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Self-powered photodetectors with bipolar photoresponse characteristics are expected to play a critical role in the field of secure optical communication, artificial neuromorphic systems, and intelligent color sensors. In this work, asymmetric heterojunction devices exhibiting wavelength-dependent bipolar photoresponse with a structure of Glass/FTO/CdSe/Bi2Se3/Au were fabricated. Under a short wavelength light irradiation, the top CdSe absorber generates a high carrier concentration; the excited carriers are quickly separated by the built-in electric field induced by the FTO/CdSe diode, resulting in a negative photocurrent. For light with wavelengths beyond the CdSe absorption edge, it is absorbed by the bottom Bi2Se3 absorber, and a positive photocurrent can be observed. Therefore, based on the bandgap difference between the top CdSe absorber and the bottom Bi2Se3 absorber, combined with the photogenerated carriers separated by asymmetric back-to-back diode, a wavelength-dependent bipolar response is realized. In this work, by employing this structure, the responsivities of -33.3 and 0.3 mA/W were achieved under the illumination of 405 and 830 nm, respectively. This work provides important indications in the preparation and performance optimization for wavelength-dependent bipolar photodetectors.
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BACKGROUND: The prognostic significance of metastasis-associated in colon cancer-1 (MACC1) has been explored in a variety of malignancies. However, its clinical relevance in patients with gastric cancer (GC) is limited, also remains controversial. METHOD: In this study, we retrospectively evaluated the prognostic value of lesion MACC1 expression in 347 GC patients. Lesion MACC1 expression was analyzed with immunohistochemistry and grouped as MACC1low (n = 172) and MACC1high (n = 175) cases. RESULTS: Data revealed that the degree of MACC1 expression is not related to patient sex, age and disease stage (all p > 0.05). Survival analysis showed that only post-operation advanced pT (p = 0.018), pN (p < 0.001), pM (p = 0.001) and AJCC stages (p < 0.001) are significantly associated with shorter survival, while no obvious difference was observed between MACC1low and MACC1high cases (p = 0.158). However, we found that survival for female (p = 0.032), older (p = 0.028), and early disease stage (pT stage I + II, p = 0.033) patients with MACC1high are remarkably worse than those with MACC1low. CONCLUSION: In summary, our findings revealed that, though MACC1 expression is not associated with the survival of the whole cohort, the prognostic risk stratification value of lesion MACC1 expression in subgroups of patients with gastric cancer should be noted.
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Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.
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Elementos de DNA Transponíveis , Humanos , Elementos de DNA Transponíveis/genética , Engenharia Genética/métodos , Genoma Humano , Animais , Evolução MolecularRESUMO
OBJECTIVES: This study aimed to compare and rank the effectiveness of aerobic exercise, resistance training, combined aerobic and resistance exercise, and high-intensity interval training on inflammatory marker levels in women with overweight and obesity by using network meta-analysis. DESIGN: Systematic review with network meta-analysis and Grading Recommendations Assessment, Development, and Evaluation of the evidence. METHODS: Literature as of April 2023 was searched from databases such as Cochrane, Embase, Pubmed, Web of Science, and EBSCO, and English-language randomized controlled trials that meet the inclusion criteria were selected. A random-effects network meta-analysis was performed within a frequentist framework. RESULTS: A total of 75 articles and 4048 participants were included. Resistance training was the most recommended type of exercise to decrease C-reactive protein levels (surface under cumulative rankingâ¯=â¯90.1; standardized mean differenceâ¯=â¯-0.79, 95â¯% confidence interval: -1.17, -0.42); aerobic exercise was the most effective exercise type to reduce tumor necrosis factor-α levels (surface under cumulative rankingâ¯=â¯87.9; standardized mean differenceâ¯=â¯-0.79, 95â¯% confidence interval: -1.19, -0.39); combined aerobic and resistance exercise was the most effective type of exercise to reduce interleukin-6 levels (surface under cumulative rankingâ¯=â¯75.8; standardized mean differenceâ¯=â¯-0.77, 95â¯% confidence interval: -1.38, -0.16) and leptin levels (surface under cumulative rankingâ¯=â¯77.1; standardized mean differenceâ¯=â¯-0.96, 95â¯% confidence interval: -1.72, -0.20), and high-intensity interval training was the type of exercise that was well suited to increase adiponectin levels (surface under cumulative rankingâ¯=â¯87.2; standardized mean differenceâ¯=â¯0.99, 95â¯% confidence interval: 0.27, 1.71). CONCLUSIONS: This network meta-analysis based on randomized controlled trials confirmed that different exercise types have different efficacies on inflammation indicators among women with overweight and obesity. The findings may provide clinicians and healthcare professionals with insights into the implementation of exercise programs for women struggling with overweight and obesity.
