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Heat shock proteins (HSPs) are a group of highly conserved proteins found in a wide range of organisms. In recent years, members of the HSP family were overexpressed in various tumors and widely involved in oncogenesis, tumor development, and therapeutic resistance. In our previous study, DNAJC24, a member of the DNAJ/HSP40 family of HSPs, was found to be closely associated with the malignant phenotype of hepatocellular carcinoma. However, its relationship with other malignancies needs to be further explored. Herein, we demonstrated that DNAJC24 exhibited upregulated expression in LUAD tissue samples and predicted poor survival in LUAD patients. The upregulation of DNAJC24 expression promoted proliferation and invasion of LUAD cells in A549 and NCI-H1299 cell lines. Further studies revealed that DNAJC24 could regulate the PI3K/AKT signaling pathway by affecting AKT phosphorylation. In addition, a series of experiments such as Co-IP and mass spectrometry confirmed that DNAJC24 could directly interact with PCNA and promoted the malignant phenotypic transformation of LUAD. In conclusion, our results suggested that DNAJC24 played an important role in the progression of LUAD and may serve as a specific prognostic biomarker for LUAD patients. The DNAJC24/PCNA/AKT axis may be a potential target for future individualized and precise treatment of LUAD patients.
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Proliferação de Células , Proteínas de Choque Térmico HSP40 , Antígeno Nuclear de Célula em Proliferação , Proteínas Proto-Oncogênicas c-akt , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP40/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de SinaisRESUMO
Many studies have shown that the actin cytoskeleton plays an essential role in the initiation and progression of cancer. As an actin-binding protein, Twinfilin1 (TWF1) plays an important role in regulating cytoskeleton-related functions. However, little is known about the expression and function of TWF1 in human tumors. The present study aimed to investigate the functional roles and the underlying molecular mechanisms of TWF1 in human lung adenocarcinoma (LUAD). By using bioinformatics databases and tumor tissues, TWF1 expression was found to be higher in LUAD tissues than in adjacent tissues and poor survival was predicted in patients with LUAD. In vitro and in vivo assays indicated that downregulation of TWF1 expression suppressed LUAD cells invasion and migration. Further studies revealed that TWF1 interacted with p62 and was involved in the regulation of autophagy. The molecular mechanisms underlying TWF1 were investigated by RNA-seq analysis and a series of functional experiments. The results showed that downregulation of TWF1 suppressed LUAD progression through the cAMP signaling pathway. Therefore, overexpression of TWF1 in LUAD promoted migration, invasion, and autophagy through the cAMP signaling pathway.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Adenocarcinoma de Pulmão/metabolismo , Transdução de Sinais , Autofagia/genética , Fenótipo , Proliferação de Células/genética , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Tirosina Quinases/metabolismoRESUMO
Cervical cancer stem cells (CCSCs) are considered major causes of chemoresistance/radioresistance and metastasis. Although several cell surface antigens have been identified in CCSCs, these markers vary among tumors because of CSC heterogeneity. However, whether these markers specifically distinguish CCSCs with different functions is unclear. Here, we demonstrated that CCSCs exist in two biologically distinct phenotypes characterized by different levels of cytosolic phospholipase A2α (cPLA2α) expression. Overexpression of cPLA2α results in a CD44+ CD24- phenotype associated with mesenchymal traits, including increased invasive and migration abilities, whereas CCSCs with cPLA2α downregulation express CD133 and show quiescent epithelial characteristics. In addition, cPLA2α regulates the reversible transition between mesenchymal and epithelial CCSC states through PKCζ, an atypical protein kinase C, which governs cancer cell state changes and the maintenance of various embryonic stem cell characteristics, further inhibiting ß-catenin-E-cadherin interaction in membrane and promoting ß-catenin translocation into the nucleus to affect the transcriptional regulation of stemness signals. We propose that reversible transitions between mesenchymal and epithelial CCSC states regulated by cPLA2α are necessary for cervical cancer metastasis and recurrence. Thus, cPLA2α might be an attractive therapeutic target for eradicating different states of CCSCs to eliminate tumors more effectively.
