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Immunogenic cell death (ICD) is a unique mode of cell death, which can release immunogenic damage-associated molecular patterns (DAMPs) and tumor-associated antigens to trigger long-term protective antitumor immune responses. Thus, amplifying "eat me signal" during tumor ICD cascade is critical for cancer immunotherapy. Some therapies (radiotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), etc.) and inducers (chemotherapeutic agents, etc.) have enabled to initiate and/or facilitate ICD and activate antitumor immune responses. Recently, nanostructure-based drug delivery systems have been synthesized for inducing ICD through combining treatment of chemotherapeutic agents, photosensitizers for PDT, photothermal transformation agents for PTT, radiosensitizers for radiotherapy, etc., which can release loaded agents at an appropriate dosage in the designated place at the appropriate time, contributing to higher efficiency and lower toxicity. Also, immunotherapeutic agents in combination with nanostructure-based drug delivery systems can produce synergetic antitumor effects, thus potentiating immunotherapy. Overall, our review outlines the emerging ICD inducers, and nanostructure drug delivery systems loading diverse agents to evoke ICD through chemoradiotherapy, PDT, and PTT or combining immunotherapeutic agents. Moreover, we discuss the prospects and challenges of harnessing ICD induction-based immunotherapy, and highlight the significance of multidisciplinary and interprofessional collaboration to promote the optimal translation of this treatment strategy.
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Antineoplásicos , Neoplasias , Humanos , Morte Celular Imunogênica , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Morte Celular , ImunoterapiaRESUMO
Matter entanglement is a common chaotic structure found in both quantum and classical systems. For classical turbulence, viscous vortices are like sinews in fluid flows, storing and dissipating energy and accommodating strain and stress throughout a complex vortex network. However, to explain how the statistical properties of turbulence arise from elemental vortical structures remains challenging. Here, we use the quantum vortex tangle as a skeleton to generate an instantaneous classical turbulent field with intertwined vortex tubes. Combining the quantum skeleton and tunable vortex thickness makes the synthetic turbulence satisfy key statistical laws, offering valuable insights for elucidating energy cascade and extreme events. By manipulating the elemental structures, we customize turbulence with desired statistical features. This bottom-up approach of designing turbulence provides a testbed for analyzing and modeling turbulence.
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Esophageal squamous cell carcinoma (ESCC) is one of the gastrointestinal malignancies with high prevalence and poor prognosis. Previous reports suggested that circular ribose nucleic acids might exert regulatory functions in ESCC. This study aims to explore the role of circ_0000592 in ESCC progression, providing novel insights into the diagnosis and therapeutic avenues for ESCC. The GSE131969 data set was utilized to assess circ_0000592 expression in ESCC. The validation was performed in the tumorous tissues of ESCC patients (n = 80) and human-immortalized ESCC cell lines. The correlation between circ_0000592 expression and prognosis was analyzed. The impact of circ_0000592 on ESCC cell activity was evaluated through downregulating circ_0000592, as well as encompassing cell viability, migration, and invasion abilities. The downstream pathway of circ_0000592 was explored by binding site prediction from the TargetScan database, followed by in vitro and in vivo experiments. An in vivo xenograft tumor model was established to highlight the role of circ_0000592 in ESCC. Patients with ESCC exhibited higher circ_0000592 expression levels compared to noncancerous patients, which were associated with reduced survival time, higher TNM stage, and increased lymph node metastasis. The circ_0000592 downregulation suppressed cell viability, migration, and invasion abilities in vitro. Mechanistically, circ_0000592 countered the inhibitory effects on the target gene Frizzled 5 (FZD5) through interactions with miR-155-5p. The overexpression of miR-155-5p curtailed the luciferase activity of circ_0000592 in ESCC cells, inhibiting downstream molecule FZD5 protein expression and subsequently mitigating the detrimental consequences of escalated circ_0000592 expression in ESCC cells. Consistently, circ_0000592 downregulation curbed proliferation and metastasis of ESCC tumors in vivo. In summary, circ_0000592 promoted the progress of ESCC by counteracting the inhibitory impact on FZD5 through its interaction with miR-155-5p. Together, our findings highlighted circ_0000592 as a prospective therapeutic target for ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Receptores Frizzled , MicroRNAs , RNA Circular , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Receptores Frizzled/metabolismo , Receptores Frizzled/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismoRESUMO
