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The cGAS-STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS-STING pathway-induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING-induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P-binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. Furthermore, we show that the STING-WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS-STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation.
Assuntos
Autofagossomos , Autofagia , Proteínas de Membrana , Autofagossomos/metabolismo , Autofagia/fisiologia , DNA/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , HumanosRESUMO
Plants deploy cell-surface and intracellular leucine rich-repeat domain (LRR) immune receptors to detect pathogens1. LRR receptor kinases and LRR receptor proteins at the plasma membrane recognize microorganism-derived molecules to elicit pattern-triggered immunity (PTI), whereas nucleotide-binding LRR proteins detect microbial effectors inside cells to confer effector-triggered immunity (ETI). Although PTI and ETI are initiated in different host cell compartments, they rely on the transcriptional activation of similar sets of genes2, suggesting pathway convergence upstream of nuclear events. Here we report that PTI triggered by the Arabidopsis LRR receptor protein RLP23 requires signalling-competent dimers of the lipase-like proteins EDS1 and PAD4, and of ADR1 family helper nucleotide-binding LRRs, which are all components of ETI. The cell-surface LRR receptor kinase SOBIR1 links RLP23 with EDS1, PAD4 and ADR1 proteins, suggesting the formation of supramolecular complexes containing PTI receptors and transducers at the inner side of the plasma membrane. We detected similar evolutionary patterns in LRR receptor protein and nucleotide-binding LRR genes across Arabidopsis accessions; overall higher levels of variation in LRR receptor proteins than in LRR receptor kinases are consistent with distinct roles of these two receptor families in plant immunity. We propose that the EDS1-PAD4-ADR1 node is a convergence point for defence signalling cascades, activated by both surface-resident and intracellular LRR receptors, in conferring pathogen immunity.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Hidrolases de Éster Carboxílico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Imunidade Vegetal , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Arabidopsis/química , Hidrolases de Éster Carboxílico/química , Proteínas de Ligação a DNA/química , Domínios Proteicos , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Multimerização Proteica , Proteínas Serina-Treonina Quinases/química , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismoRESUMO
mTORC1, the major homeostatic sensor and responder, regulates cell catabolism mainly by targeting autophagy. Here, we show that mTORC1 directly controls autophagosome formation via phosphorylation of WIPI2, a critical protein in isolation membrane growth and elongation. mTORC1 phosphorylates Ser395 of WIPI2, directing WIPI2 to interact specifically with the E3 ubiquitin ligase HUWE1 for ubiquitination and proteasomal degradation. Physiological or pharmacological inhibition of mTORC1 in cells promotes WIPI2 stabilization, autophagosome formation, and autophagic degradation. In mouse liver, fasting significantly increases the WIPI2 protein level, while silencing HUWE1 enhances autophagy, and introducing WIPI2 improves lipid clearance. Thus, regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux and may coordinate the initiation, progression, and completion of autophagy.
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Autofagia/fisiologia , Proteínas de Transporte/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Fosfato , Ubiquitinação/fisiologiaRESUMO
As one of the major acetyltransferases in mammalian cells, p300 (also known as EP300) and its highly related protein CBP (also known as CREBBP), collectively termed p300/CBP, is characterized as a key regulator in gene transcription by modulating the acetylation of histones. In recent decades, proteomic analyses have revealed that p300 is also involved in the regulation of various cellular processes by acetylating many non-histone proteins. Among the identified substrates, some are key players involved in different autophagy steps, which together establish p300 as a master regulator of autophagy. Accumulating evidence has shown that p300 activity is controlled by many distinct cellular pathways to regulate autophagy in response to cellular or environmental stimuli. In addition, several small molecules have been shown to regulate autophagy by targeting p300, suggesting that manipulation of p300 activity is sufficient for controlling autophagy. Importantly, dysfunction of p300-regulated autophagy has been implicated in a number of human disorders, such as cancer, aging and neurodegeneration, highlighting p300 as a promising target for the drug development of autophagy-related human disorders. Here, we focus on the roles of p300-mediated protein acetylation in the regulation of autophagy and discuss implications for autophagy-related human disorders.
