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1.
Curr Opin Obstet Gynecol ; 33(1): 53-58, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337614

RESUMO

PURPOSE OF REVIEW: The present review summarizes recent original publications addressing the topic of risk-adapted adjuvant therapy in early breast cancer (EBC). As neoadjuvant therapy has become a standard for triple negative and HER2+ EBC, it focusses on luminal EBC. RECENT FINDINGS: Gene expression assays have become standard of care in luminal EBC, at least for patients with node negative disease. Two prospective randomized clinical trials, TAILORx (Oncotype DX) and MINDACT (MammaPrint) have presented additional analyses underlining the clinical utility of the tests. In times of COVID-19, immunohistochemically determined ER, PR, and Ki67 and early Ki67 response to endocrine therapy can be used to safely allocate patients for preoperative endocrine therapy and delay surgeries if resources are scarce. In patients with luminal high-risk disease, adding a CDK 4/6 inhibitor (abemaciclib) improves patient outcome already after short-term follow-up. SUMMARY: Determination of recurrence risk will remain important in luminal EBC for optimal therapy decisions. In the future, risk-adapted treatment concepts will include decision making for chemotherapy but also for endocrine-based approaches.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Antígeno Ki-67/metabolismo , Terapia Neoadjuvante , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Medição de Risco
2.
Nat Commun ; 11(1): 5762, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188184

RESUMO

Occurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active ß-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/ß-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-ß-catenin axis.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Núcleo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/prevenção & controle , Fator Regulador 3 de Interferon/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Enterócitos/metabolismo , Enterócitos/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Antígeno Ki-67/metabolismo , Camundongos Endogâmicos C57BL , Ligação Proteica , Domínios Proteicos , Transporte Proteico , Análise de Sobrevida , Via de Sinalização Wnt , beta Catenina/química
3.
Sci Immunol ; 5(51)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943497

RESUMO

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Monócitos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Biomarcadores/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Reino Unido/epidemiologia
4.
Int J Nanomedicine ; 15: 6311-6324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922003

RESUMO

Background: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Hialuronoglucosaminidase/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/patologia , Polímeros/química , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
5.
Nat Commun ; 11(1): 4038, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788587

RESUMO

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.


Assuntos
Aspartato-tRNA Ligase/deficiência , Aspartato-tRNA Ligase/genética , Córtex Cerebral/patologia , Microcefalia/genética , Células-Tronco Neurais/patologia , Organoides/patologia , Aminoacil-RNA de Transferência/genética , Adolescente , Adulto , Sequência de Bases , Diferenciação Celular , Proliferação de Células , Tamanho Celular , Sobrevivência Celular , Criança , Família , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Mutação/genética , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Linhagem , Adulto Jovem
7.
Yakugaku Zasshi ; 140(8): 1051-1061, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741863

RESUMO

It has been reported that medium-chain triglyceride (MCT) have various physiological functions, such as anti-obesity and hypolipidemic effects. They can also elicit increased disaccharidase activity and intestinal cell proliferation. However, a meta-analysis of randomized controlled trials, comparing the effects of MCT on weight loss and body composition, detected commercial bias. Additional research on the physiological functions is needed in order to have conclusive evidence. Thus, we sought to evaluate the various functions of MCT by conducting a feeding study in rats. Rats fed a diet containing 15% (w/w) MCT, had significantly lower visceral fat weight, plasma and liver lipid concentrations; they had significantly higher intestinal maltase and glucoamylase activities; and they had a greater number of Ki-67 positive cells/crypt, compared to the rats fed a diet containing 15% (w/w) lard. The effects of a diet containing 5% (w/w) MCT was observed only for plasma cholesterol levels and the number of Ki-67 positive cells/crypt; in which some results were found to be inconsistent with previous reports. These results indicate that physiological functions of MCT are numerous and need to be confirmed by additional research.


