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1.
Anticancer Res ; 39(10): 5721-5724, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570473

RESUMO

BACKGROUND/AIM: This study aimed to identify risk factors for recurrence of patients with stage III colorectal cancer by assessing clinicopathological features. PATIENTS AND METHODS: The study included 231 patients with stage III colorectal cancer who underwent curative resection between 2006 and 2012 at the Department of Surgery of the Jikei University Hospital, Tokyo, Japan. Clinicopathological data of the patients were retrospectively evaluated. RESULTS: The recurrence rate was 27.7% (64/231) in the study group. The univariate analysis for recurrence identified five risk factors: site of primary tumor (rectal cancer), surgical procedure (open surgery), preoperative serum CEA level (>5 ng/ml), preoperative serum CA19-9 level (>37 U/ml), and number of metastatic lymph nodes (over three metastases). The multivariate analysis for recurrence identified three risk factors: rectal cancer, preoperative serum CEA level >5.0 ng/ml 95%, and more than three metastatic lymph nodes. CONCLUSION: The risk factors for stage III colorectal cancer recurrence seem to be rectal cancer, preoperative serum CEA level >5.0 ng/ml, and more than three metastatic lymph nodes.


Assuntos
Neoplasias Colorretais/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Antígeno CA-19-9/metabolismo , Antígeno Carcinoembrionário/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Japão , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Fatores de Risco
2.
Medicine (Baltimore) ; 98(31): e16461, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374007

RESUMO

Ultrasonography (USG)-guided fine needle aspiration (FNA) is widely used for diagnosis of lymph node (LN) metastasis in papillary thyroid cancer (PTC). However, FNA cytology sometimes shows inconclusive results. Recently, the measurement of thyroglobulin (Tg) in FNA washout fluid (aspirate-Tg) has been widely adopted, but there are some difficulties in the preparation of the sample and standardization of the procedure. Here, we examined serum Tg after FNA as a new predictive marker for LN metastasis of PTC. We performed USG-guided FNA cytology and examined aspirate-Tg in PTC patients showing suspicious metastatic LNs during follow-up. We measured baseline serum thyroid stimulating hormone (TSH), Tg, and Tg antibody levels before FNA, and serum Tg level within an hour after FNA. We defined aspirate-Tg level above 0.9 ng/mL as positive, and a 30% increase in serum Tg level after FNA compared to the baseline as elevation of serum Tg. Twenty-two patients were included in our study. Nine patients (40.9%) showed elevation of Tg level after FNA, and the mean value of Tg elevation was 24.8 ±â€Š48.0 ng/mL. Among these 9 patients, 8 were diagnosed with PTC and 1 patient showed cellular atypia on cytopathology. All these patients showed positive aspirate-Tg. Thirteen patients (59.1%) did not show elevation of Tg level after FNA. Among these patients, 2 had PTC, 2 had cellular atypia, and 9 yielded negative results for malignancy on cytopathology. Elevation of serum Tg level after FNA might have a diagnostic role for predicting LN metastasis of PTC.


Assuntos
Biópsia por Agulha/efeitos adversos , Tireoglobulina/análise , Câncer Papilífero da Tireoide/cirurgia , Adulto , Idoso , Biópsia por Agulha/métodos , Feminino , Humanos , Linfonodos/lesões , Linfonodos/metabolismo , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudos Retrospectivos , Tireoglobulina/sangue , Câncer Papilífero da Tireoide/complicações , Ultrassonografia/métodos
3.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 54(7): 481-486, 2019 Jul 09.
Artigo em Chinês | MEDLINE | ID: mdl-31288329