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Autofagia , Proteína de Ligação a CREB , Proteína p300 Associada a E1A , Proteômica , Humanos , Acetilação , Acetiltransferases , Histonas , Proteína p300 Associada a E1A/metabolismo , Proteína de Ligação a CREB/metabolismoRESUMO
Acetylation is increasingly recognized as one of the major post-translational mechanisms for the regulation of multiple cellular functions in mammalian cells. Acetyltransferase p300, which acetylates histone and non-histone proteins, has been intensively studied in its role in cell growth and metabolism. However, the mechanism underlying the activation of p300 in cells remains largely unknown. Here, we identify the homeostatic sensor mTORC1 as a direct activator of p300. Activated mTORC1 interacts with p300 and phosphorylates p300 at 4 serine residues in the C-terminal domain. Mechanistically, phosphorylation of p300 by mTORC1 prevents the catalytic HAT domain from binding to the RING domain, thereby eliminating intra-molecular inhibition. Functionally, mTORC1-dependent phosphorylation of p300 suppresses cell-starvation-induced autophagy and activates cell lipogenesis. These results uncover p300 as a direct target of mTORC1 and suggest that the mTORC1-p300 pathway plays a pivotal role in cell metabolism by coordinately controlling cell anabolism and catabolism.
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Autofagia , Lipogênese , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/genética , Fosforilação/genética , Domínios Proteicos , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição de p300-CBP/genéticaRESUMO
The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation. Inactivation of p300 induces VPS34 deacetylation, PI3P production, and autophagy, even in AMPK-/-, TSC2-/-, or ULK1-/- cells. In fasting mice, liver autophagy correlates well with p300 inactivation/VPS34 deacetylation, which facilitates the clearance of lipid droplets in hepatocytes. Thus, p300-dependent VPS34 acetylation/deacetylation is the physiological key to VPS34 activation, which controls the initiation of canonical autophagy and of non-canonical autophagy in which the upstream kinases of VPS34 can be bypassed.
Assuntos
Autofagia , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Hepatócitos/enzimologia , Metabolismo dos Lipídeos , Fígado/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Estresse Fisiológico , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetilação , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/genética , Ativação Enzimática , Feminino , Células HEK293 , Células HeLa , Hepatócitos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/genética , Fosfatos de Fosfatidilinositol/metabolismo , Ligação Proteica , Interferência de RNA , Transdução de Sinais , Transfecção , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Fatores de Transcrição de p300-CBP/genéticaRESUMO
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort).
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BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC
Assuntos
Quimiorradioterapia , Quimioterapia de Indução , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Pontuação de Propensão , Humanos , Masculino , Feminino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/tratamento farmacológico , Pessoa de Meia-Idade , Quimiorradioterapia/métodos , Adulto , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/tratamento farmacológico , Quimioterapia de Indução/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Estudos Retrospectivos , GencitabinaRESUMO
An efficient and easy-to-use approach is presented for obtaining biocompatible polysaccharide-based nanoparticles (NP) that can act as tumor-specific drug delivery agents. Two antibodies are directly immobilized onto reactive xylan phenyl carbonate (XPC) NP; namely Cetuximab (CTX) that binds to human epidermal growth factor receptor (EGFR) and Atezolizumab (ATZ) that binds to programmed death-ligandâ 1 (PD-L1). High coupling efficiency (up to 100 %) are achieved without any pre-activation and no aggregation occurs during antibody immobilization. By quartz crystal microbalance experiments with dissipation monitoring (QCM-D), flow cytometry assays, and confocal laser scanning microscopy imaging it is demonstrated that the functionalized XPC-NP specifically bind to cells carrying the corresponding antigens. Moreover, the NP retain the antibody specific bioactivities (growth inhibition for CTX and induction of T-cell cytotoxicity for ATZ).
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Polissacarídeos , Xilanos , Humanos , Especificidade de Anticorpos , Bioensaio , Carbonatos , Cetuximab/farmacologiaRESUMO
Exploring the spatiotemporal characteristics of ecosystem services (ESs) and their drivers is crucial for managers to develop significant scientific policies that further sustainable development. We used the Yangtze River Economic Belt (YREB) to explore the trends, hotspots, and drivers of water yield (WY), soil conservation (SC), carbon sequestration (CS), and food supply (FS) between 2000 and 2020. Similarly, we analyzed relationships among ESs and drivers of the multiple ecosystem services landscape index (MESLI). We used the self-organizing map method to obtain the types and distribution of the ES bundles, revealing the bundles, trade-offs, and synergies among ESs. The four ESs had an increasing trend, with CS having the highest increase; ES hotspot analysis showed differences among upper, middle, and lower reaches. Constraint lines among ESs and drivers were diverse; the corresponding SC and WY reached thresholds when CS values were 1477.81 and 460.5 t km-2, respectively. When FS values were 67.34 and 86.17 × 104 Yuan·km-2, CS and WY reached their thresholds. All critical drivers of the four ESs were natural factors. The thresholds that the MESLI reached with driver status were 1000 mm (evapotranspiration), 2121 mm (precipitation), 2.42° (slope), 1.46% (soil organic matter), 36.08% (sand), 30.75% (proportion of non-agricultural population), 18.57% (cropland proportion), 1.05 × 104 persons·km-2 (population density), and 84.84% (proportion of non-agricultural industries in total gross domestic product), respectively. FS, water supply, and ecological conservation bundles changed over the 20 years, and trade-offs and synergies among ESs within bundles differed. We revealed the complexity of ESs from multiple perspectives, which will enable the development of ecosystem management and conservation recommendations for the YREB and large-scale economic zones worldwide.
