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1.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445517

RESUMO

We introduce here a novel machine learning (ML) framework to address the issue of the quantitative assessment of the immune content in neuroblastoma (NB) specimens. First, the EUNet, a U-Net with an EfficientNet encoder, is trained to detect lymphocytes on tissue digital slides stained with the CD3 T-cell marker. The training set consists of 3782 images extracted from an original collection of 54 whole slide images (WSIs), manually annotated for a total of 73,751 lymphocytes. Resampling strategies, data augmentation, and transfer learning approaches are adopted to warrant reproducibility and to reduce the risk of overfitting and selection bias. Topological data analysis (TDA) is then used to define activation maps from different layers of the neural network at different stages of the training process, described by persistence diagrams (PD) and Betti curves. TDA is further integrated with the uniform manifold approximation and projection (UMAP) dimensionality reduction and the hierarchical density-based spatial clustering of applications with noise (HDBSCAN) algorithm for clustering, by the deep features, the relevant subgroups and structures, across different levels of the neural network. Finally, the recent TwoNN approach is leveraged to study the variation of the intrinsic dimensionality of the U-Net model. As the main task, the proposed pipeline is employed to evaluate the density of lymphocytes over the whole tissue area of the WSIs. The model achieves good results with mean absolute error 3.1 on test set, showing significant agreement between densities estimated by our EUNet model and by trained pathologists, thus indicating the potentialities of a promising new strategy in the quantification of the immune content in NB specimens. Moreover, the UMAP algorithm unveiled interesting patterns compatible with pathological characteristics, also highlighting novel insights into the dynamics of the intrinsic dataset dimensionality at different stages of the training process. All the experiments were run on the Microsoft Azure cloud platform.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Neuroblastoma/imunologia , Computação em Nuvem , Aprendizado Profundo , Feminino , Humanos , Linfócitos/metabolismo , Masculino , Redes Neurais de Computação , Neuroblastoma/diagnóstico por imagem
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360895

RESUMO

BACKGROUND: Type 2 diabetes mellitus is one of the leading causes of morbidity and mortality worldwide and is derived from an accumulation of genetic and epigenetic changes. In this study, we aimed to construct Insilco, a competing endogenous RNA (ceRNA) network linked to the pathogenesis of insulin resistance followed by its experimental validation in patients', matched control and cell line samples, as well as to evaluate the efficacy of CRISPR/Cas9 as a potential therapeutic strategy to modulate the expression of this deregulated network. By applying bioinformatics tools through a two-step process, we identified and verified a ceRNA network panel of mRNAs, miRNAs and lncRNA related to insulin resistance, Then validated the expression in clinical samples (123 patients and 106 controls) and some of matched cell line samples using real time PCR. Next, two guide RNAs were designed to target the sequence flanking LncRNA/miRNAs interaction by CRISPER/Cas9 in cell culture. Gene editing tool efficacy was assessed by measuring the network downstream proteins GLUT4 and mTOR via immunofluorescence. RESULTS: LncRNA-RP11-773H22.4, together with RET, IGF1R and mTOR mRNAs, showed significant upregulation in T2DM compared with matched controls, while miRNA (i.e., miR-3163 and miR-1) and mRNA (i.e., GLUT4 and AKT2) expression displayed marked downregulation in diabetic samples. CRISPR/Cas9 successfully knocked out LncRNA-RP11-773H22.4, as evidenced by the reversal of the gene expression of the identified network at RNA and protein levels to the normal expression pattern after gene editing. CONCLUSIONS: The present study provides the significance of this ceRNA based network and its related target genes panel both in the pathogenesis of insulin resistance and as a therapeutic target for gene editing in T2DM.


