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Obesity, which continues to increase worldwide, was shown to irreversibly impair the differentiation potential and angiogenic properties of adipose tissue mesenchymal stromal cells (ADSCs). Because these cells are intended for regenerative medicine, especially for the treatment of inflammatory conditions, and the effects of obesity on the immunomodulatory properties of ADSCs are not yet clear, here we investigated how ADSCs isolated from former obese subjects (Ex-Ob) would influence macrophage differentiation and polarization, since these cells are the main instructors of inflammatory responses. Analysis of the subcutaneous adipose tissue (SAT) of overweight (OW) and Ex-Ob subjects showed the maintenance of approximately twice as many macrophages in Ex-Ob SAT, contained within the CD68ï¼/FXIII-A- inflammatory pool. Despite it, in vitro, coculture experiments revealed that Ex-Ob ADSCs instructed monocyte differentiation into a M2-like profile, and under inflammatory conditions induced by LPS treatment, inhibited HLA-DR upregulation by resting M0 macrophages, originated a similar percentage of TNF-αï¼ cells, and inhibited IL-10 secretion, similar to OW-ADSCs and BMSCs, which were used for comparison, as these are the main alternative cell types available for therapeutic purposes. Our results showed that Ex-Ob ADSCs mirrored OW-ADSCs in macrophage education, favoring the M2 immunophenotype and a mixed (M1/M2) secretory response. These results have translational potential, since they provide evidence that ADSCs from both Ex-Ob and OW subjects can be used in regenerative medicine in eligible therapies. Further in vivo studies will be fundamental to validate these observations.
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Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has refined the prognosis of complete response (CR) cases, until now, there have been no data on the benefits of these approaches in Latin America. Here, we evaluate the benefits of M-Len and MRD using next-generation flow cytometry (NGF-MRD) at Day + 100 post-ASCT (n = 53). After ASCT, responses were evaluated based on the International Myeloma Working Group criteria and NGF-MRD. MRD was positive in 60% of patients with a median progression-free survival (PFS) of 31 months vs. not reached (NR) for MRD-negative cases (p = 0.05). The patients who received M-Len continuously had a significantly better PFS and overall survival (OS) than those without M-Len (median PFS: NR vs. 29 months, p = 0.007), with progression in 11% vs. 54% of cases after a median follow-up of 34 months, respectively. In a multivariate analysis, MRD status and M-Len therapy emerged as independent predictors of PFS (median PFS of M-Len/MRD- vs. no M-Len/MRD+ of NR vs. 35 months, respectively; p = 0.01). In summary, M-Len was associated with improved survival outcomes in our real-world MM cohort in Brazil, with MRD emerging as a useful reproducible tool to identify patients at an earlier risk of relapse. The inequity in drug access remains a hurdle in countries with financial constraints, with a negative impact on MM survival.
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O excesso de ingestão de flúor durante o desenvolvimento do órgão dental pode resultar em alterações estruturais tanto em esmalte quanto em dentina. No esmalte, observa-se um aumento de porosidades causadas pela interação do flúor com os prismas em desenvolvimento, tanto na superfície quanto em profundidade. Clinicamente essas alterações são visíveis como manchas com aspecto que vai do branco opaco ao amarelo amarronzado. A presença de manchas no esmalte dental leva ao comprometimento estético do sorriso tão valorizado atualmente. Para a homogeinização de cor, nos casos mais brandos, recomenda-se a realização do tratamento clareador com agentes oxidantes de baixa concentração (clareamento caseiro). Em casos mais severos a associação do clareamento caseiro com o procedimento de microabrasão é indicada para remoção das manchas de fluorose. Na microabrasão, o uso simultâneo da abrasão e da erosão ácida é capaz de remover as manchas decorrentes de alterações superficiais em esmalte. Portanto, utilizando tratamentos conservadores é possível devolver a autoestima do paciente de forma bastante satisfatória.
The excess fluoride intake during dental organ development may result structural changes in enamel and dentin. Increase porosity was observed by fluorine interaction with enamel prisms development, both on surface and in depth. Clinically these changes are visible as spots with aspect that goes from opaque white to brownish yellow. The enamel spots leads to unpleasant smile. In mild cases, for color homogenization, it is recommended bleaching treatment with low concentration oxidizing agents (home bleaching). In more severe cases, the home bleaching and microabrasion procedure association are indicated for fluorosis stains removal. In microabrasion, the association of abrasion and acid erosion remove stains from changes on enamel surface. Thus conservative treatments can successfully restore patient's self- esteem.
