Rapid expansion of a left atrial myxoma caused by acute multiple internal hemorrhages: a case report and literature review.

BACKGROUND: Left atrial myxoma is the most common benign tumor, with the growth rate remaining unknown because specific symptoms do not present until the tumor grows to a certain size. Early surgical management is performed in most cases once it is detected by physicians. Despite cardiac myxomas commonly being perceived as slow-growing tumors, rapid enlargement of myxomas has been reported. CASE PRESENTATION: A 64-year-old woman was referred to our hospital with a diagnosis of a left atrial tumor. The pointed tumor changed morphologically in a few hours, and her respiratory condition, which had been normal at admission, suddenly deteriorated. Emergent surgery was performed, and the diagnosis was myxoma with multiple intratumor massive hematomas. The patient recovered uneventfully and was discharged on postoperative day 12 without any complications. CONCLUSIONS: We report an extremely rare case of left atrial myxoma rapidly expanded due to acute multiple hemorrhages within itself. Massive internal hemorrhage alters the size, shape, and fragility of the tumor. We should recognize the potential risk of internal hemorrhage that may lead to acute deterioration of the so-called "slow-growing benign" tumors, such as myxomas.

Characterization and reduction of non-endocrine cells accompanying islet-like endocrine cells differentiated from human iPSC.

The differentiation of pancreatic endocrine cells from human pluripotent stem cells has been thoroughly investigated for their application in cell therapy against diabetes. Although non-endocrine cells are inevitable contaminating by-products of the differentiation process, a comprehensive profile of such cells is lacking. Therefore, we characterized non-endocrine cells in iPSC-derived pancreatic islet cells (iPIC) using single-cell transcriptomic analysis. We found that non-endocrine cells consist of (1) heterogeneous proliferating cells, and (2) cells with not only pancreatic traits but also liver or intestinal traits marked by FGB or AGR2. Non-endocrine cells specifically expressed FGFR2, PLK1, and LDHB. We demonstrated that inhibition of pathways involving these genes selectively reduced the number of non-endocrine cells in the differentiation process. These findings provide useful insights into cell purification approaches and contribute to the improvement of the mass production of endocrine cells for stem cell-derived cell therapy for diabetes.

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens.

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.

Comparison of 18FBPA uptake with 18FDG uptake in cancer patients.

For the patients who underwent 18fluorinated para-boronophenylalanine (18FBPA) positron emission tomography (PET) and 18fluorodeoxyglucose (18FDG) PET within a period of 2 weeks, maximum standardized uptake value (SUVmax), tumor-to-normal tissue ratio (TNR), and tumor-to-blood ratio (TBR) for 18FBPA were compared with SUVmax for 18FDG. A total of 30 patients were selected for comparison. SUVmax for 18FBPA was correlated the best with SUVmax for 18FDG. Subsequently, the SUVmax correlation between 18FBPA and 18FDG were verified among 82 patients. The correlation factor was 0.4825.

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban. METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM™) program. RESULTS: The nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 ml min-1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 l h-1 . When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 l. CONCLUSION: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation.

OBJECTIVES: During anticoagulant therapy, major bleeding is one of the most severe adverse effects. This study aimed to evaluate the relationships between ABCB1, ABCG2, and CYP3A5 polymorphisms and plasma trough concentrations of apixaban, a direct inhibitor of coagulation factor X. PATIENTS AND METHODS: A total of 70 plasma concentrations of apixaban from 44 Japanese patients with atrial fibrillation were analyzed. In these analyses, the plasma trough concentration/dose (C/D) ratio of apixaban was used as a pharmacokinetic index and all data were stratified according to the presence of ABCB1 (ABCB1 1236C>T, 2677G>T/A, and 3435C>T), ABCG2 (ABCG2 421C>A), and CYP3A5 (CYP3A5*3) polymorphisms. Influences of various clinical laboratory parameters (age, serum creatinine, estimated glomerular filtration rate, aspartate amino transferase, and alanine amino transferase) on the plasma trough C/D ratio of apixaban were included in analyses. RESULTS: Although no ABCB1 polymorphisms affected the plasma trough C/D ratio of apixaban, the plasma trough C/D ratio of apixaban was significantly higher in patients with the ABCG2 421A/A genotype than in patients with the ABCG2 421C/C genotype (P<0.01). The plasma trough C/D ratio of apixaban in patients with CYP3A5*1/*3 or *3/*3 genotypes was also significantly higher than that in patients with the CYP3A5*1/*1 genotype (P<0.05). Furthermore, the plasma trough C/D ratio of apixaban decreased with increased estimated glomerular filtration rate. CONCLUSION: These results indicate that ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered potential factors affecting trough concentrations of apixaban.

Development of target system for intense neutron source of p-Li reaction.

