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Biomedical subjects

W F Anderson

Publications and source records attributed to W F Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Established breast cancer risk factors by clinically important tumour characteristics.

Breast cancer is a morphologically and clinically heterogeneous disease; however, it is less clear how risk factors relate to tumour features. We evaluated risk factors by tumour characteristics (histopathologic type, grade, size, and nodal status) in a population-based case-control of 2386 breast cancers and 2502 controls in Poland. Use of a novel extension of the polytomous logistic regression permitted simultaneous modelling of multiple tumour characteristics. Late age at first full-term birth was associated with increased risk of large (> 2 cm) tumours (odds ratios (95% confidence intervals) 1.19 (1.07-1.33) for a 5-year increase in age), but not smaller tumours (P for heterogeneity adjusting for other tumour features (Phet) = 0.007). On the other hand, multiparity was associated with reduced risk for small tumours (0.76 (0.68-0.86) per additional birth; Phet = 0.004). Consideration of all tumour characteristics simultaneously revealed that current or recent use of combined hormone replacement therapy was associated with risk of small (2.29 (1.66-3.15)) and grade 1 (3.36 (2.22-5.08)) tumours (Phet = 0.05 for size and 0.0008 for grade 1 vs 3), rather than specific histopathologic types (Phet = 0.63 for ductal vs lobular). Finally, elevated body mass index was associated with larger tumour size among both pre- and postmenopausal women (Phet = 0.05 and 0.0001, respectively). None of these relationships were explained by hormone receptor status of the tumours. In conclusion, these data support distinctive risk factor relationships by tumour characteristics of prognostic relevance. These findings might be useful in developing targeted prevention efforts.

Breast Neoplasms↗
PubMed2001

Frequency distributions of breast cancer characteristics classified by estrogen receptor and progesterone receptor status for eight racial/ethnic groups.

BACKGROUND: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registries have been collecting data regarding estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer since 1990. The current study reports on some of these data for eight racial/ethnic groups. METHODS: Stratified by ER and PR status, the frequency distributions of 112,588 breast cancer cases diagnosed between 1992--1997 in 11 SEER cancer registries were examined by age at diagnosis, stage at diagnosis, histologic grade, and tumor type for white, black, Hispanic, Japanese, Chinese, Filipino, Native Hawaiian, and American Indian and Alaska Native (AI/AN) females. RESULTS: For each racial/ethnic group, the percentage of ER positive (+)/PR+ was > ER-PR- > ER+PR- > ER-PR+ tumors. For the two major ER/PR groups, the ER+PR+ tumors were different from the ER-PR- tumors in several ways. For white females, there were differences in the age distributions, stage at diagnosis, and histologic grade. For black females, the differences involved the age distributions and tumor grades. For Hispanic and Japanese females, there were differences with regard to the age distributions and tumor grades. For Filipino, Chinese, and AI/AN females, the tumor stages and grades differed. For Native Hawaiians, the histologic tumor grades were different. CONCLUSIONS: For each racial/ethnic group, the ER/PR status appeared to divide breast cancer patients into two or more subgroups with unique tumor characteristics. In general, ER status appeared to have the greatest impact on delineating these subgroups, whereas in some cases, PR status was able to modify the subgroups further. It is hoped that reporting these tumor characteristics by ER/PR status for each racial/ethnic group will spur more investigation into the significance of ER/PR status in each racial/ethnic group.

Adolescent↗
PubMed2001

Lesion-targeted injectable vectors for vascular restenosis.

