Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function.

CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer.

BACKGROUND: CaSm, the cancer-associated Sm-like oncogene, is overexpressed in greater than 80% of pancreatic tumors. We previously reported that an adenovirus expressing antisense RNA to CaSm (Ad-alpha CaSm) can decrease pancreatic tumor growth in vivo but is not curative. In the current study we investigated the mechanism of Ad-alpha CaSm's antitumor effect to rationally approach combinatorial therapy for improved efficacy. METHODS: AsPC-1 and Panc-1 human pancreatic cancer cells were treated with Ad-alpha CaSm and examined by MTT assay for in vitro proliferation changes. Flow cytometry determined the effect of CaSm down-regulation on the cell cycle, and then cells treated with Ad-alpha CaSm in combination with cisplatin, etoposide, or gemcitabine chemotherapies were reexamined by MTT assay. SCID-Bg mice bearing subcutaneous AsPC-1 tumors were treated with Ad-alpha CaSm, gemcitabine, or the combination and monitored for tumor growth and survival. RESULTS: Treatment with Ad-alpha CaSm reduced the proliferation of AsPC-1 and Panc-1 cells (59% and 44%, respectively; P <.05). The cell cycle revealed a cytostatic block with decreased G(1) phase and increased DNA content in treated cells. The combination of Ad-alpha CaSm with gemcitabine significantly reduced in vitro proliferation (66% vs 39% and 48% for controls), decreased in vivo AsPC-1 tumor growth by 71% (n = 10), and extended survival time from 57 to 100 days. CONCLUSIONS: Down-regulation of CaSm reduces the growth of pancreatic cancer cells by altering the cell cycle in a cytostatic manner. The combination of Ad-alpha CaSm with gemcitabine is more effective than either agent used separately.

Cost efficacy of routine screening for diabetes in pregnancy: 1-h versus 2-h specimen.

Undetected gestational diabetes mellitus (GDM) is associated with a two- to fivefold increase in perinatal morbidity and mortality. Widespread screening of the obstetric population (resulting in identification and treatment) should reduce these rates. Seven hundred ninety-eight women were examined during a 13-mo period of universal glucose challenge testing (GCT). A total of 2.8% of the population had an abnormal oral glucose tolerance test (OGTT). Thirty percent of those with an abnormal OGTT were less than 25 yr old. The specificity of a 1-h GCT (50-g carbohydrate load) using a threshold of either 140 or 150 mg/dl was compared with that of a 2-h specimen using a threshold of 118 mg/dl to determine whether the cost of screening could be reduced. One- and 2-h specimens were obtained in 347 of these women. A 34% reduction in the number of follow-up OGTTs required would have been achieved if a 2-h specimen had been used as the index instead of a 1-h specimen (P less than .05). As a result, the (direct and indirect) cost per patient identified with GDM would have declined 23.5%--from $866 to $662. No comment concerning the actual false-negative rate of either the 1- or 2-h GCT can be made because only select women underwent an OGTT. To assess the validity of the 2-h threshold, an OGTT was performed in an additional 190 women if either the 1- or 2-h screen was abnormal. The results were confirmatory: the 2-h screen would have reduced the cost per case identified by 32% in this small group. Screening on the basis of past medical history clearly lacked sensitivity and cost efficacy in comparison with the GCT and should be abandoned as a practice.

Endodermal sinus (yolk sac) tumors in infants and children.

Endodermal sinus tumors, as a specific entity, were first proposed and described by Teilum on the basis of morphological and histogenetic features. Recent work utilizing tumor markers (alpha-fetoprotein), immunofluorescent and electron microscopic studies have supported Teilum's original concept as to the origin of these tumors. Five typical presentations of endodermal sinus tumors seen in the pediatric age group were reviewed with reference to the original presentation, the utilization of tumor markers (alpha-fetoprotein) and the prognostic implications of this neoplasm.