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1.
Nat Commun ; 11(1): 4411, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879313

RESUMO

The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on time-of-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.


Assuntos
Aquaporina 4/metabolismo , Líquido Cefalorraquidiano/metabolismo , Ritmo Circadiano/fisiologia , Sistema Glinfático/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cisterna Magna/metabolismo , Linfonodos/metabolismo , Camundongos
2.
Nat Commun ; 11(1): 4113, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807791

RESUMO

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfonodos/metabolismo , Animais , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Concentração de Íons de Hidrogênio , Imunoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfofrutoquinase-1/genética , Fosfofrutoquinase-1/metabolismo
3.
Nat Commun ; 11(1): 3990, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778659

RESUMO

The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Here, we report that B cell-specific deletion of the X-linked gene, Cosmc, and the consequent decrease of protein O-glycosylation, induces developmental blocks of mouse B cells. After transfer into wild-type recipient, Cosmc-null B cells fail to home to lymph nodes as well as non-lymphoid organs. Enzymatic desialylation of wild-type B cells blocks their migration into lymph nodes, indicating a requirement of sialylated O-glycans for proper trafficking. Mechanistically, Cosmc-deficient B cells have normal rolling and firm arrest on high endothelium venules (HEV), thereby attributing their inefficient trafficking to alterations in the subsequent transendothelial migration step. Finally, Cosmc-null B cells have defective chemokine signaling responses. Our results thus demonstrate that Cosmc and its effects on O-glycosylation are important for controlling B cell homing.


Assuntos
Linfócitos B/metabolismo , Linfonodos/metabolismo , Chaperonas Moleculares/metabolismo , Animais , Movimento Celular , Feminino , Glicosilação , Humanos , Imunidade Humoral/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Polissacarídeos/metabolismo , Transcriptoma , Vênulas
4.
Oncol Res Treat ; 43(7-8): 346-353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645702

RESUMO

INTRODUCTION: Mammary Paget's disease (MPD) is a rare cutaneous manifestation. Epidemiologically, more than half of the MPD patients concurrently have underlying invasive ductal carcinoma (MPD-IDC), and their prognosis remains poor despite multimodal treatments of breast cancer have markedly improved patients' survival. Accordingly, it is crucial to seek out novel therapeutic targets of MPD-IDC. As an emerging biological marker, the value of androgen receptor (AR) in MPD-IDC is inconsistent. Our objectives were to investigate the associations between AR and clinicopathological factors, and to explore its prognostic value in MPD-IDC. METHODS: We retrospectively analyzed data from 103 MPD-IDC patients, and immunohistochemical staining was used to determine their AR statuses. RESULTS: AR was expressed in 44 patients (42.7%), and AR expression was significantly correlated with body mass index (BMI) (p = 0.038) and axillary lymph node (ALN) status (p = 0.025). Kaplan-Meier curves showed that AR positivity was significantly associated with better overall survival (OS) in MPD-IDC patients (p = 0.019) and estrogen receptor-negative MPD-IDC patients (p = 0.039). Multivariate Cox regression analysis revealed that AR was not an independent prognostic indicator of disease-free survival (DFS) or OS in MPD-IDC patients (p = 0.395 and p = 0.073, respectively). CONCLUSIONS: In contrast to AR-negative tumors, patients with AR-positive ones were more likely to have lower BMI, no ALN metastasis, and better OS. AR-targeted treatments for MPD-IDC may add to existing therapeutic approaches to improve their effectiveness.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Linfonodos/patologia , Doença de Paget Mamária/patologia , Receptores Androgênicos/metabolismo , Adulto , Idoso , Axila , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Feminino , Humanos , Linfonodos/metabolismo , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Doença de Paget Mamária/metabolismo , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
5.
Cancer Radiother ; 24(4): 335-339, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32444284