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Biomarcadores , Exercício Físico , Metanálise em Rede , Obesidade , Sobrepeso , Ensaios Clínicos Controlados Aleatórios como Assunto , Treinamento Resistido , Humanos , Feminino , Obesidade/sangue , Obesidade/terapia , Sobrepeso/terapia , Sobrepeso/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Fator de Necrose Tumoral alfa/sangue , Interleucina-6/sangue , Treinamento Intervalado de Alta Intensidade , Leptina/sangue , Adiponectina/sangue , Inflamação/sangueRESUMO
IMPORTANCE: Postmenopausal women affected by overweight and obesity are susceptible to a variety of diseases due to inflammation. Exercise may reduce the risk of disease by attenuating low-grade chronic inflammation. OBJECTIVE: We conducted a systematic review and meta-analysis to investigate the effects of exercise on inflammatory markers in postmenopausal women struggling with overweight and obesity. METHOD: Literature as of May 2023 was searched from databases such as Cochrane, Embase, Pubmed, Web of Science, and EBSCO and English-language randomized controlled trials (RCTs) that meet the inclusion criteria were selected. Studies were included based on the following criteria: (A) Written in English; (B) RCTs; (C) Postmenopausal women impacted by overweight and obesity as research objects; (D) Outcome measurements include CRP, TNF-α, IL-6, and adiponectin; (E) Duration of the exercise intervention is eight weeks. RESULTS: A total of 34 articles and 2229 participants were included. Exercise can significantly reduce the level of C-reactive protein (CRP) (MD: -0.59, 95 % CI: -0.87 to -0.31, p < 0.00001), tumor necrosis factor-α (TNF-α) (MD: -0.65, 95 % CI: -0.94 to -0.35, p < 0.00001), interleukin-6 (IL-6) (MD: -0.48, 95 % CI: -0.75 to -0.21, p < 0.00001), and exercise can significantly increase the level of adiponectin (MD: 0.33, 95 % CI: 0.02 to 0.65, p = 0.04) in women impacted by overweight and obesity. CONCLUSION: These results suggest that exercise may be an effective intervention for reducing pro-inflammatory markers and increasing adiponectin in postmenopausal women impacted by overweight and obesity. The findings may provide clinicians and healthcare professionals with insights into the implementation of exercise programs for postmenopausal women living with overweight and obesity.
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Interleucina-6 , Sobrepeso , Feminino , Humanos , Adiponectina , Proteína C-Reativa , Inflamação , Obesidade/terapia , Sobrepeso/terapia , Pós-Menopausa , Fator de Necrose Tumoral alfaRESUMO
Diabetes could impact many ocular tissues. However, the association of the serum aldehydes with diabetes-related eye diseases (DED) remains unclear. Thus, we aimed to examine the above relationship from the general US population of 2013-2014 National Health and Nutrition Examination Survey (NHANES). The multivariable logistic regression and Bayesian kernel machine regression (BKMR) were used to analyze the effect of serum aldehydes on the risk of DED. Pearson's correlation analysis, the restricted cubic spline (RCS) model, and the linear regression were performed to explore the association between the serum aldehydes and other parameters. The multivariable linear regression was conducted to further underlie the relationship between the serum aldehydes and the glycohemoglobin A1c (HbA1c) in DED participants. Although no significant association was observed between the serum aldehydes and the risk of DED by the multivariable logistic regression and BKMR, the Pearson correlation revealed a positive association between the HbA1c level and the serum level of heptanaldehyde and isopentanaldehyde in DED participants. The RCS model confirmed the above linear correlation. After adjusting for the cofounding factor of smoking, the multivariable linear regression revealed a significant association between the serum level of heptanaldehyde and the HbA1c level in DED participants. Our results suggest that aldehyde exposure did not significantly increase the risk of DED, while heptanaldehyde was the risk factor for increased HbA1c in DED population.
