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Biomedical subjects

L Remington

Publications and source records attributed to L Remington.

15 recordsLinked to original sources
PubMed1994

p53 status and the efficacy of cancer therapy in vivo.

The therapeutic responsiveness of genetically defined tumors expressing or devoid of the p53 tumor suppressor gene was compared in immunocompromised mice. Tumors expressing the p53 gene contained a high proportion of apoptotic cells and typically regressed after treatment with gamma radiation or adriamycin. In contrast, p53-deficient tumors treated with the same regimens continued to enlarge and contained few apoptotic cells. Acquired mutations in p53 were associated with both treatment resistance and relapse in p53-expressing tumors. These results establish that defects in apoptosis, here caused by the inactivation of p53, can produce treatment-resistant tumors and suggest that p53 status may be an important determinant of tumor response to therapy.

Animals↗
PubMed1994

Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences.

Homozygosity for a mutation in the Rb tumor suppressor gene causes mid-gestation embryonic lethality in the mouse. Using a two-step targeting protocol, we have constructed Rb homozygous mutant mouse embryonic stem cells and used them to create chimeric animals partially composed of Rb-deficient cells. Analysis of these chimeras demonstrates widespread contribution of the mutant cells to adult tissues, including the retina and mature erythrocytes. Despite the presence of large numbers of Rb-deficient cells in most tissues of these mice, they are remarkably normal but do exhibit certain histological defects including cataracts, hyperplasia of the adrenal medulla, and enlarged cells in the cerebellum and the liver. Like animals heterozygous for the Rb mutation, the chimeras develop tumors of the intermediate lobe of the pituitary, and the rate of pituitary tumorigenesis is greatly accelerated.

Adrenal Glands↗
PubMed1994

p53-dependent apoptosis suppresses tumor growth and progression in vivo.

To determine the contribution of p53 loss to tumor progression, we have induced abnormal proliferation in the brain choroid plexus epithelium of transgenic mice using a SV40 T antigen fragment that perturbs pRB family function but does not affect p53 function. Tumors induced by this mutant develop slowly compared with those induced by wild-type T antigen. Suppressed tumor growth is directly attributable to p53 function, since rapid tumor development occurs when the T antigen fragment is expressed in p53-null mice. In p53-heterozygous mice, stochastic loss of the wild-type p53 allele results in the focal emergence of aggressive tumor nodules characteristic of tumor progression. In each case, aggressive tumor development in the absence of p53 function corresponds to a decrease in the level of apoptosis. These results provide in vivo evidence that p53-dependent apoptosis, occurring in response to oncogenic events, is a critical regulator of tumorigenesis.

Animals↗
PubMed1994

Tumor spectrum analysis in p53-mutant mice.

BACKGROUND: The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung and brain. Individuals who inherit one mutant allele of p53 are susceptible to a wide range of tumor types. The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of p53 in normal cells and tumorigenesis. RESULTS: In order to study the effects of p53 mutation in vivo, we have constructed a mouse strain carrying a germline disruption of the gene. This mutation removes approximately 40% of the coding capacity of p53 and completely eliminates synthesis of p53 protein. As observed previously for a different germline mutation of p53, animals homozygous for this p53 deletion mutation are viable but highly predisposed to malignancy. Heterozygous animals also have an increased cancer risk, although the distribution of tumor types in these animals differs from that in homozygous mutants. In most cases, tumorigenesis in heterozygous animals is accompanied by loss of the wild-type p53 allele. CONCLUSION: We reaffirm that p53 function is not required for normal mouse development and conclude that p53 status can strongly influence tumor latency and tissue distribution.

Alleles↗
PubMed1994

Cooperative tumorigenic effects of germline mutations in Rb and p53.

The tumour suppressor genes Rb and p53 are mutated in several types of human cancer, and many tumour types carry mutations in both genes. To study how these genes normally function, we and others have created mouse strains with Rb and p53 mutations. Here we describe the phenotypic effects of combined germline mutations in these two tumour suppressor genes. Mice mutant for both genes have reduced viability and exhibit novel pathology including pinealoblastomas, islet cell tumours, bronchial epithelial hyperplasia and retinal dysplasia. These data indicate that mutations in Rb and p53 can cooperate in the transformation of certain cell types in the mouse.

