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- ItemAcesso aberto (Open Access)Assinaturas estromais e expressão de microRNAs relacionados à angiogênese em linfomas não-Hodgkin difuso de grandes células B(Universidade Federal de São Paulo (UNIFESP), 2014-11-26) Borges, Natalia Morais [UNIFESP]; Colleoni, Gisele Wally Braga [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive non-Hodgkin lymphoma (NHL) and, despite advances in treatment, 30% of the cases are refractory or relapse after chemoimmunotherapy. Currently, the relationship between angiogenesis and angiomiRs in DLBCL is unknown. We classified 84 DLBCL according to stromal signatures using tissue microarray and immunohistochemistry (CD34, CD68 and SPARC). We also evaluated the expression of pro- and antiangiomiRs in paraffin embedded tissues of DLBCL by real-time PCR and correlate them with MVD. Approximately 40% of cases were classified as stromal-1, 50% were classified as stromal-2 and 10% were not classified. We observed increased expression of pro-angiomiRs Let-7f, miR-17, miR-18a, miR-19b, miR-126, miR-130a, miR-210, miR-296 and miR-378 in 14%, 57%, 30%, 45%, 12%, 12%, 56%, 58% and 48% of cases, respectively. Among antiangiomiRs we found decreased expression of miR-16, miR-20b, miR-92a, miR-221 and miR-328 in, respectively, 27%, 71%, 2%, 44% and 11%. When comparing the expression of angiomiRs with molecular subtypes according to the algorithm Hans et al. (2004) we found association between increased expression pro-angiomir miR-126, pro-angiomir miR-130a e antiangiomir miR-328 and the subtype ABC (non-GCB). However, only in the case of angiomiRs miR-16, miR-221 and miR-328 we were able to verify expression values compatible with angiogenesis, i.e., higher levels of the three antiangiomiRs in patients with low MVD and stromal-1 signature. The median overall survival has not been reached, with a maximum follow-up of 146.5 months. We observed worse outcome in Ann Arbor stage III/IV, high IPI and CD34 Quartiles III/IV (automated counting). IPI and CD34 confirmed independent impact on survival of the study group. Patients with high-risk IPI showed probability of evolving to death 3.4 times greater than the rest of the group and patients with higher MVD as automated counting (Quartiles III and IV) had chance of evolving to death two times higher than the rest of the group. MicroRNAs showed no prognostic significance in independent serum samples? cohort. Therefore, the stromal-2 signature was found in 50% of cases. We confirmed association between antiangiomirs miR-16, miR-221 and miR-328 and stromal-1 signature. Four angiomiRs emerge as potential therapeutic targets (differentially expressed in ~50% of cases): pro-angiomiRs miR-17, miR-210 and miR-296 and anti-angiomiR miR-20b. Although the four microRNAs seem to be important in DLBCL pathogenesis, they are not predictive of DLBCL onset or relapse.
