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1.
Brief Bioinform ; 22(3)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32662817

RESUMO

Human leukocyte antigen (HLA) can encode the human major histocompatibility complex (MHC) proteins and play a key role in adaptive and innate immunity. Emerging clinical evidences suggest that the presentation of tumor neoantigens and neoantigen-specific T cell response associated with MHC class I molecules are of key importance to activate the adaptive immune systemin cancer immunotherapy. Therefore, accurate HLA typing is very essential for the clinical application of immunotherapy. In this study, we conducted performance evaluations of 4 widely used HLA typing tools (OptiType, Phlat, Polysolver and seq2hla) for predicting HLA class Ia genes from WES and RNA-seq data of 28 cancer patients. HLA genotyping data using PCR-SBT method was firstly obtained as the golden standard and was subsequently compared with HLA typing data by using NGS techniques. For both WES data and RNA-seq data, OptiType showed the highest accuracy for HLA-Ia typing than the other 3 programs at 2-digit and 4-digit resolution. Additionally, HLA typing accuracy from WES data was higher than from RNA-seq data (99.11% for WES data versus 96.42% for RNA-seq data). The accuracy of HLA-Ia typing by OptiType can reach 100% with the average depth of HLA gene regions >20x. Besides, the accuracy of 2-digit and 4-digit HLA-Ia typing based on control samples was higher than tumor tissues. In conclusion, OptiType by using WES data from control samples with the high average depth (>20x) of HLA gene regions can present a probably superior performance for HLA-Ia typing, enabling its application in cancer immunotherapy.


Assuntos
Técnicas de Genotipagem , Antígenos HLA/genética , Teste de Histocompatibilidade , RNA-Seq , Software , Humanos
2.
J Cell Physiol ; 234(1): 669-681, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-30132829

RESUMO

The aims of the current study were to examine the signaling mechanisms for transforming growth factor-ß1 (TGF-ß1)-induced rat airway smooth muscle cell (ASMC) proliferation and to determine the effect of activation of peroxisome proliferation-activated receptor-γ (PPAR-γ) on TGF-ß1-induced rat ASMC proliferation and its underlying mechanisms. TGF-ß1 upregulated microRNA 21 (miR-21) expression by activating Smad2/3, and this in turn downregulated forkhead box O1 (FOXO1) mRNA expression. In addition, TGF-ß1-Smad-miR-21 signaling also downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and thus de-repressed the PI3K-Akt pathway. Depletion of PTEN reduced the nuclear FOXO1 protein level without affecting its mRNA level. Inhibition of the PI3K-Akt pathway or proteasome function reversed PTEN knockdown-induced nuclear FOXO1 protein reduction. Our study further showed that loss of FOXO1 increased cyclin D1 expression, leading to rat ASMC proliferation. Preincubation of rat ASMCs with pioglitazone, a PPAR-γ activator, blocked TGF-ß1-induced activation of Smad2/3 and its downstream targets changes of miR-21, PTEN, Akt, FOXO1, and cyclin D1, resulting in the inhibition of rat ASMC proliferation. Our study suggests that the activation of PPAR-γ inhibits rat ASMC proliferation by suppressing Smad-miR-21 signaling and therefore has a potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.


Assuntos
Brônquios/citologia , MicroRNAs/genética , PPAR gama/genética , Fator de Crescimento Transformador beta1/genética , Animais , Brônquios/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclina D1/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteínas do Tecido Nervoso , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases/genética , Pioglitazona/farmacologia , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais , Proteína Smad2/genética
3.
Am J Physiol Lung Cell Mol Physiol ; 315(4): L609-L621, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29999407

