Pregnancy outcomes in female childhood cancer survivors: Nationwide survey in Japan.

BACKGROUND: The aim of this study was to investigate the outcomes of pregnancy in female childhood cancer survivors (CCS) in Japan, to encourage greater attention to the reproductive health of CCS. METHODS: This was a retrospective nationwide questionnaire survey of delivery at ≥22 weeks of gestation in CCS at perinatal centers registered with the Japanese Perinatologists Association between 2010 and 2014. We evaluated the maternal characteristics, pregnancy and neonatal outcomes and the relationship between cancer treatment and these outcomes. RESULTS: The total number of CCS was 61, and the total number of deliveries was 71, corresponding to 0.019% of total deliveries. Regarding cancer, 46% of the patients had had leukemia. Epilepsy was seen in seven (11%). Mean gestational age at delivery was 37.9 weeks. The rate of preterm delivery was 24%. Mean birthweight was 2,718 g. There were three congenital anomalies (4.2%). The rate of preterm delivery was higher and mean birthweight lower in the women treated with radiotherapy than in those without radiotherapy (42% vs 16%, P = 0.025; 2,436 ± 737 g vs 2,827 ± 483 g, P = 0.010). The adjusted OR of radiotherapy for preterm deliveries was 3.53 (P = 0.049). CONCLUSIONS: Although the number of deliveries by CCS was low in Japan, the pregnancy outcomes were favorable. The important points for managing pregnancy in CCS were preterm delivery as an obstetric complication, especially in CCS who had been treated with radiotherapy, and epilepsy as a maternal complication, which may be related to previously received treatment.

Design, synthesis, and structure-activity relationship (SAR) of N-[7-(4-hydroxyphenoxy)-6-methylindan-4-yl]malonamic acids as thyroid hormone receptor ß (TRß) selective agonists.

Highly TRß selective thyromimetics have several potential therapeutic applications. Based on the novel indane derivative KTA-439 with high receptor (TRß) and organ (liver) selectivity, a series of thyroid hormone analogues were prepared, in which the isopropyl at the 3'-position was replaced with alkyl and aralkyl moieties of variable lengths and branches. Binding assays for these human TRs and reporter cell assays showed that 2-arylethyl derivatives had higher TRß selectivity than KTA-439. KTA-574, a representative 2-arylethyl derivative, had TRß specificity in a binding assay and exhibited full agonism in a reporter cell assay.

Placental mesenchymal dysplasia: chronological observation of placental images during gestation and review of the literature.

Placental mesenchymal dysplasia (PMD) is characterized by multiple hypoechoic vesicles which are similar to molar changes in the placenta; however, the process of such morphological changes of PMD during pregnancy has not been fully understood. We performed a review of all PMD cases published in English and identified 49 articles including 110 cases. With regard to the gestational age at which the multicystic pattern was seen, approximately 70% of cases were diagnosed at 13-20 weeks of gestation. Another characteristic feature of PMD is varicose dilation of fetal chorionic vessels. As many as 90% of cases were diagnosed as placenta with dilated fetal chorionic vessels in the third trimester. We also report a case of PMD which was found at 10 weeks of gestation according to ultrasonic molar patterns. Serial observations of the placenta using ultrasound and magnetic resonance imaging revealed that multicystic lesions became smaller after 23 weeks. In contrast, dilated placental vessels on the fetal side became apparent at 38 weeks. The present review highlights that placental vesicular lesions of PMD may precede dilation of fetal chorionic vessels during pregnancy. It also indicates the potential of a gradual reduction in size of PMD's placental vesicular lesions by serial study of placental images.

Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene.

