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OBJECTIVES: To establish deep learning models for malignancy risk estimation of sub-centimeter pulmonary nodules incidentally detected by chest CT and managed in clinical settings. MATERIALS AND METHODS: Four deep learning models were trained using CT images of sub-centimeter pulmonary nodules from West China Hospital, internally tested, and externally validated on three cohorts. The four models respectively learned 3D deep features from the baseline whole lung region, baseline image patch where the nodule located, baseline nodule box, and baseline plus follow-up nodule boxes. All regions of interest were automatically segmented except that the nodule boxes were additionally manually checked. The performance of models was compared with each other and that of three respiratory clinicians. RESULTS: There were 1822 nodules (981 malignant) in the training set, 806 (416 malignant) in the testing set, and 357 (253 malignant) totally in the external sets. The area under the curve (AUC) in the testing set was 0.754, 0.855, 0.928, and 0.942, respectively, for models derived from baseline whole lung, image patch, nodule box, and the baseline plus follow-up nodule boxes. When baseline models externally validated (follow-up images not available), the nodule-box model outperformed the other two with AUC being 0.808, 0.848, and 0.939 respectively in the three external datasets. The resident, junior, and senior clinicians achieved an accuracy of 67.0%, 82.5%, and 90.0%, respectively, in the testing set. The follow-up model performed comparably to the senior clinician. CONCLUSION: The deep learning algorithms solely mining nodule information can efficiently predict malignancy of incidental sub-centimeter pulmonary nodules. CLINICAL RELEVANCE STATEMENT: The established models may be valuable for supporting clinicians in routine clinical practice, potentially reducing the number of unnecessary examinations and also delays in diagnosis. KEY POINTS: ⢠According to different regions of interest, four deep learning models were developed and compared to evaluate the malignancy of sub-centimeter pulmonary nodules by CT images. ⢠The models derived from baseline nodule box or baseline plus follow-up nodule boxes demonstrated sufficient diagnostic accuracy (86.4% and 90.4% in the testing set), outperforming the respiratory resident (67.0%) and junior clinician (82.5%). ⢠The proposed deep learning methods may aid clinicians in optimizing follow-up recommendations for sub-centimeter pulmonary nodules and may lead to fewer unnecessary diagnostic interventions.
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Aprendizado Profundo , Achados Incidentais , Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Tomografia Computadorizada por Raios X/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Medição de Risco/métodos , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulo Pulmonar Solitário/diagnóstico por imagem , Idoso , Interpretação de Imagem Radiográfica Assistida por Computador/métodosRESUMO
Ventral adult hippocampal neurogenesis may be a key factor in determining individual levels of vulnerability to stress and related psychiatric disorders. However, the underlying mechanism remains unclear. Here, we show that the expression of Tau and Tau isoforms is markedly increased in the ventral dentate gyrus (vDG) after social defeat stress in young adult mice. Furthermore, glycogen synthase kinase-3ß and calcium/calmodulin-dependent protein kinase II-α activity and calcium/calmodulin-dependent protein kinase II-ß upregulation substantially promote Tau phosphorylation, which disrupts the dendritic structural plasticity of granule cells in the vDG of the hippocampus, and this action is necessary and sufficient for the stress response. In addition, Tau substantially inhibits the proliferation of newborn neurons in the vDG by regulating the PI3K-AKT signaling pathway in a mouse model of social defeat stress. Taken together, our findings reveal a novel mechanism by which Tau exacerbates stress responses and anxiety-related behavior by inhibiting the proliferation and maturation of hippocampal vDG neurons, providing a potential molecular target for the treatment of anxiety-like behavior induced by stress.
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Cálcio , Giro Denteado , Camundongos , Animais , Giro Denteado/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Hipocampo/fisiologia , Ansiedade , Neurogênese/fisiologia , Proteínas tau/metabolismoRESUMO
Metabolic reprogramming plays a critical role in tumorigenesis and tumor progression. The metabolism and the proliferation of tumors are regulated by both intrinsic factors within the tumor and the availability of metabolites in the tumor microenvironment (TME). The metabolic niche within the TME is primarily orchestrated at 3 levels: 1) the regulation of tumor metabolism by factors intrinsic to the tumors, 2) the interaction between tumor cells and T cells, macrophages, and stromal cells, and 3) the metabolic heterogeneity of tumor cells within the tissue space. Herein, we provided a concise overview of the various metabolic regulatory modes observed in tumor cells. Additionally, we extensively analyzed the interaction between tumor cells and other cells within the TME, as well as the metabolic characteristics and functions of different types of cells. Ultimately, this review provides a theoretical basis and novel insights for the precision treatment of tumors.
