Knockout of Brca1-interacting factor Ola1 in female mice induces tumors with estrogen suppressible centrosome amplification.

Obg-like ATPase 1 (OLA1) is a binding protein of Breast cancer gene 1 (BRCA1), germline pathogenic variants of which cause hereditary breast cancer. Cancer-associated variants of BRCA1 and OLA1 are deficient in the regulation of centrosome number. Although OLA1 might function as a tumor suppressor, the relevance of OLA1 deficiency to carcinogenesis is unclear. Here, we generated Ola1 knockout mice. Aged female Ola1+/- mice developed lymphoproliferative diseases, including malignant lymphoma. The lymphoma tissues had low expression of Ola1 and an increase in the number of cells with centrosome amplification. Interestingly, the proportion of cells with centrosome amplification in normal spleen from Ola1+/- mice was higher in male mice than in female mice. In human cells, estrogen stimulation attenuated centrosome amplification induced by OLA1 knockdown. Previous reports indicate that prominent centrosome amplification causes cell death but does not promote tumorigenesis. Thus, in the current study, the mild centrosome amplification observed under estrogen stimulation in Ola1+/- female mice is likely more tumorigenic than the prominent centrosome amplification observed in Ola1+/- male mice. Our findings provide a possible sex-dependent mechanism of the tumor suppressor function of OLA1.

Dynamic ESPI Evaluation of Deformation and Fracture Mechanism of 7075 Aluminum Alloy.

The deformation and fracture mechanism in 7075 aluminum alloy is discussed based on a field theoretical approach. A pair of peak-aged and overaged plate specimens are prepared under the respective precipitation conditions, and their plastic deformation behaviors are visualized with two-dimensional electronic speckle pattern interferometry (ESPI). The in-plane velocity field caused by monotonic tensile loading is monitored continuously via the contour analysis method of ESPI. In the plastic regime, the peak-aged specimen exhibits a macroscopically uniform deformation behavior, while the annealed specimen exhibits non-uniform deformation characterized by a localized shear band. The occurrence of the shear band is explained by the transition of the material's elastic resistive mechanism from the longitudinal force dominant to shear force dominant mode. The shear force is interpreted as the frictional force that drives mobile dislocations along the shear band. The dynamic behavior of the shear band is explained as representing the motion of a solitary wave. The observed decrease in the solitary wave's velocity is accounted for by the change in the acoustic impedance with the advancement of plastic deformation.

Quantification of 23 Volatile Organic Compounds with a Single Reference Material Using Post-column Reaction Gas Chromatography Combined with a Stainless-steel Heating Furnace.

We built a heating furnace using stainless-steel instead of aluminum in gas chromatography combined with an oxidation/reduction system; it increased the oxidation temperature to 650°C. At 600°C, it completely oxidized five organochlorine compounds. This system was applied to a standard solution of 23 volatile organic compounds. The analytical results of 20 hydrocarbon and organochlorine compounds showed good agreement with the expanded uncertainty (k = 2) of the reference values. Three organobromine compounds obtained values higher than the reference; this was investigated further.

Quantitative Determination of 2-Ethyl-1-hexanol, Texanol and TXIB in In-door Air Using a Solid-Phase Extraction-type Collection Device Followed by Gas Chromatography-Mass Spectrometry.

In this study, in-door air semi-volatile organic compounds (SVOCs) including 2-ethyl-1-hexanol, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate (texanol), and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB), which are scheduled for adding as regulated compounds concerning indoor air reference values in Japan, were quantitatively extracted using a solid-phase extraction-type collection device, followed by sensitively determined by gas chromatography-mass spectrometry. The developed method has shown a good extraction recovery up to an air sampling volume of 900 L. The extracted analytes were quantitatively and rapidly eluted by 7 mL of acetone. The limit of quantification of the analytes were 0.7, 2.1 and 0.2 ng L-1 in air sample at a sampling volume of 300 mL without any concentration of a desorption solvent. The developed method was applied to simultaneous determinations of the investigated target analytes and phthalate esters in real indoor air samples.

Application and Validation of a Determination Method Using Post-column Reaction Gas Chromatography of Nitrogen-containing Organic Compounds.

In this work, we applied post-column reaction gas chromatography (GC) using a flame ionization detector (FID) system to study nitrogen-containing organic compounds (NOCs). The results were subsequently validated. After separation by column, the target components were converted to carbon dioxide using an oxidizing catalyst and then reduced to methane, followed by detection using an FID. SI-traceable testing mixtures containing NOCs (isoprocarb, napropamide, and pendimethalin) were prepared by the gravimetric blending method. These mixtures were analyzed using a post-column reaction GC-FID system; standard materials of hydrocarbons were used as calibrants in this analysis. The determined values were compared with the values obtained for samples prepared at the corresponding concentrations, and statistical analyses were performed in all cases. It was shown that the determined and prepared values agreed well with each other within the uncertainty limits.

Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose.

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose.

OBJECTIVES: In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. METHODS: Telmisartan was orally administered at MD condition (100 µg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. RESULTS: No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. CONCLUSION: The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.

Quantitative population pharmacokinetic analysis of pravastatin using an enterohepatic circulation model combined with pharmacogenomic Information on SLCO1B1 and ABCC2 polymorphisms.

The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1(*)15 significantly influenced relative bioavailability (F(rel)); F(rel) was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the (*)15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1(*)15 has a significant effect on F(rel), indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin.

Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy.