Adenoma, Islet Cell↗
PubMed1993

Cell proliferation, DNA repair, and p53 function are not required for programmed death of prostatic glandular cells induced by androgen ablation.

Androgen ablation induces programmed death of androgen-dependent prostatic glandular cells, resulting in fragmentation of their genomic DNA and the cells themselves into apoptotic bodies. Twenty percent of prostatic glandular cells undergo programmed death per day between day 2 and 5 after castration. During this same period, < 1% of prostatic glandular cells enter the S phase of the cell cycle, documenting that > 95% of these die in G0. During the programmed death of these G0 glandular cells, a futile DNA repair process is induced secondary to the DNA fragmentation. This futile DNA repair is not required, however, since inhibition of this process by > 90% with an appropriately timed hydroxy-urea dosing regimen had no effect upon the extent of the programmed death of these cells after castration. Likewise, p53 gene expression is not required since the same degree of cell death occurred in prostates and seminal vesicles after castration of wild-type and p53-deficient mice.

Animals↗
PubMed1991

Growth inhibition of Mycobacterium avium complex in human alveolar macrophages by the combination of recombinant macrophage colony-stimulating factor and interferon-gamma.

The reservoir of Mycobacterium avium complex (MAC) during human infection is the mononuclear phagocyte. In these studies, the ability of certain macrophage-active cytokines to affect MAC growth in human alveolar macrophages was evaluated. Neither recombinant interferon-gamma (2 x 10(2) to 10(3) U/well of 5 x 10(5) cells) nor recombinant macrophage colony-stimulating factor (20 to 50 ng/well), when tested alone, exhibited a consistent ability to induce macrophage targets to inhibit the growth of a clinical strain of MAC serovar 4. However, the combination of these cytokines (1 to 50 ng macrophage colony-stimulating factor + 10(3) U interferon per well) was remarkably effective in diminishing replication of MAC in all experiments. These cytokines were also able to induce alveolar macrophages to restrict MAC growth even though cells were obtained from several individuals with acquired immunodeficiency syndrome (AIDS) or from normal donors and infected in vitro with the human immunodeficiency virus type 1. The effect of this cytokine combination was not abrogated by 10(4) neutralizing U/ml of anti-tumor necrosis factor-alpha antibody. Rather, the combination of interferon-gamma and macrophage colony-stimulating factor appeared to activate intrinsic macrophage mechanisms for restricting MAC growth and deserves further study to determine the potential value of this cytokine combination in the treatment of human infection.

Cells, Cultured↗
PubMed1991

Five steps help administer successful contracts.

Healthcare trends and statistics indicate the growing number of managed care contracts will continue. For patient accounts managers, this means more challenges in managing and administering different kinds of contracts. Communication, management, and feedback will become essential tools for ensuring successful administration of managed care contracts.

Contract Services↗
PubMedDate not supplied

Sunburn and p53 in the onset of skin cancer.

Squamous cell carcinoma of the skin (SCC) can progress by stages: sun-damaged epidermis, with individual disordered keratinocytes; actinic keratosis (AK), spontaneously regressing keratinized patches having aberrant cell differentiation and proliferation; carcinoma in situ; SCC and metastasis. To understand how sunlight acts as a carcinogen, we determined the stage at which sunlight mutates the p53 tumour-suppressor gene and identified a function for p53 in skin. The p53 mutations induced by ultraviolet radiation and found in > 90% of human SCCs were present in AKs. Inactivating p53 in mouse skin reduced the appearance of sunburn cells, apoptotic keratinocytes generated by overexposure to ultraviolet. Skin thus appears to possess a p53-dependent 'guardian-of-the-tissue' response to DNA damage which aborts precancerous cells. If this response is reduced in a single cell by a prior p53 mutation, sunburn can select for clonal expansion of the p53-mutated cell into the AK. Sunlight can act twice: as tumour initiator and tumour promoter.

Animals↗