?<?0.05) at 3 h, but returned to control levels at 24 h. Our data indicate that FGF23 rapidly increases renal klotho expression and serum klotho. The present findings are consistent with the notion that PTH increases phosphate excretion at least in part through elevations of FGF23 and klotho. Moreover, our results suggest that 1,25VD increases klotho expression independently of FGF23.     

Using a High-Speed Movie Camera to Evaluate Slice Dropping in Clinical Image Interpretation with Stack Mode Viewers

The purpose of this study is to verify objectively the rate of slice omission during paging on picture archiving and communication system (PACS) viewers by recording the images shown on the computer displays of these viewers with a high-speed movie camera. This study was approved by the institutional review board. A sequential number from 1 to 250 was superimposed on each slice of a series of clinical Digital Imaging and Communication in Medicine (DICOM) data. The slices were displayed using several DICOM viewers, including in-house developed freeware and clinical PACS viewers. The freeware viewer and one of the clinical PACS viewers included functions to prevent slice dropping. The series was displayed in stack mode and paged in both automatic and manual paging modes. The display was recorded with a high-speed movie camera and played back at a slow speed to check whether slices were dropped. The paging speeds were also measured. With a paging speed faster than half the refresh rate of the display, some viewers dropped up to 52.4 % of the slices, while other well-designed viewers did not, if used with the correct settings. Slice dropping during paging was objectively confirmed using a high-speed movie camera. To prevent slice dropping, the viewer must be specially designed for the purpose and must be used with the correct settings, or the paging speed must be slower than half of the display refresh rate.     

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with ‘capsulomas’ without FCLN gene abnormality

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt–Hogg–Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small‐sized capsular angiomyolipomas known as ‘capsulomas’ in a 39‐year‐old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and ‘capsulomas’ developing in a patient without genetic features, having potential for novel genetic variation.     

Complementary functions of ATM and H2AX in development and suppression of genomic instability

Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and unique functions of ATM and H2AX, we asked whether they have synergistic functions in the development and maintenance of genomic stability by inactivating both genes in mouse germ line. Combined ATM/H2AX deficiency caused embryonic lethality and dramatic cellular genomic instability. Mechanistically, severe genomic instability in the double-deficient cells is associated with a requirement for H2AX to repair oxidative DNA damage resulting from ATM deficiency. We discuss these findings in the context of synergies between ATM and other repair factors.     

A targeting model of boron neutron-capture therapy to hepatoma cellsin vivo with a boronated anti-(α-fetoprotein) monoclonal antibody

We described previously that¹⁰B atoms delivered by monoclonal antibody (mAb) exerted a cytotoxic effect on AH66 cells in a dose-dependent manner upon thermal neutron irradiationin vitro. In the present study, the delivering capacity of boronated anti-(-fetoprotein) (AFP) mAb to carry¹⁰B atoms to AFP-producing tumor xenografts in nude mice was determined. Boronated mAb was prepared by conjugating 50 mM ¹⁰B compound to an anti-AFP mAb (2 mg/ml) usingN-succinimidyl-3-) (2-pyridyldithio) propionate. The number of¹⁰B atoms conjugated directly to the mAb was estimated to be 459/antibody by prompt -ray spectrometry. Boron concentrations in tumor tissue obtained 12, 24, 72, and 120 h after injection of 3.0 mg¹⁰B-conjugated anti-AFP mAb were 11.10±3.12 (SD,n=6), 29.30±5.11, 33.02±11.8, and 12.91±5.62 ppm respectively. For control¹⁰B-conjugated anti-dinitrophenol (DNP) mAb, the values were 9.59±0.99, 10.37±2.86, 10.00±2.95, and 8.83±4.71 ppm respectively. The concentrations in blood were less than 0.40±0.10 ppm with anti-AFP mAb and less than 0.51±0.15 ppm with anti-DNP mAb at each sampling time (12, 24, 72, and 120 h). The number of¹⁰B atoms delivered to the tumor cells was calculated to be 0.62×10⁹, 1.63×10⁹, 1.84×10⁹ and 0.72×10⁹ at each sampling time after injection of¹⁰B-anti-AFP mAb. The amount of¹⁰B atoms necessary for effective boron neutron-capture therapy was estimated to be 10⁹/tumor cell. We were able to carry 1.84×10^{9 10}B atoms to AH66 tumor cells by using¹⁰B-anti-AFP mAb. The accumulation reached its peak 72 h after injection. These data indicated that the¹⁰B-conjugated antitumor mAb could deliver a sufficient amount of¹⁰B atoms to the tumor cells to induce cytotoxic effects 72 h after injection upon thermal neutron irradiation.Abbreviations BNCT boron neutron-capture therapy - AFP -fetoprotein - SPDP N-succinimidyl-3-(2-pyridyldithia) propionate - DNP dinitrophenol