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Fosfolipases A2 do Grupo IV/genética , Neoplasias do Colo do Útero/genética , Adulto , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Transfecção , Adulto JovemRESUMO
Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure and cancer recurrence in non-small cell lung cancer (NSCLC). Approximately 30% of patients with EGFR-activating mutations exhibit primary resistance to EGFR-TKIs. However, the potential mechanisms of primary resistance to EGFR-TKIs remain poorly understood. Recent studies have shown that increased expression of programmed death ligand-1 (PD-L1) is associated with EGFR-TKIs resistance. Therefore, the present study aimed to investigate the mechanism of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma (LUAD) cells. We found that PD-L1 was associated with poor prognosis in patients with EGFR-mutant LUAD, while the combination of EGFR-TKIs with chemotherapy could improve its therapeutic efficacy. In vitro and in vivo experiments revealed that PD-L1 promoted the proliferation and autophagy and inhibited the apoptosis of LUAD cells. Mechanistic studies demonstrated that upregulation of PD-L1 was critical in inducing autophagy through the mitogen-activated protein kinase (MAPK) signaling pathway, which was beneficial for tumor progression and the development of gefitinib resistance. Furthermore, we found that gefitinib combined with pemetrexed could synergistically enhance antitumor efficacy in PD-L1-overexpression LUAD cells. Overall, our study demonstrated that PD-L1 contributed to primary resistance to EGFR-TKIs in EGFR-mutant LUAD cells, which may be mediated by inducing autophagy via the MAPK signaling pathway. These findings not only help improve the prognosis of patients with EGFR-mutant LUAD but also provide a reference for the research of other cancer types.
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Adenocarcinoma de Pulmão , Autofagia , Antígeno B7-H1 , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Sistema de Sinalização das MAP Quinases , Mutação , Inibidores de Proteínas Quinases , Humanos , Autofagia/efeitos dos fármacos , Autofagia/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Animais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Linhagem Celular Tumoral , Mutação/genética , Camundongos , Camundongos Nus , Feminino , Masculino , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) plays an important role in malignant tumor progression. Recently, accumulating evidence has shown that autophagy is involved in the regulation of EMT-induced migration. Therefore, the exploration of targets to inhibit EMT by targeting autophagy is important. In this study, we found that OVO-like zinc finger 2 (OVOL2) may be a key target for regulating autophagy-induced EMT. Firstly, we found that OVOL2 expression was dramatically downregulated in LUAD. Low expression of OVOL2 is an indicator of poor prognosis in LUAD. In vitro experiments have shown that downregulation of OVOL2 expression induces EMT, thereby promoting malignant biological behavior, such as proliferation, migration, and invasion of LUAD cells. Interestingly, autophagy is a key step in regulating OVOL2 and inducing EMT. Furthermore, OVOL2 regulates autophagy through the MAPK signaling pathway, ultimately inhibiting the malignant progression of LUAD.
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BACKGROUND: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA), as a rare primary hepatic tumor, is challenging to accurately assess in terms of the clinical outcomes and prognostic risk factors in patients. This study aimed to clarify the function of tertiary lymphoid structure (TLS) status in predicting the outcome of cHCC-CCA and to preliminarily explore the possible mechanism of TLS formation. METHODS: The TLSs, with different spatial distributions and densities, of 137 cHCC-CCA were quantified, and their association with prognosis was assessed by Cox regression and Kaplan-Meier analyses. We further validated TLS possible efficacy in predicting immunotherapy responsiveness in two cHCC-CCA case reports. TLS composition and its relationship to CXCL12 expression were analysed by fluorescent multiplex immunohistochemistry. RESULTS: A high intratumoural TLS score was correlated with prolonged survival, whereas a high TLS density in adjacent tissue indicated a worse prognosis in cHCC-CCA. Mature TLSs were related to favorable outcomes and showed more CD8 + T cells infiltrating tumor tissues. We further divided the cHCC-CCA patients into four immune grades by combining the peri-TLS and intra-TLS, and these grades were an independent prognostic factor. In addition, our reported cases suggested a potential value of TLS in predicting immunotherapy response in cHCC-CCA patients. Our findings suggested that CXCL12 expression in cHCC-CCA tissue was significantly correlated with TLS presence. CONCLUSION: The spatial distribution and density of TLSs revealing the characteristics of the cHCC-CCA immune microenvironment, significantly correlated with prognosis and provided a potential immunotherapy response biomarker for cHCC-CCA.
