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1.
Adv Exp Med Biol ; 1167: 87-103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520350

RESUMO

Cancer development originates in a single mutant cell transformed from a normal cell, including further evolution of pro-tumor cells through additional mutations into malignant cancer tissues. Data from recent studies, however, suggest that most pro-tumor cells do not develop into tumors but remain dormant within or are prophylactically eliminated from tissues unless bestowed with additional driver mutations. Drosophila melanogaster has provided very efficient model systems, such as imaginal discs and ovarian follicular epithelia, to study the initial stage of tumorigenesis. This review will focus on the behaviors of emerging pro-tumor cells surrounded by normal cells and situations where they initiate tumor development.


Assuntos
Carcinogênese , Proteínas de Drosophila , Drosophila melanogaster , Epitélio/patologia , Animais , Discos Imaginais
2.
Chemosphere ; 234: 409-418, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31228844

RESUMO

Intestinal microflora play an important role in maintaining the homeostasis of the intestinal microenvironment, but fluoride-induced changes in intestinal mechanical barrier and intestinal microflora have not been well studied. Given this paucity of information, this study aims to determine the effects of high fluoride level on intestinal mechanical barrier and intestinal microflora in the cecum of mice. Seventy-two female 21-day-old Kunming mice were randomly assigned to three groups and raised for 70 days. Changes in intestinal pathomorphology and intestinal epithelial cell proliferation were observed by haematoxylin and eosin-staining and Brdu measurement, respectively. The distribution of goblet cells, glycoproteins and mast cells was analysed through Alcian blue and periodic acid-Schiff (AB-PAS) staining, Periodic Acid-Schiff (PAS) staining, and toluidine blue staining. Results showed that excessive fluoride damaged the structure of the cecal tissues, inhibited epithelial cell proliferation and decreased the relative distribution of goblet cells, glycoproteins and mast cells that are involved in defense responses. Intestinal microflora sequencing analysis revealed that the composition of the diversity and composition of intestinal microflora was altered by excessive fluoride based on 16S rRNA amplicon sequencing. The relative abundance of Firmicutes (P = 0.03174), Bacteroidetes (P = 0.04462), Actinobacteria (P = 0.01085) and Spirochacteria (P = 0.04084) was significantly changed in the fluoride group as compared with the control group. In conclusion, excessive fluoride intake induced intestinal barrier damage, leading to changes in cecal composition, epithelium secretion and intestinal microflora.


Assuntos
Ceco/efeitos dos fármacos , Epitélio/patologia , Fluoretos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/patologia , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Ceco/microbiologia , Ceco/patologia , Epitélio/efeitos dos fármacos , Feminino , Intestinos/microbiologia , Camundongos , RNA Ribossômico 16S/genética
3.
Nat Commun ; 10(1): 2735, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227713

RESUMO

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.


Assuntos
Interleucina-33/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Neoplasias Gástricas/imunologia , Aminopiridinas/administração & dosagem , Animais , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Cromolina Sódica/administração & dosagem , Modelos Animais de Doenças , Epitélio/imunologia , Epitélio/patologia , Feminino , Mucosa Gástrica/citologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Microambiente Tumoral/imunologia
4.
Cancer Sci ; 110(8): 2658-2666, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199029

RESUMO

Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.


Assuntos
Fibrina/metabolismo , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Ascite/metabolismo , Ascite/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Peritônio/metabolismo , Peritônio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Cell Mol Biol Lett ; 24: 32, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143210

