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1.
Trials ; 22(1): 595, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488845

RESUMO

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Noma , Tecido Adiposo , Animais , Ensaios Clínicos Fase II como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Método Duplo-Cego , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
2.
Surg Innov ; : 15533506211013142, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929270

RESUMO

Objective. The aims of this study are to compare 2 origins of adipose-derived mesenchymal stem cells (MSCs) (omentum and subcutaneous) from 2 pathologies (morbid obesity and cancer) vs healthy donors. Adipose tissue has revealed to be the ideal MSC source. However, in developing adipose-derived stem cells (ASCs) for clinical use, it is important to consider the effects of different fat depots and also the effect of donor variability. Methods. We isolated and characterized the membrane markers and differentiation capacities of ASCs obtained from patients with these diseases and different origin. During the culture period, we further analysed the cells' proliferation capacity in an in vitro assay as well as their secretome. Results. Adipose-derived stem cells isolated from obese and cancer patients have mesenchymal phenotype and similar cell proliferation as ASCs derived from healthy donors, some higher in cells derived from subcutaneous fat. However, cells from these 2 types of patients do not have the same differentiation potential, especially in cancer patients from omentum, and exhibit distinct secretion of both pro-inflammatory and regulatory cytokines, which could explain the differences in use due to origin as well as pathology associated with the donor. Conclusion. Subcutaneous and omentum ASCs are slightly different; omentum generates fewer cells but with greater anti-inflammatory capacity. Adipose-derived stem cells from patients with either obesity or cancer are slightly altered, which limits their therapeutic properties.

3.
Front Cell Dev Biol ; 9: 650664, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796536

RESUMO

Mesenchymal stromal cells (MSCs) currently constitute the most frequently used cell type in advanced therapies with different purposes, most of which are related with inflammatory processes. Although the therapeutic efficacy of these cells has been clearly demonstrated in different disease animal models and in numerous human phase I/II clinical trials, only very few phase III trials using MSCs have demonstrated the expected potential therapeutic benefit. On the other hand, diverse controversial issues on the biology and clinical applications of MSCs, including their specific phenotype, the requirement of an inflammatory environment to induce immunosuppression, the relevance of the cell dose and their administration schedule, the cell delivery route (intravascular/systemic vs. local cell delivery), and the selected cell product (i.e., use of autologous vs. allogeneic MSCs, freshly cultured vs. frozen and thawed MSCs, MSCs vs. MSC-derived extracellular vesicles, etc.) persist. In the current review article, we have addressed these issues with special emphasis in the new approaches to improve the properties and functional capabilities of MSCs after distinct cell bioengineering strategies.

4.
Cytotherapy ; 23(8): 740-753, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33714705

RESUMO

BACKGROUND AIMS: Successful cell cryopreservation and banking remain a major challenge for the manufacture of cell therapy products, particularly in relation to providing a hermetic, sterile cryovial that ensures optimal viability and stability post-thaw while minimizing exposure to toxic cryoprotective agents, typically dimethyl sulfoxide (Me2SO). METHODS: In the present study, the authors evaluated the effectiveness and functionality of Limbo technology (Cellulis S.L., Santoña, Spain). This system provides a hermetic vial with two compartments (one for adding cells with the cryoprotective agent solution and the other for the diluent solution) and an automated defrosting device. Limbo technology (Cellulis S.L.) allows reduction of the final amount of Me2SO, sidestepping washing and dilution steps and favoring standardization. The study was performed in several Good Manufacturing Practice laboratories manufacturing diverse cell therapy products (human mesenchymal stromal cells, hematopoietic progenitor cells, leukapheresis products, fibroblasts and induced pluripotent stem cells). Laboratories compared Limbo technology (Cellulis S.L.) with their standard cryopreservation procedure, analyzing cell recovery, viability, phenotype and functionality. RESULTS: Limbo technology (Cellulis S.L.) maintained the viability and functionality of most of the cell products and preserved sterility while reducing the final concentration of Me2SO. CONCLUSIONS: Results showed that use of Limbo technology (Cellulis S.L.) offers an overall safe alternative for cell banking and direct infusion of cryopreserved cell products into patients.