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Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Macrófagos/metabolismo , Comunicação Celular , Linfócitos T/metabolismo , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Sepsis is a serious systemic inflammatory disease that frequently results in death. Early diagnosis and timely targeted interventions could improve the therapeutic effect. Recent work has revealed that the reactive oxygen species (ROS) in the endoplasmic reticulum (ER) and hypoxia-induced endothelial injury play significant roles in sepsis. However, the relationship between the levels of peroxynitrite (ONOO-) and hypoxia-induced endothelial injury as well as different states of sepsis remain unexplored. Herein, we developed a unique two-photon fluorescent probe (ER-ONOO-) for detecting ONOO- in aqueous solution that has high sensitivity, high selectivity, and ultrafast response time. In addition, ER-ONOO- was successfully used to evaluate the levels of ONOO- at the ER with three kinds of methods in a hypoxia-induced endothelial injury model. Furthermore, ER-ONOO- is capable of monitoring the changes in organ fluorescence through ONOO- variation in different stages of a cecum ligation and puncture (CLP) mouse model. Moreover, we also confirmed that the endoplasmic reticulum stress and oxidative stress participated in the CLP model. Consequently, this research can provide a reliable tool for studying ONOO- fluctuation in sepsis and provide new insights into the pathogenic and therapeutic mechanisms involved.
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Corantes Fluorescentes , Sepse , Camundongos , Animais , Ácido Peroxinitroso , Modelos Animais de Doenças , Retículo EndoplasmáticoRESUMO
BACKGROUND: Although several studies have confirmed the prognostic value of the consolidation to tumor ratio (CTR) in non-small cell lung cancer (NSCLC), there still remains controversial about it. METHODS: We systematically searched the PubMed, Embase, and Web of Science databases from inception to April, 2022 for eligible studies that reported the correlation between CTR and prognosis in NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and pooled to assess the overall effects. Heterogeneity was estimated by I2 statistics. Subgroup analysis based on the cut-off value of CTR, country, source of HR and histology type was conducted to detect the sources of heterogeneity. Statistical analyses were performed using STATA version 12.0. RESULTS: A total of 29 studies published between 2001 and 2022 with 10,347 patients were enrolled. The pooled results demonstrated that elevated CTR was associated with poorer overall survival (HR = 1.88, 95% CI 1.42-2.50, P < 0.01) and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS) (HR = 1.42, 95% CI 1.27-1.59, P < 0.01) in NSCLC. According to subgroup analysis by the cut-off value of CTR and histology type, both lung adenocarcinoma and NSCLC patients who had a higher CTR showed worse survival. Subgroup analysis stratified by country revealed that CTR was a prognostic factor for OS and DFS/RFS/PFS in Chinese, Japanese, and Turkish patients. CONCLUSIONS: In NSCLC patients with high CTR, the prognosis was worse than that with low CTR, indicating that CTR may be a prognostic factor.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Prognóstico , Neoplasias Pulmonares/diagnóstico por imagem , Modelos de Riscos Proporcionais , TomografiaRESUMO
The development, persistence and relapse of drug addiction require drug memory that generally develops with drug administration-paired contextual stimuli. Adult hippocampal neurogenesis (AHN) contributes to cocaine memory formation; however, the underlying mechanism remains unclear. Male mice hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the mice hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Collectively, 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction.SIGNIFICANCE STATEMENT Drug memory that generally develops with drug-paired contextual stimuli and drug administration is critical for the development, persistence and relapse of drug addiction. Previous studies have suggested that adult hippocampal neurogenesis (AHN) plays a role in cocaine memory formation. Here, we showed that Tau was significantly downregulated in the hippocampus in the cocaine memory formation. Tau knock-out (KO) promoted AHN in the hippocampal dentate gyrus (DG), resulting in the enhanced memory formation evoked by cocaine-cue stimuli. In contrast, genetically overexpressed 4R Tau in the hippocampus disrupted cocaine-cue memory by suppressing AHN. In addition, 4R Tau interacted directly with phosphoinositide 3-kinase (PI3K)-p85 and hindered its nuclear translocation, eventually repressing PI3K-AKT signaling, which is essential for hippocampal neuronal proliferation.
