The PRB-dependent FOXO1/IGFBP-1 axis is essential for progestin to inhibit endometrial epithelial growth

Progestin inhibits the growth of normal and cancerous endometria via the progesterone receptor (PR), but the distinct functions and signalings of PR subtypes have not been fully understood. The aim of the present study was to dissect the key pathways of progestin to inhibit endometrial epithelial growth. Immortalized endometrial epithelial cells (EM-E6/E7/TERT) with stable PRA or PRB expression were established and used for the experiments. In vitro growth inhibition by progestin was mainly observed in EM-E6/E7/TERT cells with PRB rather than those with PRA. RT-PCR assay confirmed that FOXO1, a key gene for progestin action, was up-regulated by progestin in a PRB-dependent manner. cDNA microarray analysis identified IGFBP-1, which contains FOXO1 binding sites on its promoter, to be induced by medroxyprogesterone acetate (MPA) in EM-E6/E7/TERT cells with PRB but not with PRA. siRNA knockdown of FOXO1 disturbed the induction of IGFBP-1 by MPA, while IGFBP-1 knockdown showed no effect on MPA-induced FOXO1 expression, indicating that FOXO1 is an upstream regulator of IGFBP-1. Luciferase reporter assays showed that MPA activated the IGFBP-1 promoter, which was cancelled by FOXO1 knockdown. Chromatin immunoprecipitation assay confirmed the in vivo binding of FOXO1 to the core promoter of IGFBP-1. IGFBP-1 knockdown significantly attenuated the growth inhibitory effects of MPA. The FOXO1/IGFBP-1 axis is essential for PRB-dependent growth inhibition of endometrial epithelial cells, offering a potential therapeutic clue to enhance the progestin effect.     

Antifungal cyclic depsipeptide, eujavanicin A, isolated from Eupenicillium javanicum

In the course of searching for new antifungal agents, a new cyclic depsipeptide, eujavanicin A (1), was isolated from Eupenicillium javanicum as an antifungal agent against the human pathogenic filamentous fungus Aspergillus fumigatus. The structure of 1 was established by spectroscopic and chemical investigations. The absolute stereochemistry was elucidated by Marfey's method and by chiral HPLC analysis.     

Recombination of a maternal pericentric inversion results in 22q13 deletion syndrome

We describe a 10-month-old boy with 22q13 deletion syndrome. Chromosomal analysis showed a partial duplication of 22p11.2-pter and a terminal deletion of 22q13.31-qter. Maternal chromosomal analysis showed a pericentric inversion of chromosome 22, with breakpoints at p11.2 and q13.31 [inv(22)(p11.2q13.31)]. The deleted chromosome resulted from a recombinant chromosome inherited from his mother. This is a rare case of 22q13 deletion syndrome associated with parental pericentric inversion of chromosome 22.     

Safety and usefulness of emergency maternal transport using helicopter

AIM: Japan has a shortage of tertiary medical care facilities for maternal and fetal medicine. Establishment of efficient medical transport systems is needed for pregnant women and fetuses with severe complications. Maternal transport by helicopters is expected to shorten transportation time to advanced facilities, although its feasibility has not yet been evaluated. The aim of the present study was to investigate the status of maternal helicopter transport, and conditions of the pregnant patients and children transferred by helicopter to Kameda Medical Center (KMC). METHODS: Between August 2005 and July 2006, 26 pregnant women were transported by helicopters to KMC. RESULTS: The median net flight time was 24 min (range 15-29 min), and the median of estimation of ground transportation time was 125 min (range 90-180 min). The causes for transfers were preterm labor in eight, preterm premature rupture of the membrane in five, cervical incompetence in five, pre-eclampsia in three and other medical reasons in five. Five of the 26 patients were discharged with restored stability of pregnancy. The remaining 21 patients underwent delivery at KMC. The median gestational age was 26 weeks (range 22-33 weeks) at the time of transfer and 31 weeks (range 22-37 weeks) at delivery. Four of 26 neonates who were born at KMC died after birth due to severe premature or congenital anomaly. Seventeen of the remaining 22 neonates, including 10 twins, received treatment in the neonatal intensive care unit. All of the 22 neonates and all the mothers were discharged in good condition. No patients developed any complications requiring treatment during flights. CONCLUSION: Helicopter transfer is feasible for pregnant patients with severe complications.     