A target cooling system was developed for an intense neutron source of p-Li reaction. The system consists of target cooling devices and protection devices for lithium evaporation. A pin-structure cooling device was developed to enhance cooling power. Functional graded material was utilized for the evaporation of lithium. Test experiments were performed by using the neutron exposure accelerator system for biological effect experiments (NASBEE) at the National Institute of Radiological Sciences (NIRS) in Japan. The target system was confirmed to be applicable for accelerator-based boron neutron capture therapy.

The Japanese national health screening and intervention program aimed at preventing worsening of the metabolic syndrome.

Similar to the healthcare systems in other industrialized countries, the Japanese healthcare system is facing the problem of increasing medical expenditure. In Japan, this situation may be primarily attributed to advanced technological developments, an aging population, and increasing patient demand. Japan also faces the problem of a declining youth population due to a low birth rate. Taken together, these problems present the healthcare system with a very difficult financial situation. Several reforms have been undertaken to contain medical expenditure, such as increasing employee copayment for health insurance from 10% to 20% in 1997 and from 20% to 30% in 2003 in order to curb unnecessary visits to medical institutions. Since the aging of the Japanese population is inevitable, a suitable method to contain medical expenditure may be to screen individuals who are likely to develop lifestyle-related diseases and conduct early intervention programs for them to prevent the development of diseases such as myocardial infarction or stroke that are costly to treat. If this goal is attained, it may contribute to the containment of medical expenditure as well as to improving the quality of life of the elderly. Therefore, the Japanese Ministry of Health, Labor and Welfare has decided to introduce a nationwide health screening and intervention program specifically targeting the metabolic syndrome commencing April 2008. Here, we discuss (1) the background of the Japanese healthcare system and the problems facing it, (2) the underlying objective and details of the new screening program, and (3) the expected impact of the program.

Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis.

Blood vessels change their caliber to adapt to the demands of tissues or organs for oxygen and nutrients. This event is mainly organized at the capillary level and requires a size-sensing mechanism. However, the molecular regulatory mechanism involved in caliber size modification in blood vessels is not clear. Here we show that apelin, a protein secreted from endothelial cells under the activation of Tie2 receptor tyrosine kinase on endothelial cells, plays a role in the regulation of caliber size of blood vessel through its cognate receptor APJ, which is expressed on endothelial cells. During early embryogenesis, APJ is expressed on endothelial cells of the new blood vessels sprouted from the dorsal aorta, but not on pre-existing endothelial cells of the dorsal aorta. Apelin-deficient mice showed narrow blood vessels in intersomitic vessels during embryogenesis. Apelin enhanced endothelial cell proliferation in the presence of vascular endothelial growth factor and promoted cell-to-cell aggregation. These results indicated that the apelin/APJ system is involved in the regulation of blood vessel diameter during angiogenesis.

[Business administration of PET facilities: a cost analysis of three facilities utilizing delivery FDG].

BACKGROUND: PET (positron emission tomography) has been proved to be a powerful imaging tool in clinical oncology. The number of PET facilities in Japan has remarkably increased over the last decade. Furthermore, the approval of delivery FDG in 2005 resulted in a tremendous expansion of the PET institutions without a cyclotron facility. The aim of this study was to conduct a cost analysis of PET institutions that utilized delivery FDG. METHODS: Three PET facilities using delivery FDG were investigated about the costs for PET service. Fixed costs included depreciation costs for construction and medical equipments such as positron camera. Variable costs consisted of costs for medical materials including delivery FDG. The break-even point was analyzed in each of three institutions. RESULTS: In the three hospitals (A, B and C), the annual number of PET scan was 1,591, 1,637 and 914, while cost per scan was accounted as yen 110,262, yen 111,091, and yen 134,192, respectively. The break-even point was calculated to be 2,583, 2,679 and 2,081, respectively. CONCLUSIONS: PET facilities utilizing delivery FDG seemed to have difficulty in business administration. Such a situation suggests the possibility that the current supply of PET facilities might exceed actual demand for the service. The efficiency of resource allocation should be taken into consideration in the future health service researches on PET.

[Business administration of PET facilities: a nationwide survey for prices of PET screening and a cost analysis of three facilities].

The purpose of this study is to analyze the business administration of PET facilities based on the survey of the price of PET cancer screening and cost analysis of PET examination. The questionnaire survey of the price of PET cancer screening was implemented for all PET facilities in Japan. Cost data of PET examination, including fixed costs and variable costs, were obtained from three different medical institutions. The marked price of the PET cancer screening was 111,499 yen in average, and the most popular range of prices was between 80,000 yen and 90,000 yen. Costs of PET per examination were accounted for 110,675 yen, 79,158 yen and Y11,644 yen in facility A, B and C, respectively. The results suggested that facilities with two or more PET/CT per a cyclotron could only secure profits. In Japan, the boom in PET facility construction could not continue in accordance with increasing number of PET facilities. It would become more essential to analyze the appropriate distribution of PET facilities and the adequate amount of PET procedures from the perspective of efficient utilization of the PET equipments and supply of PET-related healthcare.

Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP.