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Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Estruturas Linfoides Terciárias , Humanos , Colangiocarcinoma/imunologia , Colangiocarcinoma/patologia , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/imunologia , Biomarcadores Tumorais/metabolismo , Quimiocina CXCL12/metabolismo , Imunoterapia/métodos , Idoso , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologiaRESUMO
Background: Neuroblastoma (NB), which is the most frequent and fatal solid tumor in early childhood, lacks an accurate approach to prevent or forecast its recurrence. Dormant NB cells are responsible for metastasis, drug resistance, and suppressive activity in the immune system. However, there is a lack of systematic research on the interaction between dormancy and NB prognosis and its potential associations with tumor immunity. Methods: We downloaded NB gene expression data and clinical information from the Gene Expression Omnibus and ArrayExpres databases. Based on consensus clustering of the expression of dormancy-associated genes, the NB samples were classified into different groups, and differentially expressed genes (DEGs) were explored in each group. Functional analyses of DEGs were performed, followed by the establishment of a predictive dormancy signature and the assessment of tumor immunity. Finally, sex, age, International Neuroblastoma Staging System (INSS) stage, and MYCN status were identified as independent overall survival-related variables, which were incorporated into the nomogram. Results: A dormancy-associated gene signature, including CDKN2A, BHLHB3, CDKN2B, MAPK14, CDKN1B, and BMP7, was established. The gene signature showed a strong correlation with NB immune infiltration and capacity to predict NB patient prognosis. A nomogram including MYCN status, INSS stage, age and gene signature risk score was established which further divided NB into high, medium and low-risk groups. This nomogram had certain guiding significance in decision-making for clinical treatment. Conclusions: Our results suggested that the 6-gene genetic signature for NB based on dormancy could predict NB survival and response to immunotherapy.
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Cancer is a major public health issue globally and is one of the leading causes of death. Although available treatments improve the survival rate of some cases, many advanced tumors are insensitive to these treatments. Cancer cell differentiation reverts the malignant phenotype to its original state and may even induce differentiation into cell types found in other tissues. Leveraging differentiation-inducing therapy in high-grade tumor masses offers a less aggressive strategy to curb tumor progression and heightens chemotherapy sensitivity. Differentiation-inducing therapy has been demonstrated to be effective in a variety of tumor cells. For example, differentiation therapy has become the first choice for acute promyelocytic leukemia, with the cure rate of more than 90%. Although an appealing concept, the mechanism and clinical drugs used in differentiation therapy are still in their nascent stage, warranting further investigation. In this review, we examine the current differentiation-inducing therapeutic approach and discuss the clinical applications as well as the underlying biological basis of differentiation-inducing agents.
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Long-term electrocardiogram (ECG) monitoring is an important and widely-used technique in the clinic that helps with the diagnosis of possible diseases that cannot be detected in a short time monitoring. However, the clinically used electrode needs conductive gel to reduce the impedance between the skin and the electrodes, which easily causes the possibility of allergy. Moreover, as the conductive gel becomes dry, the signal's quality will decrease accordingly. In this paper, we proposed a novel adhesive Carbon Paste Electrode (CPE) to achieve convenient and long-term ECG monitoring. By comparing the time-domain waveforms, the R-R peak intervals difference, and the Signal-to-Noise Ratio (SNR) of ECG with the traditional conductive gel-based electrode (Gel) in fixed and unfixed conditions, the performance of the proposed CPE was investigated. The results showed that the CPE could achieve similar ECG monitoring both in fixed and unfixed conditions. When on Day 2, the quality acquired by Gel began to decrease while CPE was still stable, which was obvious especially in unfixed condition. The R-R peak intervals showed that on Day 2, the Gel was unreliable with some abnormal points occurring. Besides, the results of SNR and average heart rate (AHR) also confirmed that the CPE could achieve similar results as Gel on Day 1 and outperformed Gel on Day 2. It is believed that the proposed CPE opens a window of high-quality long-term ECG monitoring with more convenience.