This study offers a detailed exploration of lung adenocarcinoma (LUAD), addressing its heterogeneity and treatment challenges through a multi-faceted analysis that includes gene expression, genetic subtyping, pathway analysis, immune assessment, and drug sensitivity. It identifies 165 genes with significant expression differences and 46 genes associated with survival, revealing insights into oxidative stress and autophagy. LUAD samples were divided into three subtypes using consensus clustering on these 46 genes, with distinct survival outcomes. Gene Set Enrichment Analysis (GSEA) on HALLMARK gene sets indicated pathway variations with survival implications. The immune landscape, analyzed using the CIBERSORT algorithm, showed different immune cell distributions across subtypes, with the first subtype exhibiting a better immune environment and survival prospects. Advanced machine learning techniques developed a risk model from a set of four genes, effectively categorizing patients into high and low-risk groups, validated through external datasets and analyses. This model linked lower risk scores to better clinical stages, with a higher mutation rate and potential immunotherapy benefits observed in the high-risk group. Drug sensitivity assessments highlighted varied treatment responses between risk groups, suggesting avenues for personalized therapy. This comprehensive analysis enhances the understanding of LUAD's molecular and clinical nuances, offering valuable insights for tailored treatment approaches.
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BACKGROUND: Great improvements have been made in the prognosis of esophageal cancer (ESCA) with the application of chemotherapy and immunotherapy. However, the majority of cases remain resistant to these regimens. Hence there is an urgent need to characterize the subtypes of ESCA with favorable survival outcome and drug responsiveness. METHODS: We characterized the malignant cells of ESCA and explored their communication with immune cells using the Cellchat algorithm. The ligand-receptor interaction pairs were then used as inputting information to identify the subtypes of ESCA by unsupervised clustering analysis. Further investigation aimed to dissect the different patterns of tumor immune microenvironment (TIME), tumor mutation burden, immunotherapy responsiveness and drug sensitivity among the various subtypes of ESCA. A nomogram was also constructed to predict the survival rate of ESCA patients by conducting Cox regression and decision curve analysis. RESULTS: Three subtypes were identified based on the ligand-receptor interaction pairs. Patients in cluster 2 showed a longer survival time and less likelihood of response to immunotherapy compared with cluster 1 or 3. Eight hub genes were screened to construct a prognostic signature, which can stratify patients well into high- and low-risk groups with distinct survival outcomes and drug sensitivities. The nomogram showed quite good performance in predicting patient survival rates of 1 and 3 years. CONCLUSION: This study characterized the molecular profiling and TIME patterns of three subtypes of ESCA. The relative findings will provide emergent insights for the treatment of ESCA.
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Neoplasias Esofágicas , Humanos , Ligantes , Imunoterapia , Algoritmos , Análise por Conglomerados , Microambiente TumoralRESUMO
RATIONALE: Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis. METHODS: Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq. RESULTS: CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI. CONCLUSION: Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.
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Neoplasias Esofágicas , MicroRNAs , Animais , Carcinogênese/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Circular/genética , RNA Circular/metabolismoRESUMO
BACKGROUND: Neoadjuvant chemoradiation followed by esophagectomy has been established as the first-line treatment for locally advanced esophageal cancer. Postoperative enteral nutrition has been widely used to improve perioperative outcomes. However, whether to implement preoperative nutritional intervention during neoadjuvant therapy is yet to be verified by prospective studies. METHODS: POINT trial is a multicenter, open-labeled, randomized controlled trial. A total of 244 patients with surgically resectable esophageal cancer are randomly assigned to nutritional therapy group (arm A) or control group (arm B) with a 2:1 ratio. Both groups receive neoadjuvant chemotherapy with concurrent radiotherapy based on the CROSS regimen followed by minimally invasive esophagectomy. The primary endpoint is the rate of nutrition and immune-related complications after surgery. Secondary endpoints include completion rate of neoadjuvant chemoradiation and related adverse events, rate of pathological complete response, perioperative outcomes, nutritional status, overall survival, progression-free survival and quality of life. DISCUSSION: This trial aims to verify whether immunonutrition during neoadjuvant chemoradiation can reduce the rate of complications and improve perioperative outcomes. Frequent communication and monitoring are essential for a multicenter investigator-initiated trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04513418. The trial was prospectively registered on 14 August 2020, https://www. CLINICALTRIALS: gov/ct2/show/NCT04513418 .