Hypoxia is known to play important roles in the development and progression of tumors. We previously demonstrated that S100A4, a critical molecule for metastasis, was upregulated in ovarian cancer cells. Therefore, we examined the mechanisms of the upregulation of S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of S100A4 were found to be correlated with the invasiveness of ovarian carcinoma cells in vitro and in vivo, and the upregulation of S100A4 expression was associated with hypomethylation of CpG sites in the first intron of S100A4 in ovarian carcinoma cell lines and tissues. The expression of S100A4 was increased under hypoxia and was associated with elevated invasiveness, which was inhibited by S100A4 small interfering RNA (siRNA). In addition, exposure to hypoxia reduced the methylation of hypoxia-response elements (HRE) of the S100A4 gene in a time-dependent fashion, in association with the increased binding of HIF-1α to a methylation-free HRE in ovarian carcinoma cells. These results indicate that hypoxia-induced hypomethylation plays an essential role in S100A4 overexpression and the epigenetic transformation of ovarian carcinoma cells into the "metastatic phenotype."

Discovery of novel indane derivatives as liver-selective thyroid hormone receptor ß (TRß) agonists for the treatment of dyslipidemia.

Thyromimetics that specifically target TRß have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRß) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRß selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.

Predicting the route of delivery in women with low-lying placenta using transvaginal ultrasonography: significance of placental migration and marginal sinus.

BACKGROUND/AIMS: To examine the significance of placental migration and the presence of a placental marginal sinus to predict the eventual route of delivery in low-lying placenta. METHODS: 49 women with a low-lying placenta after 30 weeks' gestation were studied. The distance between the internal os and leading edge of the placenta was measured weekly using transvaginal ultrasonography until 37 weeks' gestation. The relationship between the rate of placental migration, the presence of a placental marginal sinus and the eventual mode of delivery was investigated. RESULTS: Although the cesarean section rate was 56.3% (9/16) in the 'slow' migration (0-2.0 mm/week) group, no patient (0/33) in the 'fast' (>2.0 mm/week) migration group underwent a cesarean section (p < 0.01). The cesarean section rate was 71.4% (5/7) in patients with a placental marginal sinus, significantly greater than the rate of 9.5% (4/42) in patients without a marginal sinus (p < 0.01). CONCLUSION: A decreased rate of placental migration until 37 weeks' gestation and the presence of a placental marginal sinus were associated with subsequent cesarean delivery because of antepartum vaginal bleeding. These parameters may be useful for predicting the route of delivery in women with a low-lying placenta.

Clinical characteristics of a novel "Type 3" vasa previa: case series at a single center.

OBJECTIVE: Vasa previa is a condition in which fetal blood vessels are located on fetal membranes within 2 cm of the internal cervical os. Vasa previa has been classified into two types: Type 1, in which vessels connect a velamentous umbilical cord to the placenta, and Type 2, in which vessels connect the lobes of a bilobed placenta or the placenta to a succenturiate lobe. However, there are also atypical cases that cannot be classified into these two types. These cases are manifested by a center or marginal cord insertion with a normal shaped placenta, and fetal vessels were also located on membranes around the internal cervical os. These cases were recently proposed as Type 3 vasa previa. The present study investigated the incidence of Type 3 vasa previa and elucidated differences in clinical and ultrasonographical characteristics between traditional types and Type 3. METHODS: This was a single-center observational study using a cohort of all vasa previa cases between January 2010 and April 2020. RESULTS: Among 8,723 deliveries, there were 14 cases (0.16%) of vasa previa, all of which were diagnosed prenatally by US, not after vaginal delivery or CS. There were 9 (64%), 0, and 5 (36%) cases of Types 1, 2, and 3, respectively. All 5 Type 3 cases had only one fetal aberrant vessel of vasa previa, while 6 out of 9 Type 1 cases (67%) had two or more aberrant vessels. Seven Type 1 cases (78%) possessed two or more known risk factors, such as velamentous cord insertion, whereas all Type 3 cases only had one. Difficulties were associated with diagnosing two out of the 14 cases of vasa previa using routine transvaginal ultrasonography (TVUS). In these cases, the aberrant fetal vessel of vasa previa was only one vein with a thin wall that was not clearly visualized by gray-scale TVUS as well as slow flow that was easily misread by color-Doppler. These cases were ultimately diagnosed as vasa previa based on non-pulsatile flow detected by color and pulsed Doppler. CONCLUSIONS: The present results suggest that Type 3 may account for a large proportion of vasa previa cases. Most Type 3 cases may present with only one fetal aberrant vessel of vasa previa and fewer risk factors, suggesting that the diagnosis of vasa previa may be more challenging in Type 3 cases than in the other types. Vasa previa with a venous vasa previa needs to be considered because of the difficulties associated with an antenatal diagnosis due to unclear imaging of the vasculature or the lack of specific color Doppler flow patterns. Pulsed Doppler imaging may be helpful for the diagnosis of these cases.