RESUMO

Objective: To investigate the feasibility and application value of toluidine bule-dextran-40 (TB-Dex-40) as the tracer for lymphatic system in head and neck region. Methods: Twenty healthy adult New Zealand white rabbits were equally divided into two groups: the experimental group (TB-Dex-40 group, n=10) and the control group (TB group, n=10). Rabbits in experimental group received submucosal injection of 1.0% (0.14 mOsm/L) TB-Dex-40, and the control group received injection of 1.0% (32.60 mOsm/L) TB.The staining time and fading time of lymphatic vessels and lymphnodes in the neck region were recorded, and the diffusion ranges of the two dyes in the tongue region were measured. Lymph nodespecimen were collected for pathological examination after 10 min, 1 hour and 4 weeks of staining. The experimental animals were sacrificed before and 4 weeks after the experiment. After death, organs of heart, lung, liver and kidney were examined pathologically. Results: TB-Dex-40 reached sentinel lymph node (SLN) and stained lymphatic vessels at an average of (21.67±0.19) s after injection, while in control group was(3.22±0.34) s (P<0.01). The time difference between the two dyes reaching sentinel lymph nodes was statistically significant.The durations from lymphatic staining to marked fading were (19.70±1.34) min in experimental group and (14.30±0.95) min in control group, respectively.The difference was statistically significant (P<0.01). SLN staining by TB-Dex-40 was still evident after 4 weeks, while TB staining has completely faded after 2 d.The average ranges of diffusionin tongue were (10.50±1.08) mm in experimental group and (20.00±1.05) mm in controlgroup, respectively. The difference was statistically significant (P<0.01).No abnormalities were found in blood test and pathological examination of main organs. Conclusions: TB-Dex-40 has high specificity forstaining lymphatic vessels and is a good tracer with potential clinical value.


Assuntos
Dextranos , Linfonodos , Vasos Linfáticos , Pescoço , Cloreto de Tolônio , Animais , Dextranos/química , Dextranos/metabolismo , Cabeça/patologia , Linfonodos/metabolismo , Linfonodos/patologia , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Pescoço/patologia , Coelhos , Fatores de Tempo , Cloreto de Tolônio/química , Cloreto de Tolônio/metabolismo
4.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
5.
J Cancer Res Clin Oncol ; 145(9): 2325-2333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317326

RESUMO

PURPOSE: Nodal positive lung adenocarcinoma includes wide range of survival. Several methods for the classification of nodal-positive lung cancer have been proposed. However, classification considering the impact of targetable genetic variants are lacking. The possibility of genetic variants for the better stratification of nodal positive lung adenocarcinoma was estimated. METHODS: Mutations of 36 genes between primary sites and metastatic lymph nodes (LNs) were compared using next-generation sequencing. Subsequently, mutations in EGFR and BRAF, rearrangements in ALK and ROS1 were evaluated in 69 resected pN1-2M0 adenocarcinoma cases. Recurrence-free survival (RFS), post-recurrence survival (PRS), and overall survival (OS) were evaluated with respect to targetable variants and tyrosine kinase inhibitor (TKI) therapy after recurrence. RESULTS: About 90% of variants were shared and allele frequencies were similar between primary and metastatic sites. In 69 pN1-2M0 cases, EGFR/ALK were positive in primary sites of 39 cases and same EGFR/ALK variants were confirmed in metastatic LNs of 96.7% tissue-available cases. Multivariate analyses indicated positive EGFR/ALK status was associated with worse RFS (HR 2.366; 95% CI 1.244-4.500; P = 0.009), and PRS was prolonged in cases receiving TKI therapy (no post-recurrence TKI therapies, HR 3.740; 95% CI 1.449-9.650; P = 0.006). OS did not differ with respect to targetable variants or TKI therapy. CONCLUSIONS: Cases harbouring targetable genetic variants had a higher risk of recurrence, but PRS was prolonged by TKI therapy. Classification according to the targetable genetic status provides a basis for predicting recurrence and determining treatment strategies after recurrence.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmão/metabolismo , Linfonodos/metabolismo , Mutação , Transcriptoma/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
6.
Int J Oncol ; 55(1): 211-222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180531

RESUMO

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent­induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co­culture system was then used to analyze the mechanisms of tumor cell­mediated disruption of lymphatic vessels. Time­lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.


Assuntos
Antígenos Nucleares/metabolismo , Autoantígenos/metabolismo , Células Endoteliais/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/metabolismo , Esferoides Celulares
7.
Biol Pharm Bull ; 42(5): 819-826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061325

RESUMO

Macrophage mannose receptor (MMR/CD206) is a promising target for the detection and identification of sentinel lymph node (SLN). MMR-targeting probes have been developed using mannosylated dextran, however, impairment of efficient targeting of SLN was often caused because of retention of injection site in which macrophages and dendritic cells exist. In this study, we prepared new MMR-targeting probes from yeast mannan (85 kDa), and its bioditribution was investigated. In-vivo evaluation showed that 11.9% of injected dose of 99mTc-labeled mannan-S-cysteines (99mTc-MSCs) was accumulated in popliteal lymph node (the SLN in this model), however, significant level of radioactivity (approximately 80%) was remained in injection site. Interestingly, 99mTc-labeled low molecular weight mannan-S-cysteine mannan (99mTc-LSC) prepared from 50 and 25 kDa mannan showed a decreased specific accumulation of 99mTc-LSC in the popliteal lymph node, while the radioactivity at the injection site remained unchanged. These results suggest that the molecular size, or nature/shape of the sugar chain is important for the specific accumulation of 99mTc-MSC in popliteal lymph node.