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Neoplasias Esofágicas , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Neoplasias Esofágicas/patologia , Humanos , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: According to the randomized multicenter phase II trial (ALTER1202), anlotinib has been approved as a third-line therapy for advanced small-cell lung cancer (SCLC). Some studies showed the predictive function of inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in the different cancers treated with anti-vascular targeting drugs. However, none of the studies showed the roles of NLR, PLR, and LMR in SCLC patients receiving anlotinib. Thus, our objective was to establish a scoring system based on inflammation to individuate patient stratification and selection based on NLR, PLR, and LMR. METHODS: NLR, PLR, and LMR and their variations were calculated in 53 advanced SCLC patients receiving anlotinib as a third- or further-line treatment at Ningbo Medical Center Lihuili Hospital between January 2019 and December 2021. Kaplan-Meier curves were plotted. Both univariate and multivariate Cox regressions were used to identify predictors of survival. RESULTS: Disease control rate was related to pre-NLR, pre-PLR, pre-LMR, post-NLR elevation, post-PLR elevation, and post-LMR elevation. The multivariate analysis determined post-NLR elevation, pre-PLR > 240.56, and pre-LMR ≤1.61 to be independently associated with progression-free survival, not overall survival. The inflammation-based prognostic scoring system demonstrated favorable predictive ability from the receiver operating characteristic curve (AUC: 0.791, 95% CI: 0.645-0.938). CONCLUSIONS: Post-NLR variation, pre-PLR, and pre-LMR were independent prognostic factors for PFS in advanced SCLC receiving anlotinib monotherapy. The inflammation-based prognostic scoring system can accurately predict effectiveness and survival.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Prognóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Linfócitos , Neutrófilos , Inflamação , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
BACKGROUND: We observed the feasibility and effectiveness of multi-injection thoracic paravertebral block (TPB) via the intrathoracic approach under thoracoscopic direct vision for analgesia after thoracoscopic-laparoscopic esophagectomy (TLE). METHODS: Sixty patients undergoing TLE were randomly divided into a control group and an observation group. All patients underwent TPB via the intrathoracic approach at the three levels of T2, 5, and 8 with a scalp needle before closing the chest. The patients in the observation group received 10 ml 0.375% ropivacaine at each level, and the patients in the control group received 10 ml of 0.9% saline at each level. A patient-controlled intravenous analgesic (PCIA) pump with sufentanil was attached to all patients after surgery. The sufentanil consumption, number of PCIA presses and use of rescue analgesia in the first 24 h after surgery were recorded. The visual analogue scale (VAS) scores (rest and coughing) were recorded at 2 h, 6 h, 12 h, 24 h, and 48 h after surgery. The duration of postoperative hospital stay, active cough rate, first ambulation, and the incidence of adverse reactions after surgery was recorded. RESULTS: The sufentanil consumption in the observation group was significantly lower than that in the control group (34.7 ± 1.9 µg vs. 52.1 ± 2.1 µg; P < 0.001). The VAS score at each postoperative time point, number of PCIA presses, use of rescue analgesia, and the incidence of adverse reactions in the observation group were significantly lower than those in the control group. The postoperative active cough rate of patients in the observation group was significantly higher than those in the control group, and the times of the first ambulation after surgery and postoperative hospital stay in the observation group were significantly shorter than those in the control group (all P < 0.05). CONCLUSIONS: Multi-injection TPB via the intrathoracic approach under thoracoscopic direct vision is easy to perform and can effectively alleviate postoperative pain after TLE with fewer adverse reactions and contributing to improved postoperative recovery.
