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1.
Tumour Biol ; 42(6): 1010428320924524, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32515296

RESUMO

OBJECTIVE: Several studies indicate that macrophage migration inhibitory factor 1 plays a role for tumor progression in colon cancer. We investigated whether determination of migration inhibitory factor 1 mRNA expression levels in lymph nodes of colon cancer patients could be used as a prognostic marker. METHODS: Expression levels of migration inhibitory factor 1 and carcinoembryonic antigen mRNAs were assessed in primary tumors and regional lymph nodes of 123 colon cancer patients (stages I-IV), and in colon cancer- and immune cell lines using quantitative reverse transcriptase-polymerase chain reaction. Expression of migration inhibitory factor 1 protein was investigated by two-color immunohistochemistry and immunomorphometry. RESULTS: Migration inhibitory factor 1 mRNA was expressed at 60 times higher levels in primary colon cancer tumors compared to normal colonic tissue (medians 8.2 and 0.2 mRNA copies/18S rRNA unit; p < .0001). A highly significant difference in mRNA expression levels was found between hematoxylin-eosin positive lymph nodes and hematoxylin-eosin negative lymph nodes (p < .0001). Migration inhibitory factor 1 and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer-tumor cells. Kaplan-Meier survival model and hazard ratio analysis, using a cutoff level at 2.19 mRNA copies/18S rRNA unit, revealed that patients with lymph nodes expressing high levels of migration inhibitory factor 1 mRNA had a 3.5-fold (p = .04) higher risk for recurrence, associated with a small, but significant, difference in mean survival time (7 months, p = .03) at 12 years of follow-up. CONCLUSION: Although migration inhibitory factor 1 mRNA expression levels were related to severity of disease and lymph node analysis revealed that colon cancer patients with high levels had a shorter survival time after surgery than those with low levels, the difference was small and probably not useful in clinical practice.


Assuntos
Antígeno Carcinoembrionário/genética , Neoplasias do Colo/genética , Hormônio Inibidor da Liberação de MSH/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Linfonodos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , RNA Mensageiro/genética , RNA Ribossômico 18S/genética
2.
In Vivo ; 34(3 Suppl): 1633-1636, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503822

RESUMO

In a previous study, we identified a 117 base severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 Orf1b gene in non-structural protein 14 (NSP14), which is an exonuclease and NSP15, an endoribonuclease. In the current study we compared the human genome with other viral genomes to determine some of the characteristics of human sequences found in the latter. Most of the viruses had human sequences, but they were short. Hepatitis A and St Louis encephalitis had human sequences that were longer than the 117 base SARS-Cov-2 sequence, but they were in non-coding regions of the human genome. The SARS-Cov-2 sequence was the only long sequence found in a human gene (NTNG1). The related coronaviruses SARS-Cov had a 41 BP human sequence on chromosome 3 that was not part of a human gene, and MERS had no human sequence. The 117 base SARS-CoV-2 human sequence is relatively close to the viral spike sequence, separated only by NSP16, a 904 base sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. We have no explanation for the NSP14 and NSP15 SARS-Cov-2 sequences we observed here or how they might relate to infectiousness. Further studies are warranted.


Assuntos
Betacoronavirus/genética , Genoma Viral , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3/genética , Vírus de DNA/genética , Endorribonucleases/genética , Proteínas Ligadas por GPI/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Netrinas/genética , Vírus de RNA/genética , Vírus da SARS/genética , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Proteínas não Estruturais Virais/genética , Proteínas Virais/genética
3.
Science ; 368(6490): 497-505, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355025

RESUMO

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cell RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1 + and Psca +) and a large population of differentiated cells (Nkx3.1 +, Pbsn +). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.


Assuntos
Androgênios/metabolismo , Próstata/fisiologia , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Regeneração , Antagonistas de Androgênios/uso terapêutico , Proteína de Ligação a Androgênios/genética , Animais , Antígenos de Neoplasias/genética , Ataxina-1/genética , Diferenciação Celular/genética , Proteínas Ligadas por GPI/genética , Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Proteínas de Neoplasias/genética , Fatores de Crescimento Neural/genética , Tamanho do Órgão , Organoides/metabolismo , Organoides/fisiologia , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Regeneração/genética , Análise de Sequência de RNA , Análise de Célula Única , Trombospondinas/genética , Fatores de Transcrição/genética
4.
Cancer Invest ; 38(5): 329-337, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32427495