Assuntos
Cisteína/farmacocinética , Linfonodos/metabolismo , Mananas/farmacocinética , Animais , Cisteína/química , Mananas/química , Camundongos , Peso Molecular , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Tecnécio , Distribuição Tecidual
8.
Anticancer Res ; 39(5): 2647-2659, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092464

RESUMO

BACKGROUND/AIM: The aim of the present study was to analyze metastasized breast cancer (BC) patients with regard to the discordance of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). We especially aimed to analyze the association between the change of tumor biology and previous treatment or metastatic sites. PATIENTS AND METHODS: Patients with metastasized BC who were treated at the Department of Gynecology/Breast Center of the University Hospital of Cologne were analyzed. RESULTS: Loss of HER2 occurred more frequently in lymph node metastases that were not in the axillary region (p=0.026). Letrozole showed a significant correlation with loss of ER and/or PR (p=0.041). Improved overall survival and post-metastasis survival were noticed with a gain of HER2 (p=0.044 and p=0.009, respectively) and concordant positive ER and PR status (p=0.002 and p=0.001, respectively). CONCLUSION: The discordance of receptors and the dependence of BC on therapies as well as metastatic sites stresses the necessity of early sample taking to offer patients suitable therapy options.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , Segunda Neoplasia Primária/genética , Adulto , Idoso , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/patologia , Receptor ErbB-2/genética , Receptores de Progesterona/genética
9.
Rinsho Ketsueki ; 60(4): 302-307, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31068560

RESUMO

A 65-year-old woman was diagnosed with rheumatoid arthritis in 2010 and was treated with methotrexate (MTX). In 2012, she was diagnosed with sarcoidosis and underwent a follow-up therapy for mild peripheral neuropathy due to neurosarcoidosis. In 2018, she experienced primary splenic diffuse large B-cell lymphoma (DLBCL) and was diagnosed with sarcoidosis-lymphoma syndrome (SLS). MTX was discontinued, and six cycles of rituximab were administered combined with chemotherapy. Positron emission tomography combined with computed tomography performed 18 weeks after the last cycle of chemotherapy showed new abnormal fluoro-2-deoxy-D-glucose (FDG) uptake in the mediastinal and hilar lymph nodes and skeletal muscles. Sarcoidosis was suspected because of increased serum angiotensin-converting enzyme levels and magnetic resonance imaging findings in the lower limb muscles. However, pathological findings of DLBCL and sarcoidosis were not confirmed in the hilar lymph node biopsy. Therefore, malignant lymphoma can be distinguished from sarcoidosis using abnormal FDG uptake after chemotherapy for SLS.


Assuntos
Fluordesoxiglucose F18/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/metabolismo , Sarcoidose/patologia , Idoso , Feminino , Humanos , Linfonodos/metabolismo , Músculo Esquelético/metabolismo , Tomografia por Emissão de Pósitrons
10.
Ann Otol Rhinol Laryngol ; 128(6_suppl): 26S-35S, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092040