RESUMO

Hodgkin lymphoma (HL) is a disease characterized by a high curability rate, and the treatment benefit-risk balance must be carefully addressed to achieve complete disease control with low risk of long-term toxicities. Most patients are treated with a combination of chemotherapy and radiotherapy, after disease staging and response to treatment evaluated by FDG PET/CT. We report the case of a 28-year-old patient concomitantly diagnosed of a Hodgkin lymphoma and active tuberculosis. Initial staging was difficult due to pulmonary and abdominal tuberculosis localization that induced FDG PET/CT hypermetabolism. Anti-tuberculosis treatment was first started, allowing secondary an early accurate Hodgkin lymphoma staging by FDG PET/CT. The patient was then treated by chemotherapy and radiotherapy. Helical TomoTherapy® was used with involved site (IS) irradiation volume was performed to decrease the high doses to organs-at-risk (OAR), especially lungs in this context of tuberculosis.


Assuntos
Doenças do Colo/tratamento farmacológico , Doença de Hodgkin/terapia , Tuberculose Gastrointestinal/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antituberculosos/uso terapêutico , Bleomicina/administração & dosagem , Doenças do Colo/complicações , Doenças do Colo/diagnóstico por imagem , Doenças do Colo/metabolismo , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Doença de Hodgkin/complicações , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/metabolismo , Humanos , Pulmão , Linfonodos/diagnóstico por imagem , Linfonodos/metabolismo , Masculino , Órgãos em Risco , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radioterapia de Intensidade Modulada , Medição de Risco , Tomografia Computadorizada por Raios X , Tuberculose Gastrointestinal/complicações , Tuberculose Gastrointestinal/diagnóstico por imagem , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico por imagem , Vimblastina/administração & dosagem
6.
Respir Investig ; 58(4): 232-238, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32305227

RESUMO

Sarcoidosis is a multisystemic granulomatous disorder of unknown etiology. Diagnosis of sarcoidosis is made by correlating clinical and radiological features along with the histopathological demonstration of non-necrotizing granulomas in tissue samples. Diagnosis is often challenging as the clinical profile may mimic other granulomatous disorders, including infections, inflammatory diseases, and lymphoid malignancies. Differentiation from tuberculosis is especially crucial in endemic regions where exclusion of mediastinal tuberculosis is necessary before any immunosuppressant treatment can be initiated for symptomatic sarcoidosis. Identification of biomarkers, which can aid in diagnosis as well as prognosis, can be helpful in clinical decision making. MicroRNAs are small non-coding regulatory RNAs that serve as post-transcriptional regulators of gene expression and have been studied as emerging biomarkers in many other respiratory diseases, including lung cancer, asthma, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. In the context of sarcoidosis, miRNA expression has been studied in the lungs, lymph nodes, bronchoalveolar lavage fluid, and peripheral blood mononuclear cells. A comprehensive search of the PubMed database was performed by two authors independently, and relevant studies were retrieved for review. This systematic review summarizes the current information on miRNAs in sarcoidosis, the biological mechanisms involved in CD4+ T-helper 1 and macrophage polarization, and the use of exhaled breath condensate as an alternative, noninvasive and potential source of miRNAs.


Assuntos
MicroRNAs/análise , Sarcoidose Pulmonar/diagnóstico por imagem , Biomarcadores/análise , Testes Respiratórios , Líquido da Lavagem Broncoalveolar , Linfócitos T CD4-Positivos , Diagnóstico Diferencial , Expressão Gênica , Humanos , Leucócitos Mononucleares , Pulmão/metabolismo , Linfonodos/metabolismo , Macrófagos , MicroRNAs/genética , Linfócitos T Auxiliares-Indutores
7.
Nat Commun ; 11(1): 1110, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111828