Assuntos
Sistemas CRISPR-Cas , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/genética , Edição de Genes/métodos , Expressão Gênica , Resistência à Insulina/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Feminino , Redes Reguladoras de Genes , Hospitais Universitários , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade
3.
Cells ; 10(7)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34359894

RESUMO

COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies (n = 12/13/group) were collected. Peripheral blood was collected from healthy pregnant women (n = 6). Second trimester placental explants (16-20 weeks, n = 5/group) were treated with lipopolysaccharide (LPS, to mimic bacterial infection) and ACE2, CCL2, IL-6/8 and TNFα mRNA was assessed. ChA-placentae exhibited increased ACE2 and CCL2 mRNA expression (p < 0.05). LPS increased cytokine and ACE2 mRNA in placental explants. Placental ACE2 protein localized to syncytiotrophoblast, fetal endothelium, extravillous trophoblast and in immune cells-subsets (M1/M2 macrophage and neutrophils) within the villous stroma. Significantly increased numbers of M1 macrophage and neutrophils were present in the ChA-placenta (p < 0.001). Subsets of peripheral immune cells from pregnant women express the ACE2 mRNA and protein. A greater fraction of granulocytes was positive for ACE2 protein expression compared to lymphocytes or monocytes. These data suggest that in pregnancies complicated by ChA, ACE2 positive immune cells in the maternal circulation have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Expressão Gênica , Placenta/metabolismo , Complicações Infecciosas na Gravidez/genética , Nascimento Prematuro/etiologia , Adulto , COVID-19/genética , COVID-19/transmissão , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Linfócitos/metabolismo , Monócitos/metabolismo , Placenta/citologia , Gravidez , Nascimento Prematuro/genética , SARS-CoV-2/isolamento & purificação
4.
J Immunol ; 207(3): 809-823, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34282003

RESUMO

The transcription factor promyelocytic leukemia zinc finger (PLZF) is encoded by the BTB domain-containing 16 (Zbtb16) gene. Its repressor function regulates specific transcriptional programs. During the development of invariant NKT cells, PLZF is expressed and directs their effector program, but the detailed mechanisms underlying PLZF regulation of multistage NKT cell developmental program are not well understood. This study investigated the role of acetylation-induced PLZF activation on NKT cell development by analyzing mice expressing a mutant form of PLZF mimicking constitutive acetylation (PLZFON) mice. NKT populations in PLZFON mice were reduced in proportion and numbers of cells, and the cells present were blocked at the transition from developmental stage 1 to stage 2. NKT cell subset differentiation was also altered, with T-bet+ NKT1 and RORγt+ NKT17 subsets dramatically reduced and the emergence of a T-bet-RORγt- NKT cell subset with features of cells in early developmental stages rather than mature NKT2 cells. Preliminary analysis of DNA methylation patterns suggested that activated PLZF acts on the DNA methylation signature to regulate NKT cells' entry into the early stages of development while repressing maturation. In wild-type NKT cells, deacetylation of PLZF is possible, allowing subsequent NKT cell differentiation. Interestingly, development of other innate lymphoid and myeloid cells that are dependent on PLZF for their generation is not altered in PLZFON mice, highlighting lineage-specific regulation. Overall, we propose that specific epigenetic control of PLZF through acetylation levels is required to regulate normal NKT cell differentiation.


Assuntos
Fatores de Transcrição Kruppel-Like , Células T Matadoras Naturais , Acetilação , Animais , Diferenciação Celular , Imunidade Inata , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Linfócitos/metabolismo , Camundongos , Células T Matadoras Naturais/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica
5.
J Coll Physicians Surg Pak ; 31(7): 93-98, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34271803

