RESUMO
The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell lines were found to express significant levels of beta-PDGFR. Interestingly, none of the tested cell lines expressed alpha-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for beta-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of beta-PDGFR and tyrosine phosphorylation of PLC-gamma, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express beta-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked beta-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express beta-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, beta-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.
Assuntos
Neoplasias Ósseas/patologia , Proteínas de Neoplasias/fisiologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/fisiologia , Sarcoma de Ewing/patologia , Animais , Becaplermina , Neoplasias Ósseas/metabolismo , Divisão Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Classe Ib de Fosfatidilinositol 3-Quinase , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/metabolismo , Camundongos , Camundongos SCID , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Fosfolipase C gama , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-sis , Receptor beta de Fator de Crescimento Derivado de Plaquetas/biossíntese , Receptor beta de Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Recombinantes/farmacologia , Sarcoma de Ewing/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/metabolismo , Fosfolipases Tipo C/metabolismo , Tirfostinas/farmacologiaRESUMO
Case management is emerging in nursing as an effective and cost efficient model of care delivery for patients with complex nursing, medical, and psychosocial needs. The term "case management" first appeared in the social welfare literature in the early seventies and then later appeared in nursing literature (ANA, 1988). Nursing's concept of case management has been defined and interpreted to fit various health care settings. The purpose of this paper is to address a case management model and demonstrate through a case study how the case management model benefits the patient, the health care team, and the health care agency.
Assuntos
Modelos de Enfermagem , Oftalmologia/normas , Planejamento de Assistência ao Paciente/normas , Especialidades de Enfermagem/normas , Adulto , Cegueira/enfermagem , Controle de Custos , Recursos em Saúde , Humanos , Masculino , Oftalmologia/economia , Avaliação de Resultados em Cuidados de Saúde , Especialidades de Enfermagem/economiaRESUMO
New Zealand Black (NZB) autoimmune mice exhibit progressive, age-dependent reduction in bone marrow pre-B cells. To ascertain the capacity of NZB bone marrow B220- cells to generate pre-B cells in a supportive environment, B-lineage (B220+) cell-depleted and T-cell-depleted bone marrow cells from NZB mice at 1 to 3, 6, and 10 to 11 months of age were adoptively transferred into irradiated (200R) C.B17 severe combined immunodeficient (SCID) mice. Bone marrow pre-B cells (sIgM- CD43[S7]- B220+) were assessed 3 and 10 weeks posttransfer. Pre-B cells and B cells were reconstituted in SCID recipients of older NZB progenitor cells by 10 weeks posttransplant, in contrast to the very low numbers of pre-B cells present in the donor bone marrow. However, B220- bone marrow progenitor cells from greater than 10-month-old NZB donors were deficient in the reconstitution of both pre-B and B cells in SCID recipients at 3 weeks post-transfer. This reflected a slower kinetics of repopulation, because older NZB-->SCID recipients had numbers of both pre-B and B cells similar to recipients of young NZB progenitor cells by 10 weeks posttransplant. Adoptive transfer of equal mixtures of BALB/c and older NZB bone marrow B220- progenitor cells into irradiated C.B17 SCID recipients failed to demonstrate active suppression. These results suggest that, with age, NZB bone marrow has reduced numbers and/or function of early B220- B-lineage progenitors. Consistent with this hypothesis, B220- bone marrow cells from older NZB mice were deficient in progenitors capable of yielding interleukin-7 (IL-7) responsive pre-B cells in vitro on stimulation with the pre-B-cell potentiating factor, insulin-like growth factor 1 (IGF-1).
Assuntos
Envelhecimento/imunologia , Antígenos de Superfície/análise , Doenças Autoimunes/patologia , Subpopulações de Linfócitos B/patologia , Medula Óssea/patologia , Hematopoese , Células-Tronco Hematopoéticas/patologia , Camundongos Endogâmicos NZB/imunologia , Animais , Doenças Autoimunes/genética , Transplante de Medula Óssea , Contagem de Células , Ensaio de Unidades Formadoras de Colônias , Feminino , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/efeitos dos fármacos , Imunoterapia Adotiva , Fator de Crescimento Insulin-Like I/farmacologia , Interleucina-7/farmacologia , Antígenos Comuns de Leucócito , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NZB/anatomia & histologia , Camundongos Endogâmicos NZB/crescimento & desenvolvimento , Camundongos SCID , Quimera por Radiação , Linfócitos T/patologiaRESUMO
Surface IgM+B220+ B cell precursors can be categorized as either leukosialin (CD43/S7) negative (late stage pre-B cells) or positive (pro-B/early pre-B cells). In autoimmune New Zealand Black (NZB) mice, bone marrow small pre-B cells (IgM-CD43-B220+) and pro-B/early pre-B cells (IgM-CD43+B220+) declined significantly with age. In particular, subpopulations of pro-B/early pre-B cells expressing the heat stable antigen (HSA) were found in lower proportions with age. Significant decreases in interleukin-7 (IL-7) colony forming units (CFU) were also seen in NZB mice by 6 to 8 months of age and accompanied alterations in the numbers of pro-B and pre-B cells in bone marrow. Concomitant with reduced numbers of B lineage precursor cells and IL-7 CFU in vivo, NZB mice produced serum IgM antibodies that strongly inhibited IL-7 CFU responses in vitro. Two monoclonal IgM antibodies (5G9, 2F5) derived from LPS stimulated 10-month-old NZB splenocytes recognized pre-B cell surface antigens on both pre-B cell lines and on IL-7 stimulated bone marrow pro-B/pre-B cells. However, these monoclonal antibodies (MoAb) failed to significantly stain ex vivo bone marrow cells. The 5G9 and 2F5 MoAbs also partially inhibited IL-7 CFU in vitro. These results suggest that NZB bone marrow becomes increasingly deficient in B cell precursors and especially in IL-7 responsive pre-B cells with age. IgM serum antibodies and monoclonal IgM antibodies derived from older NZB mice inhibit pre-B cell growth to IL-7. The production of such autoantibodies may interfere with B cell development in aging NZB mice by preventing IL-7-mediated proliferation.