Pathologic lesions caused by catheter-based revascularization procedures for occlusive artery disease include disruption of the endothelium, exposure of extracellular matrix (ECM) proteins, and proliferation of vascular smooth muscle cells, which lead to neointima formation and restenosis. We have developed matrix-collagen-targeted retroviral vectors that are able to accumulate at sites of vascular injury (Hall et al., Hum. Gene Ther. 1997;8:2183-2192; Hall et al., Hum. Gene Ther. 2000;11:983-993). The primary tissue-targeting motif, adapted from the physiological surveillance sequence found in von Willebrand factor, served to localize and concentrate the vector within vascular lesions. In the present study, we evaluated the efficiency of this vector-targeting system in rats with nonligated balloon-injured carotid arteries. Both intraarterial (by retrograde femoral artery catheterization) and intravenous (via femoral vein) injection of a matrix-targeted vector enhanced transduction of neointimal cells ( approximately 20%) at severely denuded areas when compared with the nontargeted vector (<1%). Further, intraarterial instillation of a matrix-targeted, but not a nontargeted, vector bearing an antisense cyclin G1 construct inhibited neointima lesion formation in the injured carotid arteries. Taken together, these data indicate that strategic targeting of retroviral vectors to vascular lesions would have therapeutic potential in the management of vascular restenosis and many other disorders of uncontrolled proliferation where endothelial disruption, ECM remodeling, and collagen deposition form the nexus for preferential vector localization and concentration in vivo.

3T3 Cells↗
PubMed2001

Induction of stable prenatal tolerance to beta-galactosidase by in utero gene transfer into preimmune sheep fetuses.

The successful transduction of hematopoietic stem cells and long-term (28 months) transgene expression within the hematopoietic system following the direct injection of high-titer retroviral vectors into preimmune fetal sheep was previously demonstrated. The present studies extended these analyses for 40 months postinjection and evaluated whether the longevity of transgene expression in this model system was the result of induction of prenatal tolerance to the transgene product. The intraperitoneal injection of retroviral vectors into preimmune sheep fetuses transduces thymic epithelial cells thought to present antigen and thus define self during immune system development. To directly demonstrate induction of tolerance, postnatal sheep were boosted with purified beta-galactosidase and showed that the peripheral blood lymphocytes from in utero-transduced sheep exhibited significantly lower stimulation indices to transduced autologous cells than did control animals and that the in utero-transduced sheep had a reduced ability to mount an antibody response to the vector-encoded beta-galactosidase protein compared with control sheep. Collectively, our results provide evidence that the direct injection of retroviral vectors into preimmune sheep fetuses induces cellular and humoral tolerance to the vector/transgene products and provide an explanation for the duration and stability of transgene expression seen in this model. These results also suggest that even relatively low levels of gene transfer in utero may render the recipient tolerant to the exogenous gene and thus potentially permit the successful postnatal treatment of the recipient. (Blood. 2001;97:3417-3423)

Animals↗
PubMed2001

A uniquely stable replication-competent retrovirus vector achieves efficient gene delivery in vitro and in solid tumors.

A major obstacle in cancer gene therapy is the limited efficiency of in vivo gene transfer by replication-defective retrovirus vectors in current use. One strategy for circumventing this difficulty would be to use vectors capable of replication within tumor tissues. We have developed a replication-competent retrovirus (RCR) vector derived from murine leukemia virus (MuLV). This vector utilizes a unique design strategy in which an internal ribosome entry site-transgene cassette is positioned between the env gene and the 3' long terminal repeat (LTR). The ability of this vector to replicate and transmit a transgene was examined in culture and in a solid tumor model in vivo. The RCR vector exhibited replication kinetics similar to those of wildtype MuLV and mediated efficient delivery of the transgene throughout an entire population of cells in culture after an initial inoculation with 1 plaque-forming unit (PFU) of vector per 2000 cells. After injection of 6 x 10(3) PFU of vector into established subcutaneous tumors, highly efficient spread of the transgene was observed over a period of 7 weeks, in some cases resulting in spread of the transgene throughout the entire tumor. MuLV-based RCR vectors show significant advantages over standard replication-defective vectors in efficiency of gene delivery both in culture and in vivo. This represents the first example of the use of an RCR vector in an adult mammalian host, and their first application to transduction of solid tumors.

3T3 Cells↗
PubMed2001

Receptor-specific targeting mediated by the coexpression of a targeted murine leukemia virus envelope protein and a binding-defective influenza hemagglutinin protein.