RESUMO

Sphingosine-1-phosphate (S1P), a bioactive lipid, has been shown to be elevated in the airways of individuals with asthma and modulates the airway smooth muscle cell (ASMC) functions, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue. S1P induced yes-associated protein (YAP) dephosphorylation and nuclear localization via the S1PR2/3/Rho-associated protein kinase (ROCK) pathway, and this in turn increased forkhead box M1 (FOXM1) and cyclin D1 expression leading to ASMC proliferation, migration, and contraction. Pretreatment of cells with S1PR2 antagonist JTE013, S1PR3 antagonist CAY10444, or ROCK inhibitor Y27632 blocked S1P-induced alterations of YAP, FOXM1, cyclin D1, and ASMC proliferation, migration, and contraction. In addition, prior silencing of YAP or FOXM1 with siRNA reversed the effect of S1P on ASMC functions. Taken together, our study indicates that S1P stimulates ASMC proliferation, migration, and contraction by binding to S1PR2/3 and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Miócitos de Músculo Liso/patologia , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Proteínas Reguladoras de Apoptose/genética , Células Cultivadas , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/farmacologia , Receptores de Esfingosina-1-Fosfato , Proteínas de Sinalização YAP , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
5.
Pharmacol Res ; 107: 117-124, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26993101

RESUMO

The aims of the present study were to examine signaling mechanisms for PDGF-induced pulmonary arterial smooth muscle cells (PASMC) proliferation and to determine the effect of AMPK activation on PDGF-induced PASMC proliferation and its underlying mechanisms. PDGF activated PI3K/Akt/mTOR signaling pathway, and this in turn up-regulated Skp2 and consequently reduced p27 leading to PASMC proliferation. Prior incubation of PASMC with metformin induced a dramatic AMPK activation and significantly blocked PDGF-induced cell proliferation. PASMC lacking AMPKα2 were resistant to the inhibitory effect of metformin on PDGF-induced cell proliferation. Metformin did not affect Akt activation but blocked mTOR phosphorylation in response to PDGF; these were accompanied by the reversion of Skp2 up-regulation and p27 reduction. Our study suggests that the activation of AMPK negatively regulates mTOR activity to suppress PASMC proliferation and therefore has a potential value in the prevention and treatment of pulmonary hypertension by negatively modulating pulmonary vascular remodeling.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Artéria Pulmonar/citologia , Animais , Células Cultivadas , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Ratos Sprague-Dawley , Proteínas Quinases Associadas a Fase S/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
Inflamm Res ; 64(11): 875-83, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26289094

RESUMO

OBJECTIVE: The Val66Met polymorphisms in brain-derived neurotrophic factor (BDNF) gene have been reported to be associated with asthma risk, while the results are inconclusive. Considering a single study may lack the power to provide reliable conclusion, we performed a meta-analysis to investigate the association between the Val66Met polymorphisms and asthma susceptibility. METHODS: A comprehensive literature search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases was conducted before February 12, 2015. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. RESULTS: Six eligible studies with a total of 3501 subjects were finally included in this meta-analysis. Overall, a significantly increased risk was detected in the Val66Met G allele (G vs. A: OR 1.33, 95 % CI 1.19-1.49, P = 5.61E-07; GG vs. GA + AA: OR 1.48, 95 % CI 1.20-1.83, P = 3.14E-04; GG vs. GA: OR 1.48, 95 % CI 1.17-1.89, P = 0.001; GG vs. AA: OR 1.62, 95 % CI 1.20-2.19, P = 0.002). Moreover, stratification by ethnicity indicated marked association between the Val66Met G allele and asthma risk in Caucasians (G vs. A: OR 1.29, 95 % CI 1.12-1.49, P = 0.001; GG + GA vs. AA: OR 1.59, 95 % CI 1.03-2.46, P = 0.039; GG vs. GA + AA: OR 1.32, 95 % CI 1.11-1.57, P = 0.001; GG vs. GA: OR 1.28, 95 % CI 1.07-1.53, P = 0.007; GG vs. AA: OR 1.72, 95 % CI 1.11-2.68, P = 0.015). CONCLUSION: Our present meta-analysis suggests that the Val66Met polymorphisms in BDNF gene are potentially associated with asthma risk in Caucasians. Further well-designed case-control studies with larger sample size and more ethnic groups are needed to confirm these conclusions.