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Transtornos Relacionados ao Uso de Cocaína/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Neurogênese/fisiologia , Proteínas tau/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isoformas de ProteínasRESUMO
Pyroptosis is a newly identified form of cell death that is closely correlated with many diseases. Recent studies have indicated that the inflammation in pyroptosis would accelerate the generation of reactive oxygen species (ROS). In addition, intracellular viscosity is another key microenvironmental parameter that reflects many physiological and pathological states in the early stage, hypochlorous acid (HOCl), as an important ROS, also plays significant roles in a variety of pathologies. However, the fluctuation of viscosity and HOCl in the process of pyroptosis is still unknown. Herein, we present a dual-responsive fluorescent probe (Lyso-VH) for simultaneously detecting viscosity and HOCl. Lyso-VH was successfully used to image the fluctuation of HOCl and viscosity in the lysosome of three kinds of cells with dependent and independent channels. Moreover, Lyso-VH can be employed to investigate the changes of HOCl and viscosity during the process of pyroptosis in living cells and acute lung injury (ALI). Thus, this work can not only serve as a powerful tool to simultaneously visualize the fluctuation of HOCl and viscosity in lysosomes, but also provide a new insight into drug-induced pyroptosis in living cells and acute lung injury.
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Lesão Pulmonar Aguda , Ácido Hipocloroso , Lesão Pulmonar Aguda/induzido quimicamente , Corantes Fluorescentes , Humanos , Ácido Hipocloroso/metabolismo , Piroptose , ViscosidadeRESUMO
Glioblastoma (GBM) is the most malignant tumor in human brain. High invasiveness of this tumor is the main reason causing treatment failure and recurrence. Previous study has found that LACTB is a novel tumor suppressor in breast cancer. Moreover, the function of LACTB in other tumors and mechanisms involving LACTB were also reported. However, the role and relevant mechanisms of LACTB in GBM invasion remains to be revealed. Our aim is to investigate the role LACTB in GBM migration and invasion. We found that LACTB was downregulated in gliomas compared to normal brain tissues. Overexpression of LACTB suppressed migration and invasion of LN229 and U87 cell lines. Mechanistically, LACTB overexpression downregulated the mesenchymal markers. Moreover, LACTB overexpression downregulated the expression of RHOC and inhibited RHOC/Cofilin signaling pathway. The study suggests that LACTB suppresses migration and invasion of GBM cell lines via downregulating RHOC/Cofilin signaling pathway. These findings suggest that LACTB may be a potential treatment target of GBM.
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Neoplasias Encefálicas , Glioblastoma , Fatores de Despolimerização de Actina/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Invasividade Neoplásica , Transdução de Sinais/fisiologia , beta-Lactamases/genética , Proteína de Ligação a GTP rhoC/genética , Proteína de Ligação a GTP rhoC/metabolismoRESUMO
PURPOSE: Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD, also known as Adrenomedullin 2, ADM2) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer. METHODS: Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting, immunoprecipitation, and animal tumor models were used. RESULTS: IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway. CONCLUSION: These results suggest that IMD may be a novel target for the treatment of breast cancer.
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Adrenomedulina/metabolismo , Neoplasias da Mama , Neuropeptídeos , Ribossomos , Transdução de Sinais , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Hormônios Peptídicos/genética , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ribossomos/genética , Ribossomos/metabolismoRESUMO
OBJECTIVE: Programmed death 1 (PD-1) and macrophages are the most intriguing candidates in sepsis-induced inflammatory disorders. We aimed to investigate the association between monocyte PD-1 and sepsis severity and the mechanism by which blocking macrophage-associated PD-1 causes inflammatory disorders in sepsis. MATERIALS AND METHODS: We first measured whether the expression of PD-1 on the monocyte subset is clinically associated with sepsis severity in an observational study. This study included 42 septic patients and 16 healthy controls (HCs) whose serum inflammatory factors were examined by Luminex MagPix. Then, we investigated the effect of PD-1 blockade on macrophages from septic mice (C57BL/6 mice) constructed by caecal ligation and puncture (CLP) via RNA sequencing. The positive genes screened by RNA-seq were verified in LPS-stimulated RAW264.7 cells by Western blot. RESULTS: The results showed that the expression of PD-1 on CD14+CD16+ monocytes (intermediate monocytes, IM Mo) was significantly higher in both septic and septic shock patients than in HCs. Further analysis of serum cytokines in septic patients showed that the levels of IL-6 and TNF-α were significantly higher than those in HCs, while serum PD-1 levels were decreased in septic patients. More interestingly, blockade of PD-1 on macrophages from septic mice suppressed the gene expression levels of NLRP3/Caspase-4/AKT2/STAT3. The protein levels associated with pyroptosis including NLRP3, Caspase4, GSDMD and NT-GSDMD were significantly decreased in LPS-stimulated RAW264.7 cells treated with PD-1 antibody. CONCLUSION: Our results suggested that intermediate monocytes with high expression of PD-1 may be involved in the progression of sepsis. PD-1 might play a critical role in regulating the pyroptosis signalling pathway in sepsis.