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Analgesia , Laparoscopia , Bloqueio Nervoso , Esofagectomia/efeitos adversos , Estudos de Viabilidade , Humanos , Laparoscopia/efeitos adversosRESUMO
BACKGROUND: MicroRNAs (miRNAs) and Twist1-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination are well established, but the involvement of long noncoding RNAs (lncRNAs) in Twist1-mediated signaling remains largely unknown. METHODS: RT-qPCR and western blotting were conducted to detect the expression levels of lncRNA JPX and Twist1 in lung cancer cell lines and tissues. The impact of JPX on Twist1 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by western blotting, rescue experiments, colony formation assay, flow cytometry, and xenograft animal experiment. RESULTS: We observed that lncRNA JPX was upregulated in lung cancer metastatic tissues and was closely correlated with tumor size and an advanced stage. Functionally, JPX promoted lung cancer cell proliferation in vitro and facilitated lung tumor growth in vivo. Additionally, JPX upregulated Twist1 by competitively sponging miR-33a-5p and subsequently induced EMT and lung cancer cell invasion. Interestingly, JPX and Twist1 were coordinately upregulated in lung cancer tissues and cells. Mechanically, the JPX/miR-33a-5p/Twist1 axis participated in EMT progression by activating Wnt/ß-catenin signaling. CONCLUSIONS: These findings suggest that lncRNA JPX, a mediator of Twist1 signaling, could predispose lung cancer cells to metastasis and may serve as a potential target for targeted therapy.
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Adenocarcinoma de Pulmão/secundário , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Nucleares/metabolismo , RNA Longo não Codificante/genética , Proteína 1 Relacionada a Twist/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Nucleares/genética , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteína 1 Relacionada a Twist/genética , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genéticaRESUMO
We demonstrate enhanced on-chip circulating tumor cell (CTC) detection through the incorporation of plasmonic-enhanced near-infrared (NIR) fluorescence screening. Specifically, the performance of plasmonic gold coated chips was evaluated on our previously reported immunomagnetic CTC capture system and compared to the performance of a regular chip. Three main performance metrics were evaluated: capture efficiency, capture reproducibility, and clinical efficacy. Use of the plasmonic chip to capture SK-BR-3 cells in PBS, resulted in a capture efficiency of 82%, compared to 76% with a regular chip. Both chips showed excellent capture reproducibility for all three cells lines evaluated (MCF-7, SK-BR-3, Colo 205) in both PBS and peripheral blood, with R2 values ranging from 0.983 to 0.996. Finally, performance of the plasmonic chip was evaluated on thirteen peripheral blood samples in patients with both breast and prostate cancer. The regular chip detected 2-8 cells per 5 mL of blood, while the plasmonic chip detected 8-85 cells per 5 mL of blood in parallel samples. In summary, we successfully demonstrate improved CTC capture and detection capabilities through use of plasmonic-enhanced near-infrared (NIR) fluorescence screening in both in vitro and ex vivo experiments. This work not only has the potential to improve clinical outcomes though improved CTC analysis, but also demonstrates successful interface design between plasmonic materials and cell capture for bioanalytical applications.
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Separação Imunomagnética/instrumentação , Dispositivos Lab-On-A-Chip , Limite de Detecção , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Feminino , Humanos , Células MCF-7 , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
USA and China are two leading countries engaged in nanotechnology research and development. They compete with each other for fruits in this innovative area in a parallel and compatible manner. Understanding the status and developmental prospects of nanotechnology in USA and China is important for policy-makers to decide nanotechnology priorities and funding, and to explore new ways for global cooperation on key issues. We here present the nanoscience and nanomedicine research and the related productivity measured by publications, and patent applications, governmental funding, policies and regulations, institutional translational research, industrial and enterprise growth in nanotechnology-related fields across China and USA. The comparison reveals some marked asymmetries of nanotechnology development in China and USA, which may be helpful for future directions to strengthen nanotechnology collaboration for both countries, and for the world as a whole.