Assuntos
Glucana 1,4-alfa-Glucosidase/metabolismo , Intestino Delgado/enzimologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Triglicerídeos/administração & dosagem , Triglicerídeos/farmacologia , alfa-Glucosidases/metabolismo , Animais , Fármacos Antiobesidade , Proliferação de Células/efeitos dos fármacos , Dieta , Hipolipemiantes , Intestino Delgado/citologia , Gordura Intra-Abdominal , Antígeno Ki-67/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Triglicerídeos/química
8.
J Card Surg ; 35(8): 1912-1919, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32652694

RESUMO

BACKGROUNDS: Disparities may exist between the adolescent and the adult patients with cardiac fibromas in the symptoms, surgical outcomes, and pathological characteristics. The aim of this study was to compare short and midterm surgical outcomes of cardiac fibromas and to compare the biomarker expressions of tumor tissue samples between the adult and the adolescent. METHODS: Consecutive patients with the diagnosis of cardiac fibroma were admitted and received surgeries. Primary outcomes included in-hospital mortality, low cardiac output, and readmission due to heart failure. The expression of PCNA and Ki67, two widely adopted indicators of cell proliferation, were evaluated in tissue samples. RESULTS: A total of five adolescent patients and five adult patients diagnosed as cardiac fibroma were admitted and given surgeries. When compare with the adults, the adolescent patients were more likely to present symptoms on admission (P = .048). Postoperative low cardiac output syndrome was significantly higher in the adolescents than in the adults (80.0% vs 0.0, P = .048). The tumor volume relative to ventricular end diastolic diameter had good discriminative ability for low cardiac output (c statistics: 0.96). Pathologically, the percentage of PCNA-positive cell nuclei was significantly higher in the adolescents than in the adults (36.04% ± 10.54% vs 4.15% ± 3.93%, P = .001). However, there were no Ki67-positive nuclei in the 10 cases. CONCLUSIONS: In the current study, we found that postoperative low cardiac output was more likely to occur in the adolescent patients than in the adult patients. When compared with the adult patients, significantly more PCNA-positive nuclei were observed in the adolescents.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Fibroma/patologia , Fibroma/cirurgia , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/cirurgia , Adolescente , Adulto , Fatores Etários , Baixo Débito Cardíaco/epidemiologia , Proliferação de Células/genética , Feminino , Expressão Gênica , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Resultado do Tratamento , Adulto Jovem
9.
PLoS One ; 15(6): e0233676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484812

RESUMO

In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high­risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.


Assuntos
Carcinoma de Células de Transição/patologia , Linfócitos do Interstício Tumoral/imunologia , Índice Mitótico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade
10.
Nat Commun ; 11(1): 2859, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503973

RESUMO

Mature double negative (DN) T cells are a population of αß T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.


Assuntos
Autoantígenos/imunologia , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Autoantígenos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/metabolismo
11.
Medicine (Baltimore) ; 99(24): e20324, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541455

RESUMO

Although pancreatic neuroendocrine tumors (PNETs) are generally considered to have a favorable overall prognosis after resection, disease recurrence has been observed. Few studies have specifically addressed recurrence after resection of PNETs, especially for non-functioning PNETs (NF-PNETs). The aim of our study is to analyze the recurrence of resected well-differentiated NF-PNETs.Patients who underwent surgical resection for grade 1 and 2 NF-PNETs without synchronous metastasis were identified for analysis. Patients were treated from January 2009 to December 2017 in our institution. Univariate and multivariate cox regression analysis were conducted to identify prognostic factors.Of the 88 patients, 46 were men (52%) and the mean age was 52 years. With a median follow-up of 49.1 months (range, 8-122 months), there were 12 recurrences (14%). Liver was the most common recurrence site (7/12, 58%). The 1-, 3-, and 5-year recurrence-free survival was 99%, 90%, and 88%, respectively. Univariate analysis identified that age >52 years, positive lymph nodes, tumor grade 2, and Ki67 index ≥5% were statistically significant. Multivariate analysis identified that Ki67 index ≥5% (hazard ratio [HR], 4.69; 95% confidence interval [CI], 1.36-16.75, P = .015), positive lymph nodes (HR, 6.75; 95% CI, 1.73-24.43, P = .006) were independently associated with recurrence. The 5-year disease-free survival rate was 53% (95% CI, 14.20-91.81%) for patients with Ki-67 ≥5% or (and) positive lymph nodes, while 95% (95% CI, 82.26-100%) for the patients without these 2 factors.Ki67 index and lymph node status are independently associated with recurrence after resection of well-differentiated NF-PNETs in this study.