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Adesivos , Carbono , Projetos Piloto , Eletrocardiografia/métodos , EletrodosRESUMO
Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage-to-FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell-mediated antitumor immunity. Additionally, low-dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low-dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/farmacologia , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Microambiente TumoralRESUMO
Dormant cancer cells account for cancer recurrence, distant metastasis and drug resistance which lead to poor prognosis in colorectal cancer (CRC). However, little is known about the molecular mechanisms regulating tumor cell dormancy and how to eliminate dormant cancer cells. Recent studies indicate autophagy affects dormant tumor cell survival. Here, we found that polo-like kinases 4 (PLK4), a central regulator of the cell cycle and proliferation, plays a crucial role in regulating CRC cells dormancy both in vitro and in vivo. Downregulation of PLK4 induced dormancy and inhibited migration and invasion in different CRC cell lines. Clinically, PLK4 expression was correlated with the dormancy markers (Ki67, p-ERK, p-p38) and late recurrence in CRC tissues. Mechanistically, downregulation of PLK4 induced autophagy contributed to restoring phenotypically aggressive tumor cells to a dormant state through the MAPK signaling pathway, and inhibition of autophagy would trigger apoptosis of dormant cells. Our findings reveal that downregulation of PLK4-induced autophagy contributes to tumor dormancy and autophagy inhibition leads to apoptosis of CRC dormant cells. Our study is the first to report that downregulation PLK4 induced autophagy is an early event in CRC dormancy and highlights autophagy inhibitor as a potential therapeutic target for dormant cell elimination.
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Apoptose , Neoplasias Colorretais , Humanos , Regulação para Baixo/genética , Linhagem Celular Tumoral , Apoptose/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Autofagia/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Objective. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in adolescents that can seriously impair a person's attention function, cognitive processes, and learning ability. Currently, clinicians primarily diagnose patients based on the subjective assessments of the Diagnostic and Statistical Manual of Mental Disorders-5, which can lead to delayed diagnosis of ADHD and even misdiagnosis due to low diagnostic efficiency and lack of well-trained diagnostic experts. Deep learning of electroencephalogram (EEG) signals recorded from ADHD patients could provide an objective and accurate method to assist physicians in clinical diagnosis.Approach. This paper proposes the EEG-Transformer deep learning model, which is based on the attention mechanism in the traditional Transformer model, and can perform feature extraction and signal classification processing for the characteristics of EEG signals. A comprehensive comparison was made between the proposed transformer model and three existing convolutional neural network models.Main results. The results showed that the proposed EEG-Transformer model achieved an average accuracy of 95.85% and an average AUC value of 0.9926 with the fastest convergence speed, outperforming the other three models. The function and relationship of each module of the model are studied by ablation experiments. The model with optimal performance was identified by the optimization experiment.Significance. The EEG-Transformer model proposed in this paper can be used as an auxiliary tool for clinical diagnosis of ADHD, and at the same time provides a basic model for transferable learning in the field of EEG signal classification.
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Transtorno do Deficit de Atenção com Hiperatividade , Adolescente , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Eletroencefalografia , Fontes de Energia Elétrica , Aprendizagem , Redes Neurais de ComputaçãoRESUMO
Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.
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Adenocarcinoma de Pulmão , Antineoplásicos , Neoplasias Pulmonares , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Piroptose , Leucócitos Mononucleares , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Hearing loss is a common disease affecting public health all around the world. In clinic, auditory brainstem response (ABR) has been widely used for the detection of hearing loss based on its convenience and accuracy. The different reference methods directly influence the quality of the ABR waveform which in turn affects the ABR-based diagnosis. Therefore, in this study, a reference electrode standardization technique (REST) was adopted to systematically investigate and evaluate the effect of different reference methods on the quality of ABR waveform in comparison with the conventional average reference (AR) and mean mastoid (MM) methods. In this study, ABR signals induced by click stimulus were acquired via an EEG electrode cap arrays, and those located on the six channels along the midline were compared systemically. The results showed that, when considering the different channels, the ABR in the Cz channel showed the best morphology. Then, the ABR waveforms acquired via the REST method possessed better morphologies with large amplitude (0.06 ± 0.02 µV for wave I, 0.07 ± 0.02 µV for wave III, and 0.21 ± 0.04 µV for wave V) when compared with the traditional method. Summarily, we found that the REST and MM methods improved the quality of ABR on both amplitude and morphology under different stimulation rates and levels without changing the latencies of ABR when compared with the conventional AR method, suggesting that the REST and MM methods have the potential to help physicians with high accurate ABR-based clinical diagnosis. Moreover, this study might also provide a theoretic basis of reference methods on the acquisition of electroencephalogram over public health issues.