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Complicações do Diabetes , Diabetes Mellitus , Oftalmopatias , Humanos , Inquéritos Nutricionais , Estudos Transversais , Aldeídos , Hemoglobinas Glicadas , Teorema de BayesRESUMO
Upregulation of Sirtuin Type 1 (SIRT1), a nicotinamide adeninedinucleotide (NAD+)-dependent deacetylase, has been proved to protect against ample ocular diseases, while its effect on retinitis pigmentosa (RP) has not been illustrated. The study was aimed to explore the impacts of resveratrol (RSV), a SIRT1 activator, on the photoreceptor degeneration in a rat model of RP induced by N-methyl-N-nitrosourea (MNU), an alkylation. The rats were induced RP phenotypes via the intraperitoneal injection of MNU. The electroretinogram was conducted and revealed that RSV could not prevent the decline of retinal function in the RP rats. The optical coherence tomography (OCT) and the retinal histological examination were performed and showed that the reduced thickness of the outer nuclear layer (ONL) was not preserved by RSV intervention. The immunostaining technique was applied. Afther the MNU administration, the number of the apoptotic photoreceptors in the ONL throughout the retinasand the number of microglia cells present among the outer part throughout the retinas were not significantly reduced by RSV. Western blotting was also performed. The data showed that the level of SIRT1 protein was decreased after MNU administration, while RSV was not able to obviously alleviate the downregulation. Our data together indicated that RSV was not able to rescue the photoreceptor degeneration in the MNU-induced RP rats, which might be due to the MNU-induced consumption of the NAD+.
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This study explores online fan satisfaction with the Video Assistant Referee (VAR) during the FIFA World Cup Qatar 2022. A structural equation model comprising perceived value, fan expectation, fan identification, and fan satisfaction was run. The online questionnaires were distributed among Chinese football fans. A total of 224 valid responses were received. Using indicators like Cronbach's alpha coefficient, Kaiser-Meyer-Olkin (KMO) statistic, and Bartlett's test of sphericity, the results were assessed for reliability, validity, and suitability. From the statistical results, the overall satisfaction of fans with VAR is the middle. Both fan expectation and perceived value positively affect satisfaction (p < 0.01); the path coefficients were 0.26 and 0.57. Contrastingly, fan identification exerts no significant effect on fan satisfaction (p > 0.05); and fan expectation indirectly affects fan satisfaction through perceived value (p < 0.01); the path coefficient was 0.29. The highest effect value for fan satisfaction is perceived value, followed by fan expectation. Consequently, to improve online fan satisfaction with VAR, researchers should focus on perceived value. This research contributes to a greater more comprehensive of Chinese online fans' preference towards VAR at the FIFA World Cup Qatar 2022.
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The FIFA World Cup, which represents the highest level in football, is regarded as a showcase to unfold the development trends of modern football, thus arousing great interest among researchers. However, most of the previous research designs studied the simple linear correlation between technical indicators and game outcomes, which may overlook the complex causalities in football performance. The aim of current study was to introduce a new method to examine winning patterns emerging from Qatar 2022 through a configurational lens. To this end, fuzzy-set qualitative comparative analysis (fsQCA) was conducted using 98 samples (n = 98) out of 49 Qatar 2022 matches discriminating winning and losing teams in regular time (group stage) and in 30 min of extra time (knockout stage). Then, we selected seven variables as our causal conditions, namely, shots on target, possession, defensive line breaks, crosses, receptions in the final third, forced turnovers, and direct pressures. Necessity analysis and sufficiency analysis of configurations were conducted according to fsQCA requirements. The fsQCA operation showed that no individual causal condition is necessary to winning a game and four configurations were derived from the QCA results and these combinations of conditions fall into three typologies of play style: a possession play style, direct play style, and all-round play style. The results confirmed the fact that football is a complex system and suggested that a winning outcome is often produced by combinations of multiple factors. The findings of the current study contribute to the literature by introducing the configurations of various technical and tactical indicators that could raise the possibility of winning and can be used by practitioners working within the fields of player development, coaching, and match preparation.