RESUMO

Objective: Peritoneal fibrosis remains a serious complication of long-term peritoneal dialysis (PD) leading to peritoneal membrane ultrafiltration failure. Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a key process of peritoneal fibrosis. Curcumin has been previously shown to inhibit EMT of renal tubular epithelial cells and prevent renal fibrosis. There are only limited reports on inhibition of PMCs-EMT by curcumin. This study aimed to investigate the effect of curcumin on the regulation of EMT and related pathway in PMCs treated with glucose-based PD. Methods: EMT of human peritoneal mesothelial cells (HMrSV5) was induced with glucose-based peritoneal dialysis solutions (PDS). Cells were divided into a control group, PDS group, and PDS group receiving varied concentrations of curcumin. Cell Counting Kit-8 (CCK-8) assay was used to measure cell viability, and a transwell migration assay was used to verify the capacity of curcumin to inhibit EMT in HMrSV5 cells. Real-time quantitative PCR and western blot were used to detect the expression of genes and proteins associated with the EMT. Results: High glucose PDS decreased cell viability and increased migratory capacity. Curcumin reversed growth inhibition and migration capability of human peritoneal mesothelial cells (HPMCs). In HMrSV5 cells, high glucose PDS also decreased expression of epithelial markers, and increased expression of mesenchymal markers, a characteristic of EMT. Real-time RT-PCR and western blot revealed that, compared to the 4.25% Dianeal treated cells, curcumin treatment resulted in increased expression of E-cadherin (epithelial marker), and decreased expression of α-SMA (mesenchymal markers) (P < 0.05). Furthermore, curcumin reduced mRNA expression of two extracellular matrix protein, collagen I and fibronectin. Curcumin also reduced TGF-ß1 mRNA and supernatant TGF-ß1 protein content in the PDS-treated HMrSV5 cells (P < 0.05). Furthermore, it significantly reduced protein expression of p-TAK1, p-JNK and p-p38 in PDS-treated HMrSV5 cells. Conclusions: Our results demonstrate that curcumin showed an obvious protective effect on PDS-induced EMT of HMrSV5 cells and suggest implication of the TAK1, p38 and JNK pathway in mediating the effects of curcumin in EMT of MCs.


Assuntos
Curcumina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio/patologia , MAP Quinase Quinase Quinases/metabolismo , Peritônio/patologia , Biomarcadores/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Diálise Peritoneal , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Nat Commun ; 10(1): 2225, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31110179

RESUMO

The effective prevention of tumor initiation, especially for potentially inoperable tumors, will be beneficial to obtain an overall higher quality of our health and life. Hence, thorough understanding of the pathophysiological mechanisms of early tumor formation arising from identifiable cellular origins is required to develop efficient preventative and early treatment options for each tumor type. Here, using genetically engineered mouse models, we provide preclinical experimental evidence for a long-standing open question regarding the pathophysiological potential of a microenvironmental and physiological stressor in tumor development, gastric acid-mediated regional microscopic injury in foregut squamous epithelia. This study demonstrates the association of gastric acid stress with Cyclooxygenase-2-dependent tumor formation originating from tumor-competent Krt5+/Krt15+ foregut basal progenitor cells. Our findings suggest that clinical management of microenvironmental stressor-mediated microscopic injury may be important in delaying tumor initiation from foregut basal progenitor cells expressing pre-existing tumorigenic mutation(s) and genetic alteration(s).


Assuntos
Carcinogênese/patologia , Ciclo-Oxigenase 2/metabolismo , Ácido Gástrico/metabolismo , Neoplasias Gastrointestinais/patologia , Células-Tronco/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Sistema Digestório/patologia , Células Epiteliais/patologia , Epitélio/patologia , Neoplasias Gastrointestinais/etiologia , Queratina-15/genética , Queratina-15/metabolismo , Queratina-5/genética , Queratina-5/metabolismo , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Inibidores da Bomba de Prótons/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Microambiente Tumoral
7.
Eur Arch Otorhinolaryngol ; 276(8): 2289-2292, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144013

RESUMO

PURPOSE: Vocal fold scar is one the most challenging benign laryngeal pathologies. The purpose of this paper is to propose a classification that will allow for a common description of this entity between laryngologists, prevent discrepancies in interpretation, allow for comparison of related studies, and offer a training tool for young laryngologists. METHODS/RESULTS: Based on the depth and laterality of scarring, we propose 4 types: type I, characterized by atrophy of lamina propria with/without affected epithelium; type II, where the epithelium, lamina propria, and muscle are affected; type III, where the scar is located on the anterior commissure; type IV, which includes extended scar formation in both anteroposterior and rostro-caudal axis with significant loss of vocal fold mass. CONCLUSION: We believe that our proposal is comprehensive and encompasses all existing iatrogenic and non-iatrogenic etiologies in a simple and concise manner. It also serves its purpose as a descriptive, comparative, and training tool.