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Humanos , Feminino , Adulto , Fluorose Dentária , Clareamento Dental , Microabrasão do Esmalte , FlúorRESUMO
OBJECTIVE: To demonstrate that it is possible to pursue teeth whitening treatment protocols during orthodontic treatment with no esthetic loss. CLINICAL CONSIDERATIONS: Many patients undergoing orthodontic treatment desire to have a straight and well aligned dentition, but also whiter teeth. For many years, it was believed that carrying out a whitening treatment with positioned orthodontic brackets in place would result in localized spots on the enamel labial surfaces of teeth. However, a deeper understanding of the bleaching process suggests that the oxidation caused by products, which results from hydrogen peroxide decomposition, are able to diffuse peripherally into the tooth structure and reach even that under the cemented brackets. Two in-office-bleaching treatments were performed in patients using orthodontic fixed braces in two or three 40-minute sessions using a 35% hydrogen peroxide. CONCLUSION: In-office bleaching is possible and effective, even with orthodontic brackets in position. The teeth were successfully bleached despite the presence of brackets. All biological criteria have been fulfilled satisfying patients' expectations of aligned and whitened teeth in less time than if treatments had been performed separately, with satisfactory results and no esthetic loss. CLINICAL SIGNIFICANCE: The whitening of teeth is possible during orthodontic treatment with fixed braces without any esthetic loss. The in-office bleaching treatment with brackets in position also may act as a motivation factor, preventing patient withdrawal or treatment interruption. Therefore, at the end of the orthodontic treatment, the patient is able to display an aligned, functional and whitened smile. (J Esthet Restor Dent 29:83-92, 2017).
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Visita a Consultório Médico , Ortodontia , Clareamento Dental , Adolescente , Feminino , Humanos , Braquetes OrtodônticosRESUMO
Bone marrow stromal cells (BMSCs) are considered a promising tool for bone bioengineering. However, the mechanisms controlling osteoblastic commitment are still unclear. Osteogenic differentiation of BMSCs requires the activation of ß-catenin signaling, classically known to be regulated by the canonical Wnt pathway. However, BMSCs treatment with canonical Wnts in vitro does not always result in osteogenic differentiation and evidence indicates that a more complex signaling pathway, involving cadherins, would be required to induce ß-catenin signaling in these cells. Here we showed that Wnt3a alone did not induce TCF activation in BMSCs, maintaining the cells at a proliferative state. On the other hand, we verified that, upon BMSCs osteoinduction with dexamethasone, cadherins were cleaved by the PS1/γ-secretase complex at the plasma membrane, and this event was associated with an enhanced ß-catenin translocation to the nucleus and signaling. When PS1/γ-secretase activity was inhibited, the osteogenic process was impaired. Altogether, we provide evidence that PS1/γ-secretase-mediated cadherin cleavage has as an important role in controlling ß-catenin signaling during the onset of BMSCs osteogenic differentiation, as part of a complex signaling pathway responsible for cell fate decision. A comprehensive map of these pathways might contribute to the development of strategies to improve bone repair.
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Stem cell transplantation affects patient׳s vulnerability to infections due to immunological changes related to chemotherapy. Multiple myeloma is characterized by susceptibility to infections, and IL-6 and TNF-α increased levels affect immune response (IR). Polymorphisms in promoter region of cytokine genes may alter expression levels and affect IR. We performed interaction analysis of IL-6 (-174G/C) and TNF-α (-308G/A) polymorphisms with infection susceptibility in 148 patients classified accordingly to infection status and found an interaction when compared groups with and without bacteremia (p=0.0380). The interaction may be more important than single effects for the IR associated with the infection susceptibility in ASCT.
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The aim of this study was to determine factors that influence unsuccessful peripheral blood stem cell (PBSC) harvesting in patients with multiple myeloma (MM). Retrospective data of 186 MM patients who received G-CSF as mobilization were analyzed. Patients with successful harvest were compared with those who failed (using 2 definitions of failure <2 and <4 CD34 cells×10(6)/mm(3)). The groups were compared regarding age, gender, body weight, baseline platelet count, receipt of radiotherapy, number of prior chemotherapy regimens, PBSC count before collection, processed and collected volume, collect replace, number of sessions and final number of PBSC collected. By multivariate analysis, a baseline platelet count <161,000 cells/mm(3) was associated with PBSC harvest lower than 2×10(6)/kg, and age >58 years was related to PBSC harvest lower than 4×10(6)/kg CD34 cells/kg. Patients with these parameters should not receive mobilization protocols with G-CSF alone. Alternative protocols should be tested in this high risk harvest failure population.