RESUMO

Targeted delivery of a nanovaccine loaded with a tumor antigen and adjuvant to the lymph nodes (LNs) is an attractive approach for improving cancer immunotherapy outcomes. However, the application of this technique is restricted by the paucity of suitable tumor-associated antigens (TAAs) and the sophisticated technology required to identify tumor neoantigens. Here, we demonstrate that a self-assembling melittin-lipid nanoparticle (α-melittin-NP) that is not loaded with extra tumor antigens promotes whole tumor antigen release in situ and results in the activation of antigen-presenting cells (APCs) in LNs. Compared with free melittin, α-melittin-NPs markedly enhance LN accumulation and activation of APCs, leading to a 3.6-fold increase in antigen-specific CD8+ T cell responses. Furthermore, in a bilateral flank B16F10 tumor model, primary and distant tumor growth are significantly inhibited by α-melittin-NPs, with an inhibition rate of 95% and 92%, respectively. Thus, α-melittin-NPs induce a systemic anti-tumor response serving as an effective LN-targeted whole-cell nanovaccine.


Assuntos
Vacinas Anticâncer/imunologia , Sistemas de Liberação de Medicamentos , Linfonodos/imunologia , Meliteno/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Vacinas Anticâncer/metabolismo , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Imunoterapia , Lipídeos/administração & dosagem , Lipídeos/química , Linfonodos/metabolismo , Meliteno/química , Meliteno/imunologia , Meliteno/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/terapia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nanotoxicology ; 14(4): 554-576, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32216600

RESUMO

No detailed information on in vivo biokinetics of CeO2 nanoparticles (NPs) following chronic low-dose inhalation is available. The CeO2 burden for lung, lung-associated lymph nodes, and major non-pulmonary organs, blood, and feces, was determined in a chronic whole-body inhalation study in female Wistar rats undertaken according to OECD TG453 (6 h per day for 5 days per week for a 104 weeks with the following concentrations: 0, 0.1, 0.3, 1.0, and 3.0 mg/m3, animals were sacrificed after 3, 12, 24 months). Different spectroscopy methods (ICP-MS, ion-beam-microscopy) were used for the quantification of organ burden and for visualization of NP distribution patterns in tissues. After 24 months of exposure, the highest CeO2 lung burden (4.41 mg per lung) was associated with the highest aerosol concentration and was proportionally lower for the other groups in a dose-dependent manner. Imaging techniques confirmed the presence of CeO2 agglomerates of different size categories within lung tissue with a non-homogenous distribution. For the highest exposure group, after 24 months in total 1.2% of the dose retained in the lung was found in the organs and tissues analyzed in this study, excluding lymph nodes and skeleton. The CeO2 burden per tissue decreased from lungs > lymph nodes > hard bone > liver > bone marrow. For two dosage groups, the liver organ burden showed a low accumulation rate. Here, the liver can be regarded as depot, whereas kidneys, the skeleton, and bone marrow seem to be dumps due to steadily increasing NP burden over time.


Assuntos
Cério/farmacocinética , Exposição por Inalação/análise , Pulmão/metabolismo , Linfonodos/metabolismo , Nanopartículas/metabolismo , Aerossóis , Animais , Carga Corporal (Radioterapia) , Cério/sangue , Relação Dose-Resposta a Droga , Fezes/química , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Modelos Biológicos , Especificidade de Órgãos , Tamanho da Partícula , Ratos , Ratos Wistar , Propriedades de Superfície , Distribuição Tecidual
9.
Invest Ophthalmol Vis Sci ; 61(3): 8, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150250