Assuntos
Asma/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Predisposição Genética para Doença , Humanos , Polimorfismo Genético
7.
Med Sci Monit ; 21: 3591-9, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26588249

RESUMO

BACKGROUND: Conflicting data have been reported on the association between Toll-like receptor 4 (TLR4) +896A/G and +1196C/T polymorphisms and the risk of asthma. Therefore, we conducted this meta-analysis to clarify the effect of TLR4 +896A/G and +1196C/T polymorphisms on the risk of asthma. MATERIAL AND METHODS: An electronic literature search was performed using PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Data to find relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. All statistical analyses were conducted using STATA software version 12.0. RESULTS: A total of 14 studies with 2873 asthma cases and 3110 controls were included. The pooled results indicated a significant association between TLR4 +1196C/T polymorphism and the risk of asthma (T vs. C: OR=0.79, 95%CI=0.63-0.99, P=0.04; TT+CT vs. CC: OR=0.76, 95%CI=0.59-0.96, P=0.03; CT vs. CC: OR=0.74, 95%CI=0.58-0.95, P=0.02). In subgroup analysis by ethnicity, TLR4 +1196C/T polymorphism was significantly associated with asthma risk in Asians (T vs. C: OR=0.73, 95%CI=0.54-0.98, P=0.04; TT+CT vs. CC: OR=0.70, 95%CI=0.51-0.96, P=0.03; CT vs. CC: OR=0.69, 95%CI=0.50-0.96, P=0.03), but not in whites. For TLR4 +896A/G polymorphism, no significant association was found between TLR4 +896A/G polymorphism and asthma risk under any genetic models. CONCLUSIONS: The results of this meta-analysis suggest that T allele of the TLR4 +1196C/T might act as a protective factor against the development of asthma.


Assuntos
Asma/genética , Receptor 4 Toll-Like/genética , Alelos , Povo Asiático/genética , Asma/etnologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genética
8.
RSC Adv ; 14(17): 12049-12057, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38628489

RESUMO

A novel sustained chlorine-releasing polydimethylsiloxane/Ca(ClO)2 (PDMS/Ca(ClO)2) material was fabricated by encapsulating Ca(ClO)2 in a PDMS matrix due to its high hydrophobicity and high chemical stability, which showed immediate-responsive and long-lasting antibacterial capabilities in aqueous conditions. Free chlorine could be released from the PDMS/Ca(ClO)2 after immersion in water for 2 min and could also be sustainedly released for 2 weeks, while the released concentration is negatively related to the duration time and positively with the initial Ca(ClO)2 contents. Additionally, Ca(ClO)2 powder as a filler significantly affects the crosslinking and pore size of PDMS. The PDMS/Ca(ClO)2 materials exhibited enduring antibacterial performance against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in both planktonic and multispecies-biofilm status. It is expected that this PDMS/Ca(ClO)2 material and its similar composite would be promising candidates for wide sustainable disinfection applications in biomedical and industrial fields.