Assuntos
Recidiva Local de Neoplasia/epidemiologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Incidência , Antígeno Ki-67/metabolismo , Fígado/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Recidiva Local de Neoplasia/patologia , Tumores Neuroendócrinos/cirurgia , Pancreatectomia/métodos , Pancreatectomia/estatística & dados numéricos , Pancreatectomia/tendências , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Pancreaticoduodenectomia/estatística & dados numéricos , Prognóstico , Estudos Retrospectivos
12.
PLoS One ; 15(6): e0235278, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584887

RESUMO

PURPOSE: The apparent diffusion coefficient (ADC) is increasingly used to characterize breast cancer. The peritumor/tumor ADC ratio is suggested to be a reliable and generally applicable index. However, its overall prognostication value remains unclear. We aimed to evaluate the associations between the peritumor/tumor ADC ratio and histopathological biomarkers and published prognostic tools in patients with invasive breast cancer. MATERIALS AND METHODS: This prospective study included 88 lesions (five bilateral) in 83 patients with primary invasive breast cancer who underwent preoperative 3.0-T magnetic resonance imaging. The lowest intratumoral mean ADC value on the slice with the largest tumor cross-sectional area was designated the tumor ADC, and the highest mean ADC value on the peritumoral breast parenchymal tissue adjacent to the tumor border was designated the peritumor ADC. The peritumor/tumor ADC ratio was then calculated. The tumor and peritumor ADC values and peritumor/tumor ADC ratios were compared with histopathological parameters using an unpaired t test, and their correlations with published prognostic tools were evaluated with Pearson's correlation coefficient. RESULTS: The peritumor/tumor ADC ratio was significantly associated with tumor size (p<0.001), histological grade (p = 0.005), Ki-67 index (p = 0.006), axillary-lymph-node metastasis (p = 0.001), and lymphovascular invasion (p = 0.006), but was not associated with estrogen receptor status (p = 0.931), progesterone receptor status (p = 0.160), or human epidermal growth factor receptor 2 status (p = 0.259). The peritumor/tumor ADC ratio showed moderate positive correlations with the Nottingham Prognostic Index (r = 0.498, p<0.001) and mortality predicted using PREDICT (r = 0.436, p<0.001). CONCLUSION: The peritumor/tumor ADC ratio was correlated with histopathological biomarkers in patients with invasive breast cancer, showed significant correlations with published prognostic indexes, and may provide an easily applicable imaging index for the preoperative prognostic evaluation of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/diagnóstico por imagem , Mama/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/mortalidade , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Antígeno Ki-67/metabolismo , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos Prospectivos , Receptores Estrogênicos/metabolismo , Taxa de Sobrevida
13.
Anat Sci Int ; 95(4): 523-539, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32476103

RESUMO

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic ß-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic ß-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous ß-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost ß-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.


Assuntos
Polpa Dentária/citologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Pâncreas/fisiologia , Transplante de Células-Tronco , Células-Tronco/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Movimento Celular , Sobrevivência Celular , Modelos Animais de Doenças , Transportador de Glucose Tipo 2/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Ratos , Ratos Sprague-Dawley , Regeneração , Estreptozocina
14.
J Vis Exp ; (160)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32597870

RESUMO

Neurospheres are primary cell aggregates that comprise neural stem cells and progenitor cells. These 3D structures are an excellent tool to determine the differentiation and proliferation potential of neural stem cells, as well as to generate cell lines than can be assayed over time. Also, neurospheres can create a niche (in vitro) that allows the modeling of the dynamic changing environment, such as varying growth factors, hormones, neurotransmitters, among others. Microtus ochrogaster (prairie vole) is a unique model for understanding the neurobiological basis of socio-sexual behaviors and social cognition. However, the cellular mechanisms involved in these behaviors are not well known. The protocol aims to obtain neural progenitor cells from the neurogenic niches of the adult prairie vole, which are cultured under non-adherent conditions, to generate neurospheres. The size and number of neurospheres depend on the region (subventricular zone or dentate gyrus) and sex of the prairie vole. This method is a remarkable tool to study sex-dependent differences in neurogenic niches in vitro and the neuroplasticity changes associated with social behaviors such as pair bonding and biparental care. Also, cognitive conditions that entail deficits in social interactions (autism spectrum disorders and schizophrenia) could be examined.