RESUMO

OBJECTIVE: Sublingual immunotherapy has been considered to be a painless and effective therapeutic treatment of patients with allergic rhinitis. Its mechanism of action has been elucidated, but there are still controversies among many reports between clinical efficacy and laboratory data. Therefore, its mechanism of action needs to be investigated further by using promising animal models such as rodents and monkeys. MATERIALS AND METHODS: Bearing this in mind, in our present study, we successfully constructed an effective murine model for sublingual immunotherapy (SLIT) in allergic rhinitis in which mice were sublingually administered ovalbumin (OVA), followed by intraperitoneal (ip) sensitization and intranasal (i.n.) challenge of OVA. RESULTS: To summarize our experimental data, nasal symptoms such as sneezing and nasal rubbing of sublingually treated mice were significantly attenuated in accordance with lower specific IgE antibodies in sera. Histological analysis of eosinophil recruitment in nasal mucosae reveals less allergic inflammation in sublingually treated mice. Interleukin-10 (IL-10) production and IL-10-specific mRNA gene expression of cultured submandibular lymph node (SMLN) cells with OVA, obtained from sublingually treated mice, were significantly higher than those of mice without sublingual treatment. CONCLUSION: These results demonstrate that sublingually introduced antigens can actually attenuate nasal symptoms in a murine allergic rhinitis model upon allergen exposures. Furthermore, our immunological data might indicate an important role of IL-10 producing T cells in SMLN to control nasal allergic reaction.


Assuntos
Interleucina-10/metabolismo , Linfonodos/metabolismo , Rinite Alérgica/terapia , Imunoterapia Sublingual , Linfócitos T/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Rinite Alérgica/complicações , Rinite Alérgica/metabolismo , Espirro
11.
Am J Vet Res ; 80(6): 572-577, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31140843

RESUMO

OBJECTIVE: To investigate luteinizing hormone (LH) receptor expression in canine nonneoplastic and neoplastic lymph nodes, circulating nonneoplastic lymphocytes, and T-cell lymphoma (TCL) cell lines. SAMPLE: Formalin-fixed, paraffin-embedded lymph nodes (5 neoplastic and 3 nonneoplastic) from 6 dogs, circulating lymphocytes from venous blood specimens obtained from 12 healthy dogs, and 3 TCL cell lines derived from 3 dogs with primary lymphoma. PROCEDURES: Lymph node specimens were immunohistochemically stained for determination of LH receptor expression. Circulating nonneoplastic lymphocytes and TCL cell lines were evaluated for LH receptor expression by use of flow cytometry; circulating lymphocytes were also immunophenotyped. The mean percentage of cells positive for LH receptors was determined for each type of specimen. For the healthy dogs, percentages of circulating B and T lymphocytes that expressed LH receptors were assessed on the basis of sex and reproductive status. RESULTS: The mean percentage of LH receptor-positive cells in canine neoplastic and nonneoplastic lymph nodes was 12.4% and 4.1%, respectively. For the healthy dogs, the mean percentage of circulating LH receptor-positive T lymphocytes was significantly higher in gonadectomized dogs (16.6%) than in sexually intact dogs (10.5%); the percentages of circulating LH receptor-positive B lymphocytes did not significantly differ by reproductive status. Among the 3 canine TCL cell lines, LH receptor expression ranged from 10% to 45%. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, LH receptor expression by canine neoplastic and nonneoplastic lymphocytes was detected. Research into the effects of downregulation of LH receptor activation in dogs with lymphoma is warranted.


Assuntos
Doenças do Cão/metabolismo , Linfócitos/metabolismo , Linfoma/veterinária , Receptores do LH/biossíntese , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Doenças do Cão/imunologia , Doenças do Cão/patologia , Cães , Feminino , Citometria de Fluxo/veterinária , Linfonodos/metabolismo , Linfoma/imunologia , Linfoma/metabolismo , Masculino
12.
Nature ; 569(7754): 126-130, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988509

RESUMO

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections1. Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively1-4. The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations5-7. However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the maintenance of duodenal pTreg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, with effects on both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage antigen targeting to specific gut segments for therapeutic immune modulation.


Assuntos
Duodeno/imunologia , Linfonodos/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD4/metabolismo , Diferenciação Celular , Movimento Celular , Polaridade Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Duodeno/citologia , Duodeno/microbiologia , Feminino , Linfonodos/citologia , Linfonodos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Boca/imunologia , Boca/microbiologia , Ratos , Ratos Wistar , Células Estromais/imunologia , Células Estromais/microbiologia , Linfócitos T/citologia , Linfócitos T/microbiologia
13.
Nat Immunol ; 20(5): 534-545, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962593

RESUMO

Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (TH17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of TH17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IκBζ via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a, encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating TH17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival.