9.
ACS Appl Mater Interfaces ; 15(1): 391-406, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36562459

RESUMO

The effective treatment for periodontitis is to completely and sustainedly eradicate the bacterial pathogens from the complex periodontal pockets. Local sustained-release antibiotics as a complementary treatment after scaling and root planning can sustainedly combat bacterial pathogens in the periodontal pockets to help treat the disease, but the increasing concern of bacterial resistance limits its future use. Here, we reported a local antibacterial system based on microsized multifunctional Ag-TiO2-x encapsulated in alginate (ATA) microspheres. We confirmed that ATA displayed strong photothermally enhanced dual enzyme-mimicking (peroxidase-like and catalase-like) activities and weak photocatalytic activity under 808 nm near-infrared (NIR) irradiation, which could boost the generation of reactive oxygen species (ROS) and O2 in the presence of low-level H2O2. As a result, the ATA/H2O2/NIR system exhibited efficient antibacterial activity against Porphyromonas gingivalis and Streptococcus gordonii in both planktonic and biofilm forms. With the help of ROS, ATA could release Ag+ in concentrations sufficient to inhibit periodontal pathogens as well. Moreover, the in situ-generated oxygen was supposed to alleviate the local hypoxic environment and would help downregulate the lipopolysaccharide-mediated inflammatory response of periodontal stem cells. The in vivo rat periodontitis treatment results demonstrated that the ATA/H2O2/NIR system reduced the bacterial load, relieved inflammation, and improved tissue healing. Our work developed a new local prolonged bactericidal and oxygenation system for enhanced periodontitis. Avoiding the usage of antibiotics and nanomaterials, this strategy showed great promise in adjunctive periodontitis treatment and also in other biomedical applications.


Assuntos
Alginatos , Periodontite , Ratos , Animais , Alginatos/farmacologia , Bolsa Periodontal/tratamento farmacológico , Espécies Reativas de Oxigênio/farmacologia , Peróxido de Hidrogênio/farmacologia , Microesferas , Periodontite/tratamento farmacológico , Periodontite/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Porphyromonas gingivalis
10.
Int J Nanomedicine ; 18: 1507-1520, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36998603

RESUMO

Purpose: A synergistic antibacterial system employing photocatalytic performance and low-temperature photothermal effect (LT-PTT) with the potential for infectious skin wound healing promotion was developed. Methods: Ag/Ag2O was synthesized with a two-step method, and its physicochemical properties were characterized. After its photocatalytic performance and photothermal effect were evaluated under 0.5 W/cm2 808 nm NIR laser irradiation, its antibacterial activities in both planktonic and biofilm forms were then studied in vitro targeting Staphylococcus Aureus (S. aureus), and the biocompatibility was tested with L-929 cell lines afterward. Finally, the animal model of dorsal skin wound infection was established on Sprague-Dawley rats and was used to assess infectious wound healing promotion of Ag/Ag2O in vivo. Results: Ag/Ag2O showed boosted photocatalytic performance and local temperature accumulation compared with Ag2O when exposed to 0.5 W/cm2 808 nm NIR irradiation, which therefore endowed Ag/Ag2O with the ability to kill pathogens rapidly and cleavage bacterial biofilm in vitro. Furthermore, after treatment with Ag/Ag2O and 0.5 W/cm2 808 nm NIR irradiation, infectious wounds of rats realized skin tissue regeneration from a histochemical level. Conclusion: By exhibiting excellent NIR-triggered photocatalytic sterilization ability enhanced by low-temperature photothermal effect, Ag/Ag2O was promising to be a novel, photo-responsive antibacterial agent.


Assuntos
Antibacterianos , Staphylococcus aureus , Ratos , Animais , Temperatura , Ratos Sprague-Dawley , Antibacterianos/farmacologia , Antibacterianos/química , Esterilização
11.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 43(2): 210-3, 225, 2012 Mar.
Artigo em Zh | MEDLINE | ID: mdl-22650033

RESUMO

OBJECTIVE: To investigate the prevalence of four common neuropsychiatric disorders in Tibet, with an aim to providing information support to health planning. METHODS: The survey was carried out in four regions of Tibet. The sampling strategy was adapted from that of a national psychiatric epidemiological survey in China in 1982 and 1993. The Neurosis Screening Inventory, Screening Inventory for Alcohol Dependence and Related Problems, Child Intelligence Screening Inventory, and a questionnaire for the Detection of Epileptic Seizures were administered to the respondents through face to face interview. Those with a positive response and 10% of those with a negative response were further interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders (research version) (SCID-I ). Anxiety disorders and alcohol used disorders were diagnosed according to the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM-IV). Hysteria and mental retardation were diagnosed according to the International Classification of Diseases, 10th edition (ICD-10), and the Chinese Classification of Mental Disorders, 3rd edition (CCMD-3). RESULTS: The point prevalence of neuroses, alcohol-related disorders, mental retardation and epilepsy was 2. 56%, 4. 06%, 0. 28% and 0. 68%, respectively. The lifetime prevalence of neuroses, alcohol-related disorders, mental retardation and epilepsy was 2. 62%, 4. 24%, 0. 28% and 0.72%, respectively. CONCLUSION: Alcohol-related disorders and neuroses are the two common mental health problems in Tibet. Mental retardation and epilepsy are the two serious neuropsychiatric disorders affecting Tibetan children and adolescence. These disorders should be identified as priorities in the reginonal health planning in Tibet.