Assuntos
Cicatriz/classificação , Cicatriz/patologia , Doenças da Laringe/classificação , Prega Vocal/patologia , Epitélio/patologia , Humanos , Doenças da Laringe/etiologia , Doenças da Laringe/patologia , Membrana Mucosa/patologia , Prega Vocal/cirurgia
8.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987186

RESUMO

Psoriasis is an autoimmune chronic dermatosis that is T cell-mediated, characterized by epidermal thickening, aberrant epidermal differentiation and inflammatory infiltrates, with a dominant Th1 and Th17 profile. Additional in vitro models are required to study the complex interactions between activated T cells and skin cells, and to develop new, more effective treatments. We have therefore sought to model this psoriatic inflammation by the generation of tissue-engineered immunocompetent tissues, and we have investigated the response of activated T-cell infiltration in models produced with lesional psoriatic skin cells on major hallmarks of psoriasis. The immunocompetent lesional skin model displayed a delayed onset of epidermal differentiation, an hyperproliferation of the basal keratinocytes, a drastic increase in the secretion of proinflammatory cytokines, and a disturbed expression of key transcription factors, as observed in lesional plaques, suggesting a crucial importance of combining the pathological phenotype of cutaneous cells to T cells in order to generate a relevant model for psoriasis. Finally, we found this skin model to be responsive to methotrexate treatment, making it a valuable tool for drug development.


Assuntos
Modelos Biológicos , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Diferenciação Celular , Movimento Celular , Proliferação de Células , Derme/imunologia , Derme/patologia , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Humanos , Imunocompetência , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Queratinócitos/patologia , Ativação Linfocitária/imunologia , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais
9.
Analyst ; 144(8): 2635-2642, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30839958

RESUMO

Infrared (IR) spectroscopic imaging, utilizing both the molecular and structural disease signatures, enables extensive profiling of tumors and their microenvironments. Here, we examine the relative merits of using either the fingerprint or the high frequency regions of the IR spectrum for tissue histopathology. We selected a complex model as a test case, evaluating both stromal and epithelial segmentation for various breast pathologies. IR spectral classification in each of these spectral windows is quantitatively assessed by estimating area under the curve (AUC) of the receiver operating characteristic curve (ROC) for pixel level accuracy and images for diagnostic ability. We found only small differences, though some that may be sufficiently important in diagnostic tasks to be clinically significant, between the two regions with the fingerprint region-based classifiers consistently emerging as more accurate. The work provides added evidence and comparison with fingerprint region, complex models, and previously untested tissue type (breast) - that the use of restricted spectral regions can provide high accuracy. Our study indicates that the fingerprint region is ideal for epithelial and stromal models to obtain high pixel level accuracies. Glass slides provide a limited spectral feature set but provides accurate information at the patient level.


Assuntos
Mama/anatomia & histologia , Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Tecido Conjuntivo/anatomia & histologia , Tecido Conjuntivo/patologia , Epitélio/anatomia & histologia , Epitélio/patologia , Humanos , Hiperplasia/patologia , Modelos Biológicos , Curva ROC , Espectrofotometria Infravermelho/métodos
10.
Virchows Arch ; 474(5): 609-617, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30729310

RESUMO

Immunophenotype of thyroglossal duct (TGD) cysts, including lining epithelium and thyroid remnants, is scarcely addressed in the literature. There is indirect evidence that C cells may be derived from progenitor cells of the midline thyroid primordium. This is supported by the recent concept of the endodermal origin of lateral thyroid anlagen and several case reports. We aimed to search for neuroendocrine cells in TGD cysts and to characterize immunophenotype of the thyroid follicles and epithelial lining of TGD. Out of 98 TGD cysts, 70% contained both cyst-lining epithelium and thyroid follicles, whereas 30% possessed only cyst-lining epithelium. Specimens eligible for immunohistochemistry (n = 61) were stained for thyroid-specific and neuroendocrine markers. Thyroid remnants were positive for thyroid transcription factor 1 (TTF-1) and other thyroid tissue-specific markers and negative for calcitonin. TGD epithelium showed strong p63 positivity. We found that respiratory epithelium in 9.8% of TGDs contained neuroendocrine cells positive for calcitonin, chromogranin A, and synaptophysin but negative for carcinoembryonic antigen. In 44.2% of the cases, we detected compact buds, microscopic structures appearing as nests of epithelial cells with a biphasic population of basal (p63+) and central (TTF-1+) cells. Thyroid remnants in TGD expressed full spectrum of thyroid-specific markers and contained no C cells. Instead, calcitonin-expressing neuroendocrine cells were found among the respiratory epithelium of TGD. These cells can be a potential source of neuroendocrine tumors mimicking medullary carcinoma in median anlage derivatives. We also discovered precursor compact buds with dual immunophenotype and proposed a concept of their morphogenesis.