Since the first discovery of a peptide with RFamide structure at its C-terminus (i.e., an RFamide peptide) from an invertebrate in 1977, numerous studies on RFamide peptides have been conducted, and a variety have been identified in various phyla throughout the animal kingdom. The first reported mammalian RFamide peptides were neuropeptide FF (NPFF) and neuropeptide AF (NPAF) in 1985. However, for many years after this, no new novel RFamide peptides were identified in mammals. A breakthrough in discovering mammalian RFamide peptides was made possible by reverse pharmacology on the basis of orphan G protein-coupled receptor (GPCR) research. The first report of an RFamide peptide identified from orphan GPCR research was prolactin (PRL)-releasing peptide (PrRP) in 1998. To date, a total of five RFamide peptide genes have been discovered in mammals. Orphan GPCR research has contributed considerably to the identification of these peptides and their receptor genes. This paper examines these mammalian RFamide peptides focusing especially on PrRP, RFamide-related peptides (RFRPs) and, the most recently identified, pyroglutamylated RFamide peptide (QRFP), the discovery of all of which the authors were at least partly involved in. We review here the strategies employed for the identification of these peptides and examine their characteristics, tissue distribution, receptors and functions.

N-Formylated humanin activates both formyl peptide receptor-like 1 and 2.

We have discovered that humanin (HN) acts as a ligand for formyl peptide receptor-like 1 (FPRL1) and 2 (FPRL2). This discovery was based on our finding that HN suppressed forskolin-induced cAMP production in Chinese hamster ovary (CHO) cells expressing human FPRL1 (CHO-hFPRL1) or human FPRL2 (CHO-hFPRL2). In addition, we found that N-formylated HN (fHN) performed more potently as a ligand for FPRL1 than HN: in CHO-hFPRL1 cells, the effective concentration for the half-maximal response (EC(50)) value of HN was 3.5nM, while that of fHN was 0.012nM. We demonstrated by binding experiments using [(125)I]-W peptide that HN and fHN directly interacted with hFPRL1 on the membrane. In addition, we found that HN and fHN showed strong chemotactic activity for CHO-hFPRL1 and CHO-hFPRL2 cells. HN is known to have a protective effect against neuronal cell death. Our findings contribute to the understanding of the mechanism behind HN's function.

A new peptidic ligand and its receptor regulating adrenal function in rats.

We searched for peptidic ligands for orphan G protein-coupled receptors utilizing a human genome data base and identified a new gene encoding a preproprotein that could generate a peptide. This peptide consisted of 43 amino acid residues starting from N-terminal pyroglutamic acid and ending at C-terminal arginine-phenylalanine-amide. We therefore named it QRFP after pyroglutamylated arginine-phenylalanine-amide peptide. We subsequently searched for its receptor and found that Chinese hamster ovary cells expressing an orphan G protein-coupled receptor, AQ27, specifically responded to QRFP. We analyzed tissue distributions of QRFP and its receptor mRNAs in rats utilizing quantitative reverse transcription-polymerase chain reaction and in situ hybridization. QRFP mRNA was highly expressed in the hypothalamus, whereas its receptor mRNA was highly expressed in the adrenal gland. The intravenous administration of QRFP caused the release of aldosterone, suggesting that QRFP and its receptor have a regulatory function in the rat adrenal gland.

A G protein-coupled receptor responsive to bile acids.

So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5'-O-3-thio-triphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.

Identification of a neuropeptide modified with bromine as an endogenous ligand for GPR7.

We isolated a novel gene in a search of the Celera data base and found that it encoded a peptidic ligand for a G protein-coupled receptor, GPR7 (O'Dowd, B. F., Scheideler, M. A., Nguyen, T., Cheng, R., Rasmussen, J. S., Marchese, A., Zastawny, R., Heng, H. H., Tsui, L. C., Shi, X., Asa, S., Puy, L., and George, S. R. (1995) Genomics 28, 84-91; Lee, D. K., Nguyen, T., Porter, C. A., Cheng, R., George, S. R., and O'Dowd, B. F. (1999) Mol. Brain Res. 71, 96-103). The expression of this gene was detected in various tissues in rats, including the lymphoid organs, central nervous system, mammary glands, and uterus. GPR7 mRNA was mainly detected in the central nervous system and uterus. In situ hybridization showed that the gene encoding the GPR7 ligand was expressed in the hypothalamus and hippocampus of rats. To determine the molecular structure of the endogenous GPR7 ligand, we purified it from bovine hypothalamic tissue extracts on the basis of cAMP production-inhibitory activity to cells expressing GPR7. Through structural analyses, we found that the purified endogenous ligand was a peptide with 29 amino acid residues and that it was uniquely modified with bromine. We subsequently determined that the C-6 position of the indole moiety in the N-terminal Trp was brominated. We believe this is the first report on a neuropeptide modified with bromine and have hence named it neuropeptide B. In in vitro assays, bromination did not influence the binding of neuropeptide B to the receptor.