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Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: The optimal cryopreservation cell concentration during the peripheral blood stem cell (PBSC) collection is a controversial topic. We evaluated the influence of cryopreservation concentration on the recovery of hematopoietic progenitor cells and the kinetics of hematopoietic recovery of autologous stem cell transplant patients. STUDY DESIGN AND METHODS: In this retrospective study, we compared two different cryopreservation protocols: 1×10(8) cells/mL (Protocol A) and 2×10(8) cells/mL (Protocol B). A total of 419 PBSCs were analyzed with regard to the number of viable cells and colony-forming units-granulocytes-monocytes (CFU-GM) progenitors. The hematopoietic recovery of 275 patients who received PBSCs cryopreserved at a dose of 1×10(8) cells/mL (Group A) and 2×10(8) cells/mL (Group B) were compared. RESULTS: There were no significant differences in recovery of viable cells between Protocol A and Protocol B. The median of recovery of CFU-GM progenitors was significantly higher in Protocol B (41.2 vs. 57.3, p<0.01). The median times to neutrophil recovery (≥500×10(6) /L) and platelet (PLT) recovery (≥20×10(9) /L) in Groups A and B were 11 days versus 11 days and 12 days versus 12 days, respectively. However, by Kaplan and Meier analyses, Group B recovered neutrophils with a little delay (p=0.01). No difference was observed with regard to time to PLT recovery. On multivariate analysis, we found that the number of CD34+ cells and CFU-GM progenitors had a significant influence on hematopoietic recovery. CONCLUSION: Cryopreservation of PBSCs at a dose of 2×10(8) cells/mL did not affect the recovery rate of viable cells or the hematopoietic recovery of autologous stem cell transplant patients.
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Preservação de Sangue/métodos , Criopreservação/métodos , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Contagem de Células , Sobrevivência Celular , Sobrevivência de Enxerto , Mobilização de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Neutrófilos/citologia , Modelos de Riscos Proporcionais , Recuperação de Função Fisiológica , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
BACKGROUND: Migration, proliferation, and differentiation of hematopoietic stem cells (HSCs) are dependent upon a complex three-dimensional (3D) bone marrow microenvironment. Although osteoblasts control the HSC pool, the subendosteal niche is complex and its cellular composition and the role of each cell population in HSC fate have not been established. In vivo models are complex and involve subtle species-specific differences, while bidimensional cultures do not reflect the 3D tissue organization. The aim of this study was to investigate in vitro the role of human bone marrow-derived mesenchymal stromal cells (BMSC) and active osteoblasts in control of migration, lodgment, and proliferation of HSCs. METHODOLOGY/PRINCIPAL FINDINGS: A complex mixed multicellular spheroid in vitro model was developed with human BMSC, undifferentiated or induced for one week into osteoblasts. A clear limit between the two stromal cells was established, and deposition of extracellular matrix proteins fibronectin, collagens I and IV, laminin, and osteopontin was similar to the observed in vivo. Noninduced BMSC cultured as spheroid expressed higher levels of mRNA for the chemokine CXCL12, and the growth factors Wnt5a and Kit ligand. Cord blood and bone marrow CD34(+) cells moved in and out the spheroids, and some lodged at the interface of the two stromal cells. Myeloid colony-forming cells were maintained after seven days of coculture with mixed spheroids, and the frequency of cycling CD34(+) cells was decreased. CONCLUSIONS/SIGNIFICANCE: Undifferentiated and one-week osteo-induced BMSC self-assembled in a 3D spheroid and formed a microenvironment that is informative for hematopoietic progenitor cells, allowing their lodgment and controlling their proliferation.
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Movimento Celular , Proliferação de Células , Células-Tronco Hematopoéticas/citologia , Osteoblastos/citologia , Células Estromais/citologia , Adulto , Animais , Antígenos CD34/análise , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Células Cultivadas , Quimiocina CXCL12/genética , Técnicas de Cocultura , Sangue Fetal/citologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Recém-Nascido , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Microscopia Eletrônica , Osteoblastos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Esferoides Celulares/ultraestrutura , Células Estromais/metabolismoRESUMO
Macrophage migration inhibitory factor (MIF) participates in the pathogenesis of inflammatory diseases, including asthma, in which it enhances airway hypersensitivity and tissue eosinophilia. Herein, we investigated the role of MIF in eosinophilopoiesis and tissue eosinophilia using Schistosoma mansoni infection. MIF-deficient (Mif(-/-)) mice had similar numbers of adult worms, eggs, and granulomas compared to wild-type mice, but the size of granulomas was strikingly reduced due to smaller numbers of eosinophils. MIF did not affect the acquired response to infection, as Mif(-/-) mice produced normal amounts of Th2 cytokines and IgE. Nevertheless, recombinant MIF (rMIF) behaved as a chemoattractant for eosinophils, what could partially explain the reduced eosinophilia in infected Mif(-/-) mice. Moreover, the percentage of eosinophils was reduced in bone marrows of Mif(-/-) mice chronically infected with S. mansoni compared to wild type. Mif(-/-) had impaired eosinophilopoiesis in response to interleukin (IL)-5 and addition of rMIF to bone marrow cultures from IL-5 transgenic mice enhanced the generation of eosinophils. In the absence of MIF, eosinophil precursors were unable to survive the IL-5-supplemented cell culture, and were ingested by macrophages. Treatment with pancaspase inhibitor z-VAD or rMIF promoted the survival of eosinophil progenitors. Together, these results indicate that MIF participates in IL-5-driven maturation of eosinophils and in tissue eosinophilia associated with S. mansoni infection.