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Internacionalidade , Modelos Organizacionais , Nanotecnologia/organização & administração , Objetivos Organizacionais , Pesquisa/organização & administração , Ciência/organização & administração , China , Estados UnidosRESUMO
BACKGROUND: Cancer metastasis caused by circulating tumor cells (CTCs) accounts for 90% cancer-related death worldwide. Blocking the circulation of CTCs in bloodstream and their hetero-adhesion to vascular endothelia of the distant metastatic organs may prevent cancer metastasis. Nanomaterial-based intervention with adhesion between CTCs and endothelia has not been reported. Driven by the novel idea that multivalent conjugation of EpCAM and Slex antibodies to dendrimer surface may enhance the capacity and specificity of the nanomaterial conjugates for capturing and down-regulating colorectal CTCs, we conjugated the dendrimer nanomaterial with the EpCAM and Slex antibodies, and examined the capacity of the dual antibody-coated nanomaterial for their roles in interrupting CTCs-related cancer metastasis. RESULTS: The antibody-coated nanomaterial was synthesized and characterized. The conjugates specifically bound and captured colon cancer cells SW620. The conjugate inhibited the cells' viability and their adhesion to fibronectin (Fn)-coated substrate or human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. In comparison with SW480 and LoVo cell lines, the activity and adhesion of SW620 to Fn-coated substrate and HUVECs were more specifically inhibited by the dual antibody conjugate because of the higher levels of EpCAM and Slex on SW620 cell surface. The hetero-adhesion between SW620 and Fn-coated substrate, or HUVECs was inhibited by about 60-70%. The dual conjugate showed the inhibition capacity more significant than its corresponding single antibody conjugates. CONCLUSIONS: The present study provides the new evidence that coating nanomaterials with more than one antibody against CTCs may effectively interfere with the interaction between SW620 and HUVECs.
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Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Endotélio Vascular/citologia , Nanoestruturas , Células Neoplásicas Circulantes/efeitos dos fármacos , Anticorpos/química , Antígenos de Neoplasias/imunologia , Antineoplásicos/química , Moléculas de Adesão Celular/imunologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Dendrímeros/química , Relação Dose-Resposta a Droga , Molécula de Adesão da Célula Epitelial , Fibronectinas/química , Fibronectinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanoestruturas/química , Metástase Neoplásica/prevenção & controle , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologiaRESUMO
The tumor suppressor LKB1 gene encodes a serine-threonine kinase that regulates cell proliferation and polarity. Inactivation of LKB1 by mutations in LKB1 or loss of its expression is highly correlated with lung, ovarian, and pancreatic cancers, and WNT/ß-catenin pathway is also known to be involved in many human malignancies. However, the relationship between LKB1 and WNT signaling pathway in esophageal carcinoma remains unknown. The expression of LKB1 in 62 cases of esophageal cancer patients was determined by quantitative real-time PCR. It was found that LKB1 mRNA level was significantly lower than the adjacent normal epithelium and that the LKB1 downregulation was correlating with TNM stages. Moreover, the expression of WNT target genes such as Cyclin D1, C-MYC, MMP2, and FZD2 was significantly upregulated in esophageal cancer tissues. LKB1 overexpression in TE10 cells inhibited TOPFlash luciferase reporter activity and WNT target gene expression even in the presence of WNT3A. Conversely, LKB1 knockdown enhanced WNT signaling activity in esophageal cancer cells. It was also found that LKB1 antagonized WNT signaling pathway through interaction with GSK3ß to downregulate ß-catenin expression level. Functional investigation revealed that LKB1 suppressed the promotion effects of WNT3A on the cell growth of TE10 cells. The LKB1 functions in regulating cell growth and WNT target genes expression were impaired by GSK3ß inhibition, suggesting that LKB1 antagonized WNT-induced cell proliferation through enhancement of GSK3ß activity. Together, the interaction between LKB1 and GSK3ß upregulates GSK3ß activity to suppress WNT-induced cell proliferation in esophageal carcinoma cells. Loss of LKB1 expression may result in the deregulation of WNT/ß-catenin pathway to promote malignant progression of esophageal cancer.