Assuntos
Criopreservação , Crioprotetores , Sobrevivência Celular , Terapia Baseada em Transplante de Células e Tecidos , Crioprotetores/farmacologia , Dimetil Sulfóxido , Humanos
5.
Stem Cell Res Ther ; 12(1): 124, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579367

RESUMO

BACKGROUND: Mesenchymal stromal cells (MSCs) constitute one of the cell types most frequently used in cell therapy. Although several studies have shown the efficacy of these cells to modulate inflammation in different animal models, the results obtained in human clinical trials have been more modest. Here, we aimed at improving the therapeutic properties of MSCs by inducing a transient expression of two molecules that could enhance two different properties of these cells. With the purpose of improving MSC migration towards inflamed sites, we induced a transient expression of the C-X-C chemokine receptor type 4 (CXCR4). Additionally, to augment the anti-inflammatory properties of MSCs, a transient expression of the anti-inflammatory cytokine, interleukin 10 (IL10), was also induced. METHODS: Human adipose tissue-derived MSCs were transfected with messenger RNAs carrying the codon-optimized versions of CXCR4 and/or IL10. mRNA-transfected MSCs were then studied, first to evaluate whether the characteristic phenotype of MSCs was modified. Additionally, in vitro and also in vivo studies in an LPS-induced inflamed pad model were conducted to evaluate the impact associated to the transient expression of CXCR4 and/or IL10 in MSCs. RESULTS: Transfection of MSCs with CXCR4 and/or IL10 mRNAs induced a transient expression of these molecules without modifying the characteristic phenotype of MSCs. In vitro studies then revealed that the ectopic expression of CXCR4 significantly enhanced the migration of MSCs towards SDF-1, while an increased immunosuppression was associated with the ectopic expression of IL10. Finally, in vivo experiments showed that the co-expression of CXCR4 and IL10 increased the homing of MSCs into inflamed pads and induced an enhanced anti-inflammatory effect, compared to wild-type MSCs. CONCLUSIONS: Our results demonstrate that the transient co-expression of CXCR4 and IL10 enhances the therapeutic potential of MSCs in a local inflammation mouse model, suggesting that these mRNA-modified cells may constitute a new step in the development of more efficient cell therapies for the treatment of inflammatory diseases.


Assuntos
Células-Tronco Mesenquimais , Animais , Movimento Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Expressão Ectópica do Gene , Interleucina-10/genética , Células-Tronco Mesenquimais/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais
6.
Clin Transplant ; 35(4): e14226, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33465824

RESUMO

BACKGROUND: Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). MATERIAL/METHODS: Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. RESULTS: Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. CONCLUSION: Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Estudos de Viabilidade , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressão
7.
Front Cell Dev Biol ; 8: 584074, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324641

RESUMO

Mesenchymal stromal cells (MSCs) constitute the cell type more frequently used in many regenerative medicine approaches due to their exclusive immunomodulatory properties, and they have been reported to mediate profound immunomodulatory effects in vivo. Nevertheless, MSCs do not express essential adhesion molecules actively involved in cell migration, a phenotypic feature that hampers their ability to home inflamed tissues following intravenous administration. In this study, we investigated whether modification by fucosylation of murine AdMSCs (mAdMSCs) creates Hematopoietic Cell E-/L-selectin Ligand, the E-selectin-binding CD44 glycoform. This cell surface glycan modification of CD44 has previously shown in preclinical studies to favor trafficking of mAdMSCs to inflamed or injured peripheral tissues. We analyzed the impact that exofucosylation could have in other innate phenotypic and functional properties of MSCs. Compared to unmodified counterparts, fucosylated mAdMSCs demonstrated higher in vitro migration, an altered secretome pattern, including increased expression and secretion of anti-inflammatory molecules, and a higher capacity to inhibit mitogen-stimulated splenocyte proliferation under standard culture conditions. Together, these findings indicate that exofucosylation could represent a suitable cell engineering strategy, not only to facilitate the in vivo MSC colonization of damaged tissues after systemic administration, but also to convert MSCs in a more potent immunomodulatory/anti-inflammatory cell therapy-based product for the treatment of a variety of autoimmune, inflammatory, and degenerative diseases.

8.
Regen Med ; 15(9): 2053-2065, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33245008

RESUMO

Venous leg ulcers (VLU) represent an uphill economic, health and social burden, aggravated in the elderly. Best-practice care interventions are often insufficient and alternative therapies need to be explored. Herein, we have treated for the first time a chronic VLU in an elderly patient by combining cell therapy and tissue engineering in the context of a compassionate use. The administration of allogeneic adipose-derived mesenchymal stromal cells (MSCs) embedded in a plasma-based bioengineered dermis covering the ulcer bed and also injected into the ulcer margins led to the complete closure of a 10-year recalcitrant VLU in an 85-year-old patient. Regenerative properties of MSCs might be boosted by the use of bioengineered matrices for their delivery.

