DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer.

The gene encoding 'deleted in breast cancer 2' (DBC2), also referred to as RHOBTB2 (Rho-related BTB domain-containing protein 2), is classified as a tumor suppressor gene. DBC2 is a substrate-specific adaptor protein for a novel class of Cullin-3 (CUL3)-based E3 ubiquitin ligases; however, it is unclear if the substrate adaptor function of DBC2 is required for its tumor suppressor activity. Furthermore, the key substrates of DBC2-mediated ubiquitination have yet to be identified. In the present study, we established a genome-wide human cDNA library-based in vitro ubiquitination target screening assay and identified Musashi-2 (MSI2) as a novel ubiquitination target protein of DBC2. MSI2 directly interacted with DBC2, and this interaction promoted MSI2 polyubiquitination and proteasomal degradation in breast cancer cells. Overexpression and knockdown experiments demonstrated that DBC2 suppressed MSI2-associated oncogenic functions and induced apoptosis. Immunohistochemistry analysis of a breast cancer tissue microarray revealed that DBC2 and MSI2 protein levels are inversely correlated in both normal breast tissues and breast cancer tissues. Taken together, these findings provide evidence that DBC2 suppresses tumorigenesis in breast cancer by ubiquitinating MSI2.

Phosphatidylinositol 3-kinase stimulates muscle differentiation by activating p38 mitogen-activated protein kinase.

The activation of both phosphatidylinositol 3-kinase (PI3-kinase) and p38 mitogen-activated protein kinase (p38 MAPK) is required for muscle differentiation. However, it is not known whether the signals from these two kinases interact during this process. In this work, we have investigated this using H9c2 cardiac myoblasts. The p38 MAPK-specific inhibitor SB203580 blocked muscle differentiation and suppressed the expression of myogenin and myosin heavy chain in a concentration-dependent manner. Consistent with this, expression of a wild-type p38 MAPK (Ha-p38) or a constitutively active MAPK kinase 6 (MKK6(glu)) promoted the rate of differentiation into multinucleated myotubes. LY294002, a PI3-kinase inhibitor, suppressed in a dose-dependent manner not only muscle differentiation but also activation of p38 MAPK. In addition, expression of a constitutively active form of PI3-kinase (p110*) enhanced myotube formation and p38 MAPK activation, while expression of a dominant negative form of PI3-kinase (Deltap85) attenuated these responses. Furthermore, SB203580 suppressed differentiation of H9c2 cells expressing p110*. Interestingly, LY294002 also suppressed differentiation of H9c2 cells expressing Ha-p38 or MKK6(glu). However, SB203580 did not affect PI3-kinase activity, suggesting that PI3-kinase myogenic signaling to p38 MAPK is unidirectional. Taken together, we concluded that PI3-kinase activates p38 MAPK, which in turn stimulates muscle differentiation, but that p38 MAPK does not substitute for PI3-kinase in this process.

No significant correlation exists between core promoter mutations, viral replication, and liver damage in chronic hepatitis B infection.

Hepatitis B virus (HBV) core promoter mutants have been proposed to contribute to severe liver damage by increasing viral loads, but this has not yet been clearly shown. To examine the effects of core promoter mutants on viral load and liver damage, we first developed a polymerase chain reaction (PCR)-based semiquantitative HBV DNA detection method with a high sensitivity (able to detect as low as 10(3) molecules/mL). Then we cloned 12 predominant core promoter mutants from 41 chronic hepatitis B patients. The in vitro promoter and replication activities of these mutants were similar to those of wild-type virus. However, viral load was highly variable, and this was dependent on individual patients rather than mutant type. In addition, there was no mutant type that showed any unique correlation with alanine transaminase (ALT) levels. Viral load was not significantly correlated with ALT level in both cross-sectional and longitudinal studies. Quantitation of HBV levels also revealed no clear correlation between hepatitis B e antigen (HBeAg) status and viral load. Taken together, these results indicated that the replication activity of core promoter mutants has little effect on viral load, and that viral load does not correlate with the severity of liver damage or with HBeAg status.

Arrangement of the systemic and pulmonary venous components of the atrial chambers in hearts with isomeric atrial appendages.

BACKGROUND: The morphological definition of atrial chambers, and the determination of atrial laterality, are based on analysis of the structure of the atrial appendages. The systemic and pulmonary venous connections to the heart, nonetheless, are important in the management of patients having isomeric appendages. In this study, therefore, we analysed the morphology of the postero-superior walls of the atrial chambers so as to provide evidence concerning the morphogenetic background of those hearts, and to improve operative management. METHODS: We reviewed 15 autopsied specimens with isomeric right appendages, and 10 with isomeric left appendages, paying particular attention to the morphology of the systemic and pulmonary venous connections. The postero-superior walls of the atrial chambers can be made up of the atrial body, the systemic venous components, or the pulmonary venous component. We analysed the contributions made by each of these components. RESULTS: The postero-superior walls of the atrial chambers were markedly variable, but could be grouped into five patterns. Bilaterally well-developed systemic venous components and absence of the pulmonary venous component within the hypoplastic atrial body were present in 9 hearts with extracardiac pulmonary venous connections in the setting of right isomerism. Bilaterally well-developed systemic venous components, and a hypoplastic pulmonary venous component within the hypoplastic atrial body, were present in 5 hearts with intracardiac pulmonary venous connections in right isomerism. Bilaterally well-developed systemic venous components, and a hypoplastic pulmonary venous component within the sizable atrial body, were present in 1 heart with an intracardiac pulmonary venous connection in right isomerism. A well-developed pulmonary venous component within the atrial body, and hypoplasia of one systemic venous component, were present in 7 hearts with left isomerism. A well-developed pulmonary venous component within the atrial body, and hypoplasia of bilateral systemic venous components, were present in 3 hearts with left isomerism. CONCLUSIONS: The postero-superior walls of the atrial chambers in hearts with isomeric atrial appendages can be analysed on the basis of a compound structure made of bilateral systemic venous components, a central pulmonary venous component, and the body of the atrium. Hearts with isomeric right appendages have absence or hypoplasia of the pulmonary venous component, while hearts with isomeric left appendages have hypoplastic systemic venous components.