Fractal analysis of the maternal surface of the placenta: preliminary report

AIMS: The objective of this study was to determine whether the maternal surface of the placenta is fractal, and whether the mean fractal dimension differs according to the gestational age and clinically or pathologically different conditions. METHODS: Using digitized images of the maternal surface of 75 placentas, fractal dimensions were measured with a fractal analysis software. RESULTS: The mean fractal dimension of the maternal surface of the placentas significantly exceeded the topological dimension of a surface (= 2). This means that the morphological pattern of the maternal surface fulfills the mathematical definition of fractal structures. Among the three different groups of gestational age, the mean fractal dimension in 22-29 weeks was significantly lower than that in 30-36 and 37-41 weeks (p = 0.022 and 0.014, respectively). Although not significantly different (p = 0.149), in 30-36 weeks the mean fractal dimension of the placentas complicated by pregnancy-induced hypertension (PIH) was greater than that without PIH. CONCLUSION: Fractal geometry, a vocabulary of irregular shapes, can be useful for describing quantitatively the architecture of the maternal surface of the placenta and become a useful tool for analyzing physiological and pathological placental formation mathematically.     

Juvenile Hepatocellular Carcinoma in a Healthy Liver

Primary hepatocellular carcinoma (HCC) in patients ＜30 years old is extremely rare. In younger patients, HCC develops against a background of persistent hepatitis B virus infection. We herein report a 23-year-old woman with HCC with all-negative hepatitis virus markers developing in an apparently healthy liver. Imaging studies showed a 50-mm hypervascular mass in segment 4 of the left liver lobe, compatible with HCC. The patient underwent surgical resection. A histological examination showed the presence of poorly differentiated HCC. The patient was diagnosed with HCC developing in a healthy liver. This is an extremely rare case of non-B non-C HCC.     

Abnormal neurogenesis in the dentate gyrus of adult mice lacking 1,25-dihydroxy vitamin D3 (1,25-(OH)2 D3)

In this study, we employed 1α-hydroxylase knockout (1α-(OH)ase(-/-) ) mice to investigate the influence of 1,25-dihydroxy vitamin D(3) (1,25-(OH)(2) D(3) ) deficiency on the adult neurogenesis in the hippocampal dentate gyrus (DG). The numbers of both 24-hr-old BrdU(+) cells and proliferating cell nuclear antigen positive cells in 8-week-old 1α-(OH)ase(-/-) mice increased approximately twofold compared with wild-type littermates. In contrast, the numbers of 7- and 28-day-old BrdU(+) cells in 1α-(OH)ase(-/-) mice decreased by 50% compared with wild-type mice, while the proportion of BrdU(+) /NeuN(+) cells in BrdU(+) population showed no difference between 1α-(OH)ase(-/-) and wild-type mice. Apoptotic cells in the subgranular zone (SGZ) of DG markedly increased in 1α-(OH)ase(-/-) mice. Replenishment of 1,25-(OH)(2) D(3) , but not correction of serum calcium and phosphorus levels, completely prevented changes in the neurogenesis in 1α-(OH)ase(-/-) mice. The absence of 1,25-(OH)(2) D(3) led to an increase in the expression of L-type voltage-gated calcium channel (L-VGCC) and a decrease in the nerve growth factor (NGF) mRNA level. Treatment with the L-VGCC inhibitor nifedipine blocked the increased cell proliferations by 1,25-(OH)(2) D(3) deficiency. Administration of NGF significantly attenuated the loss of newborn neurons in 1α-(OH)ase(-/-) mice.