Assuntos
Calcitonina/metabolismo , Diferenciação Celular/fisiologia , Tumores Neuroendócrinos/patologia , Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Carcinoma Medular/patologia , Carcinoma Papilar/patologia , Criança , Pré-Escolar , Células Epiteliais/patologia , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Lactente , Masculino , Pessoa de Meia-Idade , Células Neuroendócrinas/patologia , Cisto Tireoglosso/patologia , Adulto Jovem
11.
Med Sci (Paris) ; 35(2): 187-190, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30774090

RESUMO

Careful sequencing studies on small samples of normal oesophageal epithelium reveal the presence of very abundant cellular clones harbouring mutations in known cancer genes (and elsewhere). The number and size of these clones increases with age. This surprising finding confirms previous studies on sun-exposed epidermis. It has important implications for the understanding of cancer initiation and will hopefully lead to conceptual and clinical advances.


Assuntos
Células Clonais/patologia , Epitélio/patologia , Células-Tronco Neoplásicas/patologia , Lesões Pré-Cancerosas/patologia , Nicho de Células-Tronco , Envelhecimento/patologia , Células Clonais/metabolismo , Células Epidérmicas/metabolismo , Células Epidérmicas/patologia , Humanos , Mutação/fisiologia , Lesões Pré-Cancerosas/genética , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Nicho de Células-Tronco/genética , Luz Solar/efeitos adversos
12.
Acta Histochem ; 121(3): 311-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30745250

RESUMO

Peyer's patches are known as the immune sensors of the intestine because of their ability to transport luminal antigens. The objective of this study was both to assess the prenatal and postnatal development of sheep ileal Peyer's patches with respect to histomorphology, distribution of CD4+ and CD8+ cells, and localization of proliferating and apoptotic cells, and to examine the morphology of M cells and expression of CK18 in follicle associated epithelium (FAE). We also hypothesized that CK18 could be a potential marker for M cell. Peyer's patches completed their histomorphological development in prenatal period and involuted in the postnatal period. The distribution of the CD4+ and CD8+ cells was similar in the last trimester of pregnancy (days 120-150) and the postnatal period, but differed in the early stages of foetal development (days 70-120). In the prenatal period, the follicular area displayed high levels of proliferation and apoptosis. We observed CK18 immunoreaction only in FAE. While M cells were devoid of microfolds in the early stages of the prenatal period, these cells acquired a prismatic shape and bore distinct apical microfolds in the late prenatal period and postnatal period. As a result, it was determined that, in sheep, the development of the ileal Peyer's patches occurred in the prenatal period, independent of exogenous antigenic stimulation, and in association with high levels of lymphopoiesis and apoptosis in the follicles. We found, for the first time, that CK18 is a novel and reliable marker for FAE in sheep ileal Peyer's patches. We suggest that CK18 positive cells in FAE are M cells.