RESUMO

Purpose: Thymic stromal lymphopoietin (TSLP) is a pro-allergic cytokine that initiates allergic inflammatory reaction between epithelial and dendritic cells (DCs). miR-19b was reported to suppress TSLP expression. The present study aimed to examine miR-19b expression, regulation, and function in allergic conjunctivitis (AC). Methods: A murine model of experimental AC was induced in BALB/c mice by short ragweed pollen. The serum, eye balls, conjunctiva, and cervical lymph nodes (CLN) were used for the study. Gene expression was determined by RT-PCR, whereas protein production and activation were evaluated by immunostaining, ELISA, and Western blotting. Results: In the murine AC model, miR-19b was aberrantly downregulated, whereas the levels of TSLP and p-STAT3, as well as the number of CD11c+ pSTAT3+ DCs were increased. Moreover, Th2 inflammatory cytokine expression was significantly increased. These severe phenotypes could be counteracted by either applying exogenous miR-19b mimic microRNAs or the JAK/STAT inhibitor CYT387. Moreover, overexpression of miR-19b repressed p-STAT3 expression and the number of CD11c+ cells in AC eye and CLN tissues. Conclusions: These findings suggested that miR-19b reduced ocular surface inflammation by inhibiting Stat3 signaling via TSLP downregulation in a murine AC model. Moreover, the present study further demonstrated the clinical potential of applying miR-19b and anti-JAK/STAT therapies in the treatment of AC.


Assuntos
Conjuntivite Alérgica/genética , Janus Quinases/fisiologia , MicroRNAs/genética , Fatores de Transcrição STAT/fisiologia , Animais , Antígenos de Plantas , Antígenos CD11/metabolismo , Vértebras Cervicais , Túnica Conjuntiva/metabolismo , Conjuntivite Alérgica/imunologia , Conjuntivite Alérgica/metabolismo , Córnea/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Janus Quinases/antagonistas & inibidores , Linfonodos/metabolismo , Camundongos Endogâmicos BALB C , MicroRNAs/biossíntese , Fenótipo , Extratos Vegetais , Fatores de Transcrição STAT/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
10.
PLoS One ; 15(3): e0229463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214355

RESUMO

Food and feeds contaminated with mycotoxins have been a threat to the rearing industry by causing some of the most fatal toxic reactions not only in the farm animals but also in humans who consume them. Toxicity to juvenile goats was induced by feed contamination with T-2 toxin (at 10 and 20 ppm dosage; group I and II, respectively). The toxicity impact was assessed on days 15 and 30 post treatment with respect to growth performance, oxidative stress, apoptotic studies and detailed pathomorphology. The study revealed that apart from the obvious clinical toxicosis (weakness, lethargy, and retardation in growth), the toxin fed groups also exhibited significant haematological (reduced hemoglobin, total leukocyte and thrombocyte counts) and biochemical changes (increased levels of oxidative stress markers with concomitant decrease in levels of serum and tissue catalase and superoxide dismutase). The pathomorphological and histological alterations suggested that the liver and intestine were the most affected organs. Ultra-structurally, varying degrees of degeneration, cytoplasmic vacuolations and pleomorphic mitochondria were observed in the hepatocytes and the enterocytes of the intestine. Kidney also revealed extensive degeneration of the cytoplasmic organelles with similar condensation of the heterochromatin whereas the neuronal degeneration was characterized by circular, whirling structures. In addition, the central vein and portal triad of the hepatocytes, cryptic epithelial cells of the intestine, MLNs in the lymphoid follicles, PCT and DCT of the nephronal tissues and the white pulp of the spleen exhibited extensive apoptosis. In this study, it was also observed that the expression of HSPs, pro-apoptotic proteins and pro-inflammatory cytokines were significantly upregulated in response to the toxin treatment. These results suggest that the pathogenesis of T-2 toxicosis in goats employs oxidative, apoptotic and inflammatory mechanisms.


