In VivoStudies of Adenovirus-Based p53 Gene Therapy for Ovarian Cancer

Objectives.To test the safety, efficacy, and toxicity of gene therapy using wild-type p53-expressing adenovirus (Ad-CMV-p53) in a nude mouse model with intraperitoneal (ip) 2774 human ovarian cancer cell line that contains a p53 mutation.Study design.An initial study of adenovirus tolerance was determined in nude mice by a single ip injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD₁₀₀dose of 1 × 10⁷cells. To study the efficacy and specificity of Ad-CMV-p53 treatment, the mice received treatment with different adenovirus constructs. One group received Ad-CMV-p53 and another group received a control adenovirus construct, Ad-CMV-βgal. To study the treatment response to Ad-CMV-p53, the mice were divided into groups and received various treatment schedules of 1 × 10⁸pfu of Ad-CMV-p53.Results.The mice tolerated Ad-CMV-p53 without adverse effects at doses of 1 × 10⁸pfu. The response to Ad-CMV-p53 showed significant survival duration in each dose regimen, with a survival time greater than that of untreated animals (P= 0.0173). However, no statistically significant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-βgal-treated mice.Conclusions.These studies show that at the adenovirus dose and administration regimen used, there is effective but not specific 2774 tumor growth inhibitionin vivo.Efficient introduction of biologically active genes into tumor cells would greatly facilitate cancer therapy. Thus, although promising, these results caution that much effort will be required to realize the potential for clinical application of adenovirus-based ovarian cancer gene therapy.     

Temporal ranges of central nervous processing: clinical evidence

 The organization of the time frames for perceiving, generating, and updating information in the CNS has as of yet received little attention despite its elementary character for human behavior. We investigated temporal epochs in perceiving, acting, and updating in patients with anterior and posterior lesions of the left and right hemisphere, in patients with lesions in the left hemisphere without aphasia, and in healthy controls. Three temporal ranges, 30, 300, and 3000 ms, were assessed with different psychophysical paradigms. Prolongation of the temporal perception of order (30 ms) was most pronounced with left posterior lesions, of repetitive action (300 ms) with left anterior lesions, and updating (3000 ms) with left and right anterior lesions. Temporal deficits are group as well as parameter specific. Our results support the notion of coordinated coexistence of different temporal mechanisms.     

Lines of Murine Oligodendroglial Precursor Cells Immortalized by an Activated neu Tyrosine Kinase Show Distinct Degrees of Interaction with Axons In Vitro and In Vivo

Replication-defective retroviruses expressing the t- neu oncogene, or a hybrid protein with the neu tyrosine kinase linked to the external region of the human epidermal growth factor receptor ( egfr-neu ), were used to establish lines of murine oligodendroglial precursor cells. Differentiation of the t- neu lines into myelin-associated glycoprotein (MAG)-positive oligodendrocytes was induced by dibutyryl cAMP, and the egfr-neu line showed limited differentiation in vitro upon withdrawal of epidermal growth factor. Cerebellar granule cell neurons expressed mitogens for the cell lines. Upon transplantation into demyelinated lesions, t- neu line cells engaged with the demyelinated axons whereas the egfr-neu line cells differentiated further and ensheathed the axons. These cell lines thus interact with neurons in vitro and in vivo and can be used as tools to define the molecules involved in different stages of neuron-glia interaction.     

Malignant peripheral neuroectodermal tumors in urology

Summary During the past few years, a new tumor type has emerged in the pediatric and adolescent group of cancer patients, which has been designated malignant peripheral neuroectodermal tumor (MPNT). This tumor has some clinical and pathological signs in common with either soft-tissue sarcomas or classic Ewing's sarcoma, but is defined as a distinct entity because of its immunohistological characteristics. The tumor expresses neuronal markers, but the pattern varies: chromogranin, neuron-specific enolase, synaptophysin, protein S-100 and others. MPNT can occur in the urogenital region. The differential diagnosis on clinical grounds must include Ewing's and soft tissue sarcomas, and also Wilms' tumor and its variants. MPNT are often wide spread in the urogenital region when first diagnosed. Response to radiotherapy and combination chemotherapy is limited. Radical surgery is not always possible. The prognosis therefore remains rather poor at this time. A selection of MPNT patients is presented to demonstrate the various problems associated with this diagnosis. MRI and CT of all patients showed large tumors with direct infiltration of the surrounding structures. MRI is the best imaging modality for diagnosis and therapy monitoring in these tumors, because of its high soft-tissue contrast.     

Andrology: Transrectal electroejaculation in combination with in-vitro fertilization: an effective treatment of anejaculatory infertility after testicular cancer

Treatment of non-seminomatous testicular cancer often leadsto infertility due to anejaculation/retrograde ejaculation andpoor sperm quality. In these men spermatozoa may be obtainedby transrectal electroejaculation (TE), but the optimal strategyfor assisted procreation in these couples is not known. Ouraim was to examine whether TE and conventional in-vitro fertilization(IVF) would be successful. A total of 10 couples, with long-standinginfertility due to anejaculation or retrograde ejaculation aftertreatment for testicular cancer 5–14 years earlier, werereferred to our unit. All men underwent diagnostic TE undergeneral anaesthesia. Spermatozoa were recovered in nine cases.The antegrade fraction was prepared and used for IVF. Spermquality was variable and conventional IVF was considered impossiblein three cases. Altogether six IVF treatment cycles in six couplesresulted in five pregnancies, of which four resulted in a deliveryand one resulted in a spontaneous abortion. One additional pregnancyis ongoing after transfer of cryopreserved embryos. The fertilizationrate was 54% (33/61) and the cleavage rate was 97% (32/33).No complications relating to the procedure have been encountered.     

Comparison of three immunoassays for diagnosing sensitization to latex in children with spina bifida

As natural rubber latex (latex) has become more widespread in our environment, physicians have become increasingly aware of the problem of possible allergic reactions. Many fatal and near-fatal incidents have been reported (mainly during surgery) (1—3) and data has been published on groups frequently exposed to latex, such as patients with spina bifida (4—9), healthcare professionals (10—12) and occupationally exposed persons (13). The incidence of latex allergy in children seems to be increasing (14). Tests are therefore needed which can reliably detect sensitization to latex. Our aim was to compare the diagnostic accuracy of three commercial immunoassays for measuring specific IgE in serum to latex.     

Nonsteroidal cardiotonics. 3. New 4,5-dihydro-6-(1H-indol-5-yl)pyridazin-3(2H)-ones and related compounds with positive inotropic activities

A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.