10.
Stem Cells Transl Med ; 9(12): 1500-1508, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32864818

RESUMO

We evaluated the safety and feasibility of adipose-derived mesenchymal stem cells to treat endoscopically urinary incontinence after radical prostatectomy in men or female stress urinary. We designed two prospective, nonrandomized phase I-IIa clinical trials of urinary incontinence involving 9 men (8 treated) and 10 women to test the feasibility and safety of autologous mesenchymal stem cells for this use. Cells were obtained from liposuction containing 150 to 200 g of fat performed on every patient. After 4 to 6 weeks and under sedation, endoscopic intraurethral injection of the cells was performed. On each visit (baseline, 1, 3, 6, and 12 months), clinical parameters were measured, and blood samples, urine culture, and uroflowmetry were performed. Every patient underwent an urethrocystoscopy and urodynamic studies on the first and last visit. Data from pad test, quality-of-life and incontinence questionnaires, and pads used per day were collected at every visit. Statistical analysis was done by Wilcoxon signed-rank test. No adverse effects were observed. Three men (37.5%) and five women (50%) showed an objective improvement of >50% (P < .05) and a subjective improvement of 70% to 80% from baseline. In conclusion, intraurethral application of stem cells derived from adipose tissue is a safe and feasible procedure to treat urinary incontinence after radical prostatectomy or in female stress urinary incontinence. A statistically significant difference was obtained for pad-test improvement in 3/8 men and 5/10 women. Our results encourage studies to confirm safety and to analyze efficacy.

11.
Transl Oncol ; 13(11): 100837, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32736333

RESUMO

Differential presence of exons (DPE) is a method of interpretation of exome sequencing, which has been proposed to design a predictive algorithm with clinical value in patients with colorectal cancer (CRC). The goal of the present study was to examine the reproducibility in a rat model of metastatic colon cancer. DHD/K12-TRb cells were injected in syngenic immunocompetent BD-IX rats. Cells were from two stocks with low and normal metastatic potential, and injected into two separate groups of rats. Five to ten weeks after injection, blood samples were taken prior euthanasia and whole exome sequencing performed. Through DPE analysis, we identified a set of exons whose differential presence in plasma allowed us to compare both groups of tumor-bearing animals. A verification test was performed to confirm that the algorithm was able to classify extracted samples into their corresponding groups of origin. The highest mean probability was 0.8954. In conclusion, the DPE analysis in tumor-bearing animals was able to discriminate between different disease status, which fully supports previous results in CRC patients.

12.
EClinicalMedicine ; 25: 100454, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32838232

RESUMO

Background: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. Methods: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters. Findings: First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement. Interpretation: Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects. Funding: None.

13.
Ther Adv Med Oncol ; 12: 1758835920928233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636940

RESUMO

Background: Acellular pseudomyxoma peritonei (aPMP) is a rare peritoneal malignancy characterized by the accumulation of large amounts of mucin (lacking tumor cells) in the peritoneum. Many cases account for several kilograms of mucin to be screened by the pathologist. This is a comprehensive study of three patients with aPMP, whose tumors showed KRAS mutation, allowing for the tracking of this marker by liquid biopsy. Methods: Pre and post-surgery plasma, and mucin removed during cytoreductive surgery were collected from the patients. KRAS mutations were analyzed using droplet digital polymerase chain reaction (ddPCR). Mucin was injected in mice. KRAS and cytokine levels were measured in plasma of the mice using ddPCR and a magnetic bead-based assay. Mucin microbiome was analyzed by 16S rRNA sequencing. Results: KRAS mutations were detected in mucin cell-free DNA (cfDNA) from the three patients but not in the pre or post-surgery plasma. Electron microscopy detected microparticles (diameter <0.4 µm) in mucin. Mucin from one patient grew up inside the peritoneal cavity of mice and human KRAS was identified in mucin cfDNA, but not in plasma. All mucins showed the same bacterial profile. Cytokine levels were slightly altered in mice. Conclusions: The three aPMP patients included in this study shared some common aspects: the absence of tumor cells in mucin, the presence of KRAS mutated cfDNA in mucin, and the absence of this tumor-derived mutation in the bloodstream, providing additional information to the routine pathological examinations and suggesting that mucin cfDNA could potentially play a role in aPMP recurrence and prognosis.