The entry of retroviral vectors into cells requires two events: binding to a cell surface receptor and the subsequent fusion of viral and cellular membranes. The host range of a vector is therefore determined largely by the receptor specificity of the fusion protein contained in the outer viral envelope. Previous attempts to generate targeted retroviral vectors have included the addition of targeting ligands to the murine leukemia virus envelope protein (MuLV Env). Although such proteins frequently display modified cell-binding characteristics, the interaction with the targeted receptors fails to trigger virus-cell fusion. Here, we report the use of a binding-defective but fusion-competent hemagglutinin (HA) protein to complement the fusion defect in a chimeric MuLV Env targeted to the Flt-3 receptor. Retroviral vectors containing both proteins showed enhanced transduction of cells expressing Flt-3, which was abrogated by preincubating the target cells with soluble Flt-3 ligand. Furthermore, the fusion function of HA was absolutely required. These data demonstrate that it is possible to separate the binding and fusion events of retroviral entry, using two separate proteins, and suggest that varying the binding protein component in this scheme may allow a general strategy for targeting retroviral vectors.

3T3 Cells↗
PubMed2001

Systemic administration of a matrix-targeted retroviral vector is efficacious for cancer gene therapy in mice.

Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demonstrated that intravenous infusion of a matrix (i.e., collagen)-targeted retroviral vector provided efficacious gene delivery of a cytocidal mutant cyclin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mice. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted vector bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without associated toxicity. Kaplan-Meier survival studies were conducted in mice treated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-targeted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value for comparing all three groups simultaneously was 0.003, with a trend that was significant to a level of 0.004, indicating that the probability of long-term control of tumor growth was significantly greater with the matrix-targeted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS placebo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficiency, and (3) enhanced therapeutic gene delivery and long-term efficacy without eliciting appreciable toxicity.

Animals↗
PubMed2001

Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database.

PURPOSE: Hormone receptor expression (presence-positive or absence-negative) may reflect different stages of one disease or different breast cancer types. Determining whether hormone receptor expression represents one or more breast cancer phenotypes would have important paradigmatic and practical implications. METHODS: Breast cancer records were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. The study included 19,541 non-Hispanic white women with node-negative breast cancer. Standard tumor cell characteristics and breast cancer-specific survival were analyzed by independent estrogen receptor (ER+ and ER-), independent progesterone receptor (PR+ and PR-), and joint ERPR expression (ER+PR+, ER+PR-, ER-PR+, and ER-PR-). RESULTS: Age frequency density plots by hormone receptor expression showed two overlapping breast cancer populations with early-onset and/or late-onset etiologies. Independent ER+ and PR+ phenotype were associated with smaller tumor sizes, better grade, and better cancer-specific survival than ER- and PR- breast cancer types. Joint ERPR phenotype exhibited biologic gradients for tumor size, grade, and cancer-specific survival, which ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR-. CONCLUSION: Variations of standard tumor cell characteristics and breast cancer-specific survival by hormone receptor expression in white patients with node-negative breast cancer suggested two breast cancer phenotypes with overlapping etiologies and distinct clinical features.

Adult↗
PubMed2001

Secondary chemoprevention of upper aerodigestive tract tumors.

Patients with successfully treated upper aerodigestive tract (UADT) tumors commonly develop second primary tumors (SPTs). These tumors occur more often than chance would predict, arise in both the upper or lower aerodigestive tracts, are frequently preceded by leukoplakia, and are a major cause of treatment-related failure. Measures to control SPTs include primary prevention with tobacco and alcohol abstinence, surveillance endoscopy, and secondary chemoprevention. Chemoprevention is the administration of natural or synthetic substances to suppress or reverse the malignant process. Secondary chemoprevention of the UADT is the suppression or reversal of leukoplakia and/or SPTs. Classic antioxidant micronutrients such as retinoids, carotenoids, and certain other agents have been effective in nonrandomized and randomized clinical trials, but treatment is uncertain and recurrences common. These facts, coupled with recent harmful effects of beta-carotene in two clinical trials, stress the need for additional basic science, translational, and clinical research. Chemoprevention is a promising new technology, but is not currently standard therapy for the secondary prevention of UADT tumors.