Assuntos
Apoptose , Regulação da Expressão Gênica/efeitos dos fármacos , Cabras/fisiologia , Mediadores da Inflamação/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Toxina T-2/toxicidade , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Proteínas de Choque Térmico/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
11.
PLoS One ; 15(2): e0229007, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049988

RESUMO

BACKGROUND AND AIMS: Curative surgery saves ≈50% of all patients with colorectal cancer (CRC) while remaining patients have synchronous or will develop metachronous metastases. Presently, the single most important prognostic factor is histopathological detection of disseminated tumor cells in regional lymph nodes. However, the routine method has several limitations. The aim was to identify biomarker mRNAs that could be combined in a formula that would allow better prediction of patients' survival after surgery. METHODS: Screening for biomarker mRNAs overexpressed in CRC was performed by genome-wide hybridization bead array, with verification by qRT-PCR. Specific qRT-PCR assays with copy standards were developed for 5 selected genes and mRNA expression levels determined in lymph nodes from 174 CRC patients (517 nodes) and 24 control patients (118 nodes). Prognostic value of biomarker mRNAs was estimated. A cut-off was set using univariate Cox regression analysis and used for calculation of differences between patient groups in disease-free survival 12 years after surgery (Kaplan-Meier survival model) and risk for recurrent disease (Cox's regression analysis). A formula was constructed for evaluation of the prognostic value of the biomarkers in combination. RESULTS: Two new biomarkers, SLC35D3 and POSTN with prognostic value were identified. SLC35D3 was expressed in the epithelium derived tumor cells and POSTN in fibroblasts. Combined with CEACAM5, KLK6 and MUC2 they could be used to identify risk groups. A formula was constructed using CEACAM5 as denominator for KLK6, SLC35D3 and MUC2 and 18S rRNA as denominator for POSTN. The formula yielded 5 categories (-1, 0, 1, 2, 3). Categories (-1 and 0) had good prognosis, categories (1 and 2) relatively poor prognosis and category (3) very poor prognosis. CONCLUSION: Lymph node analysis using 5 selected biomarker mRNAs and 18S rRNA in combination allowed allocation of CRC patients to different risk categories with respect to recurrent disease.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Linfonodos , RNA Neoplásico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Células Jurkat , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Mensageiro , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Medição de Risco
12.
Ann Hematol ; 99(2): 241-253, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897674

RESUMO

This study aims to investigate the clinicopathological features of in situ follicular neoplasm (ISFN) in Japan. ISFN is a rare condition formerly considered as an early precursor of follicular lymphoma (FL). This is a first original report of ISFN from Asian country. We reviewed 19 biopsy samples of ISFN. ISFNs were categorized into two groups: (1) ISFN, consisting of ISFN with strong positivity for BCL-2 immunohistochemical staining (IHC), and obvious translocation of BCL-2; and (2) ISFN-like FL, featuring cases without obvious translocation but having morphological features and characteristic IHC findings of ISFN. As control, we adopted obvious FL. For some cases showing coexisting ISFN and FL lesions in the same lymph node, we could conduct further clonality analysis for each lesion. Nine of the 19 cases of ISFN coexisted with FL or had a history of overt B- or T-cell lymphoma including FL. Statistical comparison among ISFN-like FL and FL showed no significant differences in pathological features. Molecular analysis suggested that ISFN lesion and FL lesion in the same lymph node each have a different clonality. ISFN coexists or associates with other overt lymphomas frequently.


Assuntos
Linfonodos/metabolismo , Linfoma Folicular , Segunda Neoplasia Primária , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Japão , Linfonodos/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia
13.
Asian Pac J Cancer Prev ; 21(1): 37-41, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31983161

RESUMO

OBJECTIVE: The aim of current study was to investigate the expression of Cyclin D1 and Ki-67 in primary and metastatic oral squamous cell carcinoma (OSCC) and their different histological grades. METHODS: Paraffin embedded 30 oral squamous cell carcinoma (15 each of primary and cervical lymph node metastatic OSCC) were included in the study. Cyclin D1 and Ki 67 expressions were evaluated by immunohistochemistry and compared in primary and lymph node metastasis of OSCC and their histological grades. The data was analyzed using SPSS software. RESULTS: The mean age of patients with primary OSCC was 53.47 ±16.67 years and 61.47 ±11.94 years in patients with metastasis. Males were comparatively affected more than females with tongue as the most common site involved in both primary and metastatic tumours. The mean size of primary and metastatic tumour biopsies were 1.16 mm and 3.93 mm respectively. Comparison of the expression of Cyclin D1 in these primary and metastatic OSCC revealed a statistically significant difference (p = 0.003) whereas it was insignificant for Ki-67 (p = 0.715). CONCLUSION: Cyclin D1 can be a useful marker in predicting aggressive or metastatic behaviour of OSCC on premier biopsies.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ciclina D1/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Bucais/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Prognóstico , Estudos Retrospectivos
14.
Monoclon Antib Immunodiagn Immunother ; 39(1): 23-26, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916900