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Neoplasias Esofágicas/genética , Quinase 3 da Glicogênio Sintase/genética , Proteínas Serina-Treonina Quinases/metabolismo , Via de Sinalização Wnt/genética , Quinases Proteína-Quinases Ativadas por AMP , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/biossíntese , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/biossíntese , beta Catenina/biossíntese , beta Catenina/metabolismoRESUMO
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an important enzyme which can catalyze the two-electron reduction of quinoid compounds into hydroquinones. NQO1 Pro187Ser polymorphism can change the enzymatic activity of NQO1, and it has been proposed to be associated with risk of esophageal cancer. We performed a meta-analysis to examine the association between NQO1 Pro187Ser polymorphism and esophageal cancer. Odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the association. Twelve case-control studies with 1,725 cases with esophageal cancer and 2,341 controls were finally included in the meta-analysis. Overall, there was an obvious association between NQO1 Pro187Ser polymorphism and esophageal cancer (allele model: OR = 1.24, 95% CI 1.06-1.46, P OR = 0.009; homozygote model: OR = 1.59, 1195% CI 1.10-2.30, P OR = 0.013; dominant model: OR = 1.31, 95% CI 1.05-1.64, P OR = 0.018). In the subgroup analysis by ethnicity, there was an obvious association between NQO1 Pro187Ser polymorphism and esophageal cancer in Asians but not in Caucasians. Therefore, the meta-analysis suggests that NQO1 Pro187Ser polymorphism is associated with esophageal cancer risk.
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Neoplasias Esofágicas/genética , Predisposição Genética para Doença/genética , NAD(P)H Desidrogenase (Quinona)/genética , Polimorfismo de Nucleotídeo Único/genética , Povo Asiático/genética , Estudos de Casos e Controles , Humanos , Razão de Chances , População Branca/genéticaRESUMO
OBJECTIVE: The objective of this study is to assess the use of a novel, double-lumen electrocautery tube (DLET) device for ablating the sympathetic nerve chain in patients with primary palmar hyperhidrosis (PPH). METHODS: Forty-six patients with severe PPH were recruited into the study between November 2010 and February 2012. All patients underwent single port, bilateral video-assisted thoracoscopic sympathicotomy. Twenty-four patients were randomized to receive sympathicotomy using a conventional 5-mm electrocautery hook (hook group) and 22 patients were randomized to the DLET group. RESULTS: The mean postoperative follow-up period was 8.1 months (range: 1 to 15 months). After surgery the hands of all patients became dry and warm. Mean incision size was 10.6 ± 1.0 in the hook group and 6.5 ± 0.5 mm in the DLET group (p = 0.001). The mean pain score was 1.4 ± 0.6 with hook surgery and 0.9 ± 0.6 with the DLET device (p = 0.016). The mean operative time was longer in the hook group (36.8 ± 3.4 min) than in the DLET group (30.5 ± 3.9 min; p = 0.001). There were no significant differences between the two procedures in terms of hospital stay and compensatory sweating, or patient satisfaction. Pneumothorax occurred in two (8.3%) patients in the hook group and in one (4.5%) patient in the DLET group. None of the patients required chest drainage and none developed Horner syndrome. CONCLUSIONS: Single-port video-assisted thoracoscopic sympathicotomy using hook or DLET procedures is effective, safe, and minimally invasive method for palmar hyperhidrosis. The DLET device allows a shorter operation time, smaller incision, better cosmetic results, less pain, and better clarity of video, making it suitable for single-port thoracoscopic sympathicotomy.
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Hiperidrose/cirurgia , Simpatectomia/instrumentação , Sistema Nervoso Simpático/cirurgia , Cirurgia Torácica Vídeoassistida/instrumentação , Adolescente , Adulto , Eletrocoagulação/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Observational studies have suggested a link between severe mental illness (SMI) and risk of lung carcinoma (LC); however, causality has not been established. In this study, we conducted a two-sample, two-step Mendelian randomization (MR) investigation to uncover the etiological influence of SMI on LC risk and quantify the mediating effects of known modifiable risk factors. We obtained summary-level datasets for schizophrenia, major depressive disorder (MDD), and bipolar disorder (BD) from the Psychiatric Genomics Consortium (PGC). Data on single nucleotide polymorphisms (SNPs) associated with lung carcinoma (LC) were sourced from a recent large meta-analysis by McKay et al. We employed two-sample MR and two-step MR utilizing the inverse variance weighted method for causal estimation. Sensitivity tests were conducted to validate causal relationships. In two-sample MR, we identified schizophrenia as a risk factor for LC (ORâ =â 1.06, 95% CI 1.02-1.11, Pâ =â 3.48E-03), while MDD (ORâ =â 1.18, 95% CI 0.98-1.42, Pâ =â .07) and BD (ORâ =â 1.07, 95% CI 0.99-1.15, Pâ =â .09) showed no significant association with LC. In the two-step MR, smoking accounted for 24.66% of the schizophrenia-LC risk association, and alcohol consumption explained 7.59% of the effect. Schizophrenia is a risk factor for lung carcinoma, and smoking and alcohol consumption are the mediating factors in this causal relationship. LC screening should be emphasized in individuals with schizophrenia, particularly in those who smoke and consume alcohol regularly.