Assuntos
Proliferação de Células , Fibroblastos/imunologia , Interleucina-17/imunologia , Linfonodos/imunologia , Células Estromais/imunologia , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Colite/genética , Colite/imunologia , Colite/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Fibroblastos/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Linfonodos/citologia , Linfonodos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismo , Células Estromais/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
14.
Biomed Res Int ; 2019: 7084734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941370

RESUMO

Butyrate produced by the intestinal microbiota is essential for proper functioning of the intestinal immune system. Total dependence on parenteral nutrition (PN) is associated with numerous adverse effects, including severe microbial dysbiosis and loss of important butyrate producers. We hypothesised that a lack of butyrate produced by the gut microbiota may be compensated by its supplementation in PN mixtures. We tested whether i.v. butyrate administration would (a) positively modulate intestinal defence mechanisms and (b) counteract PN-induced dysbiosis. Male Wistar rats were randomised to chow, PN, and PN supplemented with 9 mM butyrate (PN+But) for 12 days. Antimicrobial peptides, mucins, tight junction proteins, and cytokine expression were assessed by RT-qPCR. T-cell subpopulations in mesenteric lymph nodes (MLN) were analysed by flow cytometry. Microbiota composition was assessed in caecum content. Butyrate supplementation resulted in increased expression of tight junction proteins (ZO-1, claudin-7, E-cadherin), antimicrobial peptides (Defa 8, Rd5, RegIIIγ), and lysozyme in the ileal mucosa. Butyrate partially alleviated PN-induced intestinal barrier impairment and normalised IL-4, IL-10, and IgA mRNA expression. PN administration was associated with an increase in Tregs in MLN, which was normalised by butyrate. Butyrate increased the total number of CD4+ and decreased a relative amount of CD8+ memory T cells in MLN. Lack of enteral nutrition and PN administration led to a shift in caecal microbiota composition. Butyrate did not reverse the altered expression of most taxa but did influence the abundance of some potentially beneficial/pathogenic genera, which might contribute to its overall beneficial effect.


Assuntos
Butiratos/farmacologia , Suplementos Nutricionais , Microbioma Gastrointestinal , Intestinos/patologia , Nutrição Parenteral , Animais , Biodiversidade , Colo/efeitos dos fármacos , Colo/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/patologia , Intestino Delgado/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Modelos Animais , Mucinas/biossíntese , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Permeabilidade , Fenótipo , Filogenia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Proteínas de Junções Íntimas/metabolismo
15.
Methods Mol Biol ; 1979: 9-21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31028629

RESUMO

The starting material for all single-cell protocols is a cell suspension. The particular functions and spatial distribution of immune cells generally make them easy to isolate them from the tissues where they dwell. Here we describe tissue dissociation protocols that have been used to obtain human immune cells from lymphoid and nonlymphoid tissues to be then used as input to single-cell methods. We highlight the main factors that can influence the final quality of single-cell data, namely the stress signatures that can bias its interpretation.


Assuntos
Perfilação da Expressão Gênica/métodos , RNA/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Manejo de Espécimes/métodos , Fracionamento Celular/métodos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Linfonodos/citologia , Linfonodos/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , RNA/sangue , RNA/isolamento & purificação , Pele/citologia , Pele/metabolismo , Baço/citologia , Baço/metabolismo
16.
Drug Deliv ; 26(1): 393-403, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30929532

RESUMO

Our previous work indicates the lymphatic network and perivascular spaces or tissues might be involved in the facial intradermal brain-targeted delivery of Evans blue (EB). In this article, we presented the detailed involvement of both, and the linkage between lymphatic network and perivascular spaces or tissues. The in-vivo imaging, the trigeminal transection and immunohistochemistry were used. In-vivo imaging indicated intradermal injection in the mystacial pad (i.d.) delivered EB into the brain at 2-, 6- and 24 h, while intranasal injection (i.n.) delivered EB into the rostral head and intravenous injection (i.v.) diffused EB weakly into the brain. Trigeminal perineurial and epineurial EB occurred along the perivascular spaces or tissues and along brain vessels. EB diffused into the lymphatic vessels and submandibular lymph nodes. Moreover, perineurial and epineurial EB co-located or overlaid with Lyve1 immuno-reactivity and VEGF antibody, and lymphatic network connected with perivascular spaces or tissues, suggesting lymphatic system-perivascular spaces might involve in the EB delivery with i.d. The trigeminal transection reduced the trigeminal epineurial and perineurial EB and brain EB along vessels. EB diffused in the fasciculus and the perineurium, blood and lymphatic vessels in the mystacial pad, mystacial EB overlaid VEGF or Lyve1 antibody. In summary, the dermal-trigeminal-brain perivascular spaces or tissues and the linkage to the lymphatic network mediated the intradermal brain-targeted delivery.