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Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva , Estimulação Acústica/métodos , Limiar Auditivo/fisiologia , Eletroencefalografia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , HumanosRESUMO
Introduction: Intrahepatic cholangiocarcinoma (ICC) is one of the most highly heterogeneous malignant solid tumors; it is generally insensitive to clinical treatment and has a poor prognosis. Evidence suggests that abnormal neovascularization in the tumor microenvironment is an important cause of treatment resistance as well as recurrence and metastasis, but the key regulatory molecules are still largely unknown and should be identified. Method: We assessed the novel extracellular matrix protein (ECM) Sushi, von Willebrand factor type A, EGF and pentraxin containing 1 (SVEP1) expression pattern in the ICC by using immunohistochemistry. Multiplex immunofluorescence and Kaplan-Meier analysis were applied to explore the correlation between the low expression of SVEP1 and abnormal blood vessels and the clinical prognosis of ICC. Results: Our study showed that the expression of SVEP1 in most ICC samples was relatively lower than in the adjacent tissues. Statistical analysis suggested that patients with decreased SVEP1 expression always had shorter overall survival (OS) and disease-free survival (DFS). Moreover, the expression of SVEP1 was negatively correlated with the proportion of abnormal neovascularization in the tumor microenvironment of the ICC. Consistently, the key molecule of promoting vascular normalization, Ang-1, is positively correlated with the SVEP1 expression and prognosis in the ICC. In addition, the proportion of high Ki-67 expression was higher in the ICC samples with low SVEP1 expression, suggesting that the SVEP1 low expressed sample is in a malignant phenotype with high proliferation. Conclusion: This study reveals that SVEP1 is a promising prognostic biomarker for ICC and provides fresh insight into the role and potential new mechanism of abnormal neovascularization in ICC progression.
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Otoacoustic emissions (OAEs) are low-level sounds generated by the cochlea and widely used as a noninvasive tool to inspect cochlear impairments. However, only the amplitude information of OAE signals is used in current clinical tests, while the OAE phase containing important information about cochlear functions is commonly discarded, due to the insufficient frequency-resolution of existing OAE tests. In this study, swept tones with time-varying frequencies were used to measure stimulus frequency OAEs (SFOAEs) in human subjects, so that high-resolution phase spectra that are not available in existing OAE tests could be obtained and analyzed. The results showed that the phase of swept-tone SFOAEs demonstrated steep gradients as the frequency increased in human subjects with normal hearing. The steep phase gradients were sensitive to auditory functional abnormality caused by cochlear damage and stimulus artifacts introduced by system distortions. At low stimulus levels, the group delays derived from the phase gradients decreased from around 8.5 to 3 ms as the frequency increased from 1 to 10 kHz for subjects with normal hearing, and the pattern of group-delay versus frequency function showed significant difference for subjects with hearing loss. By using the swept-tone technology, the study suggests that the OAE phase gradients could provide highly sensitive information about the cochlear functions and therefore should be integrated into the conventional methods to improve the reliability of auditory health screening.
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Pitch, as a sensation of the sound frequency, is a crucial attribute toward constructing a natural voice for communication. Producing intelligible sounds with normal pitches depend on substantive interdependencies among facial and neck muscles. Clarifying the interrelations between the pitches and the corresponding muscular activities would be helpful for evaluating the pitch-related phonating functions, which would play a significant role both in training pronunciation and in assessing dysphonia. In this study, the speech signals and the high-density surface electromyography (HD sEMG) signals were synchronously acquired when phonating [a:], [i:], and [Ó:] vowels with increasing pitches, respectively. The HD sEMG energy maps were constructed based on the root mean square values to visualize spatiotemporal characteristics of facial and neck muscle activities. Normalized median frequency (nMF) and root-mean square (nRMS) were correspondingly extracted from the speech and sEMG recordings to quantitatively investigate the correlations between sound frequencies and myoelectric characteristics. The results showed that the frame-wise energy maps built from sEMG recordings presented that the muscle contraction strength increased monotonously across pitch-rising, with left-right symmetrical distribution for the face/neck. Furthermore, the nRMS increased at a similar rate to the nMF when there were rising pitches, and the two parameters had a significant correlation across different vowel tasks [(a:) (0.88 ± 0.04), (i:) (0.89 ± 0.04), and (Ó:) (0.87 ± 0.05)]. These findings suggested the possibility of utilizing muscle contraction patterns as a reference for evaluating pitch-related phonation functions. The proposed method could open a new window for developing a clinical approach for assessing the muscular functions of dysphonia.
