RESUMO
The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.
Assuntos
Neoplasias de Cabeça e Pescoço/genética , Células-Tronco Hematopoéticas/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Medula Óssea/patologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Humanos , CamundongosRESUMO
Pseudomonas aeruginosa is the most frequently isolated microorganism from whirlpool water and lesions associated with outbreaks of dermatitis and folliculitis related to whirlpool exposure. Strains were selected from 19 outbreaks of P. aeruginosa infections (1977 to 1983) associated with whirlpool use; they were examined to determine if the strains possessed unique virulence factors or characteristics that might aid in their selection in the environment. P. aeruginosa, 011, was the predominant serotype isolated from whirlpool water as well as from bathers with dermatitis or folliculitis, followed by serotypes 09, 04, and 03. Antimicrobial susceptibility patterns were similar for all strains. Strains of P. aeruginosa from bathers and water demonstrated statistically significant differences in extracellular enzyme production compared with control strains. P. aeruginosa, serotypes 09 and 011, were found to be sensitive to low levels of chlorine. These data suggest that, if adequate levels of free available chlorine are maintained, P. aeruginosa should have little opportunity to persist in whirlpools. A bather's risk of P. aeruginosa dermatitis or folliculitis appears to be affected primarily by three factors: immersion in water colonized by P. aeruginosa, skin hydration with altered skin flora, and toxic reactions to extracellular enzyme or exotoxins produced by P. aeruginosa. Although a single virulence factor was not identified from the results of this study, there are some indications that the enzymes produced by these microorganisms play an important role in the pathogenesis of disease associated with whirlpool use.