Tadalafil treatment for fetuses with early-onset growth restriction: a protocol for a multicentre, randomised, placebo-controlled, double-blind phase II trial (TADAFER IIb).

INTRODUCTION: TheTADAlafil treatment for Fetuses with early-onset growth Restriction: multicentrer, randomizsed, phase II trial (TADAFER II) study showed the possibility of prolonging the pregnancy period in cases of early-onset fetal growth restriction; however, it was an open-label study. To establish further evidence for the efficacy of tadalafil in this setting, we planned a multicentre, randomised, placebo-controlled, double-blind trial. METHODS AND ANALYSIS: This trial will be conducted in 180 fetuses with fetal growth restriction enrolled from medical centres in Japan; their mothers will be randomised into three groups: arm A, receiving two times per day placebo; arm B, receiving one time per day 20 mg tadalafil and one time per day placebo and arm C, receiving 20 mg two times per day tadalafil. The primary endpoint is the prolongation of gestational age at birth, defined as days from the first day of the protocol-defined treatment to birth. To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery as in TADAFER II will be established in this trial. The investigator will evaluate fetal baseline conditions at enrolment and decide the timing of delivery based on this indication. ETHICS AND DISSEMINATION: This study has been approved by Mie University Hospital Clinical Research Review Board on 22 July 2019 (S2018-007). Written informed consent will be obtained from all mothers before recruitment. Our findings will be widely disseminated through peer-reviewed publications. TRIAL REGISTRATION: jRCTs041190065.

Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin.

Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.

Fetal goitrous hypothyroidism due to maternal thyroid stimulation-blocking antibody: a case report.

Most fetal goitrous hypothyroidisms are reportedly caused by the maternal use of an antithyroid drug or fetal dyshormonogenesis. However, fetal goitrous hypothyroidism due to the transplacental passage of maternal thyroid stimulation-blocking antibody (TSBAb) is extremely rare. A woman at 28 weeks of gestation was found to have a fetal goiter by ultrasonography. Because the maternal serum showed hypothyroidism with an elevated titer of TSBAb, levothyroxine sodium was administered. The patient delivered a male infant, 3,412 g, with a goiter at term. Umbilical blood revealed primary hypothyroidism with increased TSBAb, and the infant was given levothyroxine sodium. After a month, neonatal thyroid function and TSBAb levels became normal. Attention should be paid to possible fetal hypothyroidism when a fetal goiter is observed to avoid impaired mental development of the neonate.

Sawtooth fetal heart rate pattern associated with a favorable neurological outcome in an infant: a case report.

BACKGROUND: The sawtooth fetal heart rate pattern is rare, and has been reported as a possible indicator of neurological sequelae in newborns. However, we observed this fetal heart rate pattern in an infant with normal neurological function. CASE PRESENTATION: A 29-year-old primigravida Japanese woman presented to our hospital at 40 weeks and 1 day of gestation with marked vaginal bleeding. Since admission, fetal heart rate tracing consistently demonstrated a sawtooth-like pattern. There were 3-4 oscillations per minute, and their amplitude was 30-40 beats per minute. An emergency cesarean section was performed because of non-reassuring fetal status. Evidence of placental abruption was not observed. The newborn was a male weighing 2936 g, with an Apgar score of 1 and 3 at 1 minute and 5 minutes, respectively. The infant received brain cooling, but was discharged uneventfully. A follow-up examination at age 3 years demonstrated no developmental restriction. CONCLUSION: Although the Apgar score of the newborn was low, the infant had no neurological sequelae. Thus, the sawtooth fetal heart rate pattern may not be linked to in utero irreversible fetal central nervous system injury.