RESUMO

OBJECTIVE: To investigate the symptoms and laboratory results of children hospitalised with the diagnosis of COVID-19, aiming to reveal the characteristics of symptomatic cases. STUDY DESIGN: A descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Kastamonu Training and Research Hospital, Kastamonu, Turkey from March to December 2020. METHODOLOGY: Seventy-nine children, hospitalised with the diagnosis of COVID-19, were included in the study and were divided into two groups as symptomatic and asymptomatic. The demographic data, laboratory results and clinics of the patients of the two groups were compared. RESULTS: The mean age of participants was 10.43 ± 5.91 (0-17) years, and 57% (n=45) of them were girls. Five patients in the symptomatic group had comorbidities (2 allergic asthma,  cerebral palsy, type-1 diabetes mellitus and anorexia nervosa). The most common symptom was fever (36.7%, n=29). It was noteworthy that everyone with an NLR >3.13 (high-NLR) was symptomatic. Significantly more patients in the high-NLR group were symptomatic compared with the low-NLR group (p=0.005). On the other hand, symptomatic children had significantly higher levels of C-reactive protein (2.8 (IQR: 1.2-10.0) mg/L vs. 1.4 (IQR: 0.4-2.0) mg/L, p=0.011); and procalcitonin (0.05 (IQR: 0.02-0.10) ng/mL vs. 0.01 (IQR: 0.00-0.03) ng/mL, p<0.001) than those without symptoms. One of the children with cerebral palsy died from pneumonia during the study. CONCLUSION: C-reactive protein, procalcitonin and NLR levels were found to be significantly higher in symptomatic children. NLR can be suggested as a potential marker associated with disease severity in COVID-19 patients, which needs to be supported by other studies. Key Words: COVID-19, Children, Neutrophil / lymphocyte ratio, C-reactive protein, Procalcitonin.


Assuntos
COVID-19 , Pediatria , Adolescente , COVID-19/sangue , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Linfócitos/metabolismo , Masculino , Neutrófilos/metabolismo , Estudos Retrospectivos , SARS-CoV-2 , Turquia/epidemiologia
6.
Anticancer Res ; 41(7): 3673-3682, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230166

RESUMO

AIM: This study aimed to investigate useful prognostic factors of immunotherapy in patients with lung cancer. PATIENTS AND METHODS: We retrospectively observed 73 patients who underwent immunotherapy (nivolumab, pembrolizumab, and atezolizumab) for lung cancer. The systemic inflammatory score (SIS) was calculated as the sum of the following factors scored one point each: Hemoglobin <12.5 g/dl and serum albumin <3.6 g/dl, resulting in scores of 0-2. We examined the correlation between the SIS and initial tumor response and progression-free and overall survival with other existing markers, namely tumor programmed death-ligand 1 (PD-L1) expression level; neutrophil-to-lymphocyte ratio (NLR); modified Glasgow prognostic score; and prognostic nutritional index, etc. Results: SIS ≤1 was significantly associated with better initial tumor response. In multivariate analysis, PD-L1 expression ≥50% (p=0.010), SIS ≤1 (p=0.028) and NLR <5.6 (p=0.047) were significantly associated with longer progression-free survival, and SIS ≤1 (p=0.030) and NLR <5.6 (p=0.037) were associated with longer overall survival. CONCLUSION: SIS is a useful marker of the efficacy of immunotherapy that can be obtained via routine blood tests.


Assuntos
Inflamação/patologia , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Nivolumabe/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
7.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299236

RESUMO

Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn's disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.


Assuntos
Imunidade Inata/imunologia , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Imunidade Adaptativa/imunologia , Animais , Colite , Colite Ulcerativa , Doença de Crohn , Trato Gastrointestinal , Homeostase/fisiologia , Humanos , Tolerância Imunológica , Inflamação , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Microbiota , Células Th17
8.
Viruses ; 13(6)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207913

RESUMO

The emergence of a novel goose nephritic astrovirus (GNAstV) has caused economic losses to the Chinese goose industry. High viral load is found in the spleen of goslings infected with GNAstV, but pathological injuries to the spleen due to GNAstV are largely unknown. In this study, 50 two-day-old goslings were infected orally with GNAstV, and 50 goslings were treated with PBS as control. Spleens were collected at different times following infection to assess damage. GNAstV infection caused visceral gout and urate deposition in joints, and resulted in 16% mortality. GNAstV was found in the lymphocytes and macrophages within the spleen. Lymphocyte loss, especially around the white pulp, and destruction and decline in the number of reticular fibers was observed in GNAstV-infected goslings. Moreover, in GNAstV-infected goslings, ultrahistopathological examination found that splenic lymphocytes exhibited condensed chromatin and apoptotic bodies, and reticular cells displayed damage to plasma membrane integrity and swollen mitochondria. Furthermore, TUNEL staining confirmed apoptosis of lymphocytes, and the mRNA levels of Fas and FasL were significantly increased in the GNAstV-infected goslings. In addition, GNAstV infection reduced the number and protein expression of CD8. In conclusion, GNAstV infection causes lymphocyte depletion, reticular cell necrosis, reticular fiber destruction, lymphocyte apoptosis, and reduction in CD8 levels, which contribute to spleen injury.