RESUMO

Bone marrow stromal antigen 2 (BST2) is a transmembrane glycoprotein and plays an essential role in innate immunity. Here we firstly found that BST2 expression was significantly elevated in hepatocellular carcinoma (HCC) tissues. High BST2 was closely related to the larger tumor size and more tumor number. Moreover, HCC patients with higher expression of BST2 had poorer overall survival and BST2 was identified as an independent unfavorable prognosis factor. Finally, we demonstrated that BST2 can promote proliferation capacity of tumor cells. In conclusion, HCC patients with higher BST2 expression were more predisposed to poorer clinical symptoms and unfavorable prognosis.


Assuntos
Antígenos CD/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Imunidade Inata/genética , Masculino , Pessoa de Meia-Idade , Prognóstico
5.
Chemosphere ; 251: 126642, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32345545

RESUMO

The ubiquitous presence of aluminum in the environment leads to a high likelihood of human exposure. Neurotoxicity of the trivalent cationic form of this metal (Al3+) occurs in the central nervous system via accumulation of Al in cells of neural origin, including neural progenitor cells (NPCs). NPCs play a key role in the development and regeneration of the brain throughout life; therefore, this metal may contribute to neuropathological conditions. Here, we evaluated the effects of different Al3+ concentrations (0-50 µM) on the purinergic system of NPCs isolated from embryonic telencephalons, cultured as neurospheres. Al3+ adhered to the cell surface of neurospheres reducing extracellular ATP release, as well as ATP, ADP, and AMP hydrolysis by NTPDase and 5'-nucleotidase, respectively. In addition, impaired nucleotide release by Al3+ reduced P2Y1 and adenosine A2A receptors expression in differentiated neurospheres. These receptors are crucial for NPC proliferation during brain development and self-repair against external stimuli, such as metal exposure. Thus, Al3+ represents an environmental agent linked to neurodegeneration through alterations in the ATP-signalling pathway, proving to be a potential mechanism associated with NPC proliferation and brain degeneration.


Assuntos
Alumínio/toxicidade , 5'-Nucleotidase , Trifosfato de Adenosina/metabolismo , Alumínio/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Sistema Nervoso Central/metabolismo , Proteínas Ligadas por GPI , Humanos , Transdução de Sinais/efeitos dos fármacos , Células-Tronco , Testes de Toxicidade
6.
Scand J Immunol ; 92(1): e12882, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32243627

RESUMO

Intelectin (ITLN) is a new type of glycan-binding lectin. It has been demonstrated to agglutinate bacteria probably due to its carbohydrate-binding capacity, suggesting its role in an innate immune response. It is involved not only in many physiological processes but also in some human diseases such as asthma, heart disease, inflammatory bowel disease, chronic obstructive pulmonary disease and cancer. Up to now, intelectin orthologs have been identified in placozoans, urochordatas, cephalochordates and several vertebrates, such as cyclostomata, fish, amphibians and mammals. Although the sequences of intelectins in different species are conserved, their expression patterns, quaternary structures and functions differ considerably among and within species. We summarize the evolution of the intelectin gene family, the tissue distribution, structure and functions of intelectins. We conclude that intelectin plays a role in innate immune response and there are still potential functions of intelectin awaiting discovery.


Assuntos
Bactérias/imunologia , Citocinas/genética , Citocinas/metabolismo , Imunidade Inata/imunologia , Lectinas/genética , Lectinas/metabolismo , Reconhecimento Fisiológico de Modelo/fisiologia , Sequência de Aminoácidos , Animais , Citocinas/farmacocinética , Evolução Molecular , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/farmacocinética , Humanos , Lectinas/farmacocinética , Estrutura Secundária de Proteína , Alinhamento de Sequência , Distribuição Tecidual/fisiologia
7.
Medicine (Baltimore) ; 99(17): e19839, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332633

RESUMO

The present study was designed to investigate the expression of tumor-associated macrophages (TAMs) in gastric cancer and its clinicopathological relationship. In addition, we also aimed to analyze the relationship between helicobacter pylori (HP) infection and TAMs in gastric cancer.The protein expression of CD16 and CD163 in 90 gastric cancer tissues and 30 margin tissues was detected by immunohistochemistry. HP infection was detected in 90 gastric cancer tissues and 30 margin tissues by gram staining and immunohistochemistry.There was no clear correlation between CD16 macrophages and gastric cancer. The density of CD163 macrophages was not correlated with the general condition of tumor patients, but with tumor size, tumor differentiation, lymphatic metastasis, depth of invasion and TNM stage. Additionally, the infection rate of HP in gastric cancer tissues was significantly higher.In summary, TAMs are associated with tumor size, degree of differentiation, depth of invasion, lymph node metastasis and TNM stage, suggesting their critical role in the invasion and metastasis of gastric cancer.