Antioxidants↗
PubMed2001

Infectious entry by amphotropic as well as ecotropic murine leukemia viruses occurs through an endocytic pathway.

Infectious entry of enveloped viruses is thought to proceed by one of two mechanisms. pH-dependent viruses enter the cells by receptor-mediated endocytosis and are inhibited by transient treatment with agents that prevent acidification of vesicles in the endocytic pathway, while pH-independent viruses are not inhibited by such agents and are thought to enter the cell by direct fusion with the plasma membrane. Nearly all retroviruses, including amphotropic murine leukemia virus (MuLV) and human immunodeficiency virus type 1, are classified as pH independent. However, ecotropic MuLV is considered to be a pH-dependent virus. We have examined the infectious entry of ecotropic and amphotropic MuLVs and found that they were equally inhibited by NH4Cl and bafilomycin A. These agents inhibited both viruses only partially over the course of the experiments. Agents that block the acidification of endocytic vesicles also arrest vesicular trafficking. Thus, partial inhibition of the MuLVs could be the result of virus inactivation during arrest in this pathway. In support of this contention, we found that that the loss of infectivity of the MuLVs during treatment of target cells with the drugs closely corresponded to the loss of activity due to spontaneous inactivation at 37 degrees C in the same period of time. Furthermore, the drugs had no effect on the efficiency of infection under conditions in which the duration of infection was held to a very short period to minimize the effects of spontaneous inactivation. These results indicate that the infectious processes of both ecotropic and amphotropic MuLVs were arrested rather than aborted by transient treatment of the cells with the drugs. We also found that infectious viruses were efficiently internalized during treatment. This indicated that the arrest occurred in an intracellular compartment and that the infectious process of both the amphotropic and ecotropic MuLVs very likely involved endocytosis. An important aspect of this study pertains to the interpretation of experiments in which agents that block endocytic acidification inhibit infectivity. As we have found with the MuLVs, inhibition of infectivity may be secondary to the block of endocytic acidification. While this strongly suggests the involvement of an endocytic pathway, it does not necessarily indicate a requirement for an acidic compartment during the infectious process. Likewise, a lack of inhibition during transient treatment with the drugs would not preclude an endocytic pathway for viruses that are stable during the course of the treatment.

3T3 Cells↗
PubMed2001

Quantitation of retroviral-mediated transfer using luciferase in living and lysed cells.

We have developed a murine retroviral vector containing an improved luciferase gene for the study of retroviral gene transfer and expression in living or lysed cells. We used a cytosolic form of luciferase gene (luc+) with transcriptional enhancements that yielded greater expression levels. The luc+ gene was subcloned into the retroviral plasmids pDON-AI, in which almost the entire U3 region has been replaced with the heterologous human cytomegalovirus immediate-early promoter A stable ecotropic and amphotropic retrovirus-producing cell line was generated with a titer 1 x 10(6) cfu/mL. NIH/3T3(tk-) cells transduced with ecotropic luciferase retrovirus demonstrated a high level of luminescence on the third day. Lysed NIH/3T3(tk-) cells demonstrated a 10-fold increase in activity as compared to living cultures. The creation of a new retroviral system allowed a substantial decrease to 5 days from the 10-14 days previously needed to evaluate viral transfer using the standard neomycin method. Our assay also provides a quantitative assessment in contrast to the beta-galactosidase detection method, which also takes 5-6 days but lacks quantitative evaluation. Thus, the expression of an integrated luc+ gene in eukaryotic cells provides a powerful tool for the study of retroviral gene transfer and will greatly facilitate functional studies in both living and lysed cells.

3T3 Cells↗
PubMed2001

Retroviral vectors bearing IgG-binding motifs for antibody-mediated targeting of vascular endothelial growth factor receptors.