Assuntos
Carcinoma , Transtorno Depressivo Maior , Neoplasias Pulmonares , Transtornos Mentais , Humanos , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Causalidade , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Pulmão , Análise da Randomização Mendeliana , Estudo de Associação Genômica AmplaRESUMO
Background: The esophagectomy surgical Apgar score (eSAS) has been found to be a predictor of postoperative complications in esophagectomy. In our previous study, we built a graphic nomogram based on eSAS and demonstrated that it can effectively predict the risk of major morbidity after esophagectomy. In this study, we aimed to assess the benefits of using an eSAS-based nomogram model as a postoperative risk-based triage system for patients undergoing esophagectomy. Methods: We enrolled 119 patients diagnosed with esophageal carcinoma and randomly assigned them to a nomogram group (NG) or control group (CG) from January 2019 to December 2020. Patients in the NG were assigned to a low-risk group and high-risk group based on the nomogram. Patients in the high-risk group were admitted to the intensive care unit (ICU) after esophagectomy. Risk estimation in the CG patients was based on the surgeon's clinical experience. Thirty-day major complications, postoperative hospital stay, hospital costs, and quality of life (QOL) during the follow-up were compared between the two groups. Results: Baseline clinicopathological characteristics were comparable between the NG (n=58) and CG (n=61). All patients underwent esophagectomy. Postoperative complications were significantly higher in the CG (30, 49.2%) than in the NG (14, 24.1%) (P=0.008), with pneumonia being the most common (CG: 23, 37.7%; NG: 12, 20.7%; P=0.042). There was no significant difference in anastomotic leakage (NG: 1, 1.7%; CG: 6, 9.8%; P=0.12). Postoperative median hospital stay was shorter in the NG (14 days) than in the CG (16 days) (P=0.041). Hospital costs (NG: ¥60,045.1; CG: ¥63,961.5; P=0.21) and postoperative QOL did not differ significantly between groups. Conclusions: An eSAS-based nomogram as a triage system can reduce the overall occurrence of postoperative complications and shorten postoperative hospital stay without increasing hospital costs. Trial Registration: Chinese Clinical Trial Registry ChiCTR1900021636.
RESUMO
The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.
Assuntos
Lesão Pulmonar Aguda , Pulmão , Nanoestruturas , Ácido Oleanólico , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Ácido Oleanólico/farmacologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/química , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Nanoestruturas/química , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Portadores de Fármacos/química , Masculino , Camundongos , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Pneumonia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Endogâmicos C57BL , Lipídeos/química , Anticorpos/farmacologia , Líquido da Lavagem Broncoalveolar/química , Humanos , Sistemas de Liberação de Medicamentos/métodos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacosRESUMO
Chronic obstructive pulmonary disease (COPD) is a leading cause of global death. As a molecule beyond adhesion, CD146 is involved in COPD pathogenesis. However, the mechanisms of CD146 in COPD remain largely elusive. We hypothesized that CD146 regulates the production of matrix metalloproteinase-9 (MMP-9) in macrophages and thereby contributes to COPD. Here, we constructed a murine model of COPD using lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). In COPD-like mice, LPS and PPE decreased the pulmonary expression of CD146. MMP-9 expression and bioactivity were increased in CD146 knockout COPD-like mice. In vitro, LPS decreased CD146 expression in macrophages. With or without LPS challenge, CD146-defective macrophages produced more MMP-9. Transcriptome analysis based on next-generation sequencing (NGS) revealed that S100A9 regulated MMP-9 production in CD146-defective macrophages. Targeting S100A9 with paquinimod decreased lung inflammation and alleviated alveolar destruction in COPD-like mice. Collectively, our study suggests that CD146 negatively regulates MMP-9 production in macrophages via the S100A9 pathway in COPD.