14.
Stem Cells Transl Med ; 9(3): 295-301, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31886629

RESUMO

The aim of this clinical trial (ID Number NCT01803347) was to determine the safety and efficacy of autologous adipose-derived stem cells (ASCs) for treatment of cryptoglandular fistula. This research was conducted following an analysis of the mistakes of a same previous phase III clinical trial. We designed a multicenter, randomized, single-blind clinical trial, recruiting 57 patients. Forty-four patients were categorized as belonging to the intent-to-treat group. Of these, 23 patients received 100 million ASCs plus intralesional fibrin glue (group A) and 21 received intralesional fibrin glue (group B), both after a deeper curettage of tracks and closure of internal openings. Fistula healing was defined as complete re-epithelialization of external openings. Those patients in whom the fistula had not healed after 16 weeks were eligible for retreatment. Patients were evaluated at 1, 4, 16, 36, and 52 weeks and 2 years after treatment. Results were assessed by an evaluator blinded to the type of treatment. After 16 weeks, the healing rate was 30.4% in group A and 42.8% in group B, rising to 55.0% and 63.1%, respectively, at 52 weeks. At the end of the study (2 years after treatment), the healing rate remained at 50.0% in group A and had reduced to 26.3% in group B. The safety of the cellular treatment was confirmed and no impact on fecal continence was detected. The main conclusion was that autologous ASCs for the treatment of cryptoglandular perianal fistula is safe and can favor long-term and sustained fistula healing.

15.
Ther Adv Med Oncol ; 12: 1758835920981351, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425029

RESUMO

Background: Positive cytology has been identified as an independent negative prognostic factor in patients with peritoneal metastases (PM) of colorectal origin. Liquid biopsy in plasma may detect increasing levels of circulating tumor DNA (ctDNA) and could help predict systemic relapse in patients with colorectal cancer, but little is known about the role of liquid biopsy in peritoneal fluid. The aim of this study was to evaluate the prognostic value of peritoneal fluid and plasma liquid biopsy in patients undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CC-HIPEC). Methods: A longitudinal prospective study was designed in patients with KRAS-mutated colorectal or appendiceal primary tumor, including PM of colorectal origin, pseudomyxoma peritonei and patients at high risk of developing PM (selected for second-look surgery). Eleven patients were recruited according to inclusion and exclusion criteria. ctDNA from plasma and peritoneal fluid before and after HIPEC was studied by droplet digital PCR looking for KRAS mutation. A close follow-up was scheduled (mean of 28.5 months) to monitor for systemic and peritoneal recurrences. Results: All patients with positive plasma postHIPEC had systemic relapse and four patients died as a result, while those with negative plasma postHIPEC did not relapse. Patients with negative peritoneal ctDNA after CC-HIPEC did not present peritoneal relapse. Of six patients with positive peritoneal ctDNA postHIPEC, two presented peritoneal recurrence and four systemic relapses. Conclusions: Treatment with CC-HIPEC does not always neutralize ctDNA in peritoneal fluid, and its persistence after treatment may predict adverse outcome. Despite being a proof of concept, an adequate correlation between liquid biopsy in plasma and peritoneal fluid with both systemic and peritoneal relapse has been observed.

16.
PeerJ ; 7: e7160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367480

RESUMO

Myocardial infarction has been carefully studied in numerous experimental models. Most of these models are based on electrophysiological and functional data, and pay less attention to histological discoveries. During the last decade, treatment using advanced therapies, mainly cell therapy, has prevailed from among all the options to be studied for treating myocardial infarction. In our study we wanted to show the fundamental histological parameters to be evaluated during the development of an infarction on an experimental model as well as treatment with mesenchymal stem cells derived from adipose tissue applied intra-lesionally. The fundamental parameters to study in infarcted tissue at the histological level are the cells involved in the inflammatory process (lymphocytes, macrophages and M2, neutrophils, mast cells and plasma cells), neovascularization processes (capillaries and arterioles) and cardiac cells (cardiomyocytes and Purkinje fibers). In our study, we used intramyocardial injection of mesenchymal stem cells into the myocardial infarction area 1 hour after arterial occlusion and allowed 1 month of evolution before analyzing the modifications on the normal tissue inflammatory infiltrate. Acute inflammation was shortened, leading to chronic inflammation with abundant plasma cells and mast cells and complete disappearance of neutrophils. Another benefit was an increase in the number of vessels formed. Cardiomyocytes and Purkinje fibers were better conserved, both from a structural and metabolic point of view, possibly leading to reduced morbidity in the long term. With this study we present the main histological aspects to be evaluated in future assays, complementing or explaining the electrophysiological and functional findings.