Assuntos
Macrófagos/patologia , Neoplasias Gástricas/patologia , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Contagem de Células , Feminino , Proteínas Ligadas por GPI/análise , Mucosa Gástrica/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/patologia , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Receptores de Superfície Celular/análise , Receptores de IgG/análise , Estudos Retrospectivos , Neoplasias Gástricas/complicações , Carga Tumoral
8.
Cancer Sci ; 111(5): 1652-1662, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32133706

RESUMO

Lung cancer is the most commonly diagnosed cancer worldwide, and metastasis in lung cancer is the leading cause of cancer-related deaths. Thus, understanding the mechanism of lung cancer metastasis will improve the diagnosis and treatment of lung cancer patients. Herein, we found that expression of cluster of differentiation 109 (CD109) was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. CD109 is upregulated in tumorous tissues, and CD109 overexpression was associated with tumor progression, distant metastasis, and a poor prognosis in patient with lung adenocarcinoma. Mechanistically, expression of CD109 regulates protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling via its association with the epidermal growth factor receptor (EGFR). Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF-elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor. Taken together, our results show that CD109 is a potential diagnostic and therapeutic target in lung cancer patients.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antígenos CD/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Antígenos CD/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , Fosforilação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais
9.
Cancer Invest ; 38(4): 214-227, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32157913

RESUMO

Cripto-1 is a plasma membrane protein which is not expressed in adult tissue, but some tumors are accompanied by re-activation. We studied the clinical and biological significance of Cripto-1 in colorectal cancer. Cripto-1 was positive in 68 out of 192 cases (35%) by immunohistochemistry. Cripto-1 expression was correlated with worse prognosis and was an independent prognostic factor. Cripto-1-silenced colorectal cancer cell lines had reduced cell proliferation, migration, and activation of Akt and MAPK signaling pathways in vitro, and decreased tumor growth and lymph node metastasis in vivo. Cripto-1 could be a useful prognostic biomarker and therapeutic target in colorectal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Proteínas Ligadas por GPI/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Neoplasias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Seguimentos , Proteínas Ligadas por GPI/genética , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estimativa de Kaplan-Meier , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prognóstico , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Clin Chim Acta ; 505: 167-171, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32145276

RESUMO

BACKGROUND: Prior studies suggested that ischemic stroke patients with high omentin-1 concentrations were at a decreased risk of unstable carotid plaque and 3-month poor functional outcome. We aim to evaluate the association between serum omentin-1 and 1-y mortality after ischemic stroke. METHODS: A total of 303 ischemic stroke patients were prospectively followed up at 1 y. Outcome was defined as death occurred during the follow-up period. A multivariable Cox model was used to evaluate the association between serum omentin-1 concentrations and 1-y mortality among ischemic stroke patients. RESULTS: From lowest to highest tertile of serum omentin-1, the 1-y cumulative death rate was 12%, 3.7% and 2.1%, respectively (P = 0.006). The hazard ratio (95% confidence interval) of the highest tertile compared with the lowest tertile was 0.19 (0.04-0.88) for mortality after multivariable adjustment (P for trend < 0.01). The net reclassification index and integrated discrimination improvement were significantly improved in predicting 1-y mortality when omentin-1 data was added to the multivariable Cox regression model. CONCLUSIONS: Among patients with ischemic stroke, high baseline serum omentin-1 was associated with a decreased risk of 1-y mortality. These findings, if confirmed by clinical trials, suggest that increasing omentin-1 concentrations may lower the risk of mortality among ischemic stroke patients.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/mortalidade , Citocinas/sangue , Lectinas/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/mortalidade , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/classificação , Estudos de Coortes , Feminino , Seguimentos , Proteínas Ligadas por GPI/sangue , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/classificação , Análise de Sobrevida , Resultado do Tratamento
11.
Exerc Immunol Rev ; 26: 116-131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32139354