Targeting retroviral vectors to tumor vasculature is an important goal of cancer gene therapy. In this study, we report a novel targeting approach wherein IgG-binding peptides were inserted into the Moloney murine leukemia virus (MuLV) envelope (env) protein. The modifications on the viral env included replacement of the entire receptor binding region of the viral env with protein A (or ZZ) domains. The truncated env incorporating IgG-binding motifs (known as proteins) provided the targeting function, while the co-expressed wild-type (WT) env protein enabled viral fusion and cell entry. An anti-human VEGF receptor (Flk-1/KDR) antibody served as a molecular bridge, directing the retroviral vector to the endothelial cell. Hence, the IgG-targeted vectors bound to the Flk-1/KDR antibody which in turn bound to VEGF receptors on Kaposi sarcoma, KSY1, endothelial cells. The net effect was increased viral fusion and infectivity of IgG-bound retroviral vectors when compared to non-targeted vectors bearing WT env alone. These data provide the proof of concept that IgG-binding vector/VEGF receptor antibody complexes may be used to enhance retroviral gene delivery to activated endothelial cells.

Amino Acid Sequence↗
PubMed2001

Recent advances in retrovirus vector-mediated gene therapy: teaching an old vector new tricks.

Oncoretrovirus-based vectors have been shown to be a safe and reliable vector system that can achieve permanent integration of delivered transgenes. Successful application of these vectors for gene therapy has proven difficult due to their relatively low transduction efficiency; however, cumulative improvements in methodology have recently yielded promising clinical results. Furthermore, significant improvements in basic retrovirus vector technology now promise to revitalize the field. This review focuses on these important recent developments in the field of retrovirus-mediated gene transfer technology and its application to human diseases.

Animals↗
PubMed2000

Murine hematopoietic stem cell characterization and its regulation in BM transplantation.

Using 5-color fluorescence-activated cell sorting, we isolated a subset of murine pluripotent hematopoietic stem cells (PHSC) with the phenotype Lin(-) Sca(+) kit(+) CD38(+) CD34(-) that appears to fulfill the criteria for most primitive PHSC. In the presence of whole bone marrow (BM) competitor cells, these cells produced reconstitution in lethally irradiated primary, secondary, and tertiary murine transplant recipients over the long term. However, these cells alone could not produce reconstitution in lethally irradiated recipients. Rapid proliferation of these cells after BM transplantation required the assistance of another BM cell subset, which has the phenotype Lin(-) Sca(+) kit(+) CD38(-) CD34(+).

ADP-ribosyl Cyclase↗
PubMed2000

Functional implications from crystal structures of the conserved Bacillus subtilis protein Maf with and without dUTP.

Three-dimensional structures of functionally uncharacterized proteins may furnish insight into their functions. The potential benefits of three-dimensional structural information regarding such proteins are particularly obvious when the corresponding genes are conserved during evolution, implying an important function, and no functional classification can be inferred from their sequences. The Bacillus subtilis Maf protein is representative of a family of proteins that has homologs in many of the completely sequenced genomes from archaea, prokaryotes, and eukaryotes, but whose function is unknown. As an aid in exploring function, we determined the crystal structure of this protein at a resolution of 1.85 A. The structure, in combination with multiple sequence alignment, reveals a putative active site. Phosphate ions present at this site and structural similarities between a portion of Maf and the anticodon-binding domains of several tRNA synthetases suggest that Maf may be a nucleic acid-binding protein. The crystal structure of a Maf-nucleoside triphosphate complex provides support for this hypothesis and hints at di- or oligonucleotides with either 5'- or 3'-terminal phosphate groups as ligands or substrates of Maf. A further clue comes from the observation that the structure of the Maf monomer bears similarity to that of the recently reported Methanococcus jannaschii Mj0226 protein. Just as for Maf, the structure of this predicted NTPase was determined as part of a structural genomics pilot project. The structural relation between Maf and Mj0226 was not apparent from sequence analysis approaches. These results emphasize the potential of structural genomics to reveal new unexpected connections between protein families previously considered unrelated.

Amino Acid Sequence↗