Trophoblast type-specific expression of senescence markers in the human placenta.

OBJECTIVES: Cell senescence is irreversible cell cycle arrest. The human placenta is a unique organ that grows and matures during pregnancy until 40 weeks of gestation. However, the role of senescence in placental villi, particularly in the two types of trophoblast, has not yet been elucidated in detail. Therefore, we herein investigated the expression of cell senescence-related markers in trophoblast. METHODS: Seventy normal placental tissues were used. The expression of senescence-associated beta-galactosidase (SA-ß-gal), cell senescence-related markers (p16, p21, and promyelocytic leukemia; PML), and a growth marker (MCM2) was immunohistochemically examined. The expression of these markers in BeWo cells before and after cell fusion using forskolin was also investigated. RESULTS: The expression of MCM2 is detected in cytotrophoblast (CT). The expression of SA-ß-gal in CT is strong in the first and second trimesters, but weaker in the third trimester. Syncytiotrophoblast (ST) are negative in the first and second trimesters, but become positive in the third trimester. The immunohistochemical expression of p16, p21, and PML is stronger in CT than in ST throughout pregnancy. Furthermore, the expression of these markers in ST significantly increases as pregnancy advances. The expression of SA-ß-gal, PML, and p21 in BeWo cells is stronger after than before cell fusion. CONCLUSIONS: The proliferation and senescence of CT occurred in early to mid-pregnancy in association with syncytial fusion, while senescence was observed in ST in late pregnancy. This coordinated trophoblastic senescence may be essential for maintaining placental function.

Association between adolescent pregnancy and adverse birth outcomes, a multicenter cross sectional Japanese study.

We aimed to clarify how maternal physical characteristics explains the association between adolescent pregnancy and adverse birth outcomes, focusing on their height. We used a national multicenter-based delivery registry among 30,831 women under age 25 years with a singleton pregnancy between 2005 and 2011. Adolescent pregnancy was defined as younger than 20 years of age, and categorized into "junior adolescent" (aged ≤15 years) and "senior adolescent" (aged 16-19 years). We used multivariate Poisson regression and mediation analysis to assess the extent to which maternal height explained the association between adolescent pregnancy and risk of adverse birth outcomes. Risks for preterm birth [(adjusted risk ratio (aRR) 1.17, 95% confidence interval (95% CI), 1.08-1.27], low birthweight (aRR 1.08, 95% CI, 1.01-1.15), and low Apgar score (aRR 1.41 95%CI, 1.15-1.73) were significantly higher among adolescent women compared to women of 20-24 years of age. The mediation effect of maternal height on these outcomes were moderate for low birthweight (45.5%) and preterm birth (10.5%), and smaller for low Apgar score (6.6%). In all analyses, we did not detect significant differences between junior adolescent and senior adolescent. Adolescent women have higher risk of adverse birth outcomes. This association is partially mediated by shorter maternal height.

Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer.

Small guanosine triphosphatase RhoA has been known to re-organize cytoskeletons and regulate cell migration. The present authors have previously reported that expression of RhoA is significantly increased in advanced ovarian carcinomas and also in the peritoneal disseminated lesions. The present study investigated whether overexpression of RhoA could alter the progressive behavior of ovarian cancer cells. The effect of various Rho inhibitors on the biological behavior of ovarian cancer cells in vitro and in vivo was also examined. A stable RhoA-transfectant of an ovarian cancer cell line SKOV3 was generated and examined in vitro for alterations of proliferative activity and invasiveness, and also in the nude mice model for peritoneal dissemination. In addition, the effect of a specific Rho inhibitor (C3 exoenzyme), Rho kinase inhibitor (Y27632) and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (Lovastatin and Pravastatin) were studied in vitro and in vivo. Forced overexpression of RhoA did not alter proliferative activity but significantly increased the invasiveness in vitro, which was suppressed by addition of C3 exoenzyme, Y27834, Lovastatin and Pravastatin. In the nude mice model, the frequency of dissemination and the number of disseminated lesions were significantly increased in the RhoA transfectant than in the control. In addition, oral administration of Lovastatin significantly decreased the number of metastatic sites compared with the control. These findings suggest that upregulation and/or activation of RhoA play an important role in the peritoneal dissemination of ovarian carcinoma, and that Lovastatin might be a candidate for the possible, novel treatment for ovarian carcinoma patients with peritoneal dissemination.

Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy.

A series of novel and potent 3-amidinophenylsulfonamide derivatives of factor Xa inhibitors were designed and synthesized using an amidoxime prodrug strategy. We focused on systemic clearance of parent compounds in rats, and performed in vivo pharmacokinetic screening. Incorporation of a carboxymethoxy group markedly improved systemic clearance (compound 43), and the related amidoxime 44 showed sufficient prodrug conversion. Compound 45, the double prodrug of 43, exhibited practicable bioavailability after oral administration in rats. Among the various compounds under investigation, KFA-1982 was selected for clinical development.

Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma.

The hypoxia-inducible factor (HIF) is a transcriptional factor with important roles in tumor biology. To clarify the possible involvement of the HIF-alpha subunit and von Hippel-Lindau (VHL) protein in the development and progression of ovarian carcinoma, we analyzed the immunohistochemical expressions of HIF-1alpha, HIF-2alpha, and VHL in 107 cases of epithelial ovarian tumors. In addition, we examined loss of heterozygosity (LOH) at VHL gene loci. The frequency of the cytoplasmic expression of HIF-2alpha in carcinomas was higher than that in benign and borderline tumors (P < .0001). Furthermore, the nuclear expression of HIF-1alpha and the cytoplasmic expression of HIF-2alpha were significantly higher in tumors of FIGO (International Federation of Gynecology and Obstetrics) stages III and IV than in those of stages I and II. On the other hand, the cytoplasmic expression of HIF-1alpha did not show differences among histological malignancies. There was a positive correlation between nuclear HIF-1alpha expression and vascular endothelial growth factor (rho = 0.320, P < .001). Although LOH at the VHL gene locus was frequent in ovarian carcinomas (24%), there is no significant correlation between LOH and loss of VHL expression. In 22 clear cell carcinomas, VHL expression showed a significantly negative correlation with the nuclear expression of HIF-1alpha (rho = -0.529, P = .0153). The log-rank test showed that nuclear positive immunostaining for HIF-1alpha (P = .002) and cytoplasmic positive immunostaining for HIF-2alpha (P = .0112) in tumor cells are associated with poor prognosis of patients with ovarian carcinoma. Multivariate analysis also showed that the nuclear expression of HIF-1alpha is an independent prognostic factor. These results show that the HIF-alpha subunit represents an important biomarker in the evaluation of the prognosis of patients with ovarian carcinoma.

Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas.

Semaphorins (SEMAs) compete with vascular endothelial growth factor (VEGF) for receptor neuropilin 1 (NP1) and 2 (NP2) and suppress angiogenesis. To clarify the involvement of SEMA and VEGF in the development and progression of ovarian carcinoma, we analyzed the immunohistochemical expression of SEMA, VEGF, NP1, and NP2 in 105 epithelial ovarian tumors. In addition, loss of heterozygosity at SEMA gene loci was examined. Strong expression of SEMA was found in 48% of benign, 33% of borderline tumors, and 13% of carcinomas (P < .05). Positivity for SEMA was significantly decreased in stage IV carcinomas and the expression of SEMA was significantly lower in peritoneal metastases than in primary lesions. Expression of SEMA showed a weak inverse correlation with microvessel density, but the correlation was not statistically significant. Loss of heterozygosity at SEMA3B or SEMA3F was demonstrated in none of the benign tumors, 8% of borderline tumors, and 29% of carcinomas. Expression of NP1 and NP2 was significantly higher in carcinomas than in benign tumors (P < .0001 and .0002, respectively). Patients with ovarian carcinoma with a high VEGF/SEMA ratio showed poorer survival than those with a low VEGF/SEMA ratio (P = .005). Decreased expression of SEMA and increased expression of NP1 and NP2 are characteristics of ovarian carcinomas, and loss of SEMA expression may play an important role in ovarian carcinoma progression. A high VEGF/SEMA ratio has adverse prognostic significance in patients with ovarian carcinoma.