Assuntos
Epitélio/patologia , Íleo/citologia , Intestinos/citologia , Queratina-18/metabolismo , Animais , Apoptose/fisiologia , Biomarcadores/metabolismo , Feminino , Folículo Ovariano/citologia , Ovinos
13.
Gynecol Oncol ; 153(2): 405-415, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30797592

RESUMO

OBJECTIVE: Ovarian cancer (OvCa) metastasis requires the coordinated motility of both cancer and stromal cells. Cellular movement is a dynamic process that involves the synchronized assembly of f-actin bundles into cytoskeletal protrusions by fascin. Fascin directly binds f-actin and is an integral component of filopodia, lamellapodia and stress fibers. Here, we examine the expression pattern and function of fascin in the cancer and stromal cells of OvCa tumors. METHODS: Fascin expression was evaluated in human cells and tissues using immunohistochemistry and immunofluorescence. The functional role of fascin in cancer and stromal cells was assessed with in vitro functional assays, an ex vivo colonization assay and in vivo metastasis assays using siRNA/shRNA and an inhibitor. The effect of fascin inhibition on Cdc42 and Rac1 activity was evaluated using GTPase activity assays and immunofluorescence. RESULTS: Fascin expression was found to be higher in the stromal cell, when compared to the cancer cell, compartment of ovarian tumors. The low expression of fascin in the cancer cells of the primary tumor indicated a favorable prognosis for non-serous OvCa patients. In vitro, both knockdown and pharmacologic inhibition of fascin decreased the migration of cancer and stromal cells. The inhibition of fascin impaired Cdc42 and Rac1 activity in cancer cells, and cytoskeletal reorganization in the cancer and stromal cells. Inhibition of fascin ex vivo blocked OvCa cell colonization of human omental tissue and in vivo prevented and reduced OvCa metastases in mice. Likewise, knockdown of fascin specifically in the OvCa cells using a fascin-specific lentiviral-shRNA also blocked metastasis in vivo. CONCLUSION: This study reveals the therapeutic potential of pharmacologically inhibiting fascin in both cancer and stromal cells of the OvCa tumor microenvironment.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Proteínas de Transporte/antagonistas & inibidores , Proteínas dos Microfilamentos/antagonistas & inibidores , Células Estromais/patologia , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Movimento Celular , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Proteínas dos Microfilamentos/biossíntese , Proteínas dos Microfilamentos/genética , Metástase Neoplásica , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Arch. Soc. Esp. Oftalmol ; 94(2): 85-89, feb. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-180370

RESUMO

Paciente de 66 años en seguimiento por retinopatía diabética refractaria a múltiples modalidades de tratamiento a pesar del buen control metabólico que refiere pérdida de peso progresiva. Por este motivo se decide realizar un estudio sistémico, detectándose anemia, elevación de la velocidad de sedimentación globular e hiperproteinemia a expensas de un pico monoclonal de IgM. Posteriormente, mediante la biopsia de médula ósea y el estudio genético, se llega al diagnóstico de macroglobulinemia de Waldenström. La macroglobulinemia de Waldenström es una patología linfoproliferativa de escasa frecuencia cuya principal manifestación es a través del síndrome de hiperviscosidad. Este puede producir signos oftalmológicos detectables mediante funduscopia y pruebas de imagen. El estudio multimodal es útil en el diagnóstico y seguimiento de la afectación retiniana. La incorporación de la angiografía por tomografía de coherencia óptica permite un estudio más preciso de los trastornos microvasculares que se pueden presentar a nivel del polo posterior


A 66 year-old patient, monitored for diabetic retinopathy refractory to multiple treatment methods despite a good metabolic control, referred to progressive weight loss. For this reason, a systemic study was performed, detecting anaemia, elevation of the erythrocyte sedimentation rate, and hyperproteinaemia due to elevated serum levels of monoclonal IgM. Subsequently, by performing a bone marrow biopsy and genetic study, the diagnosis of Waldenström macroglobulinaemia was made. Waldenström's macroglobulinaemia is a low frequency lymphoproliferative disease, for which the main manifestation is a hyperviscosity syndrome that can produce ophthalmological signs detectable by funduscopy and imaging tests. A multimodal study is useful in the diagnosis and monitoring of retinal involvement. The incorporation of angiography by optical coherence tomography allows a more precise study of the microvascular disorders that may occur at the posterior pole level


Assuntos
Idoso , Retinopatia Diabética/complicações , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/patologia , Macroglobulinemia de Waldenstrom/classificação , Macroglobulinemia de Waldenstrom/diagnóstico , Pacientes/classificação , Doenças Hematológicas/sangue , Doenças Hematológicas/classificação , Doenças Hematológicas/diagnóstico , Epitélio/diagnóstico por imagem , Epitélio/patologia
15.
Arch. Soc. Esp. Oftalmol ; 94(2): 95-99, feb. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-180372