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OBJECTIVE: To evaluate the prognostic significance of peripheral lymphocyte count and its derived inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), in a cohort of patients with gastric cancer (GC). METHODS: In this retrospective study, the clinical characteristics and follow-up information, both pre- and post-operative within one week of laboratory findings, of 338 patients with GC who underwent radical gastrectomy were retrieved, and their prognostic significance was evaluated. RESULTS: Both lower pre- and post-operative lymphocyte counts and higher NLR and SSI were significantly related to advanced tumour (pT) and disease stages (American Joint Committee on Cancer [AJCC]) in patients with GC. Log-rank survival analysis showed that, in addition to traditional pT, pN, pM, and AJCC stages, both lower pre- (p = 0.041) and post-operative (p = 0.002) lymphocyte counts and higher NLR (ppre < 0.001 and ppost = 0.008) and SSI (ppre = 0.014 and ppost = 0.145) were associated with worse survival. Cox proportional hazards analysis revealed that pre-operative NLR (p = 0.018; hazard ratio = 1.778) was an independent predictor of prognosis in patients with GC. Moreover, when the pre-operative NLR was divided into NLRlow and NLRhigh, NLRhigh showed stratified prognostic value for patient sex (male, p = 0.001; female, p = 0.044), age (younger, p = 0.005; older, p = 0.005), and AJCC stage III (p = 0.007). CONCLUSION: Pre-operative NLR is an independent prognostic factor for patients with GC and has stratified prognostic value for patients with AJCC stage III GC.
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Neutrófilos , Neoplasias Gástricas , Humanos , Masculino , Feminino , Neutrófilos/patologia , Neoplasias Gástricas/patologia , Prognóstico , Estudos Retrospectivos , Linfócitos/patologia , Contagem de LinfócitosRESUMO
Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Bevacizumab/genética , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/uso terapêutico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosRESUMO
OBJECTIVE: Human leukocyte antigen-G (HLA-G) and its receptors, including immunoglobulin-like transcripts (ILT)-2 and ILT-4, are closely associated with cancer development and clinical outcomes of patients. However, the clinical significance of HLA-G and ILT-2/-4 in gastric cancer (GC) is limited. METHODS: In this study, the percentage of HLA-G-, ILT-2 and ILT-4 positive tumor cells in 127 GC lesion suspensions of tumor cells gated for epithelialcelladhesionmolecule(EpCAM) was determined using multicolor flow cytometry and their clinical significance was evaluated. RESULTS: Our data showed that the median percentages of HLA-G-, ILT-2, and ILT-4 expressing GC cells were 18.0%, 67.80%, and 1.42%, respectively, and co-expression of HLA-G/ILT-2, HLA-G/ILT-4, and ILT-2/ILT-4 was 16.9%, 1.42%, and 1.70%, respectively. Kaplan-Meier survival results revealed that besides post-operation N status (p = 0.006), M status (p = 0.001), and AJCC clinical stage (p < 0.001), only high percentage of ILT-4+ GC cells was a significant factor for worse survival of patients with GC (overall survival [OS]: 42.9 months vs. 84.5 months; p = 0.031). However, among female patients with GC (n = 31), high percentage of either HLA-G+ (OS: 18.5 months vs. 89.3 months; p = 0.001) or ILT-4+ (OS: 17.9 months vs. 85.8 months; p = 0.002) GC cells was markedly associated with a poor prognosis. CONCLUSION: Our findings revealed that among HLA-G, ILT-2, and ILT-4, only a high percentage of ILT-4+ GC cells was significantly related to poor prognosis in the entire cohort of patients with GC. However, high percentage of HLA-G+ and ILT-4+ GC cells is associated with poor clinical outcome among female patients with GC.
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Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Neoplasias Gástricas , Contagem de Células , Feminino , Citometria de Fluxo , Antígenos HLA-G/genética , Humanos , Prognóstico , Neoplasias Gástricas/patologiaRESUMO
Lung ischemiareperfusion (I/R) injury poses a serious threat to human health, worldwide. The current study aimed to determine the role of lidocaine in A549 cells, in addition to the involvement of the p38 MAPK pathway. Oxygen deprivation/reoxygenationinduced A549 cells were utilized to simulate I/R injury in vitro. Cell viability and apoptosis were detected using MTT and TUNEL assays, respectively. The levels of IL6, IL8, TNFα, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, iron and reactive oxygen species (ROS) were measured using corresponding commercial kits. The corresponding protein expression levels were also measured using western blotting. Moreover, a monolayer cell paracellular permeability assay was performed to determine the permeability of A549 cells. The results demonstrated that, whilst lidocaine had no influence on untreated A549 cells, it significantly increased the viability of hypoxia/reoxygenation (H/R)induced A549 cells. A549 cell apoptosis and the release of inflammatory cytokines in the H/R group were decreased after the addition of lidocaine. When compared with the H/R group, increased MDA level and decreased SOD level were observed in H/Rinduced A549 cells following lidocaine treatment. In addition, the permeability of H/Rinduced A549 cells was markedly decreased following lidocaine treatment. Compared with the H/R group, the expression levels of tight junction and ferroptosisrelated proteins were significantly upregulated by lidocaine, whereas the expression of transferrin was downregulated. However, p79350, an agonist of p38, reversed the effects of lidocaine on H/Rinduced A549 cells. In conclusion, lidocaine exerted a protective role in HRinduced lung epithelial cell injury, which may serve as a potential agent for the treatment of patients with lung I/R injury.