Assuntos
Arvicolinae/fisiologia , Pradaria , Neurogênese , Neurônios/citologia , Animais , Adesão Celular , Células Cultivadas , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Imageamento Tridimensional , Antígeno Ki-67/metabolismo , Masculino , Microdissecção , Proteínas Associadas aos Microtúbulos/metabolismo , Nestina/metabolismo , Neuropeptídeos/metabolismo , Esferoides Celulares/citologia
15.
Sci Rep ; 10(1): 7648, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376868

RESUMO

This retrospective analysis evaluated the interaction between Ki-67 and histological grade and their prognostic role in different breast cancer subtypes. In total, 2,573 breast cancer patients underwent surgery, and their histological grade and Ki-67 values were evaluated by breast pathologists. The median Ki-67 index was 15%, which was used as the cut-off for low/high Ki-67 expression. Recurrence-free survival (RFS) was calculated and compared, and the results indicated that Ki-67 expression was significantly associated with histological grade in all breast cancer patients (p < 0.001) and in each immunohistochemical (IHC)-based subtype (p < 0.001). Both high Ki-67 expression and grade 3 tumours were independent predictors of inferior RFS in all patients, especially in those with luminal-like tumours (p < 0.05). Ki-67 was an independent prognostic factor for RFS in grade 1, 2 patients with luminal-like tumours (adjusted hazard ratio [HR] = 1.92, 95% confidence interval [CI]: 1.22-3.03, p = 0.005), but not in the other subtypes. Similarly, histological grade predicted shorter RFS in patients with low Ki-67 expression who had luminal-like tumours (adjusted HR = 2.12, 95% CI: 1.13-3.99, p = 0.02) but not in the other subtypes. Conversely, Ki-67 showed no prognostic value for patients with grade 3 tumours and vice versa.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno Ki-67/metabolismo , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Recidiva , Fatores de Risco , Adulto Jovem
17.
Medicine (Baltimore) ; 99(20): e20136, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443327

RESUMO

BACKGROUND: This study will investigate the diagnostic accuracy of Ki67 expression in colorectal cancer (CC). METHODS: A comprehensive search in electronic bibliographic databases (MEDLINE, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure) will be performed from inception to the February 29, 2020 with no restrictions to the language and publication status. Two authors will examine the collected studies, extract essential data, and appraise study quality separately. If possible, we will estimate receiver operating characteristic (ROC), sensitivity and specificity by utilizing bivariate random effects and hierarchical summary ROC models. RESULTS: This study will summarize present evidence to explore the diagnostic accuracy of Ki67 expression in CC. CONCLUSION: The findings of this study will clarify the diagnostic accuracy of Ki67 expression in CC. SYSTEMATIC REVIEW REGISTRATION: INPLASY202030009.


Assuntos
Neoplasias do Colo/imunologia , Neoplasias Colorretais/imunologia , Antígeno Ki-67/metabolismo , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Confiabilidade dos Dados , Humanos , Sensibilidade e Especificidade
18.
Medicine (Baltimore) ; 99(20): e20140, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443328

RESUMO

Primary central nervous system lymphoma (PCNSL) typically shows a strong uptake of F-fludeoxyglucose (FDG) imaged by positron emission tomography (PET). Uncommonly, PCNSL demonstrates a low uptake on FDG PET. We investigated the clinicopathological characteristics of the unusual cases of PCNSL with low FDG uptake.We retrospectively enrolled 104 consecutive patients with newly diagnosed PCNSL who underwent baseline brain FDG PET. The degree of FDG uptake of PCNSL was visually scored by 4 grades (0, ≤contralateral white matter; 1, >contralateral white matter and contralateral gray matter). Grades 0-2 were considered as PCNSL with low uptake. We investigated association of low uptake of PCNSL with the following clinicopathological factors: age, sex, steroid treatment, lactate dehydrogenase level, cerebrospinal fluid protein level, condition of PET scanning, immunohistochemical markers (cluster of differentiation 10 [CD10], B-cell lymphoma 6 [BCL-6], B-cell lymphoma 2 [BCL-2], multiple myeloma oncogene 1 [MUM1], Epstein-Barr virus [EBV] protein, and Ki67), location of lesions, tumor size, multiplicity of lesions, involvement of deep brain structures, and cystic or necrotic appearance of lesions.Of the 104 patients with PCNSL, 14 patients (13.5%) showed PCNSL with low FDG uptake on PET. Among various clinicopathological factors, MUM1 negativity was the only factor associated with low FDG uptake PCNSL by univariate (P = .002) and multivariate analysis (P = .007).This study suggests that the different clinicopathological characteristics between patients with high uptake and low uptake of PCNSL on FDG PET is closely associated with lack of MUM1, a protein known to be a crucial regulator of B-cell development and tumorigenesis.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/patologia , Carcinogênese/metabolismo , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/patologia , Proteínas do Líquido Cefalorraquidiano/análise , Feminino , Herpesvirus Humano 4/metabolismo , Humanos , Fatores Reguladores de Interferon/metabolismo , Antígeno Ki-67/metabolismo , L-Lactato Desidrogenase/análise , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Estudos Retrospectivos , Esteroides/uso terapêutico
19.
PLoS One ; 15(5): e0233152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453755