RESUMO

La glomerulonefritis membranoproliferativa mediada por complemento es una enfermedad rara, pero puede asociarse a alteraciones retinianas. Por ello, el propósito de este estudio fue valorar una serie de casos con dicho diagnóstico en seguimiento por nefrología en nuestro centro. Se realizó un estudio transversal de 8 pacientes diagnosticados de glomerulonefritis membranoproliferativa mediada por complemento. Se realizó funduscopia, tomografía de coherencia óptica (OCT) y angio-OCT de dominio Swept Source. Uno de los 8 pacientes presentaba depósitos drusenoides que se localizaron bajo el epitelio pigmentario retiniano en la OCT, descartándose la presencia de neovascularización coroidea asociada en la angio-OCT. Por tanto, la glomerulonefritis membranoproliferativa puede producir alteraciones retinianas con drusas o desprendimientos del epitelio pigmentario retiniano, por lo que debe hacerse un adecuado diagnóstico diferencial con la degeneración macular asociada a la edad. Es crucial realizar un seguimiento en estos pacientes ante las posibles complicaciones que pueden desembocar en una pérdida de visión


Complement-mediated membranoproliferative glomerulonephritis is a rare progressive glomerular disease. In some patients it can be associated with retinal lesions. Therefore, the purpose of this study was to assess a case series with this diagnosis in our hospital. A cross-sectional study was conducted on 8 patients diagnosed with complement-mediated membranoproliferative glomerulonephritis. Funduscopy, optical coherence tomography (OCT) and Swept Source domain OCT angiography were performed. Only 1 of the 8 patients showed drusen-like deposits that were located under the retinal pigment epithelium in the OCT, with the presence of associated choroidal neovascularization being ruled out in OCT angiography. Therefore, membranoproliferative glomerulonephritis may produce retinal alterations with drusen or retinal pigment epithelium detachment, and requires an appropriate differential diagnosis to be made with age-related macular degeneration. The follow-up of these patients is important in order to detect vision-threatening complications


Assuntos
Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Glomerulonefrite Membranoproliferativa , Retina/patologia , Pacientes/classificação , Tomografia/classificação , Epitélio/patologia , Drusas Retinianas/classificação , Degeneração Macular/classificação , Degeneração Macular/diagnóstico
16.
Yonsei Med J ; 60(2): 163-173, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30666838

RESUMO

PURPOSE: This study was undertaken to explore how miR-206 represses osteosarcoma (OS) development. MATERIALS AND METHODS: Expression levels of miR-206, PAX3, and MET mRNA were explored in paired OS and adjacent tissue specimens. A patient-derived OS cell line was established. miR-206 overexpression and knockdown were achieved by lentiviral transduction. PAX3 and MET overexpression were achieved by plasmid transfection. Treatment with hepatocyte growth factor (HGF) was utilized to activate c-Met receptor. Associations between miR-206 and PAX3 or MET mRNA in OS cells were verified by AGO2-RNA immunoprecipitation assay and miRNA pulldown assay. OS cell malignancy was evaluated in vitro by cell proliferation, metastasis, and apoptosis assays. PAX3 and MET gene expression in OS cells was assayed by RT-qPCR and Western blot. Activation of PI3K-AKT and MAPK-ERK in OS cells were assayed by evaluating Akt1 Ser473 phosphorylation and total threonine phosphorylation of Erk1/2, respectively. RESULTS: Expression levels of miR-206 were significantly decreased in OS tissue specimens, compared to adjacent counterparts, and were inversely correlated with expression of PAX3 and MET mRNA. miR-206 directly interacted with PAX3 and MET mRNA in OS cells. miR-206 overexpression significantly reduced PAX3 and MET gene expression in OS cells in vitro, resulting in significant decreases in Akt1 and Erk1/2 activation, cell proliferation, and metastasis, as well as increases in cell apoptosis, while miR-206 knockdown showed the opposite effects. The effects of miR-206 overexpression on OS cells were reversed by PAX3 or MET overexpression, but only partially attenuated by HGF treatment. CONCLUSION: miR-206 reduces OS cell malignancy in vitro by targeting PAX3 and MET gene expression.