Tetralogy of Fallot in the fetus: findings at targeted sonography.

OBJECTIVES: To evaluate the findings of tetralogy of Fallot in various fetal sonographic views. METHODS: We reviewed the fetal sonograms and medical records of 20 fetuses with prenatal diagnosis of tetralogy of Fallot. We analyzed the indications for targeted sonography, the abnormalities seen in various sonographic views, the postnatal echocardiographic and angiographic findings and autopsy findings. RESULTS: The most common indication for targeted sonography was an abnormal (n = 12) or inadequate (n = 3) finding on sonographic screening in which the abnormality was most frequently found on the three-vessel view (n = 9). The key pathological features of tetralogy of Fallot were uniformly demonstrated in the ventricular outflow tract, three-vessel and short-axis views. The ductus arteriosus was small in 70% of cases and not identifiable in the remaining fetuses. In three of six fetuses with no identifiable ductus, the ductus was shown to be absent at autopsy. The direction of ductal flow was variable. CONCLUSION: The key features of tetralogy of Fallot were always demonstrable in the ventricular outflow tract, three-vessel and short-axis views. The most common reason for referral was the abnormal three-vessel view.

Correlation between mammographic manifestations and averaged histopathologic nuclear grade using prognosis-predict scoring system for the prognosis of ductal carcinoma in situ.

This retrospective study correlated the mammographic manifestations and averaged nuclear grades using Holland, Van-Nuys, and Lagios classifications in 37 cases of ductal carcinoma in situ (DCIS); microcalcifications alone were seen in 59.4%, microcalcifications with associated mass in 19%, and mass alone in 21.6%. DCIS is more likely to be accompanied by microcalcifications than mass on mammography. Correlation is good between the nuclear grades of DCIS and mammographic manifestations.

Ovarian mucinous cystadenoma with mural nodule of anaplastic carcinoma.

The occurrence of malignant mural nodule in benign cystic common epithelial tumor of the ovary have been reported in only three cases; the case one was mucinous cystadenoma with a mural nodule of fibrosarcoma and the others were of carcinomas. Our case was another rare case of ovarian mucinous cystadenoma with mural nodule of anaplastic carcinoma in a 42-year-old woman. The cystadenoma had an unilocular cystic cavity and a mural nodule with thick multinodular solid wall. The internal cystic wall was lined with mucinous cystadenoma without any malignant features. The mural nodule showed anaplastic carcinomatous differentiation and its nature was confirmed by immunohistochemistry and electron microscopy. This tumor had metastasized to the right salpinx, uterus, cul-de-sac, periureter and mesentery.

Neonatal adenoviral pneumonia--report of three autopsy cases.

Adenovirus pneumonia, while common in infancy and childhood, is rarely documented but may be fatal in the neonatal period. In regard to the serious outcome and no responsiveness to common anti-viral agents, adenovirus infection should be considered in the differential diagnosis of pneumonia in neonates. We report three cases of fatal neonatal adenovirus pneumonia, all of which were diagnosed by postmortem examination. Two patients were born by cesarean section at 35 or 36 weeks of gestation, and the other was a 5100 gm postmature baby born by vaginal delivery at 43 weeks of gestation. Respiratory insufficiency was detected just after birth or in the immediate postnatal period, and was associated with lethargy and chest X-ray findings of pneumonic infiltration. The postmortem findings of these patients were remarkably consistent and characterized by predominant lung involvement. The lungs showed diffuse massive consolidation with scattered patchy hemorrhage, and histologically revealed multifocal necrotizing alveolitis and/or bronchiolitis, often with hemorrhage. Alveolar lining cells and desquamated cells contained numerous smudge ells and many cells with characteristic inclusion bodies. Electron microscopy revealed that these inclusion bodies consisted of arrays of icosahedral particles of adenovirus. It is unusual that one of the patients, who was born by cesarean section without any evidence of prenatal infection, developed adenoviral pneumonia; this indicates that infection may occur in the immediate postnatal period as well as during passage of the birth canal.

Mixed tumour of schwannoma and meningioma components in a patient with NF-2.

The authors present the case of an intracranial tumour consisting of both schwannoma and meningioma within the same tumour, in a patient with neurofibromatosis-2 (NF-2). A pre-operative diagnosis of this mixed tumour was not made. However, retrospectively, a meningiomatous area was found inside the acoustic neurinoma on magnetic resonance (MR) images. Predominant schwannoma with a minor component of meningioma was confirmed by histopathological and immunohistochemical examinations. The transitional zones of these two different tumours were macroscopically sharp but microscopically interdigitated. The patient had another meningioma and schwannoma in a separate section of the cranial cavity. Based on this patient, it is suggested that the collision of two kinds of tumours is the most likely hypothesis to explain the development of mixed components of schwannoma and meningioma within the same tumour.