- ItemSomente MetadadadosEstudo da fibrose no músculo esquelético mediada por receptores de angiotensina e tratamento do músculo lesionado por prp e terapia gênica(Universidade Federal de São Paulo (UNIFESP), 2015-12-17) Stilhano, Roberta Sessa [UNIFESP]; Han, Sang Won Han [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)process, which frequently occurs in cases of deeper muscle injury, leads to imperfect tissue regeneration. The current therapies have a low efficacy for prevention or treatment of the complications caused by fibrosis, such as atrophy, contraction and pain followed by functional loss and post-traumatic fibrosis. Hypertension is a contributing factor in fibrosis, and angiotensin II (Ang II), which is the main responsible for vasoconstriction, seems to trigger signaling fibrosis. There is communication between TGFB1 and Ang II signaling pathway in cardiac muscle. In parallel, there is a discordant discussion of GM-CSF role in skeletal muscle fibrosis. To better understand the fibrotic process occurring after injury in skeletal muscle, first of all, we established a muscle injury model followed by suture, which produces a deep lesion developing fibrosis largely muscle. To evaluate the possible role of the AT1 and GM-CSF in promoting fibrosis, multiple vectors were constructed, including, Lv-mirAT1a expressing a microRNA to silence the expression of AT1a protein and Lv-GM-CSF expressing GM-CSF. Considering that the injection of lentiviral solution in skeletal muscle may not be efficient for transduction of these vectors and cause leakage to other tissues, an alginate hydrogel was formulated for carrying lentivetores. The animals treated with alginate hydrogel loaded with Lv-GM-CSF and Lv-mirAT1a drastically reduced muscle fibrosis. Thus, it was inferred that the AT1a should participate in the fibrotic process of skeletal muscle and its inhibition is a good strategy for reducing post-injury fibrosis. On the other hand, the effect of the expression of GM-CSF in the control of fibrosis varied depending on the inflammatory progression, or its expression and the onset of inflammation-accentuated fibrosis, but expression in late stage drastically reduced fibrosis, confirming the results of our previous work. The mediators of fibrosis, such as angiotensin and growth factors are present in plasma and in sports medicine, the platelet rich plasma (PRP) is widely used to treat various types of lesions, including muscle injury. In an attempt to correlate the above studies with these factors in PRP, the molecular and cellular content of that preparation was evaluated. Two methods for preparation of PRP were established in the literature database and were named LPRP and PPRP. The main difference between the two preparations is the presence of leukocytes (LPRP) or not (PPRP), but the molecular and cellular contents thereof vary markedly PRPs. NIH3T3 cell lines (fibroblasts) and C2C12 (myoblast) grown with 1% PRP, and 10% FBS promoted cell proliferation in different patterns. The expression gene expression profile of 6 growth factors were analyzed and showed that each PRP for each cell type expression level of these genes is significantly variable. In conclusion, it was demonstrated that AT1 participates in skeletal muscle fibrosis and the inhibition of AT1 via microRNA is a good alternative to reduce fibrosis. Forced expression of GM-CSF early in the muscle injury promotes the formation of fibrosis, but their expression days later drastically reduces fibrosis. For late expression of GM-CSF via lentivetor contained in loco, the alginate hydrogel formulation with lentivetor developed here was ideal. As for PRPs, leukocytes contained in LPRP takes the PRP formation with different quality and amount of cells and molecules, hence its effect on the target cells were different.
- ItemSomente MetadadadosPapel dos micrornas 135-a e 210 na fisiopatologia da pre-eclâmpsia(Universidade Federal de São Paulo (UNIFESP), 2016) Korkes, Henri Augusto [UNIFESP]; Oliveira, Leandro Gustavo de Oliveira [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introduction: Preeclampsia affects 3 to 5% of all pregnancies. The disease is characterized by endothelial dysfunction and systemic inflammatory response. Recent researches on microRNAs suggest important roles for these molecules on several biological processes, including preeclampsia. Objectives: To evaluate the participation of miR-135-a and miR-210 in the pathophysiology of preeclampsia. Methods: This is a case-control study, involving in vitro and in vivo experimental models to evaluate the role of miR-135-a and miR-210 on trophoblastic invasion and hypoxia and angiogenic imbalance in placentas of women with preeclampsia. Results: miR-135-a increased trophoblastic invasion in vitro and its mechanism of action was affected by hypoxia (p<0.05). miR-135-a was able to promote spiral artery remodeling in pregnant mice (p<0.05). Preeclamptic placentas expressed higher amount of mir-210 and it was positively correlated with higher expression of total Flt (p<0.05). These results demonstrated correlation between miR-210 and the angiogenic imbalance found in preeclampsia. Conclusion: Either miR-135-a or miR-210 seem to be involved in the pathophysiology of preeclampsia. Additional functional studies must be developed in order to elucidate the role of these molecules as cause or consequence of preeclampsia and to identify specific target genes.