RESUMO

Stromal cell-derived factor-2 (SDF-2) is reportedly involved in multiple endoplasmic reticulum (ER) functions, including the misfolded protein catabolic process, protein glycosylation, and ER protein quality control. However, the precise molecular and cellular functions of SDF-2 remain unknown. Previously, we discovered that SDF-2 mediates acquired resistance to oxaliplatin in human gastric cancer cells. In this study, we have generated SDF-2-specific monoclonal antibodies (mAbs), using the rat medial iliac lymph node method, as a tool to explore novel mechanisms of oxaliplatin resistance. The antibodies detected endogenous human SDF-2 in immunoblotting analyses. In addition, immunoprecipitation analyses revealed the availability of these antibodies for human SDF-2. Thus, these mAbs will be available to elucidate molecular and cellular functions of SDF-2 in cancer cells.


Assuntos
Anticorpos Monoclonais/imunologia , Proteínas/imunologia , Animais , Immunoblotting , Imunoprecipitação , Linfonodos/imunologia , Linfonodos/metabolismo , Oxaliplatina , Ratos
15.
Sci Rep ; 10(1): 1214, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988383

RESUMO

The study examined germinal centre (GC) reaction in lymph nodes draining inflamed joints and adjacent tissues (dLNs) in male and female Dark Agouti rat collagen type II (CII)-induced arthritis (CIA) model of rheumatoid arthritis. Female rats exhibiting the greater susceptibility to CIA mounted stronger serum CII-specific IgG response than their male counterparts. This correlated with the higher frequency of GC B cells in female compared with male dLNs. Consistently, the frequency of activated/proliferating Ki-67+ cells among dLN B cells was higher in females than in males. This correlated with the shift in dLN T follicular regulatory (Tfr)/T follicular helper (Tfh) cell ratio towards Tfh cells in females, and greater densities of CD40L and CD40 on their dLN T and B cells, respectively. The higher Tfh cell frequency in females was consistent with the greater dLN expression of mRNA for IL-21/27, the key cytokines involved in Tfh cell generation and their help to B cells. Additionally, in CII-stimulated female rat dLN cell cultures IFN-γ/IL-4 production ratio was shifted towards IFN-γ. Consistently, the serum IgG2a(b)/IgG1 CII-specific antibody ratio was shifted towards an IgG2a(b) response in females. Thus, targeting T-/B-cell interactions should be considered in putative further sex-based translational pharmacology research.


Assuntos
Artrite Experimental/patologia , Linfócitos B/metabolismo , Fatores Sexuais , Animais , Artrite Experimental/sangue , Artrite Experimental/metabolismo , Linfócitos B/imunologia , Células Cultivadas , Colágeno Tipo II/imunologia , Colágeno Tipo II/metabolismo , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Linfonodos/metabolismo , Masculino , Ratos , Caracteres Sexuais , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
16.
Am J Physiol Heart Circ Physiol ; 318(1): H116-H123, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809213