Assuntos
Apoptose , Avastrovirus/fisiologia , Gansos/virologia , Linfócitos/metabolismo , Doenças das Aves Domésticas/etiologia , Doenças das Aves Domésticas/metabolismo , Animais , Avastrovirus/classificação , Avastrovirus/genética , Biópsia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos , Imuno-Histoquímica , Contagem de Linfócitos , Linfócitos/imunologia , Linfócitos/patologia , Doenças das Aves Domésticas/diagnóstico , Baço/imunologia , Baço/metabolismo , Baço/patologia , Baço/virologia , Carga Viral
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202925

RESUMO

Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs.


Assuntos
Imunomodulação , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Acetilcolina/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Regulação da Expressão Gênica , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade , Linfócitos/imunologia , Linfócitos/metabolismo , Especificidade de Órgãos , Peptídeos/metabolismo , Peptídeos/farmacologia , Receptores Muscarínicos/genética , Receptores Nicotínicos/genética , Transdução de Sinais
10.
Medicine (Baltimore) ; 100(28): e26335, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260524

RESUMO

ABSTRACT: Cervical intraepithelial neoplasia (CIN) is the abnormal growth of cells on the surface of the cervix that could potentially lead to cervical cancer. In the present study, we investigated whether measuring the neutrophil-lymphocyte ratio (NLR) can be useful for predicting the risks of developing cervical lesions.This is a retrospective analysis of 212 women who were enrolled in this study. Among them, 106 patients with histologically confirmed CIN1-3 who were treated with loop electrosurgical excision procedure or cold knife cone in the Department of Gynecology, The Affiliated Hospital of Inner Mongolia Medical University between July 30th 2016 and January 30th 2019.Among the 106 patients in the CIN group, cytology showed minor abnormality which included atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion in 42, high-grade squamous intraepithelial lesion in 62, and squamous cell carcinoma in 2 patients. We found that the NLR has no significant difference between the control group and the CIN1 group, while there were significant differences between CIN1 and CIN2, and CIN2 and CIN3 group. The median of the NLR was higher in the HPV16-persistent groups than in the HPV-negative group.In conclusion, a high NLR value independently predicts CIN and the stage of CIN. The NLR may help doctors evaluate outcomes of patients received conization and choose alternative therapies for patients with high NLR value.


Assuntos
Neoplasia Intraepitelial Cervical/sangue , Linfócitos/metabolismo , Neutrófilos/metabolismo , Neoplasias do Colo do Útero/sangue , Adulto , Idoso , Biomarcadores Tumorais , Neoplasia Intraepitelial Cervical/epidemiologia , Neoplasia Intraepitelial Cervical/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/epidemiologia , Estudos Retrospectivos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem
11.
Medicine (Baltimore) ; 100(28): e26503, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260527

RESUMO

ABSTRACT: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been rapidly spreading on a global scale and poses a great threat to human health. However, efficient indicators for disease severity have not been fully investigated. Here, we aim to investigate whether dynamic changes of lymphocyte counts can predict the deterioration of patients with COVID-19.We collected data from 2923 patients with laboratory-confirmed COVID-19. Patients were then screened, and we focused on 145 severe cases and 60 critical cases (29 recovered cases, 31 deaths). The length of hospitalization was divided into five time points, namely admission, 25%, 50%, 75% and discharge or death, according to the principle of interquartile distance. A series of laboratory findings and clinical data were collected and analyzed during hospitalization. The results showed that there were differences in levels of leukocytes, neutrophils and lymphocytes at almost every time point in the severe cases and 60 critical cases (29 recovered cases, 31 deaths). Further analysis showed that 70.2% of the COVID-19 cases had low circulating lymphocyte count, of which 64.1% were severe cases and 85.0% were critical cases (75.9% recovered cases and 93.5% died). Moreover, the lymphocyte count in dead cases was significantly lower than that of critical cases who recovered, at almost every time point in the critical groups. We also divided critical patients into group A (<1.1 × 109/L) and group B (>1.1 × 109/L) according to number of lymphocytes. Through survival analysis, we found that there was no significant difference in survival between group A and group B at admission (P = .3065). However, the survival rate according to lymphocyte levels in group A was significantly lower than that of group B at 25% hospital stay (on average day 6.5), 50% and 75% time points (P < .001).Lymphocyte counts that remain lower after the first week following symptom onset are highly predictive of in-hospital death of adults with COVID-19. This predictor may help clinicians identify patients with a poor prognosis and may be useful for guiding clinical decision-making at an early stage.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Contagem de Linfócitos/estatística & dados numéricos , Linfócitos/metabolismo , SARS-CoV-2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/virologia , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Adulto Jovem
12.
Medicine (Baltimore) ; 100(28): e26537, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260530