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Ferroptose , Proteínas Quinases p38 Ativadas por Mitógeno , Células A549 , Apoptose , Humanos , Hipóxia , Inflamação/tratamento farmacológico , Lidocaína/farmacologia , Pulmão/metabolismo , Estresse Oxidativo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has threatened public health worldwide. Host antiviral immune responses are essential for viral clearance and disease control, however, remarkably decreased immune cell numbers and exhaustion of host cellular immune responses are commonly observed in patients with COVID-19. This is of concern as it is closely associated with disease severity and poor outcomes. Human leukocyte antigen-G (HLA-G) is a ligand for multiple immune inhibitory receptors, whose expression can be upregulated by viral infections. HLA-G/receptor signalling, such as engagement with immunoglobulin-like transcript 2 (ILT-2) or ILT-4, not only inhibit T and natural killer (NK) cell immune responses, dendritic cell (DC) maturation, and B cell antibody production. It also induces regulatory cells such as myeloid-derived suppressive cells (MDSCs), or M2 type macrophages. Moreover, HLA-G interaction with CD8 and killer inhibitory receptor (KIR) 2DL4 can provoke T cell apoptosis and NK cell senescence. In this context, HLA-G can induce profound immune suppression, which favours the escape of SARS-CoV-2 from immune attack. Although detailed knowledge on the clinical relevance of HLA-G in SARS-CoV-2 infection is limited, we herein review the immunopathological aspects of HLA-G/receptor signalling in SARS-CoV-2 infection, which could provide a better understanding of COVID-19 disease progression and identify potential immunointerventions to counteract SARS-CoV-2 infection.
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COVID-19/imunologia , Antígenos HLA-G/imunologia , Tolerância Imunológica/imunologia , Humanos , SARS-CoV-2/imunologiaRESUMO
BACKGROUND: Bladder cancer is the 10th most common cancer and most common urothelial malignancy worldwide. Prognostic biomarkers for bladder cancer patients are required for individualized treatment. Monocarboxylate transporter 4 (MCT4), encoded by SLC16A3 gene, is a potential biomarker for bladder cancer because of its crucial role in the lactate efflux in the aerobic glycolysis process. We aimed to study the association between MCT4 expression and the overall survival (OS) of bladder cancer patients. METHODS: The published single-cell RNA sequencing data of 49,869 bladder cancer cells and 15,827 normal bladder mucosa cells and The Cancer Genome Atlas (TCGA) bladder cancer cohort data were used to explore the mRNA expression of SLC16A3 in bladder cancer. Eighty-nine consecutive bladder cancer patients who had undergone radical cystectomy were enrolled as a validation cohort. The expression of MCT4 proteins in bladder cancer specimens was detected using immunohistochemistry staining. The Kaplan-Meier survival analysis and Cox regression were performed to analyze the association between MCT4 protein expression and OS in bladder cancer patients. RESULTS: SLC16A3 mRNA was upregulated in bladder cancer cells. The upregulated genes in SLC16A3-positive epithelial cells were enriched in the glycolysis process pathway and monocarboxylic acid metabolic process pathway. Patients with high SLC16A3 mRNA expression showed significantly poor OS (p = 0.016). High MCT4 protein expression was also found to be an independent predictor for poor OS in bladder cancer patients (HR: 2.462; 95% CI: 1.202~5.042, p = 0.014). A nomogram was built based on the results of the multivariate Cox analysis. CONCLUSION: Bladder cancer with high SLC16A3 mRNA expression has a poor OS. High MCT4 protein expression is an independent prognostic factor for bladder cancer patients who had undergone radical cystectomy.
