Five infants (two girls and three boys) from four families all had severe pre- and postnatal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%-83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%-41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2-16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483-486]), was discussed in connection with tumor development and progression.

Abstract:Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype.

The clinical features and morphological findings in 31 Japanese infants with trisomy 18 are presented. The majority were small-for-date infants. There was no sex predominance in our series, as opposed to male:female ratios of 1:3 reported in the literature. The average age at death was greater in females than in males. Cardiovascular anomalies were consistently present; ventricular septar defect and patent ductus arteriosus being the most common malformations. Various other internal malformations including the Arnold-Chiari malformation were observed.

To study the functional role of individual ␣ 1 -adrenergic (AR) subtypes in blood pressure (BP) regulation, we used mice lacking the ␣ 1B -AR and/or ␣ 1D -AR with the same genetic background and further studied their hemodynamic and vasoconstrictive responses. Both the ␣ 1D -AR knockout and ␣ 1B -/ ␣ 1D -AR double knockout mice, but not the ␣ 1B -AR knockout mice, had significantly (p Ͻ 0.05) lower levels of basal systolic and mean arterial BP than wild-type mice in nonanesthetized condition, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. All mutants showed a significantly (p Ͻ 0.05) reduced catecholamine-induced pressor and vasoconstriction responses. It is noteworthy that the infusion of norepinephrine did not elicit any pressor response at all in ␣ 1B -/␣ 1D -AR double knockout mice. In an attempt to further examine ␣ 1 -AR subtype, which is involved in the genesis or maintenance of hypertension, BP after salt loading was monitored by tail-cuff readings and confirmed at the endpoint by direct intra-arterial recording. After salt loading, ␣ 1B -AR knockout mice developed a comparable level of hypertension to wild-type mice, whereas mice lacking ␣ 1D -AR had significantly (p Ͻ 0.05) attenuated BP and lower levels of circulating catecholamines. Our data indicated that ␣ 1B -and ␣ 1D -AR subtypes participate cooperatively in BP regulation; however, the deletion of the functional ␣ 1D -AR, not ␣ 1B -AR, leads to an antihypertensive effect. The study shows differential contributions of ␣ 1B -and ␣ 1D -ARs in BP regulation.Catecholamines released from sympathetic nerve terminals cause vascular smooth muscle contraction primarily by activating ␣ 1 -adrenergic receptors (␣ 1 -ARs) in arteries (Hoffman, 2001). Thus, blockade of ␣ 1 -AR leads to a fall in peripheral vascular resistance. Because of their consistent effect in lowering systemic blood pressure (BP), ␣ 1 -AR blockers have been widely used as an antihypertensive drug. However, a large clinical trial unexpectedly disclosed that doxazosin, a nonselective ␣ 1 -AR antagonist, was associated with an increased incidence of heart failure (ALLHAT Collaborative Research Group, 2000). This raised a serious concern about the long-term use of ␣ 1 -AR antagonists in the treatment of hypertension (HT) (ALLHAT Collaborative Research Group, 2000). On the other hand, clinical efficacy of a subtypeselective inhibition of ␣ 1 -AR has not been fully determined.This work was supported in part by research grants from the Scientific Fund of the Ministry of Education, Science, and Culture of Japan, the Japan Health Science Foundation and Ministry of Human Health and Welfare.C.H. and T.K. contributed equally to this work. Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.104.007500. ABBREVIATIONS: ␣

The ability of 17 beta-estradiol to induce morphological transformation of Syrian hamster embryo cells was examined and dose-dependent increases were observed over the concentration range of 1-10 micrograms/ml. However, treatment of the cells with 17 beta-estradiol failed to induce any detectable increases in gene mutations, chromosome aberrations, sister chromatid exchanges or unscheduled DNA synthesis. In contrast, over the dose range that was effective in inducing cell transformation, 17 beta-estradiol induced numerical chromosome changes (both chromosome gains and losses). These findings are similar to the reported observations with the synthetic estrogen, diethylstilbestrol, and support the hypothesis that aneuploidy induction is important in cell transformation and possibly carcinogenesis induced by estrogens.

Hypoxic events may play a crucial aetiologic role in the pathogenesis of late-onset neonatal intussusception.

Our results suggest that aldosterone induces kidney injury via activation of NFκB and mineralocorticoid receptor, and that decreased ACE2 expression may play an important role in aldosterone-induced kidney injury.

The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has a clinical promise for treatment of cancer including hepatocellular carcinoma (HCC). To investigate effect of SAHA on hepatitis C virus (HCV) replication, we treated the HCV replicon cell OR6 with SAHA. HCV replication was significantly inhibited by SAHA at concentrations below 1 μM with no cellular toxicity. Another HDAC inhibitor, tricostatin A, also showed reduction of HCV replication. The microarray analysis and quantitative RT-PCR demonstrated up-regulation of osteopontin (OPN) and down-regulation of apolipoprotein-A1 (Apo-A1) after SAHA treatment. Direct gene induction of OPN and knockdown of Apo-A1 also showed reduction of HCV replication. The liver specific microRNA-122, which is involved in HCV replication, was not affected by SAHA treatment. These results suggest that SAHA has suppressive effect on HCV replication through alterations of gene expression such as OPN and Apo-A1 in host cells. Epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for diseases associated with HCV infection such as chronic hepatitis, liver cirrhosis, and HCC.