RESUMO

Obesity is associated with significantly higher mortality rates, and excess adipose tissue is involved in respective pathologies. Here we established a human adipose tissue slice cultures (HATSC) model ex vivo. HATSC match the in vivo cell composition of human adipose tissue with, among others, mature adipocytes, mesenchymal stem cells as well as stroma tissue and immune cells. This is a new method, optimized for live imaging, to study adipose tissue and cell-based mechanisms of obesity in particular. HATSC survival was tested by means of conventional and immunofluorescence histological techniques, functional analyses and live imaging. Surgery-derived tissue was cut with a tissue chopper in 500 µm sections and transferred onto membranes building an air-liquid interface. HATSC were cultured in six-well plates filled with Dulbecco's Modified Eagle's Medium (DMEM), insulin, transferrin, and selenium, both with and without serum. After 0, 1, 7 and 14 days in vitro, slices were fixated and analyzed by morphology and Perilipin A for tissue viability. Immunofluorescent staining against IBA1, CD68 and Ki67 was performed to determine macrophage survival and proliferation. These experiments showed preservation of adipose tissue as well as survival and proliferation of monocytes and stroma tissue for at least 14 days in vitro even in the absence of serum. The physiological capabilities of adipocytes were functionally tested by insulin stimulation and measurement of Phospho-Akt on day 7 and 14 in vitro. Viability was further confirmed by live imaging using Calcein-AM (viable cells) and propidium iodide (apoptosis/necrosis). In conclusion, HATSC have been successfully established by preserving the monovacuolar form of adipocytes and surrounding macrophages and connective tissue. This model allows further analysis of mature human adipose tissue biology ex vivo.


Assuntos
Adipócitos , Tecido Adiposo , Modelos Biológicos , Obesidade , Técnicas de Cultura de Tecidos , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adolescente , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Sobrevivência Celular , Feminino , Humanos , Antígeno Ki-67/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia
20.
Invest Ophthalmol Vis Sci ; 61(5): 12, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396633

RESUMO

Purpose: Adiponectin is an insulin-sensitizing and anticarcinogenic hormone that is encoded by a gene on chromosome 3. Here, we analyzed the expression of adiponectin and its receptor Adipor1 in primary uveal melanoma (UM) with regard to the monosomy-3 status and clinical factors, as well as the physiological response of UM cells to adiponectin. Methods: Immunohistochemistry was performed on the primary UM of 34 patients. Circulating melanoma cells (CMC) were isolated by immunomagnetic enrichment. Monosomy-3 was evaluated by Immuno-FISH. Gene expression was analyzed using the RNAseq data of The Cancer Genome Atlas study. Cultures of choroidal melanocytes and UM were established from the samples of two patients. The proliferative potential of the UM cell lines Mel-270 and OMM-2.5 was determined by immunocytochemistry, immunoblotting, cell cycle analysis, nucleolar staining, and adenosine triphosphate (ATP) levels. Results: UM with monosomy-3 exhibited a lower immunoreactivity for adiponectin and Adipor1, which was associated with monosomy-3-positive CMC and the development of extraocular growth or metastases. Both proteins were more abundant in the irradiated tumors and present in the cultured cells. Gene expression profile indicated the impairment of adiponectin-mediated signaling in the monosomy-3 tumors. Adiponectin induced a significant decline in the ATP levels, Ki-67 expression, cells in the G2/M phase, and nucleolar integrity in UM cultures. Conclusions: Adiponectin deficiency appears to enhance the metastatic potential of the UM cells with monosomy-3 and the termination of tumor dormancy. Counteracting insulin resistance and improving the serum adiponectin levels might therefore be a valuable approach to prevent or delay the UM metastases.


Assuntos
Adiponectina/metabolismo , Cromossomos Humanos Par 3 , Melanoma/metabolismo , Monossomia , Receptores de Adiponectina/metabolismo , Neoplasias Uveais/metabolismo , Trifosfato de Adenosina/metabolismo , Idoso , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Melanoma/genética , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Neoplasias Uveais/genética
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