Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice.

Background: Because pancreatic adenocarcinoma is poorly responsive to chemotherapy and radiation therapy, novel treatments such as antiangiogenic gene therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma.

Methods: In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment.

Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice.

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency that is caused by mutations in the recently identified WASP gene. WASP plays an important role in T-cell receptor-mediated signaling to the actin cytoskeleton. In these studies we assessed the feasibility of using retroviral gene transfer into WASP-deficient hematopoietic stem cells (HSCs) to rescue the T-cell signaling defect that is characteristic of WAS.

Genetic interventions for vein bypass graft disease: a review.

The failure of vein bypass grafting in the coronary or lower extremity circulation is a common clinical occurrence that incurs significant morbidity, mortality, and cost. Vein grafts are uniquely amenable to intraoperative genetic modification because of the ability to manipulate the tissue ex vivo with controlled conditions. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated.

"Stemness": transcriptional profiling of embryonic and adult stem cells.

The transcriptional profiles of mouse embryonic, neural, and hematopoietic stem cells were compared to define a genetic program for stem cells. A total of 216 genes are enriched in all three types of stem cells, and several of these genes are clustered in the genome. When compared to differentiated cell types, stem cells express a significantly higher number of genes (represented by expressed sequence tags) whose functions are unknown.

Advanced renal cell carcinoma treated with granulocyte-macrophage colony-stimulating factor gene therapy: a clinical course of the first Japanese experience.

A phase I study of granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor vaccine for patients with metastatic renal cell carcinoma (RCC) was initiated in 1998, as the first cancer gene therapy in Japan. The study is still ongoing, but the first patient is presented here as a case report. The patient was a 60-year-old man with Stage IV CRC with multiple lung metastases.

Use of CD9 expression to enrich for porcine hematopoietic progenitors.

Objective: The aim of this study was to develop novel markers for enrichment of hematopoietic progenitors from bone marrow of swine.

Materials And Methods: We previously showed that pig bone marrow contains a "side population" (SP) of Hoechst dye-effluxing cells that resembles the hematopoietic stem cell (HSC)-containing murine SP and therefore represents a putative pig stem cell population. We screened a panel of monoclonal antibodies for those that allowed positive or negative enrichment of porcine SP cells and tested one of these for enrichment of hematopoietic progenitors in short-term and long-term in vitro assays.

Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors.

The demonstration that angiogenesis is required for the growth of solid tumors has fueled an intense interest in the development of new therapeutic strategies that target the tumor vasculature. Here we report the development of an immune-based antiangiogenic strategy that is based on the generation of T lymphocytes that possess a killing specificity for cells expressing vascular endothelial growth factor receptors (VEGFRs). To target VEGFR-expressing cells, recombinant retroviral vectors were generated that encoded a chimeric T cell receptor comprised of VEGF sequences linked to intracellular signaling sequences derived from the zeta chain of the T cell receptor.

Heat stress results in incomplete C-to-U editing of maize chloroplast mRNAs and correlates with changes in chloroplast transcription rate.

The editing status rps14 and rpl20 mRNAs decreased rapidly from nearly 100% edited to about 30% edited when maize plants were shifted from 20 degrees C to 37 degrees C. A decrease in the extent of editing was easily detected within 2 h and decreased to a steady-state level of about 40% C-to-U conversion at 37 degrees C. In contrast, the editing status of these chloroplast mRNAs increased relatively slowly after plants were shifted from 37 degrees C to 20 degrees C.

N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility.

The Wiskott-Aldrich syndrome protein (WASP) family of molecules integrates upstream signalling events with changes in the actin cytoskeleton. N-WASP has been implicated both in the formation of cell-surface projections (filopodia) required for cell movement and in the actin-based motility of intracellular pathogens. To examine N-WASP function we have used homologous recombination to inactivate the gene encoding murine N-WASP.

The Psychogeriatric Assessment Scales (PAS): psychometric properties in French and German speaking populations.

Objectives: To investigate the structure and measurement properties of the Psychogeriatric Assessment Scales (PAS) in a community sample, to study the performance of French and German translations of the PAS, and to determine the power of PAS scales to discriminate dementia and depression diagnosed to DSM-IV criteria. Design and measures The measures were gathered as part of a large community survey. Responses to PAS items were obtained in the course of the administration of the 'Canberra Interview for the Elderly'.

Accuracy of diagnoses of HIV-related oral lesions by medical clinicians. Findings from the Women's Interagency HIV Study.

Objective: To determine if medical clinicians are as accurate as dental clinicians in recognizing diagnostic characteristics of HIV-related oral lesions.

Methods: In 355 HIV-infected participants at five Women's Interagency HIV Study sites, we paired oral examinations conducted within 7 days of each other by dental and medical clinicians. We used the former as a gold standard against which to evaluate the accuracy of the latter.

In vivo 5-HT2A receptor blockade by quetiapine: an R91150 single photon emission tomography study.

Background: Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms.

Method: 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning.