RESUMO

In humans, loss of central tolerance for the cardiac self-antigen α-myosin heavy chain (α-MHC) leads to circulation of cardiac autoreactive T cells and renders the heart susceptible to autoimmune attack after acute myocardial infarction (MI). MI triggers profound tissue damage, releasing danger signals and self-antigen by necrotic cardiomyocytes, which lead to recruitment of inflammatory monocytes. We hypothesized that excessive inflammation by monocytes contributes to the initiation of adaptive immune responses to cardiac self-antigen. Using an experimental model of MI in α-MHC-mCherry reporter mice, which specifically express mCherry in cardiomyocytes, we detected α-MHC antigen in myeloid cells in the heart-draining mediastinal lymph node (MLN) 7 days after MI. To test whether monocytes were required for cardiac self-antigen trafficking to the MLN, we blocked monocyte recruitment with a C-C motif chemokine receptor type 2 (CCR2) antagonist or immune modifying nanoparticles (IMP). Blockade of monocyte recruitment reduced α-MHC antigen detection in the MLN after MI. Intramyocardial injection of the model antigen ovalbumin into OT-II transgenic mice demonstrated the requirement for monocytes in antigen trafficking and T-cell activation in the MLN. Finally, in nonobese diabetic mice, which are prone to postinfarction autoimmunity, blockade of monocyte recruitment reduced α-MHC-specific responses leading to improved tissue repair and ventricular function 28 days after MI. Taken together, these data support a role for monocytes in the onset of pathological cardiac autoimmunity following MI and suggest that therapeutic targeting of monocytes may mitigate postinfarction autoimmunity in humans.NEW & NOTEWORTHY Our study newly identifies a role for inflammatory monocytes in priming an autoimmune T-cell response after myocardial infarction. Select inhibition of monocyte recruitment to the infarct prevents trafficking of cardiac self-antigen and activation of cardiac myosin reactive T cells in the heart-draining lymph node. Therapeutic targeting of inflammatory monocytes may limit autoimmune responses to improve cardiac remodeling and preserve left ventricular function after myocardial infarction.


Assuntos
Imunidade Adaptativa , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Comunicação Celular , Ativação Linfocitária , Monócitos/imunologia , Infarto do Miocárdio/imunologia , Miocárdio/imunologia , Animais , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Feminino , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Monócitos/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Cadeias Pesadas de Miosina/imunologia , Cadeias Pesadas de Miosina/metabolismo , Transdução de Sinais , Função Ventricular Esquerda , Remodelação Ventricular
18.
Cancer Lett ; 469: 287-300, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31705928

RESUMO

Cervical cancer remains the first leading cause of cancer-related mortality among female reproductive system malignancies worldwide, and invasion and lymph node metastasis of cervical cancer represent the major reason for its poor prognosis. In this study, we found that RACK1 facilitated tumor cell invasion and lymphatic tube formation in vitro, as well as promoted lymphangiogenesis and lymph node metastasis in vivo in a galectin-1-dependent manner. Mechanism studies revealed that RACK1 promoted the expression and secretion of galectin-1 by reducing miR-1275 levels. Additionally, RACK1 also augmented galectin-1-induced downstream MEK/ERK, FAK, and AKT signaling via integrin-ß1 in cervical cancer cells. Tissue microarray confirmed that RACK1 was upregulated in squamous intraepithelial lesion and cancer, and RACK1 was positively correlated with invasion/metastasis phenotype, galectin-1 expression, and unfavorable prognosis in cervical cancer cases. Human papillomavirus E6 oncogene contributes to increased expression of RACK1 via the enhancement of its O-GlcNAcylation and protein stability. Together, our results demonstrate that RACK1 stimulates tumor invasion and lymph node metastasis of cervical cancer via galectin-1 and imply that targeting RACK1/galectin-1 axis provides promising means for cervical cancer treatment.