RESUMO

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that targets and destroys insulin-secreting pancreatic beta cells. Although T cell mediated, a number of other immune cells are also critically involved in coordinating the events leading to T1D. Specifically, innate subsets play an important role in the pathogenesis of T1D. NK cells are one of the first cell types to infiltrate the pancreas, causing damage and release of beta cell antigens. Previous work in our group has shown differential mobilisation of highly differentiated CD8+ T cells during vigorous intensity exercise in T1D compared to a control cohort. Here, we aimed to explore exercise-induced mobilisation of other cell types involved in T1D pathogenesis. In this study, we investigated the effects of a single bout of vigorous (80% predicted VO2max) intensity exercise on innate cell mobilisation in T1D and control participants. T1D (N=12, mean age 33.2yrs, predicted VO2max 32.2 ml.kg.min⁻¹, BMI 25.3 kg.m⁻²) and control (N=12, mean age 29.4yrs, predicted VO2 max 38.5 ml.kg.min⁻¹, BMI 23.7 kg.m⁻² male participants completed a 30-minute bout of cycling at 80% predicted VO2 max in a fasted state. Peripheral blood was collected at baseline, immediately post-exercise, and 1 hour post-exercise. NK cell subsets mobilised during vigorous intensity exercise in both control and T1D participants. However, mature NK cells, defined as the CD56dimCD16bright subset, displayed a lower percentage increase following vigorous intensity exercise in T1D participants (Control: 185.12%, T1D: 97.06%). This blunted mobilisation was specific to early mature NK cells (KIR+) but not later differentiated NK cells (KIR+CD57+). Myeloid lineage subsets mobilised to a similar extent in both control and T1D participants. In conclusion, vigorous exercise mobilises innate immune cells in people with T1D albeit to a different extent to those without T1D. This mobilisation of innate immune cells provides a mechanistic argument to support exercise in people with T1D where it has the potential to improve surveillance for infection and to modulate the autoimmune response to the beta cell.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Exercício Físico , Células Matadoras Naturais/citologia , Ativação Linfocitária , Adulto , Antígeno CD56 , Proteínas Ligadas por GPI , Humanos , Masculino , Receptores de IgG
12.
Life Sci ; 253: 117533, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151690

RESUMO

HEADING AIMS: Abdominal aortic aneurysm (AAA) is featured by the growth impediment and apoptosis surge of VSMCs (vascular smooth muscle cells). MicroRNAs (miRNAs) are suggested to affect cellular behaviors including cell growth and apoptosis. This study concentrated on unraveling the emerging role of miR-28-5p in abdominal aortic aneurysm. MATERIALS AND METHODS: Previously, miR-28-5p was reported to be highly expressed in AAA. Functional assays were utilized to determine the role of miR-28-5p in VSMC apoptosis. To narrow down the downstream mRNAs, bioinformatics methods were utilized. The interaction between miR-28-5p and GRIA4 (glutamate ionotropic receptor AMPA type subunit 4) or LYPD3 (LY6/PLAUR domain containing 3) was explored. Candidate circRNAs (circular RNAs) of miR-28-5p were identified. Rescue analyses validated function of circCBFB (core-binding factor subunit beta)/miR-28-5p/GRIA4/LYPD3 axis in VSMC apoptosis and growth. KEY FINDINGS: MiR-28-5p acted as an apoptosis driver while circCBFB, GRIA4 and LYPD3 exerted anti-apoptosis effects in VSMCs. Mechanically, GRIA4 and LYPD3 were suppressed by miR-28-5p. Moreover, circCBFB served as a sponge of miR-28-5p, releasing GRIA4 and LYPD3 from miR-28-5p suppression. Functionally, GRIA4, LYPD3 and miR-28-5p were required in circCBFB-mediated VSMC apoptosis. SIGNIFICANCE: This work unveiled an innovative axis of circCBFB/miR-28-5p/GRIA4/LYPD3 in VSMC apoptosis, exerting its potential in providing new thoughts in AAA management.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Moléculas de Adesão Celular/genética , MicroRNAs/metabolismo , Receptores de AMPA/genética , Apoptose , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Movimento Celular , Proliferação de Células , Regulação para Baixo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA Mensageiro/metabolismo , Receptores de AMPA/metabolismo , Transfecção
13.
Cancer Immunol Immunother ; 69(5): 789-797, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32055919

