RESUMO
Targeted mutagenesis in mice, a powerful tool for the analysis of gene function and human disease, makes extensive use of 129 mouse substrains. Although all are named 129, we document that outcrossing of these substrains, both deliberate and accidental, has lead to extensive genetic variability among substrains and embryonic stem cells derived from them. This clearer understanding of 129 substrain variability allows consideration of its negative impact on targeting technology, including: homologous recombination frequencies, preparation of inbred animals, and availability of appropriate controls. Based on these considerations we suggest a number of recommendations for future experimental design.
Assuntos
Cruzamentos Genéticos , Variação Genética , Camundongos Endogâmicos/genética , Mutagênese , Animais , Biomarcadores , Linhagem Celular , Embrião de Mamíferos/citologia , Feminino , Rejeição de Enxerto/genética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Polimorfismo Genético , Proteínas/genética , Transplante de Pele , Células-Tronco/citologiaRESUMO
BACKGROUND: Docetaxel induces an anti-tumor response in men with advanced prostate cancer (PCa); however, the side effects associated with docetaxel treatment can be severe, resulting in discontinuation of therapy. Thus, identification of an effective adjuvant therapy to allow lower doses of docetaxel is needed. Advanced PCa is typically accompanied by skeletal metastasis. Receptor activator of NFkB ligand (RANKL) is a key pro-osteoclastic factor. Targeting RANKL decreases establishment and progression of PCa growth in bone in murine models. METHODS: The efficacy of inhibiting RANKL, using a recombinant soluble RANK extracellular domain fused with the immunoglobulin Fc domain (RANK-Fc), was tested as an adjuvant therapy with docetaxel for PCa bone metastasis in a murine intra-tibial model. RESULT: The combination of RANK-Fc and docetaxel reduced tumor burden in bone greater than either treatment alone. CONCLUSION: The combination of docetaxel with a RANKL-inhibiting agent merits further investigation for treatment of advance PCa.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Próstata/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Taxoides/uso terapêutico , Adjuvantes Farmacêuticos/uso terapêutico , Animais , Neoplasias Ósseas/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Quimioterapia Adjuvante , Modelos Animais de Doenças , Docetaxel , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos SCID , Neoplasias da Próstata/patologia , Radiografia , Taxoides/administração & dosagemRESUMO
McManus advanced a genetic hypothesis to explain differences of lateralization between HI and LO lines of mice selectively bred for degree of handedness. It states that lateralization is a function of heterozygosity. Specifically it predicts that (a) the HI line will be more heterozygous than the LO line and (b) populations with a greater average heterozygosity (AH) will be more strongly lateralized. Both genetic and behavioral predictions were tested here. Results using coat color and biochemical variants show that AH in the HI line is somewhat less (not greater) than that in the LO line. The handedness of HET control mice and HI by LO reciprocal hybrids, where AH is greater than that of the HI line, exhibits lessened (not greater) lateralization. Results reject the heterozygosity hypothesis. A model for the inheritance of human handedness that accounts for difficulty in detecting heritable differences in degree of asymmetry is presented.
Assuntos
Lateralidade Funcional/genética , Heterozigoto , Fenótipo , Seleção Genética , Animais , Mapeamento Cromossômico , Feminino , Cor de Cabelo/genética , Masculino , Camundongos , Camundongos Endogâmicos/genética , Desempenho PsicomotorRESUMO
To search for host genes for resistance/susceptibility to cancer metastasis, mutation analysis was employed. Ten putative mutants of resistance to lymphoma EL4 and four putative mutants of resistance to sarcoma MCA/77-23 of C57BL/6J (B6) mice were produced. These mutants were designated S (for "survivor") mutants; they do not reject parental strain B6 skin grafts. S-mutants resist moderate tumor cell doses: TD50 values in them were increased by a factor of 12 to 600. Genetic linkage tests showed that five S-mutants were linked to mouse major histocompatibility complex (H-2) and five other S-mutants were not linked to this locus. A group of H-2-linked S-mutants resisting EL4 and a mutant, S-87/2, resisting MCA/77-23 were tested for resistance to spontaneous metastases of the same two tumors, EL4 and MCA/77-23. Two of the mutants, S-31 (lymphoma-resisting) and S-87/2 (sarcoma-resisting), were shown to carry mutations of mouse gene(s) for resistance to tumor metastases. In both of these mutants resistance to the original tumor transplant coexisted with highly increased susceptibility to metastasis. These mutants are a new tool to study genes for resistance to cancer metastasis and of mechanism of resistance controlled by each individual gene.