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More than half of HNSCC patients are diagnosed with advanced disease. Locally advanced HNSCC is characterized by tumors with marked local invasion and evidence of metastasis to regional lymph nodes. CAV2 is a major coat protein of caveolins, important components of the plasma membrane. In this study, CAV2 was found to profoundly promote invasion and stimulate metastasis in vivo and in vitro. CAV2 was demonstrated to be a key regulator of S100 protein expression that upregulates the proteins levels of S100s, which promotes the invasion and migration and downregulates the expression of tumor suppressors. Mechanistically, CAV2 directly interacts with S100s in HNSCC cells, and CAV2 reduces S100A14 protein expression by promoting its ubiquitylation and subsequent degradation via the proteasome. Moreover, we discovered that CAV2 promotes the interaction between S100A14 and the E3 ubiquitin ligase TRIM29 and increases TRIM29 expression. Taken together, our findings indicate that CAV2 promotes HNSCC invasion and metastasis by regulating the expression of S100 proteins, presenting a novel potential target for anticancer therapy in HNSCC.
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Background: The efficacy of current therapeutic schedule is limited owing to fibroproliferative tumor microenvironment (TME) of cholangiocarcinoma, compelling a search for new therapeutic targets. Methods: Gene expression profiles and methylation profiles were obtained from UCSC Xena. Consensus clustering was performed on the transcriptome data of cholangiocarcinoma to determine the different immune subtypes. The differentially expressed genes (DEGs) between hot tumor and cold tumors were identified. ESTIMATE was used to assess immune score, and the cases were separated into relatively superior and inferior immune score groups. Single-sample gene set enrichment analysis was applied to assess 28 immune cells in the cholangiocarcinoma microenvironment. Unsupervised consensus was applied for methylation profiling to distribute the high and low methylation groups. The correlation between DNA methylation and mRNA expression was investigated, and the relationship between the ATP2B1 gene and the immune microenvironment was explored. Finally, 77 cases of intrahepatic cholangiocarcinoma (ICC) were collected for verification. Results: Seven subtypes were related to patient outcomes (P=0.005). The proportions of CD8+ T cells in the "hot" immune type was significantly greater than that in the "cold" immune type (P<0.05). Next, DEGs and DNA methylation-governed genes were intersected, and ATP2B1 was identified as a prognosis factor in ICC (P=0.035). ATP2B1 expression was positively correlated with immune scores (P=0.005, r=0.458), the levels of infiltrating CD8+ T cells (P=0.004, r=0.47), and CD4+ T cells (P=0.027, r=0.37). Immunohistochemistry confirmed that the amounts of CD8+ and CD4+ T cells were significantly higher in ICC tissue samples than in tissues with ATP2B1 overexpression (P<0.05). Conclusions: ATP2B1 overexpression can activate immune signals and prompt cold tumor response.
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Electrocardiogram (ECG) is a critical physiological indicator that contains abundant information about human heart activities. However, it is a kind of weak low-frequency signal, which is easy to be interfered by various noises. Therefore, wearable biosensors (WBS) technique is introduced to overcome this challenge. A flexible non-contact electrode is proposed for wearable biosensors (WBS) system, which is made up of flexible printed circuits materials, and can monitor the ECG signals during exercise for a long time. It uses the principle of capacitive coupling to obtain high-quality signals, and reduces the impact of external noise through active shielding; The results showed that the proposed non-contact electrode was equivalent to a medical wet electrode. The correlation coefficient was as high as 99.70 ± 0.30% when the subject was resting, while it was as high as 97.53 ± 1.80% during exercise. High-quality ECG could still be collected at subjects walking at 7 km/h. This study suggested that the proposed flexible non-contact electrode would be a potential tool for wearable biosensors for medical application on long-term monitoring of patients' health and provide athletes with physiological signal measurements.