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Human leukocyte antigen G (HLA-G) is known as a novel immune checkpoint molecule in cancer; thus, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. The aim of this study was to systematically identify the roles of checkpoint HLA-G molecules across various types of cancer. ONCOMINE, GEPIA, CCLE, TRRUST, HAP, PrognoScan, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, STRING, GeneMANIA, DAVID, TIMER, and CIBERSORT were utilized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In this study, we comprehensively analysed the heterogeneous expression of HLA-G molecules in various types of cancer and focused on genetic alterations, coexpression patterns, gene interaction networks, HLA-G interactors, and the relationships between HLA-G and pathological stage, prognosis, and tumor-infiltrating immune cells. We first identified that the mRNA expression levels of HLA-G were significantly upregulated in both most tumor tissues and tumor cell lines on the basis of in-depth analysis of RNAseq data. The expression levels of HLA-G were positively associated with those of the other immune checkpoints PD-1 and CTLA-4. Abnormal expression of HLA-G was significantly correlated with the pathological stage of some but not all tumor types. There was a significant difference between the high and low HLA-G expression groups in terms of overall survival (OS) or disease-free survival (DFS). The results showed that HLA-G highly expressed have positive associations with tumor-infiltrating immune cells in the microenvironment in most types of tumors (P<0.05). Additionally, we identified the key transcription factor (TF) targets in the regulation of HLA-G expression, including HIVEP2, MYCN, CIITA, MYC, and IRF1. Multiple mutations (missense, truncating, etc.) and the methylation status of the HLA-G gene may explain the differential expression of HLA-G across different tumors. Functional enrichment analysis showed that HLA-G was primarily related to T cell activation, T cell regulation, and lymphocyte-mediated immunity. The data may provide novel insights for blockade of the HLA-G/ILT axis, which holds potential for the development of more effective antitumour treatments.
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Perfilação da Expressão Gênica , Antígenos HLA-G/genética , Antígenos HLA-G/imunologia , Proteínas de Checkpoint Imunológico/genética , Neoplasias/genética , Transcriptoma/imunologia , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas de Checkpoint Imunológico/imunologia , Estimativa de Kaplan-Meier , Neoplasias/classificação , Neoplasias/imunologiaRESUMO
Immune checkpoint inhibitors (ICIs) have become a promising immunotherapy for cancers. Human leukocyte antigen-G (HLA-G), a neoantigen, its biological functions and clinical relevance have been extensively investigated in malignancies, and early clinical trials with "anti-HLA-G strategy" are being launched for advance solid cancer immunotherapy. The mechanism of HLA-G as a new ICI is that HLA-G can bind immune cell bearing inhibitory receptors, the immunoglobulin-like transcript (ILT)-2 and ILT-4. HLA-G/ILT-2/-4 (HLA-G/ILTs) signaling can drive comprehensive immune suppression, promote tumor growth and disease progression. Though clinical benefits could be expected with application of HLA-G antibodies to blockade the HLA-G/ILTs signaling in solid cancer immunotherapy, major challenges with the diversity of HLA-G isoforms, HLA-G/ILTs binding specificity, intra- and inter-tumor heterogeneity of HLA-G, lack of isoform-specific antibodies and validated assay protocols, which could dramatically affect the clinical efficacy. Clinical benefits of HLA-G-targeted solid cancer immunotherapy may be fluctuated or even premature unless major challenges are addressed.
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Antígenos HLA-G/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Antígenos HLA-G/efeitos dos fármacos , HumanosRESUMO
OBJECTIVE: To carry out prenatal diagnosis for a fetus with partial 18p deletion detected by non-invasive prenatal testing (NIPT). METHODS: Peripheral blood and amniotic fluid samples of the pregnant woman and her husband were subjected to G-banded chromosomal karyotyping and more accurate chromosomal microarray analysis (CMA). The deletion sites were verified by fluorescence in situ hybridization (FISH) using centromeric probe Cep11 Aqua and telomeric probes Tel11q SO and Tel18 SG. RESULTS: The karyotype of the fetus was determined as 46,XN,del(18)(p11.3). CMA has detected a 6.66 Mb deletion at 18p11.32-p11.31 (136 226-6 796 178). FISH confirmed the presence of a partial deletion at 18p. The mother was found to harbor the same deletion by chromosomal karyotyping as well as CMA analysis. No abnormality was found with the husband. CONCLUSION: Although the fetus and its mother have both carried the same 18p deletion, no clinical manifestation was detected in the mother, which may be attributed to a low penetrance of the disorder. The fetus had died at 33 weeks of gestation with unknown cause.
Assuntos
Deleção Cromossômica , Testes Genéticos , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-NatalRESUMO
Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.