Prenatal sonographic diagnosis of fetal valproate syndrome: a case report.

BACKGROUND: Prenatal exposure of mother to valproate (VPA) causes teratogenic effects in the fetus, namely fetal valproate syndrome (FVS). We report a case of fetal valproate syndrome rarely diagnosed by prenatal sonographic examination. CASE PRESENTATION: Our patient was a female infant who was born to a 27-year-old nulliparous Japanese woman with epilepsy. The mother was diagnosed with infantile epilepsy at 1 year of age and had been using three antiepileptic drugs, including valproate, but preconceptional counseling was not performed. At 25 weeks of gestation, contracture of the fetal right wrist joint suggestive of a radial ray defect was observed by transabdominal ultrasonography. The fetus demonstrated growth retardation starting from 32 weeks of gestation. In addition, saddle nose as a facial anomaly was detected by three-dimensional ultrasound at 37 weeks of gestation. Accordingly, we suspected that the fetus had fetal valproate syndrome. At 39 weeks of gestation, the mother delivered an infant weighing 2056 g. The neonate had characteristic features of fetal valproate syndrome, such as facial configuration, slight muscular hypotonia of the whole body, breathing problems, right-hand articular contracture accompanied by radial ray defect, and cardiovascular malformation. CONCLUSIONS: When obstetricians manage epileptic pregnant women without enough preconceptional counseling or adjustment for antiepileptic drugs, careful sonographic observation of the fetus is mandatory.

Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout.

To test the hypothesis that inhibitors of human concentrative nucleoside transporter 2 (hCNT2) suppress increases in serum urate levels derived from dietary purines, we previously identified adenosine derivative 1 as a potent hCNT2 inhibitor (IC50 = 0.64 µM), but further study was hampered due to its poor solubility. Here we describe the results of subsequent research to identify more soluble and more potent hCNT2 inhibitors, leading to the discovery of the benzimidazole nucleoside 22, which is the most potent hCNT2 inhibitor (IC50 = 0.062 µM) reported to date. Compound 22 significantly suppressed the increase in plasma uric acid levels after oral administration of purine nucleosides in rats. Because compound 22 was poorly absorbed orally in rats (F = 0.51%), its pharmacologic action was mostly limited to the gastrointestinal tract. These findings suggest that inhibition of hCNT2 in the gastrointestinal tract can be a promising approach for the treatment of hyperuricemia.

Elevated expression of E-cadherin and alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas.

E-cadherin and catenins play key roles in cell adhesion and motility. Little is known about the changes in expression of these molecules in the progression of ovarian carcinomas. In the present study, the immunohistochemical expression of E-cadherin and alpha-, beta-, and gamma-catenins was examined in 77 cases of ovarian carcinoma. In addition, the expression of these molecules was evaluated in 26 matched pairs of primary and metastatic lesions of advanced ovarian carcinomas. Of the 77 primary lesions, positive staining for E-cadherin and alpha-, beta-, and gamma-catenin was observed in 75 (97%), 63 (82%), 71 (92%) and 57 (74%) cases, respectively. Positivity for E-cadherin and alpha-, beta-, and gamma-catenin was significantly decreased in stage III and IV tumors compared with stage I and II tumors, suggesting that expression of the cadherin-catenin complex is reduced with the advancing stages of a tumor. Interestingly, expression of E-cadherin and alpha-, beta-, and gamma-catenin in the lesions of peritoneal dissemination was significantly increased compared with the primary lesions. These findings suggest that expression of the cadherin-catenin complex changes markedly and that reexpression may occur during the peritoneal dissemination of ovarian carcinoma cells.