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Macrófagos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Piroptose , Sepse/metabolismo , Adulto , Idoso , Animais , Citocinas/metabolismo , Feminino , Humanos , Inflamação , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/citologia , Células RAW 264.7 , Choque Séptico/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this "sunitinib resistance" remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence. METHODS: 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated ß-galactosidase (SA-ß-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of "pre-metastatic niche" which promotes MBC to metastasize to the lungs. RESULTS: We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a "pre-metastatic niche"-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis. CONCLUSION: Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib "correctly" playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.
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Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/patologia , Senescência Celular , Células Endoteliais/patologia , Neoplasias Pulmonares/secundário , Sunitinibe/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Intermedin plays an important role in vascular remodeling and significantly improves blood perfusion, but the precise mechanism remains unclear. Herein, we aimed to define whether vascular lumen enlargement is responsible for the intermedin-increased blood perfusion and explore the underlying cellular and molecular mechanisms. APPROACH AND RESULTS: To study the role of intermedin, we generated the IMD-KO (Adm2-/-) mice using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) system. Intermedin significantly promoted vascular lumen enlargement in vitro (fibrin beads assay) and in vivo (murine retinas), which contributed to the improved blood perfusion in both physiological (retinal) and pathological (tumor) angiogenic models. We designed experiments to calculate the endothelial cell (EC) size and found that the lumen enlargement is because of EC proliferation but not because of a change in cell shape. ECs that construct vessel walls are considered quiescent cells because they are in a state of contact inhibition and show reduced responsiveness to VEGF (vascular endothelial growth factor). Using immunoprecipitation, Western blot assay, and fluorescent microscopy, we found that intermedin induced the formation of a signaling complex containing CRLR (calcitonin receptor-like receptor)/ß-arr1 (ß-arrestin1)/Src in ECs and promoted it internalizing into cytoplasm in a clathrin-dependent manner to activate downstream ERK1/2 (extracellular signal-regulated kinase 1/2). Importantly, this effect was not abrogated by cell-cell contacts of ECs. Through this mechanism, intermedin could reactivate the quiescent ECs to proliferate, resulting in continuous lumen expanding and a more effective blood perfusion. CONCLUSIONS: Our findings suggest a novel mechanism that may explain how quiescent ECs overcome the contact inhibition and regain the ability to proliferate for continuous vascular lumen enlargement.
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Carcinoma Pulmonar de Lewis/irrigação sanguínea , Proliferação de Células , Senescência Celular , Neoplasias do Colo/irrigação sanguínea , Células Endoteliais/metabolismo , Neovascularização Patológica , Neovascularização Fisiológica , Neuropeptídeos/metabolismo , Vasos Retinianos/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Hormônios Peptídicos/genética , Hormônios Peptídicos/metabolismo , Fluxo Sanguíneo Regional , Transdução de Sinais , Remodelação VascularRESUMO
Vessel sprouting from pre-existing vasculature is a key step for the formation of a functional vasculature. The low level of vascular endothelial growth factor (VEGF) induces normal and stable angiogenesis, whereas high level of VEGF causes irregular and over sprouted vasculature. Intermedin (IMD) is a novel member of calcitonin family, and was found to be able to restrict the excessive vessel sprouting. However, the underlying mechanism had not been elucidated. In this study, using in vitro and in vivo angiogenic models, we found that the loosening of endothelial junction could significantly increase the ability of low-dose VEGF to induce vessel sprouting. IMD inhibited the junction dissociation-induced vessel sprouting by re-establishing the complex of vascular endothelial cadherin on the cell-cell contact. Our findings suggested a novel mechanism through which IMD could restrict the excessive vessel sprouting by preventing the endothelial junction from dissociation, and provide new insight into the understanding of the regulation of sprouting angiogenesis.