Assuntos
Transtornos Relacionados ao Uso de Álcool/epidemiologia , Epilepsia/epidemiologia , Deficiência Intelectual/epidemiologia , Transtornos Neuróticos/epidemiologia , Adolescente , Adulto , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos de Amostragem , Inquéritos e Questionários , Tibet/epidemiologia , Adulto Jovem
12.
Aging (Albany NY) ; 14(10): 4586-4605, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35613927

RESUMO

BACKGROUND: Only a minority of patients clinically benefit from immune checkpoint therapy. Tumor clones with neoantigens have immunogenicity; therefore, they are eliminated by T-cell-mediated immune editing. Identifying neoantigen clones with the ability to induce immune elimination may better predict the clinical outcome of immunotherapy. METHODS: We developed ioTNL model, which indicates the immunoediting-based optimized tumor neoantigen load, by identifying tumor clones that could induce immune elimination. Data of more than two hundred patients from our patient pool and previously reported studies who underwent anti-PD-(L)1 therapy were collected to validate the prediction performance of ioTNL model. Clonal architectures, immune editing scores and ioTNL scores were identified. The association between the response as well as prognosis and the ioTNL were evaluated. Panel sequencing of genes from 2,469 patients within 20 cancer types was performed to profile the landscape of immunoediting. RESULTS: As expected, the ioTNL score could predict the response in patients who underwent immune checkpoint inhibitor (ICI) immunotherapy for various cancers, including non-small cell lung cancer (NSCLC; p = 0.0066), skin cutaneous melanoma (SKCM; p = 0.026) and nasopharyngeal carcinoma (NPC; p = 0.0025). Patients with a high ioTNL score demonstrated longer survival than those with a low score. We verified the ioTNL on our cohort through panel sequencing and found that the ioTNL was associated with the response (p = 0.025) and prognosis (p = 0.00082) in anti-PD-(L)1 monotherapy. In addition, we found that the immune editing score correlated with the tumor mutation burden (TMB) and the objective response rate of immunotherapy. CONCLUSIONS: Identifying neoantigen clones with the ability to induce immune elimination would better predict the efficacy of immunotherapy. We have proved that the reliable method of ioTNL can be applied to whole-exome sequencing (WES) and panel data and would have a broad application in precision diagnosis in immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Neoplasias Cutâneas , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/genética , Mutação , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Melanoma Maligno Cutâneo
13.
Brain Res ; 1785: 147875, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35271821

RESUMO

Retinal stimulation has become a widely utilized approach to restore visual function for individuals with retinal degenerative diseases. Although the rectangular electrical pulse is the primary stimulus waveform used in retinal neuromodulation, it remains unclear whether alternate waveforms may be more effective. Here, we used the optical intrinsic signal imaging system to assess the responses of cats' visual cortex to sinusoidal electrical stimulation through contact lens electrode, analyzing the response to various stimulus parameters (frequency, intensity, pulse width). A comparison between sinusoidal and rectangular stimulus waveform was also investigated. The results indicated that the optimal stimulation frequency for sinusoidal electrical stimulation was approximately 20 Hz, supporting the hypothesis that low-frequency electrostimulation induces more responsiveness in retinal neurons than high-frequency electrostimulation in case of sinusoidal stimulation. We also demonstrated that for low-frequency retinal neuromodulation, sinusoidal pulses are more effective than rectangular ones. In addition, we found that compared to current intensity, the effect of the sinusoidal pulse width on cortical responses was more prominent. These results suggested that sinusoidal electrical stimulation may provide a promising strategy for improved retinal neuromodulation in clinical settings.