Assuntos
Encéfalo/metabolismo , Corantes/administração & dosagem , Sistemas de Liberação de Medicamentos , Azul Evans/administração & dosagem , Administração Intranasal , Animais , Corantes/farmacocinética , Azul Evans/farmacocinética , Imuno-Histoquímica , Injeções Intradérmicas , Injeções Intravenosas , Linfonodos/metabolismo , Vasos Linfáticos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição Tecidual , Nervo Trigêmeo/metabolismo
17.
Dokl Biol Sci ; 484(1): 10-12, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31016496

RESUMO

Endothelium-dependent relaxation mechanisms have been studied in phenylephrine-precontracted capsules of bovine mesenteric lymph nodes studied in vitro. Tetraethylammonium chloride and TRAM-34 in a solution with L-NAME and Indomethacin, which suppress the production NO and prostacyclin of endothelium, increased the tone of the lymph nodes. We believe that in bovine mesenteric lymph nodes, the dilation mechanism is mediated by hyperpolarization of the endothelium, which is associated with activation of large- and intermedium conductance Ca2+-activated potassium channels.


Assuntos
Endotélio/fisiologia , Linfonodos/fisiologia , Potenciais da Membrana , Animais , Bovinos , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Epoprostenol/metabolismo , Indometacina/farmacologia , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Masculino , Mesentério , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Pirazóis/farmacologia
18.
Cell Mol Life Sci ; 76(16): 3249-3261, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30830241

RESUMO

In addition to their modulation through de novo expression and degradation, surface levels of chemokine receptors are tuned by their ligand-dependent recycling to the plasma membrane, which ensures that engaged receptors become rapidly available for further rounds of signaling. Dysregulation of this process contributes to the pathogenesis of chronic lymphocytic leukemia (CLL) by enhancing surface expression of chemokine receptors, thereby favoring leukemic cell accumulation in the protective niche of lymphoid organs. In this review, we summarize our current understanding of the process of chemokine receptor recycling, focusing on the impact of its dysregulation in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Receptores de Quimiocinas/metabolismo , Arrestinas/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfonodos/metabolismo , Fosforilação , Transdução de Sinais
19.
Pancreas ; 48(3): 367-373, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30768574

RESUMO

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a peritumoral proliferation of fibroblasts and extracellular matrix production known as desmoplasia. We aimed to study desmoplasia in PDAC lymph node (LN) metastases. METHODS: We evaluated LNs from 66 patients with PDAC and LN metastases. We used immunohistochemistry and real-time polymerase chain reaction to phenotype the desmoplastic response. RESULTS: Desmoplasia was identified in 57% of patients with LN metastases (Des+). Cancer-associated fibroblasts (CAFs) in Des+ expressed α-smooth muscle actin and collagen 11A1. The latter expression was present only in CAFs but not in LN stroma or in LN metastases without desmoplasia (Des-). Desmoplasia was associated with upregulation of transforming growth factor ß messenger RNA. Whereas numbers of CD8+ in tumor vicinity were not different between Des+ and Des- patients (78 [standard deviation {SD}, 57] vs 92 [SD, 52], P = 0.48, respectively), the numbers of GATA-3+ cells, a marker of T-helper 2 immune response was significantly increased (3.7 [SD, 6.3] for Des+ vs 1.3 [SD, 2.7] for Des-, P < 0.05). CONCLUSIONS: Lymph node desmoplasia is associated with CAF pattern activation and Th2 infiltration. Therapeutic modulation of desmoplasia may be relevant in the metastatic phase and influence antitumor immune response.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Células Th2/patologia , Idoso , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Colágeno Tipo XI/genética , Colágeno Tipo XI/metabolismo , Matriz Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Células Th2/metabolismo
20.
Oncogene ; 38(22): 4215-4231, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30705401

RESUMO

Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.


Assuntos
Metástase Linfática/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteína Quinase C/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Humanos , Hialuronan Sintases/metabolismo , Linfonodos/metabolismo , Linfonodos/patologia , Linfangiogênese/fisiologia , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Células PC-3 , Próstata/metabolismo , Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
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