RESUMO

ABSTRACT: The clinical significance of hemoglobin-to-red blood cell distribution width (Hb/RDW) for the diagnosis of nasopharyngeal cancer (NPC) has not been reported yet. This study aimed to evaluate the value of preoperative Hb/RDW, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for the diagnosis of NPC.A total of 180 NPC patients (NPC group) and 149 healthy subjects (control group) were recruited to assess the value of Hb/RDW, NLR, and PLR for the diagnosis of NPC.It was noted that NLR and PLR were significantly higher in the NPC group than those in the control group (P < .001); however, Hb/RDW was lower in the NPC group compared with that in the control group (P < .001). NLR was also remarkably different between patients of stage I+II and those of stage III+IV (P = .043), and that was different in patients with lymph node metastases or not (P = .030). Besides, PLR was significantly different in patients with serosal invasion or not (P = .031). In receiver operating characteristic curve, compared with Hb/RDW alone (sensitivity, 66.67%; specificity, 85.23%), the sensitivity (67.78%, 72.78%) and specificity (89.62%, 90.6%) of Hb/RDW with NLR and PLR were both increased. Furthermore, Hb/RDW combined with NLR area under the ROC (AUC), 0.824; 95% confidence interval (CI): 0.779-0.864, P = .0080) or PLR (AUC: 0.851, 95% CI: 0.808-0.888, P = .0002) had a greater AUC value for the diagnosis of NPC compared with Hb/RDW alone (AUC: 0.781, 95% CI: 0.732-0.824).Hb/RDW can be used as a valuable indicator for auxiliary diagnosis of NPC. Preoperative Hb/RDW combined with NLR or PLR is of great significance in the auxiliary diagnosis and pathological staging of NPC.


Assuntos
Índices de Eritrócitos , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/diagnóstico , Adulto , Idoso , Plaquetas/metabolismo , Estudos de Casos e Controles , Eritrócitos/metabolismo , Feminino , Hemoglobinas/análise , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Estudos Retrospectivos
13.
Int J Mol Sci ; 22(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299056

RESUMO

The glycolytic modulator TP53-Inducible Glycolysis and Apoptosis Regulator (TIGAR) is overexpressed in several types of cancer and has a role in metabolic rewiring during tumor development. However, little is known about the role of this enzyme in proliferative tissues under physiological conditions. In the current work, we analysed the role of TIGAR in primary human lymphocytes stimulated with the mitotic agent Concanavalin A (ConA). We found that TIGAR expression was induced in stimulated lymphocytes through the PI3K/AKT pathway, since Akti-1/2 and LY294002 inhibitors prevented the upregulation of TIGAR in response to ConA. In addition, suppression of TIGAR expression by siRNA decreased the levels of the proliferative marker PCNA and increased cellular ROS levels. In this model, TIGAR was found to support the activity of glucose 6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentose phosphate pathway (PPP), since the inhibition of TIGAR reduced G6PDH activity and increased autophagy. In conclusion, we demonstrate here that TIGAR is upregulated in stimulated human lymphocytes through the PI3K/AKT signaling pathway, which contributes to the redirection of the carbon flux to the PPP.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Concanavalina A/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Linfócitos/metabolismo , Mitógenos/farmacologia , Fosfatidilinositol 3-Quinases/química , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Apoptose , Proteínas Reguladoras de Apoptose/genética , Autofagia , Glicólise , Humanos , Linfócitos/efeitos dos fármacos , Via de Pentose Fosfato , Monoéster Fosfórico Hidrolases/genética , Transdução de Sinais
14.
Front Immunol ; 12: 676828, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290701