Assuntos
Degeneração Retiniana , Córtex Visual , Estimulação Elétrica/métodos , Humanos , Retina/fisiologia , Córtex Visual/fisiologia
14.
Front Oncol ; 12: 930589, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832540

RESUMO

Background: Immune checkpoint inhibitors (ICIs) induce durable responses, but only a minority of patients achieve clinical benefits. The development of gene expression profiling of tumor transcriptomes has enabled identifying prognostic gene expression signatures and patient selection with targeted therapies. Methods: Immune exclusion score (IES) was built by elastic net-penalized Cox proportional hazards (PHs) model in the discovery cohort and validated via four independent cohorts. The survival differences between the two groups were compared using Kaplan-Meier analysis. Both GO and KEGG analyses were performed for functional annotation. CIBERSORTx was also performed to estimate the relative proportion of immune-cell types. Results: A fifteen-genes immune exclusion score (IES) was developed in the discovery cohort of 65 patients treated with anti-PD-(L)1 therapy. The ROC efficiencies of 1- and 3- year prognosis were 0.842 and 0.82, respectively. Patients with low IES showed a longer PFS (p=0.003) and better response rate (ORR: 43.8% vs 18.2%, p=0.03). We found that patients with low IES enriched with high expression of immune eliminated cell genes, such as CD8+ T cells, CD4+ T cells, NK cells and B cells. IES was positively correlated with other immune exclusion signatures. Furthermore, IES was successfully validated in four independent cohorts (Riaz's SKCM, Liu's SKCM, Nathanson's SKCM and Braun's ccRCC, n = 367). IES was also negatively correlated with T cell-inflamed signature and independent of TMB. Conclusions: This novel IES model encompassing immune-related biomarkers might serve as a promising tool for the prognostic prediction of immunotherapy.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33507871

RESUMO

Retinal electrical stimulation is a widely utilized method to restore visual function for patients with retinal degenerative diseases. Transcorneal electrical stimulation (TES) represents an effective way to improve the visual function due to its potential neuroprotective effect. However, TES with single electrode fails to spatially and selectively stimulate retinal neurons. Herein, a computational modeling method was proposed to explore the feasibility of spatially selective retinal stimulation via temporally interfering electric fields. An eyeball model with multiple electrodes was constructed to simulate the interferential electric fields with various electrode montages and current ratios. The results demonstrated that the temporal interference (TI) stimulation would gradually generate an increasingly localized high-intensity region on retina as the return electrodes moved towards the posterior of the eyeball and got closer. Additionally, the position of the convergent region could be modulated by regulating the current ratio of different electrode channels. The TI strategy with multisite and steerable stimulation can stimulate local retinal region with certain convergence and a relatively large stimulation range, which would be a feasible approach for the spatially selective retinal neuromodulation.


Assuntos
Retina , Visão Ocular , Estimulação Elétrica , Eletrodos , Humanos
16.
Front Immunol ; 11: 607416, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33584678