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Hormônios Peptídicos/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Junções Intercelulares/metabolismo , Camundongos Endogâmicos C57BL , Neuropeptídeos/metabolismo , Hormônios Peptídicos/farmacologia , Retina/citologia , Retina/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Although significant progress has been made in early lung cancer screening over the past decade, it remains one of the most prevalent and deadliest forms of cancer worldwide. Exosomal proteomics has emerged as a transformative field in lung cancer research, with the potential to redefine diagnostics, prognostic assessments, and therapeutic strategies through the lens of precision medicine. This review discusses recent advances in exosome-related proteomic and glycoproteomic technologies, highlighting their potential to revolutionise lung cancer treatment by addressing issues of heterogeneity, integrating multiomics data, and utilising advanced analytical methods. While these technologies show promise, there are obstacles to overcome before they can be widely implemented, such as the need for standardization, gaps in clinical application, and the importance of dynamic monitoring. Future directions should aim to overcome the challenges to fully utilize the potential of exosomal proteomics in lung cancer. This promises a new era of personalized medicine that leverages the molecular complexity of exosomes for groundbreaking advancements in detection, prognosis, and treatment.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune-inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single-cell level. METHODS: We performed single-cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co-culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single-cell analyses. RESULTS: LSCC with COPD showed increased proportions of tumour-associated macrophages (TAMs) and higher levels of CD8+ T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74+ tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-programmed cell death-1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion. CONCLUSIONS: Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy. HIGHLIGHT: Our results demonstrated higher proportions of tumour-associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8+ T cells in the microenvironment of LSCC with COPD. CD74+tumour cells were associated with poor disease prognosis. Migration inhibitory factor (MIF)-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-PD-L1 signalling pathway, facilitating immune evasion.
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Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Análise da Expressão Gênica de Célula Única , Humanos , Antígenos de Diferenciação de Linfócitos B/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Evasão da Resposta Imune/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Análise da Expressão Gênica de Célula Única/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Neuropsychiatric diseases, like depression, have a considerable and persistent impact on human health; however, little is known about their underlying pathogenesis. Social defeat is a model for stress-induced psychopathologies that could present with behaviors resembling those observed in humans with depression. However, previous animal models of social defeat mainly focus on adults. Here, we re-design the protocol of early-life stress-induced social defeat paradigm, which is based on a classic resident-intruder model. Briefly, each two-week-old experimental mouse of C57BL/6 strain is introduced into the home cage of an unfamiliar CD1 aggressor mouse for 30 min per day for 10 consecutive days. Later, all experimental mice are raised individually for another month. Finally, the mice are identified as defeated through social interaction and open field tests. This model has been shown to be etiological and predictive and provide high validity and could be a powerful tool to investigate the underlying pathogenesis of early onset depression. Graphical overview.
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OBJECTIVE: To explore the efficacy of hemodialysis and hemofiltration in the management of uremia complicated with refractory hypertension (RH). METHODS: In this retrospective study, 80 patients with uremia complicated with RH who were admitted to the First People's Hospital of Huoqiu County from March 2019 to March 2022 were included. Patients who received routine hemodialysis were assigned to the control group (C group, n=40), whereas patients received routine hemodialysis and hemofiltration were assigned to the observational group (R group, n=40). The clinical indexes of the two groups were recorded and compared. Differences in diastolic blood pressure, systolic blood pressure, mean pulsating blood pressure, urinary protein, blood urea nitrogen (BUN) and urinary microalbumin, cardiac function parameters and plasma toxic metabolites were observed after one month of treatment. RESULTS: The effective rate of the treatment in the observation group was 97.50%, whereas that for the control group was 75.00%. The observation group showed significantly better improvement of diastolic blood pressure, systolic blood pressure and mean arterial pressure compared with the control group (all P<0.05). The levels of urinary microalbumin were lower after treatment than those before treatment. The levels of urinary protein and BUN were higher in the observation group than those in the control group; and the levels of urinary microalbumin were significantly lower in the observation group compared with the levels in the control group (all P<0.05). The cardiac parameters of the study cohort were significantly lower after treatment. The levels of plasma toxic metabolites in the observation group were significantly lower after the 12-week treatment. CONCLUSION: Hemodialysis combined with hemofiltration is effective in the management of uremic patients with refractory hypertension. This treatment strategy effectively reduces blood pressure and average pulsation, improves cardiac function, and promotes the clearance of toxic metabolites. The method is associated with fewer adverse reactions and is safe for clinical applications.