Assuntos
Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Mesoderma/patologia , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Fator de Transcrição PAX3/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , MicroRNAs/genética , Metástase Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Nature ; 565(7739): 312-317, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30602793

RESUMO

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Epitélio , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Mutação , Lesões Pré-Cancerosas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/genética , Biópsia , Contagem de Células , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Células Clonais/metabolismo , Células Clonais/patologia , Variações do Número de Cópias de DNA , Epitélio/metabolismo , Epitélio/patologia , Evolução Molecular , Feminino , Interação Gene-Ambiente , Genoma Humano/genética , Humanos , Lactente , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Acúmulo de Mutações , Proteína Fosfatase 2C/genética , Receptor Notch1/genética , Fatores de Risco , Análise de Sequência de DNA , Análise de Célula Única , Fumar/genética , Adulto Jovem
18.
J Coll Physicians Surg Pak ; 29(1): 33-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30630566

RESUMO

OBJECTIVE: To differentiate between adenocarcinoma cells and reactive mesothelial cells (RMC) in serous effusions using a limited immuno-panel of Ber-EP4 and Calretinin. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Pathology, Allama Iqbal Medical College, Lahore, in collaboration with the Departments of Surgery, Pulmonology and Oncology, Jinnah Hospital, Lahore, from March 2015 to March 2016. METHODOLOGY: Ninety-seven clinically and radiologically proven cases of peritoneal and pleural effusion and peritoneal wash of patients with suspicion of malignancy were included in the present study. Diagnostic accuracy of a limited immuno-panel of Calretinin and Ber-EP4 for diagnosis of malignant effusions was calculated using histopathology as gold standard. RESULTS: The sensitivity of Ber-EP4 for malignant cases was 98.6%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value (NPV) 96%, and diagnostic accuracy 98.9%. Sensitivity of Calretinin as positive staining for RMC was 79.2%, specificity and positive predictive value (PPV) 100%, negative predictive value (NPV) 93.6%, and diagnostic accuracy 94.8%. CONCLUSION: Limited immuno-panel of Calretinin and Ber-EP4 had a high positive and negative predictive value and is cost-effective in resource limited set-up for identification of adenocarcinoma cells and reactive mesothelial cells in challenging cases of serous effusions.


Assuntos
Biomarcadores Tumorais/imunologia , Calbindina 2/imunologia , Mesotelioma/diagnóstico , Mesotelioma/patologia , Derrame Pericárdico/patologia , Derrame Pleural Maligno/patologia , Derrame Pleural/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Biópsia , Calbindina 2/metabolismo , Células Epiteliais/metabolismo , Epitélio/patologia , Humanos , Imuno-Histoquímica , Mesotelioma/metabolismo , Derrame Pericárdico/diagnóstico , Derrame Pleural/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/imunologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade
20.
Mater Sci Eng C Mater Biol Appl ; 94: 484-492, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423733

RESUMO

In the present study, we investigated the applications of ultrasonicated graphene oxide (UGO) for bone regeneration and skin wound healing. Ultrasonication of a GO suspension increased the dispersion and stability (by increasing the zeta potential) of the GO suspension. UGO has fewer oxygen-containing groups but still displays excellent water dispersion. The UGO supension showed high biocompatibility for human fetal osteoblast (hFOB cells), human endothelial cells (EA.hy 926 cells), and mouse embryonic fibroblasts. Importantly, UGO could support cell attachment and proliferation, in addition to promoting the osteogenesis of seeded cells and the promotion of new bone formation. In addition, a 1% UGO supension enhanced cell migration in an in vitro skin scratch assay and promoted wound closure in an in vivo rat excisional skin defect model. These results showed that UGO offers a good environment for cells involved in bone and skin healing, suggesting its potential application in tissue regeneration.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Osso e Ossos/fisiologia , Grafite/farmacologia , Teste de Materiais , Pele/patologia , Ultrassom/métodos , Cicatrização/efeitos dos fármacos , Animais , Osso e Ossos/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/patologia , Humanos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Pele/efeitos dos fármacos , Sus scrofa
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