17.
Sci Rep ; 9(1): 10516, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324877

RESUMO

Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a "unique" CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Ilhas de CpG , Metilação de DNA , Neoplasias Primárias Múltiplas/genética , Adenoma/genética , Adulto , Idade de Início , Idoso , Diferenciação Celular , Feminino , Genes Neoplásicos , Genes ras , Mutação em Linhagem Germinativa , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética
18.
Med. oral patol. oral cir. bucal (Internet) ; 24(4): e529-e536, jul. 2019. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-185667

RESUMO

Background: Bisphosphonate-related osteonecrosis of the jaw is a pathological condition without effective established treatment and preventive strategies. The aim of this study was to analyse the effect of adipose-derived stem cells (ASC) in an experimental murine model of osteonecrosis. Material and Methods: 38 Wistar rats were injected intraperitoneally with zoledronic acid. After treatment, upper jaw molars were extracted. The animals were randomly assigned to one of two groups. In the control group, saline solution was applied over the alveolar sockets after the tooth extractions. In the treatment group, ASCs were applied instead of saline solution. The control and treatment groups were subdivided based on the time of euthanasia. A clinical and histological analysis was performed. Results: The presence of osteonecrosis in alveolar bone was observed in a similar distribution in both groups. In the ASC-treated group, new bone formation was greater than in controls. Conclusions: In this study, application of ASCs showed greater new bone formation in an osteonecrosis-like murine model. Previous inhibited post-extraction bone remodelling could be reactivated, and these findings appeared to be secondary to implantation of ASCs


No disponible


Assuntos
Animais , Camundongos , Ratos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Osteonecrose , Difosfonatos , Modelos Animais de Doenças , Imidazóis , Células-Tronco , Extração Dentária , Ratos Wistar
19.
Front Immunol ; 10: 1151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231366

RESUMO

Cell therapy is a progressively growing field that is rapidly moving from preclinical model development to clinical application. Outcomes obtained from clinical trials reveal the therapeutic potential of stem cell-based therapy to deal with unmet medical treatment needs for several disorders with no therapeutic options. Among adult stem cells, mesenchymal stem cells (MSCs) are the leading cell type used in advanced therapies for the treatment of autoimmune, inflammatory and vascular diseases. To date, the safety and feasibility of autologous MSC-based therapy has been established; however, their indiscriminate use has resulted in mixed outcomes in preclinical and clinical studies. While MSCs derived from diverse tissues share common properties depending on the type of clinical application, they markedly differ within clinical trials in terms of efficacy, resulting in many unanswered questions regarding the application of MSCs. Additionally, our experience in clinical trials related to critical limb ischemia pathology (CLI) shows that the therapeutic efficacy of these cells in different animal models has only been partially reproduced in humans through clinical trials. Therefore, it is crucial to develop new research to identify pitfalls, to optimize procedures and to clarify the repair mechanisms used by these cells, as well as to be able to offer a next generation of stem cell that can be routinely used in a cost-effective and safe manner in stem cell-based therapies targeting CLI.

20.
Int J Mol Sci ; 20(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813366

RESUMO

Our aim was to characterize and validate that the location and age of onset of the tumor are both important criteria to classify colorectal cancer (CRC). We analyzed clinical and molecular characteristics of early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and we compared each tumor location between both ages-of-onset. In right-sided colon tumors, early-onset cases showed extensive Lynch syndrome (LS) features, with a relatively low frequency of chromosomal instability (CIN), but a high CpG island methylation phenotype. Nevertheless, late-onset cases showed predominantly sporadic features and microsatellite instability cases due to BRAF mutations. In left colon cancers, the most reliable clinical features were the tendency to develop polyps as well as multiple primary CRC associated with the late-onset subset. Apart from the higher degree of CIN in left-sided early-onset cancers, differential copy number alterations were also observed. Differences among rectal cancers showed that early-onset rectal cancers were diagnosed at later stages, had less association with polyps, and more than half of them were associated with a familial LS component. Stratifying CRC according to both location and age-of-onset criteria is meaningful, not only because it correlates the resulting categories with certain molecular bases, but with the confirmation across larger studies, new therapeutical algorithms could be defined according to this subclassification.


Assuntos
Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Idade de Início , Neoplasias Colorretais/genética , Dosagem de Genes , Humanos
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