RESUMO

In coronavirus disease 2019 (COVID-19), ulcerative lesions have been episodically reported in various segments of the gastrointestinal (GI) tract, including the oral cavity, oropharynx, esophagus, stomach and bowel. In this report, we describe an autopsy case of a COVID-19 patient who showed two undiagnosed ulcers at the level of the anterior and posterior walls of the hypopharynx. Molecular testing of viruses involved in pharyngeal ulcers demonstrated the presence of severe acute respiratory syndrome - coronavirus type 2 (SARS-CoV-2) RNA, together with herpes simplex virus 1 DNA. Histopathologic analysis demonstrated full-thickness lympho-monocytic infiltration (mainly composed of CD68-positive cells), with hemorrhagic foci and necrosis of both the mucosal layer and deep skeletal muscle fibers. Fibrin and platelet microthrombi were also found. Cytological signs of HSV-1 induced damage were not found. Cells expressing SARS-CoV-2 spike subunit 1 were immunohistochemically identified in the inflammatory infiltrations. Immunohistochemistry for HSV1 showed general negativity for inflammatory infiltration, although in the presence of some positive cells. Thus, histopathological, immunohistochemical and molecular findings supported a direct role by SARS-CoV-2 in producing local ulcerative damage, although a possible contributory role by HSV-1 reactivation cannot be excluded. From a clinical perspective, this autopsy report of two undiagnosed lesions put the question if ulcers along the GI tract could be more common (but frequently neglected) in COVID-19 patients.


Assuntos
COVID-19/complicações , Hipofaringe/patologia , SARS-CoV-2/isolamento & purificação , Úlcera/patologia , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Autopsia , Plaquetas/metabolismo , Plaquetas/patologia , COVID-19/mortalidade , COVID-19/patologia , COVID-19/fisiopatologia , Trato Gastrointestinal/patologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/isolamento & purificação , Humanos , Hipofaringe/virologia , Imuno-Histoquímica , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/virologia , Linfócitos/metabolismo , Monócitos/metabolismo , Membrana Mucosa/patologia , Músculo Esquelético/patologia , Necrose/patologia , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/patologia , Úlcera/virologia
15.
Biomark Med ; 15(11): 807-820, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34284639

RESUMO

Aim: We aimed to determine the prognostic values of the National Early Warning Score 2 (NEWS2) and laboratory parameters during the first week of COVID-19. Materials & methods: All adult patients who were hospitalized for confirmed COVID-19 between 11 March and 11 May 2020 were retrospectively included. Results: Overall, 611 patients were included. Our results showed that NEWS2, procalcitonin, neutrophil/lymphocyte ratio and albumin at D0, D3, D5 and D7 were the best predictors for clinical deterioration defined as a composite of ICU admission during hospitalization or in-hospital death. Procalcitonin had the highest odds ratio for clinical deterioration on all days. Conclusion: This study provides a list of several laboratory parameters correlated with NEWS2 and potential predictors for clinical deterioration in patients with COVID-19.


Assuntos
COVID-19/metabolismo , Pró-Calcitonina/metabolismo , Albuminas/metabolismo , Mortalidade Hospitalar , Humanos , Linfócitos/metabolismo , Neutrófilos/metabolismo , Razão de Chances
16.
Cell Death Dis ; 12(8): 732, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301919

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by symptoms of lymphopenia and multiorgan damage, but the underlying mechanisms remain unclear. To explore the function of N6-methyladenosine (m6A) modifications in COVID-19, we performed microarray analyses to comprehensively characterize the m6A epitranscriptome. The results revealed distinct global m6A profiles in severe and mild COVID-19 patients. Programmed cell death and inflammatory response were the major biological processes modulated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Further, RBM15, a major m6A methyltransferase, was significantly elevated and positively correlated with disease severity. Silencing RBM15 drastically reduced lymphocyte death in vitro. Knockdown of RBM15 remarkably suppressed the expression levels of multitarget genes related to programmed cell death and inflammatory response. This study shows that SARS-CoV-2 infection alters the m6A epitranscriptome of lymphocytes, particularly in the case of severe patients. RBM15 regulated host immune response to SARS-CoV-2 by elevating m6A modifications of multitarget genes. These findings indicate that RBM15 can serve as a target for the treatment of COVID-19.


