Cancer stem cells (CSCs) are a small population of resistant cells inhabiting the tumors. Although comprising only nearly 3% of the tumor mass, these cells were demonstrated to orchestrate tumorigenesis and differentiation, underlie tumors’ heterogeneity and mediate therapy resistance and tumor relapse. Here we show that CSCs may be formed by dedifferentiation of terminally differentiated tumor cells under stress conditions. Using a elegant co-culture cellular system, we were able to prove that nutrients and oxygen deprivation activated non-malignant stromal fibroblasts, which in turn established with tumor cells a paracrine loop mediated by Interleukine-6 (IL-6), Activin-A and Granulocyte colony-stimulating factor (G-CSF), that drove subsequent tumor formation and cellular dedifferentiation. However, by scavenging these cytokines from the media and/or blocking exosomes’ mediated communication it was possible to abrogate dedifferentiation thus turning these mechanisms into potential therapeutic targets against cancer progression.
Polyglutamine diseases are hereditary degenerative disorders of the nervous system that have remained, to this date, untreatable. Promisingly, investigation into their molecular etiology and the development of increasingly perfected tools have contributed to the design of novel strategies with therapeutic potential. Encouraging studies have explored gene therapy as a means to counteract cell demise and loss in this context. The current chapter addresses the two main focuses of research in the area: the characteristics of the systems used to deliver nucleic acids to cells and the molecular and cellular actions of the therapeutic agents. Vectors used in gene therapy have to satisfyingly reach the tissues and cell types of interest, while eliciting the lowest toxicity possible. Both viral and non-viral systems have been developed for the delivery of nucleic acids to the central nervous system, each with its respective advantages and shortcomings. Since each polyglutamine disease is caused by mutation of a single gene, many gene therapy strategies have tried to halt degeneration by silencing the corresponding protein products, usually recurring to RNA interference. The potential of small interfering RNAs, short hairpin RNAs and microRNAs has been investigated. Overexpression of protective genes has also been evaluated as a means of decreasing mutant protein toxicity and operate beneficial alterations. Recent gene editing tools promise yet other ways of interfering with the disease-causing genes, at the most upstream points possible. Results obtained in both cell and animal models encourage further delving into this type of therapeutic strategies and support the future use of gene therapy in the treatment of polyglutamine diseases.
Objective: to make Pediatricians aware of the fact that they must investigate Behcet's disease while performing differential diagnosis of recurrent aphthous stomatitis, even though it is a vasculitis of rare occurrence in early life. Methods: between June 1996 and December 2000, we retrospectively evaluated seven patients of our Pediatric Rheumatology Unit. Demographic, clinical, and laboratory data as well as data regarding treatment and follow-up were presented. Results: five out of seven patients were female (71.4%), four were non-Caucasian (57.1%), the mean age at onset was 8 years and 11 months (variation of 6 months to 13 years and 8 months), the mean period until diagnosis was 2 years and 3 months (variation of 2 months to 8 years) and the mean follow-up period was 4 years and 2 months (three patients without follow-up). The major criteria of diagnosis were: oral ulcers in seven patients (100%), genital ulcers in three patients (42.8%), ophthalmic alterations in four patients (57.1%) cutaneous vasculitis in one patient (14.2%) and positive pathergy test in one patient (14.2%). The minor criteria were: arthralgia/arthritis in five patients (71.4%), family history in two patients (28.5%), and sagittal sinus thrombosis in one patient (14.2%). The initial symptoms included recurrent aphthous stomatitis (more than three painful aphthous ulcers episodes in the period of 1 year), genital ulcers, arthralgia, fever and weight loss. The laboratory findings were: mild anemia in 1/6 patients, ESR>25 in 3/6 patients, increased serum gammaglobulin level in 2/4 patients, B5 histocompatibility antigen in 2/ 7 patients. The treatment included corticosteroids for 5/7 patients (4 oral, 1 intravenous and one local use), thalidomide for 4/7 patients, colchicine for 2/7 patients and dapsone for 1/7 patient. The outcome was favorable in 4/6, and 3/6 patients presented relapse. Conclusion: our results confirm the importance of considering the diagnosis of Behcet's disease in patients with recurrent oral and genital ulcers.
25 em 3/6 pacientes, hipergamaglobulina em 2/4 pacientes, presença do antígeno de histocompatibilidade B5 em apenas 2/7 pacientes. O tratamento constou de corticoesteróides em 5/7 pacientes (4 VO, 1 EV e 1 uso tópico), talidomida em 4/7 pacientes, colchicina em 2/7 pacientes e dapsona em 1/7 pacientes. A resposta foi favorável em 4/6, porém recorrente em 3/6 pacientes.Conclusão: nossos resultados confirmam a importância de considerar o diagnóstico de doença de Behçet em regiões com úlceras orais e genitais, especialmente úlceras orais recorrentes.]]>
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