RESUMO

CD160 is an Ig-like glycoprotein expressed by the majority of circulating natural killer cells and γδ T cells. Whether CD160 could regulate CD8+ T-cell functions remains unknown. In this study, we investigated the effects of CD160 on CD8+ T cells in pancreatic cancer. First, we found that the frequency of PD-1+ cells was comparable between CD160+ and CD160-CD8+ T cells, with the former presenting significantly higher PD-1 expression level. In contrast, the frequency of TIM-3+ cells was higher among CD160+ cells but the expression level was comparable between CD160+ and CD160-CD8+ T cells. The IFN-γ and IL-2-expressing CD8+ T cells, directly ex vivo, were highly enriched in the CD160+ subset. However, when CD160+ and CD160-CD8+ T cells were stimulated, the proliferation levels of CD160+ and CD160- cells were initially comparable, but were significantly lower in CD160+CD8+ T cells than in CD160-CD8+ T cells later on. The IFN-γ and IL-2 transcription levels were initially higher in CD160+CD8+ T cells, but eventually reduced in CD160+CD8+ T cells compared to CD160-CD8+ T cells. Also, CD160+CD8+ T cells presented lower cytotoxic capacity than CD160-CD8+ T cells. Interestingly, we observed that tumor-infiltrating CD8+ T cells were significantly enriched with the CD160+ subset in pancreatic cancer patients. In addition, patients with higher frequencies of tumor CD160+CD8+ T cells presented lower survival. Overall, these data demonstrated that tumor-infiltrating CD8+ T cells were enriched with the CD160+ subset in pancreatic cancer, with active effector responses directly ex vivo but limited potential for further activation.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Antígenos CD/imunologia , Biópsia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Pâncreas/citologia , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Receptores Imunológicos/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/metabolismo , Fatores de Tempo
14.
Anal Bioanal Chem ; 412(8): 1723-1728, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32030492

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM-5) assays are employed in routine clinical settings to diagnose tumor. We selected two nanobodies with high-affinity to CEACAM-5, termed Nb11C12 and Nb2D5, using phage-display technology. The Nb2D5 fused with calf intestinal alkaline phosphatase (CAP), human placental alkaline phosphatase (HAP), or Pyrococcus abyssi alkaline phosphatase (PAP) were expressed in human embryonic kidney (HEK293) cells. The enzymatic activity of Nb2D5-HAP fusion protein was the best and remained stable at 60 °C for 7 days. The affinity of Nb2D5-HAP fusion protein to CEACAM-5 reached 42 pM. A chemiluminescent enzyme immunoassay (CLEIA) based on Nb2D5-HAP fusion protein was established for quantitative CEACAM-5 assay in clinical settings. The CLEIA exhibited a wide linear range of 0.31-640 ng/mL toward CEACAM-5, with a limit of detection (LOD) of 0.85 ng/mL. No cross-reactivity occurred with CEACAM-1, CEACAM-3, CEACAM-6, or CEACAM-8, and no interference was observed with rheumatoid factors. The CLEIA based on Nb2D5-HAP fusion protein was stable for 8 weeks at 37 °C and 50% relative humidity. The CLEIA developed from Nb2D5-HAP fusion protein had much better stability and linearity with similar reproducibility compared with the enzyme-linked immunosorbent assay developed from conventional monoclonal antibodies, which have been widely used in clinics over the past several decades. Graphical abstract.


Assuntos
Fosfatase Alcalina/metabolismo , Antígeno Carcinoembrionário/metabolismo , Técnicas Imunoenzimáticas/métodos , Proteínas Recombinantes de Fusão/metabolismo , Anticorpos de Domínio Único , Antígeno Carcinoembrionário/imunologia , Proteínas Ligadas por GPI/imunologia , Células HEK293 , Humanos , Limite de Detecção , Luminescência , Reprodutibilidade dos Testes
15.
DNA Cell Biol ; 39(4): 522-532, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32040344