Assuntos
Adenosina/análogos & derivados , COVID-19/genética , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/metabolismo , Transcriptoma , Adenosina/metabolismo , COVID-19/patologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética , Células THP-1
17.
Nat Immunol ; 22(7): 851-864, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099918

RESUMO

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.


Assuntos
Anticorpos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-33/farmacologia , Linfócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo
18.
J Photochem Photobiol B ; 221: 112244, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34174487

RESUMO

The delta-amino acid 5-aminolevulinic acid (ALA), is the precursor of the endogenous photosensitiser Protoporphyrin IX (PpIX), and is currently approved for Photodynamic Therapy (PDT) of certain superficial cancers. However, ALA-PDT is not very effective in diseases in which T-cells play a significant role. Cutaneous T-cell lymphomas (CTCL) is a group of non-Hodgkin malignant diseases, which includes mycosis fungoides (MF) and Sézary syndrome (SS). In previous work, we have designed new ALA esters synthesised by three-component Passerini reactions, and some of them showed higher performance as compared to ALA. This work aimed to determine the efficacy as pro-photosensitisers of five new ALA esters of 2-hydroxy-N-arylacetamides (1f, 1 g, 1 h, 1i and 1 k) of higher lipophilicity than ALA in Myla cells of MF and HuT-78 cells of SS. We have also tested its effectiveness against ALA and the already marketed ALA methyl ester (Me-ALA) and ALA hexyl ester (He-ALA). Both cell Myla and SS cells were effectively and equally photoinactivated by ALA-PDT. Besides, the concentration of ALA required to induce half the maximal porphyrin synthesis was 209 µM for Myla and 169 µM for HuT-78 cells. As a criterion of efficacy, we calculated the concentration of the ALA derivatives necessary to induce half the plateau porphyrin values obtained from ALA. These values were achieved at concentrations 4 and 12 times lower compared to ALA, according to the derivative used. For He-ALA, concentrations were 24 to 25 times lower than required for ALA for inducing comparable porphyrin synthesis in both CTCL cells. The light doses for inducing 50% of cell death (LD50) for He-ALA, 1f, 1 g, 1 h and 1i were around 18 and 25 J/cm2 for Myla and HuT-78 cells respectively, after exposure to 0.05 mM concentrations of the compounds. On the other hand, the LD50s for the compound 1 k were 40 and 57 J/cm2 for Myla and HuT-78, respectively. In contrast, 0.05 mM of ALA and Me-ALA did not provoke photokilling since the concentration employed was far below the porphyrin saturation point for these compounds. Our results suggest the potential use of ALA derivatives for topical application in PDT treatment of MF and extracorporeal PDT for the depletion of activated T-cells in SS.


Assuntos
Ácido Aminolevulínico/análogos & derivados , Fármacos Fotossensibilizantes/farmacologia , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Luz , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/fisiologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico
19.
Sci Rep ; 11(1): 13026, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158545