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Intermedin (IMD) is a member of the calcitonin gene-related peptide (CGRP)/calcitonin (CT) superfamily, and it is expressed extensively throughout the body. The typical receptors for IMD are complexes composed of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP), which leads to a biased activation towards Gαs. As a diagnostic and prognostic biomarker, IMD regulates the initiation and metastasis of multiple tumors. Additionally, IMD functions as a proangiogenic factor that can restrain excessive vascular budding and facilitate the expansion of blood vessel lumen, ultimately resulting in the fusion of blood vessels. IMD has protective roles in various diseases, including ischemia-reperfusion injury, metabolic disease, cardiovascular diseases and inflammatory diseases. This review systematically elucidates IMD's expression, structure, related receptors and signal pathway, as well as its comprehensive functions in the context of acute kidney injury, obesity, diabetes, heart failure and sepsis. However, the precise formation process of IMD short peptides in vivo and their downstream signaling pathway have not been fully elucidated yet. Further in-depth studies are need to translate IMD research into clinical applications.
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Background and objectives: Disease severity and prognosis of coronavirus disease 2019 (COVID-19) disease with other viral infections can be affected by the oropharyngeal microbiome. However, limited research had been carried out to uncover how these diseases are differentially affected by the oropharyngeal microbiome of the patient. Here, we aimed to explore the characteristics of the oropharyngeal microbiota of COVID-19 patients and compare them with those of patients with similar symptoms. Methods: COVID-19 was diagnosed in patients through the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Characterization of the oropharyngeal microbiome was performed by metatranscriptomic sequencing analyses of oropharyngeal swab specimens from 144 COVID-19 patients, 100 patients infected with other viruses, and 40 healthy volunteers. Results: The oropharyngeal microbiome diversity in patients with SARS-CoV-2 infection was different from that of patients with other infections. Prevotella and Aspergillus could play a role in the differentiation between patients with SARS-CoV-2 infection and patients with other infections. Prevotella could also influence the prognosis of COVID-19 through a mechanism that potentially involved the sphingolipid metabolism regulation pathway. Conclusion: The oropharyngeal microbiome characterization was different between SARS-CoV-2 infection and infections caused by other viruses. Prevotella could act as a biomarker for COVID-19 diagnosis and of host immune response evaluation in SARS-CoV-2 infection. In addition, the cross-talk among Prevotella, SARS-CoV-2, and sphingolipid metabolism pathways could provide a basis for the precise diagnosis, prevention, control, and treatment of COVID-19.
Assuntos
COVID-19 , Microbiota , Humanos , SARS-CoV-2/genética , Teste para COVID-19 , Prevotella/genética , EsfingolipídeosRESUMO
As one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, including in HCC. However, how IMD affects the behavior of HCC cells and the underlying mechanisms have not been fully elucidated. Here, we show that IMD maintains an important homeostatic state by activating the ERK1/2-EGR1 (early growth response 1) signaling cascade, through which HCC cells acquire a highly invasive ability via significantly enhanced filopodia formation. The inhibition of IMD blocks the phosphorylation of ERK1/2, resulting in EGR1 downregulation and endoplasmic reticulum stress (ER) stress, which is evidenced by the upregulation of ER stress marker DDIT3 (DNA damage-inducible transcript 3). The high level of DDIT3 induces HCC cells into an ER-stress related apoptotic pathway. Along with our previous finding that IMD plays critical roles in the vascular remodeling process that improves tumor blood perfusion, IMD may facilitate the acquisition of increased invasive abilities and a survival benefit by HCC cells, and it is easier for HCC cells to obtain blood supply via the vascular remodeling activities of IMD. According to these results, blockade of IMD activity may have therapeutic potential in the treatment of HCC.