Assuntos
Carcinoma de Células Escamosas/genética , Galectina 1/genética , Metástase Linfática/genética , Proteínas de Neoplasias/genética , Receptores de Quinase C Ativada/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfangiogênese/genética , Metástase Linfática/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Transdução de Sinais/genética , Neoplasias do Colo do Útero/patologia
19.
PLoS One ; 14(12): e0226357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826004

RESUMO

Lymphoma is the most common hematopoietic tumour in dogs and is remarkably similar to the human disease. Tumour biomarker discovery is providing new tools for diagnostics and predicting therapeutic response and clinical outcome. MicroRNAs are small non-coding RNAs that participate in post-transcriptional gene regulation and their aberrant expression can impact genes involved in cancer. The aim of this study was to characterize microRNA expression in lymph nodes and plasma from dogs with multicentric B or T cell lymphoma compared to healthy control dogs. We further compared expression between lymph nodes and corresponding plasma samples and assessed changes in expression at relapse compared to time of diagnosis. Lastly, we investigated microRNAs for association with clinical outcome in patients treated with CHOP chemotherapy. A customized PCR array was utilized to profile 38 canine target microRNAs. Quantification was performed using real time RT-qPCR and relative expression was determined by the delta-delta Ct method. In lymph nodes, there were 16 microRNAs with significantly altered expression for B cell lymphoma and 9 for T cell lymphoma. In plasma, there were 15 microRNAs altered for B cell lymphoma and 3 for T cell lymphoma. The majority of microRNAs did not have correlated expression between lymph node and plasma and only 8 microRNAs were significantly different between diagnosis and relapse. For B cell lymphoma, 8 microRNAs had differential expression in the non-remission group compared to dogs that completed CHOP in complete remission. Four of these microRNAs were also altered in patients that died prior to one-year. Kaplan-Meier survival curves for high versus low microRNA expression revealed that 10 microRNAs were correlated with progression-free survival and 3 with overall survival. This study highlights microRNAs of interest for canine multicentric lymphoma. Future goals include development of microRNA panels that may be useful as biomarkers with the intent to provide improved outcome prediction to veterinary cancer patients.


Assuntos
Doenças do Cão/diagnóstico , Linfoma de Células B/diagnóstico , Linfoma de Células T/diagnóstico , MicroRNAs/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclofosfamida/uso terapêutico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/genética , Doenças do Cão/mortalidade , Cães , Doxorrubicina/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Imunofenotipagem , Estimativa de Kaplan-Meier , Linfonodos/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/mortalidade , Masculino , MicroRNAs/sangue , Recidiva Local de Neoplasia , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Resultado do Tratamento , Vincristina/uso terapêutico
20.
Acta Clin Croat ; 58(2): 343-347, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31819332

RESUMO

Twenty to thirty percent of patients with clinical stage I testicular tumor have metastases in the retroperitoneum. The aim of this study was to evaluate the role of OCT4 immunohistochemistry in histopathologic diagnosis of lymph node metastases in patients with nonseminomatous germ cell testicular tumors. All clinical stage I patients with staging laparoscopic retroperitoneal lymphadenectomy from 2001 until 2009 were included. Archived materials of dissected lymph nodes were reassessed and additional immunohistochemical staining with OCT4 antibody was performed in patients diagnosed as free from metastases. Each slide was visually estimated for the percentage of tumor cells showing nuclear immunoreactivity for OCT4. The study included 93 patients, of which 30 (32.3%) had initially positive retroperitoneal lymph nodes. Of the remaining 63 patients, materials were missing for 5 patients, so additional immunohistochemical staining was performed in 58 patients. Of these, two (3.4%) patients were OCT4 positive, suggesting a conclusion that they were initially misdiagnosed as stage I and metastasis free. OCT4 proved its value in detecting retroperitoneal metastases. Staging laparoscopic retroperitoneal lymphadenectomy for nonseminomatous germ cell testicular tumors in clinical stage I is a reasonable option for selected patients.


Assuntos
Linfonodos/metabolismo , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/secundário , Fator 3 de Transcrição de Octâmero/metabolismo , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Adolescente , Adulto , Humanos , Imuno-Histoquímica , Laparoscopia , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Espaço Retroperitoneal , Estudos Retrospectivos , Neoplasias Testiculares/secundário , Adulto Jovem
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