RESUMO

The objective of the study was to develop and validate a prediction model that identifies COVID-19 patients at risk of requiring oxygen support based on five parameters: C-reactive protein (CRP), hypertension, age, and neutrophil and lymphocyte counts (CHANeL). This retrospective cohort study included 221 consecutive COVID-19 patients and the patients were randomly assigned randomly to a training set and a test set in a ratio of 1:1. Logistic regression, logistic LASSO regression, Random Forest, Support Vector Machine, and XGBoost analyses were performed based on age, hypertension status, serial CRP, and neutrophil and lymphocyte counts during the first 3 days of hospitalization. The ability of the model to predict oxygen requirement during hospitalization was tested. During hospitalization, 45 (41.8%) patients in the training set (n = 110) and 41 (36.9%) in the test set (n = 111) required supplementary oxygen support. The logistic LASSO regression model exhibited the highest AUC for the test set, with a sensitivity of 0.927 and a specificity of 0.814. An online risk calculator for oxygen requirement using CHANeL predictors was developed. "CHANeL" prediction models based on serial CRP, neutrophil, and lymphocyte counts during the first 3 days of hospitalization, along with age and hypertension status, provide a reliable estimate of the risk of supplement oxygen requirement among patients hospitalized with COVID-19.


Assuntos
Proteína C-Reativa/análise , COVID-19/patologia , Hipertensão/complicações , Linfócitos/citologia , Neutrófilos/citologia , Oxigenoterapia , Fatores Etários , Idoso , Área Sob a Curva , Biomarcadores/análise , Biomarcadores/metabolismo , COVID-19/complicações , COVID-19/virologia , Feminino , Humanos , Modelos Logísticos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Curva ROC , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Máquina de Vetores de Suporte
20.
J Clin Neurosci ; 89: 56-64, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119295

RESUMO

BACKGROUND: Red blood cell distribution width to platelet ratio (RPR), Monocyte to high-density lipoprotein ratio (MHR), and Neutrophil to lymphocyte ratio (NLR) are novel inflammatory biomarkers in laboratory tests, which are associated with clinical outcomes in malignancy, cardiovascular and cerebrovascular diseases. This study aimed to determine their predictive value for the prognosis of acute ischemic stroke after mechanical thrombectomy (MT). METHODS: A total of 286 patients with acute ischemic stroke (AIS) admitted to a tertiary stroke center in China between January 2018 and February 2020 were treated by MT. Demographic characteristics, risk factors, clinical data, laboratory parameters, and clinical outcomes were recorded. The clinical outcome was disability or death at discharge or 90 days (defined as a modified Rankin Scale score of 3-6). The relationship between RPR, MHR, and NLR and functional outcomes was investigated by binary Logistic regression analysis, and further assessed by receiver operating characteristic curve (ROC). The Kaplan-Meier method was used to analyze the survival rate of prognosis factors. RESULTS: A total of 286 patients with AIS underwent MT (median age, 70.00; Interquartile range [IQR], 63.00-77.00; 41.6% female). Patients with unfavorable outcome showed higher RPR, MHR, and NLR than those with favorable outcome (RPR, [8.63; IQR, 6.30-10.78] vs [6.17; IQR, 5.11-7.35], P < 0.001; MHR, [0.40; IQR, 0.31-0.53] vs [0.34; IQR, 0.27-0.47], P = 0.005; NLR, [5.28; IQR, 3.63-8.02] vs [3.44; IQR, 2.63-4.63], P < 0.001). In multivariate and ROC curve analysis, higher RPR (>8.565) (odds ratio [OR], 1.671; 95% confidence interval [CI], 1.127-2.479; P = 0.011) and higher MHR (>0.368) (OR, 9.374; 95% CI, 1.160-75.767; P = 0.036), higher NLR (>4.030) (OR, 1.957; 95% CI, 1.382-2.770; P < 0.001) were independently associated with unfavorable outcome. The combined predictive value of the three indexes was higher than that of a single index. Kaplan-Meier survival curve analysis showed that the 90-day survival rate (82.1% vs 66.2%) was significantly different between the low RPR group and the high RPR group (χ2 = 4.960, P = 0.026). CONCLUSION: Higher RPR, MHR, and NLR might be independent risk factors for predicting 3-month poor prognosis in patients with AIS who underwent MT.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/cirurgia , AVC Isquêmico/sangue , AVC Isquêmico/cirurgia , Leucócitos Mononucleares/metabolismo , Trombectomia/tendências , Idoso , Biomarcadores/sangue , Plaquetas/metabolismo , Isquemia Encefálica/diagnóstico , Feminino , Humanos , AVC Isquêmico/diagnóstico , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Neutrófilos/metabolismo , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
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