RESUMO

Aberrant expression of LYPD3 plays an oncogenic role in several types of cancer. However, the functions of LYPD3 in lung adenocarcinoma (LUAD) remain unclear. Here, we investigated the regulatory function, clinical value, and prognostic significance of LYPD3 in LUAD patients. The gene expression and DNA methylation data of LUAD tumor and paracancerous tissues were obtained from The Cancer Genome Atlas (TCGA) database. The association between LYPD3 expression and clinicopathological variables was analyzed. The results showed that LYPD3 was highly expressed in LUAD tumor compared with paracancerous tissues, which was positively correlated with the race (p = 0.0448), tumor stage (p = 0.0191), and survival status (p < 0.001). Furthermore, the expression of LYPD3 was able to be regulated by the methylation in LYPD3 promoter region, which was positively associated with the overall survival. Furthermore, we explored the related pathways through which LYPD3 affects the pathogenesis and prognosis of LUAD by gene set enrichment analysis, and found that LYPD3 might affect the clinical manifestations of LUAD by regulating the P53 signaling pathway. In the future, we would focus on exploring the molecular mechanism of LYPD3 in the regulation of the occurrence and development of LUAD to provide a research basis for the screening of methylation markers related to the treatment and prognosis.


Assuntos
Adenocarcinoma de Pulmão/patologia , Moléculas de Adesão Celular/metabolismo , Neoplasias Pulmonares/patologia , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Moléculas de Adesão Celular/genética , Linhagem Celular , Proliferação de Células , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética
16.
Cancer Immunol Immunother ; 69(4): 641-651, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32016503

RESUMO

Prostate cancer is a candidate for immunotherapy because cancer cells express tissue-specific proteins that can be therapeutic targets. However, immune checkpoint inhibitors and active immunization have performed poorly in clinical trials. We developed a novel virus-like particle (VLP) vaccine composed of bovine papillomavirus L1 protein engineered to display surface docking sites. We decorated VLPs with peptides encoding T cell epitopes from two prostate cancer-associated tumor antigens, prostate stem cell antigen (PSCA), and prostatic acid phosphatase (PAP-1 and PAP-2), and a neo-antigen, stimulator of prostatic adenocarcinoma-specific T cells (SPAS-1). The VLP vaccines induced a mean frequency of antigen-specific IFN-γ secreting CD8 + T cells of 2.9% to PSCA, 9.5% to SPAS-1, 0.03% to PAP-1, and 0.03% to PAP-2 in tumor-bearing TRAMP mice. We treated TRAMP mice at 19-20 weeks of age, when mice have advanced stages of carcinogenesis, with either VLP vaccine, anti-PD1 antibody, or combination immunotherapy. The VLP vaccine alone or in combination with anti-PD1 antibody significantly reduced tumor burden, while anti-PD1 antibody had a modest non-significant therapeutic effect. All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Proteínas do Capsídeo/imunologia , Proteínas de Neoplasias/imunologia , Antígeno Prostático Específico/imunologia , Neoplasias da Próstata/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Fosfatase Ácida/imunologia , Fosfatase Ácida/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Proteínas Ligadas por GPI/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos Transgênicos , Neoplasias da Próstata/terapia , Resultado do Tratamento , Vacinação
17.
Infect Immun ; 88(3)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31907195

RESUMO

Natural killer (NK) cells are key effector cells of innate resistance capable of destroying tumors and virus-infected cells through cytotoxicity and rapid cytokine production. The control of NK cell responses is complex and only partially understood. PD-1 is an inhibitory receptor that regulates T cell function, but a role for PD-1 in regulating NK cell function is only beginning to emerge. Here, we investigated PD-1 expression on NK cells in children and adults in Mali in a longitudinal analysis before, during, and after infection with Plasmodium falciparum malaria. We found that NK cells transiently upregulate PD-1 expression and interleukin-6 (IL-6) production in some individuals during acute febrile malaria. Furthermore, the percentage of PD-1 expressing NK cells increases with age and cumulative malaria exposure. Consistent with this, NK cells of malaria-naive adults upregulated PD-1 following P. falciparum stimulation in vitro Additionally, functional in vitro studies revealed that PD-1 expression on NK cells is associated with diminished natural cytotoxicity but enhanced antibody-dependent cellular cytotoxicity (ADCC). These data indicate that PD-1+ NK cells expand in the context of chronic immune activation and suggest that PD-1 may contribute to skewing NK cells toward enhanced ADCC during infections such as malaria.