RESUMO

Immune checkpoint inhibitors have revolutionized the treatments of lung cancers, and multiple predictive biomarkers alone or in combination help clinicians with the appropriate therapeutic selections. Recently, chemo-immunotherapy has been recommended for treating advanced non-small cell lung cancers in patients without driver mutations. However, the clinical relevance of predictive biomarkers and the treatment efficacy of chemo-immunotherapy in large cell lung carcinoma (LCLC) remain unclear. Here, we reported a rare case of LCLC with none driver gene mutations and low values of multiple predictive biomarkers. These biomarkers included a low PD-L1 expression of 5-10%, a low tumor mutational burden (TMB) of 2.5 muts/mb, a low CD8(+) tumor-infiltrating lymphocyte density of 147.91 psc/mm². After one-cycle chemotherapy, the patient progressed rapidly and then was switched to pembrolizumab combining paclitaxel plus cisplatin. Interestingly, he achieved a partial response after two cycles of chemo-immunotherapy, showing multiple lymph nodes obviously shrunk on CT scan, and other clinical symptoms were relieved when compared with the baseline findings. After five cycles of chemo-immunotherapy, this advanced patient still benefited and was changed to maintenance immunotherapy monotherapy. This case suggests that chemo-immunotherapy may provide an effective therapeutic option for those LCLC patients with low values of multiple predictive biomarkers, particularly for those who progressed from first-line classical treatments.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma de Células Grandes/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Adulto , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Grandes/imunologia , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Cisplatino/uso terapêutico , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Paclitaxel/uso terapêutico , Indução de Remissão , Resultado do Tratamento , Microambiente Tumoral
17.
IEEE Trans Neural Syst Rehabil Eng ; 27(5): 905-915, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31021770

RESUMO

Transcorneal electrical stimulation (TES) has become an effective strategy to modulate retinal neural activities and partially restore visual function in ophthalmic diseases. However, the exact responses in different retinal layers still need to be clarified. This paper's goal was to evaluate the depth-resolved retinal physiological responses evoked by TES by using optical coherence tomography (OCT). A custom-built spectral-domain OCT system was used to record the intrinsic optical signals (IOSs) in different retinal layers. TES and flickers were used to stimulate the retina electrically and visually. Tetrodotoxin was used to inhibit the retinal neural activity for confirming the origin of TES-induced IOSs. We found both positive and negative IOSs could be evoked by TES in three segmented retinal layers, especially in the inner retina and subretinal space. The TES-induced IOSs correlated with the TES intensity. After tetrodotoxin injection, the IOSs evoked by TES were significantly declined, peculiarly in the inner retina. The IOSs elicited by flickers kept increasing during the stimulation, while those evoked by TES kept at a stable level. In conclusion, TES could elicit IOSs that originated from retinal neural activity in all segmented layers. The TES-induced IOSs were highly synchronized to the electrical field in the retina.


Assuntos
Percepção de Profundidade/fisiologia , Estimulação Elétrica , Retina/diagnóstico por imagem , Retina/fisiologia , Algoritmos , Anestésicos Locais/farmacologia , Animais , Gatos , Eletrorretinografia , Estimulação Luminosa , Retina/efeitos dos fármacos , Processamento de Sinais Assistido por Computador , Tetrodotoxina/farmacologia , Tomografia de Coerência Óptica
18.
J Neural Eng ; 15(2): 026025, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29076459

RESUMO

OBJECTIVE: Retinal prosthesis devices have shown great value in restoring some sight for individuals with profoundly impaired vision, but the visual acuity and visual field provided by prostheses greatly limit recipients' visual experience. In this paper, we employ computer vision approaches to seek to expand the perceptible visual field in patients implanted potentially with a high-density retinal prosthesis while maintaining visual acuity as much as possible. APPROACH: We propose an optimized content-aware image retargeting method, by introducing salient object detection based on color and intensity-difference contrast, aiming to remap important information of a scene into a small visual field and preserve their original scale as much as possible. It may improve prosthetic recipients' perceived visual field and aid in performing some visual tasks (e.g. object detection and object recognition). To verify our method, psychophysical experiments, detecting object number and recognizing objects, are conducted under simulated prosthetic vision. As control, we use three other image retargeting techniques, including Cropping, Scaling, and seam-assisted shrinkability. MAIN RESULTS: Results show that our method outperforms in preserving more key features and has significantly higher recognition accuracy in comparison with other three image retargeting methods under the condition of small visual field and low-resolution. SIGNIFICANCE: The proposed method is beneficial to expand the perceived visual field of prosthesis recipients and improve their object detection and recognition performance. It suggests that our method may provide an effective option for image processing module in future high-density retinal implants.