Memory Clinics in Switzerland. Collaborative Group of Swiss Memory Clinics.

Currently, eleven Memory Clinics (MC) in Switzerland offer their services to patients, caregivers and family doctors. Their primary goal is the early diagnosis and management of dementia in elderly outpatients. Special emphasis is put on the detection of reversible causes of dementing disorders.

Glucose-induced toxicity in insulin-producing pituitary cells that coexpress GLUT2 and glucokinase. Implications for metabolic engineering.

We have shown that intermediate lobe (IL) pituitary cells can be engineered to produce sufficient amounts of insulin (ins) to cure diabetes in nonobese diabetic mice but, unlike transplanted islets, ILins cells evade immune attack. To confer glucose-sensing capabilities into these cells, they were further modified with recombinant adenoviruses to express high levels of GLUT2 and the beta-cell isoform of glucokinase (GK). Although expression of GLUT2 alone had negligible effects on glucose usage and lactate production, expression of GK alone resulted in approximately 2-fold increase in glycolytic flux within the physiological (3-20 mm) glucose range.

Economic considerations of Alzheimer's disease and related disorders.

Economic analyses of geriatric syndromes are seldom performed. However, demographic and epidemiological imperatives have led to significant interest in the evaluation of AD-related costs. Over 300 papers devoted to economic considerations of Alzheimer's disease have been published in peer-reviewed journals, within the last five years.

HIV risk assessment: building on dentistry's history of promoting health.

Dentists have demonstrated a willingness to look beyond the mouth and consider the patient's overall presentation in a number of health-related areas. The HIV pandemic is another opportunity to involve the dentist in overall health issues through identification of those individuals at risk for acquiring HIV. This risk assessment activity can be facilitated through the use of a structured risk assessment algorithm that is presented in detail.

Rural dentistry: opportunities for the next millennium in fixed and mobile practices.

Many dentists assume that practice in California's rural counties would be hindered by lower income potential, professional isolation, and lack of specialists for assistance. The evidence suggests otherwise, however. Income data show that the population of many rural counties can well afford dental care.

Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer.

Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.

Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.

Collagen XVIII (c18) is a triple helical endothelial/epithelial basement membrane protein whose noncollagenous (NC)1 region trimerizes a COOH-terminal endostatin (ES) domain conserved in vertebrates, Caenorhabditis elegans and Drosophila. Here, the c18 NC1 domain functioned as a motility-inducing factor regulating the extracellular matrix (ECM)-dependent morphogenesis of endothelial and other cell types. This motogenic activity required ES domain oligomerization, was dependent on rac, cdc42, and mitogen-activated protein kinase, and exhibited functional distinction from the archetypal motogenic scatter factors hepatocyte growth factor and macrophage stimulatory protein.

Cross-sectional comparison of dental students' knowledge and attitudes before geriatric training: 1984-1999.

The existence of negative attitudes toward aging and a lack of factual information has been voiced in the dental and other health professions. With increasing numbers of elderly in society, intergenerational social contact is more likely to occur and has the potential to reduce negative attitudes and increase knowledge about aging. The purposes of this study were to determine if the level of intergenerational social contact of dental students in one dental school had changed over the last fifteen years and whether any such changes were related to shifts in students' baseline knowledge about aging and attitudes toward elderly patients.

Direct delivery of leptin to the hypothalamus using recombinant adeno-associated virus vectors results in increased therapeutic efficacy.

The hormone leptin has been shown to be an afferent signal in a negative-feedback loop regulating body weight, and consequently, the administration of the gene product for the treatment of obesity has recently attracted considerable attention. Leptin is produced by adipocytes in response to increased trigyceride storage, and appears to affect body weight primarily through target cells in the hypothalamus. Although plasma levels of leptin correlate positively with adipose tissue mass in normal humans and animals, recent studies have shown that obese humans and animals appear to be relatively resistant to the increased plasma levels of leptin.

Plasmid DNA encapsulation and release from solvent diffusion nanospheres.

The first step toward hydrophobic polymer-based nanospheres for gene delivery is to encapsulate and release plasmid DNA. However, encapsulating large hydrophilic molecules in very small nanospheres has been difficult, and only a few examples exist in the literature. For example, maximizing protein and peptide as well as small molecule encapsulation requires adjustments in pH or addition of excipients to charge neutralize, and make less hydrophilic, the compound to be encapsulated.

Targeting avian leukosis virus subgroup A vectors by using a TVA-VEGF bridge protein.

Previously, we have demonstrated that bridge proteins comprised of avian leukosis virus (ALV) receptors fused to epidermal growth factor (EGF) can be used to selectively target retroviral vectors with ALV envelope proteins to cells expressing EGF receptors. To determine whether another type of ligand incorporated into an ALV receptor-containing bridge protein can also function to target retroviral infection, the TVA-VEGF110 bridge protein was generated. TVA-VEGF110 consists of the extracellular domain of the TVA receptor for ALV subgroup A (ALV-A), fused via a proline-rich linker peptide to a 110-amino-acid form of vascular endothelial growth factor (VEGF).