Assuntos
Células Matadoras Naturais/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/patogenicidade , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Fatores Etários , Animais , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CD56/metabolismo , Linhagem Celular , Criança , Proteínas Ligadas por GPI/metabolismo , Humanos , Interleucina-6/metabolismo , Células K562 , Estudos Longitudinais , Malária/imunologia , Camundongos , Receptores de IgG/metabolismo
18.
Nat Commun ; 11(1): 15, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900413

RESUMO

DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.


Assuntos
Proteínas Sanguíneas/genética , Inflamação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL10/genética , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Epigenoma , Epigenômica , Feminino , Proteínas Ligadas por GPI/genética , Alemanha , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Proteômica , Receptores de IgG/genética
19.
Medicine (Baltimore) ; 99(1): e18596, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895808

RESUMO

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Because the molecular mechanisms of DKD are not fully understood, exploration of hub genes and the mechanisms underlying this disease are essential for elucidating the pathogenesis and progression of DKD. Accordingly, in this study, we performed an analysis of gene expression in DKD. The differentially expressed genes (DEGs) included 39 upregulated genes and 113 downregulated genes in the GSE30528 dataset and 127 upregulated genes and 18 downregulated genes in the GSE30529 dataset. Additionally, functional analyses were performed to determine the roles of DEGs using glomeruli samples from patients with DKD and healthy controls from the GSE30528 dataset and using tubule samples from patients with DKD and healthy controls from the GSE30529 dataset. These DEGs were enriched in pathways such as the Wnt signaling pathway, metabolic pathways, and the mammalian target of rapamycin signaling pathway in the GSE30528 dataset and the longevity regulating pathway and Ras signaling pathway in the GSE30529 dataset. Moreover, a protein-protein interaction network was constructed using the identified DEGs, and hub gene analysis was performed. Furthermore, correlation analyses between key genes and pathological characteristics of DKD indicated that CCR4, NTNG1, HGF and ISL1 are related to DKD, and NTNG1 and HGF may server as diagnostic biomarkers in DKD using the receiver-operator characteristic (ROC) curve. Collectively, our findings established 2 reliable biomarkers for DKD.


Assuntos
Nefropatias Diabéticas/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Rim/metabolismo , Netrinas/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Proteínas Ligadas por GPI/metabolismo , Humanos
20.
World J Gastroenterol ; 26(2): 168-183, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31988583

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection and its consequent complications are undeniably a public health burden worldwide, particularly in Egypt. Emerging evidence suggests that many lncRNAs have relevant roles in viral infections and antiviral responses. AIM: To investigate the expression profiles of circulating lncRNAGAS5, lncRNAHEIH, lncRNABISPR and mRNABST2 in naïve, treated and relapsed HCV Egyptian patients, to elucidate relation to HCV infection and their efficacy as innovative biomarkers for the diagnosis and prognosis of HCV GT4. METHODS: One hundred and thirty HCV-infected Egyptian patients and 20 healthy controls were included in this study. Serum lncRNAs and mRNABST2 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our results indicated that serum lncRNAGAS5 and LncRNABISPR were upregulated, whereas mRNA BST2 and LncRNA HEIH were downregulated in naïve patients. In contrast, HCV patients treated with sofosbuvir and simeprevir; with sofosbuvir and daclatasvir; or with sofosbuvir, daclatasvir and ribavirin exhibited lower levels of lncRNAGAS5 and lncRNABISPR with higher mRNABST2 compared to naïve patients. Notably, patients relapsed from sofosbuvir and simeprevir showed higher levels of these lncRNAs with lower mRNABST2 compared to treated patients. LncRNAGAS5 and lncRNABISPR were positively correlated with viral load and ALT at P < 0.001, whereas mRNABST2 was negatively correlated with viral load at P < 0.001 and ALT at P < 0.05. Interestingly, a significant positive correlation between lncRNA HEIH and AFP was observed at P < 0.001. CONCLUSION: Differential expression of these RNAs suggests their involvement in HCV pathogenesis or antiviral response and highlights their promising roles in diagnosis and prognosis of HCV.


Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , RNA Longo não Codificante/sangue , RNA Mensageiro/sangue , Adulto , Antígenos CD/genética , Antivirais/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Ácidos Nucleicos Livres/isolamento & purificação , Ácidos Nucleicos Livres/metabolismo , Regulação para Baixo , Quimioterapia Combinada/métodos , Egito , Feminino , Proteínas Ligadas por GPI/genética , Perfilação da Expressão Gênica/métodos , Voluntários Saudáveis , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
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