Assuntos
Estimulação Luminosa/métodos , Implantação de Prótese/normas , Campos Visuais/fisiologia , Percepção Visual/fisiologia , Próteses Visuais/normas , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
19.
Artif Intell Med ; 84: 64-78, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29129481

RESUMO

BACKGROUND AND OBJECTIVE: Current retinal prostheses can only generate low-resolution visual percepts constituted of limited phosphenes which are elicited by an electrode array and with uncontrollable color and restricted grayscale. Under this visual perception, prosthetic recipients can just complete some simple visual tasks, but more complex tasks like face identification/object recognition are extremely difficult. Therefore, it is necessary to investigate and apply image processing strategies for optimizing the visual perception of the recipients. This study focuses on recognition of the object of interest employing simulated prosthetic vision. METHOD: We used a saliency segmentation method based on a biologically plausible graph-based visual saliency model and a grabCut-based self-adaptive-iterative optimization framework to automatically extract foreground objects. Based on this, two image processing strategies, Addition of Separate Pixelization and Background Pixel Shrink, were further utilized to enhance the extracted foreground objects. RESULTS: i) The results showed by verification of psychophysical experiments that under simulated prosthetic vision, both strategies had marked advantages over Direct Pixelization in terms of recognition accuracy and efficiency. ii) We also found that recognition performance under two strategies was tied to the segmentation results and was affected positively by the paired-interrelated objects in the scene. CONCLUSION: The use of the saliency segmentation method and image processing strategies can automatically extract and enhance foreground objects, and significantly improve object recognition performance towards recipients implanted a high-density implant.


Assuntos
Inteligência Artificial , Processamento de Imagem Assistida por Computador/métodos , Visão Ocular , Percepção Visual , Próteses Visuais , Pessoas com Deficiência Visual/reabilitação , Adulto , Movimentos Oculares , Reconhecimento Facial , Feminino , Humanos , Masculino , Cadeias de Markov , Fosfenos , Desenho de Prótese , Reconhecimento Psicológico , Pessoas com Deficiência Visual/psicologia , Adulto Jovem
20.
Brain Stimul ; 11(4): 667-675, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29525237

RESUMO

BACKGROUND: Electrical stimulation has been widely used in many ophthalmic diseases to modulate neuronal activities or restore partial visual function. Due to the different processing pathways and mechanisms, responses to visual and electrical stimulation in the primary visual cortex and higher visual areas might be different. This differences would shed some light on the properties of cortical responses evoked by electrical stimulation. OBJECTIVE: This study's goal was to directly compare the cortical responses evoked by visual and electrical stimulation and investigate the cortical processing of visual information and extrinsic electrical signal. METHODS: Optical imaging of intrinsic signals (OIS) was used to probe the cortical hemodynamic responses in 11 cats. Transcorneal electrical stimulation (TES) through an ERG-jet contact lens electrode was used to activate visual cortices. Full-field and peripheral drifting gratings were used as the visual stimuli. RESULTS: The response latency evoked by TES was shorter than that responding to visual stimulation (VS). Cortical responses evoked by VS were retinotopically organized, which was consistent with previous studies. On the other hand, the cortical region activated by TES was preferentially located in the secondary visual cortex (Area 18), while the primary visual cortex (Area 17) was activated by a higher current intensity. Compared with the full-field VS, the cortical response in Area 18 to TES with a current intensity above 1.2 mA was significantly stronger. CONCLUSION: According to our results, we provided some evidence that the cortical processing of TES was influenced by the distribution of the electrical field in the retina and the activating threshold of different retinal ganglion cells.


Assuntos
Potenciais Evocados Visuais , Estimulação Luminosa , Retina/fisiologia , Animais , Gatos , Estimulação Elétrica , Tempo de Reação , Córtex Visual/fisiologia
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