INTRODUCTION: To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes. CASE REPORT: A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m(2)) on days 1, 8 and 15 in combination with docetaxel (60 mg/m(2)) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1*6/*28 and SLCO1B1*15/*15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs. CONCLUSION: The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and transport (SLCO1B1*15/*15) capabilities.

A ruptured middle cerebral artery aneurysm originating from the site of anastomosis 20 years after extracranial-intracranial bypass for moyamoya disease: case report.

BACKGROUND: Direct revascularization through a superficial temporal artery-middle cerebral artery (STA-MCA) bypass is often performed to prevent ischemic or hemorrhagic attack in patients with moyamoya disease. This is the first reported case of aneurysm formation and rupture due to an STA-MCA bypass in a patient with moyamoya disease. CASE DESCRIPTION: A 52-year-old man who had undergone bilateral STA-MCA bypass for caudate hemorrhage due to moyamoya disease 20 years previously suffered from sudden-onset unconsciousness. Computed tomography revealed a massive intracerebral hematoma (ICH) in the left frontoparietal region. Angiography showed good patency of the anastomoses and stage IV moyamoya disease. However, no other abnormality was found. Emergency evacuation of the hematoma was performed. The patient's postoperative course was uneventful, but consciousness disturbance of sudden onset occurred 1 month later. Computed tomography showed a hematoma in the lateral ventricle and acute hydrocephalus. Repeat angiography revealed an aneurysm on the left side of the anastomosis. Bilateral ventricle drainage tubes were inserted, and the aneurysm was clipped. A ventriculoperitoneal shunt was later performed. CONCLUSION: In patients with moyamoya disease who have undergone extracranial-intracranial bypass surgery, progressive hemodynamic stress may cause the formation of de novo aneurysms after a postoperative period of several decades. Imaging examinations should therefore be performed periodically for follow-up, and a de novo aneurysm should be suspected in a patient who has an unusual ICH.

Mature bovine articular cartilage contains abundant aggrecan that is C-terminally truncated at Ala719-Ala720, a site which is readily cleaved by m-calpain.

Extracts of normal mature articular cartilage contain aggrecan molecules which bear the G1 domain (the N-terminal globular domain of aggrecan) and are C-terminally truncated by proteolysis at a number of sites. A proportion of these molecules are generated by an aggrecanase and/or matrix-metalloproteinase-mediated cleavage in the IGD (interglobular domain between the G1 and G2 domains of aggrecan). However, the proteinase(s) responsible for formation of the majority of the larger G1-G2 and glycosaminoglycan-bearing truncated species is (are) unknown. N-terminal sequencing of aggrecan core fragments generated by m-calpain digestion of bovine aggrecan has identified four novel cleavage sites: one within the CS (chondroitin sulphate)-1 domain (at one or more of the bonds Ser1229-Val1230, Ser1249-Val1250, Ser1287-Val1288, Gly1307-Val1308 and Ser1346-Val1347), two within the IGD (at bonds Ala474-Ala475 and Gly365-Gly366) and one within the KS (keratan sulphate) domain (at Ala719-Ala720). A new monoclonal antibody (SK-28) to the C-terminal neoepitope at M710VTQVGPGVA719 showed that aggrecan products generated by this cleavage are present in high abundance in mature bovine articular cartilage extracts. We conclude that m-calpain, or an unidentified proteinase with the capacity to cleave at the same site, is active during aggrecan biosynthesis/secretion by mature chondrocytes or in the matrix of mature bovine articular cartilage in vivo.

[A case of subcutaneous malignant lymphoma with dura mater lesion].

A 63-year-old male was admitted to our hospital, complaining of a scalp mass located at the frontoparietal area of his head. He noticed that it had been growing for 2 months. The mass was elastic hard and non-moving. Computed tomography demonstrated a subcutaneous mass with low density and which was enhanced homogeneously. The skull just below the mass was slightly destroyed, but the structure remained. Magnetic resonance imaging (MRI) demonstrated a mass with low signal intensity on both the T1 weighted image and the T2 weighted image. Gd-DTPA study showed homogeneous enhancement and showed also that the dura just below the mass was enhanced. At this point we couldn't diagnose it confidently, but suspected this lesion to be a malignant lymphoma. We made a general examination, but no other lesion was found. A biopsy of the subcutaneous mass was performed under local anesthesia. The histological diagnosis was large-cell type B-Cell lymphoma. The tumor was treated with chemotherapy, CHOP (cyclophosphamid, doxorubicin, vincristin predonisolone). It responded to this chemotherapy and disappeared. We treated this lesion without radiation therapy. We report a case of subcutaneous malignant lymphoma treated successfully with a minimum invasive method.

[An intradiploic epidermoid cyst of the skull in infancy: case report].

An intradiploic epidermoid cyst of the skull in infancy is rare. We report a case of a 7-month-old girl with an intradiploic epidermoid cyst of the left parietal bone. The patient was admitted to the department of pediatrics in, our hospital in March, 2000, complaining of a lump in the scalp with a diameter of 1.5 cm. The pediatrician doubted that it was a case of Langerhans cell histiocytosis (LCH). In addition, as a result of further tests there were no systemic findings to suggest LCH. The skull x-ray showed round radiolucency of the left parietal bone. CT scans showed an iso density intradiploic mass with destruction of the outer table. Because of the fact that the mass was enlarging, the patient was admitted to our neurosurgical service in April, 2000. We excised the lesion to confirm the histological findings. The histological diagnosis was epidermoid cyst. We discuss the clinical feature and treatment strategy for intradiploic epidermoid cyst in infancy.