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Conservação dos Recursos Naturais , Ecossistema , Conservação dos Recursos Naturais/métodos , Rios , Solo , ChinaRESUMO
BACKGROUND: This study aims to explore the nursing effect of a multimodal pre-rehabilitation programme guided by BCW theory on elderly women patients with breast cancer. METHODS: The participants were divided into two groups. The study group was administered with the pre-rehabilitation model guided by BCW theory; the control group was administered with conventional methods. The rehabilitation effects of the two groups were compared.. RESULTS: The scores of RISC, PTGI and FACT-B were higher in the study group(P < 0.05). The SUPPH score and ROM compliance rate were higher in the study group (P < 0.05) (96% vs 72%). The avoidance score and yield score were lower in the study group(P < 0.05). CONCLUSION: A multimodal pre-rehabilitation program guided by BCW theory can significantly improve the quality of life and functional status of elderly women patients with breast cancer, and its popularisation and application are recommended.
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Neoplasias da Mama , Qualidade de Vida , Humanos , Feminino , Neoplasias da Mama/reabilitação , Neoplasias da Mama/psicologia , IdosoRESUMO
Lysosomes are acidic intracellular organelles with autophagic functions that are critical for protein degradation and mitochondrial homeostasis, while abnormalities in lysosomal physiological functions are closely associated with neurological disorders. Transmembrane protein 175 (TMEM175), an ion channel in the lysosomal membrane that is essential for maintaining lysosomal acidity, has been proven to coordinate with V-ATPase to modulate the luminal pH of the lysosome to assist the digestion of abnormal proteins and organelles. However, there is considerable controversy about the characteristics of TMEM175. In this review, we introduce the research progress on the structural, modulatory, and functional properties of TMEM175, followed by evidence of its relevance for neurological disorders. Finally, we discuss the potential value of TMEM175 as a therapeutic target in the hope of providing new directions for the treatment of neurodegenerative diseases.
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Canais Iônicos , Doenças Neurodegenerativas , Humanos , Canais Iônicos/análise , Canais Iônicos/metabolismo , Doenças Neurodegenerativas/metabolismo , Lisossomos/metabolismo , Autofagia , Canais de Potássio/químicaRESUMO
BACKGROUND: Global climate change poses a grave threat to biodiversity and underscores the importance of identifying the genes and corresponding environmental factors involved in the adaptation of tree species for the purposes of conservation and forestry. This holds particularly true for spruce species, given their pivotal role as key constituents of the montane, boreal, and sub-alpine forests in the Northern Hemisphere. RESULTS: Here, we used transcriptomes, species occurrence records, and environmental data to investigate the spatial genetic distribution of and the climate-associated genetic variation in Picea crassifolia. Our comprehensive analysis employing ADMIXTURE, principal component analysis (PCA) and phylogenetic methodologies showed that the species has a complex population structure with obvious differentiation among populations in different regions. Concurrently, our investigations into isolation by distance (IBD), isolation by environment (IBE), and niche differentiation among populations collectively suggests that local adaptations are driven by environmental heterogeneity. By integrating population genomics and environmental data using redundancy analysis (RDA), we identified a set of climate-associated single-nucleotide polymorphisms (SNPs) and showed that environmental isolation had a more significant impact than geographic isolation in promoting genetic differentiation. We also found that the candidate genes associated with altitude, temperature seasonality (Bio4) and precipitation in the wettest month (Bio13) may be useful for forest tree breeding. CONCLUSIONS: Our findings deepen our understanding of how species respond to climate change and highlight the importance of integrating genomic and environmental data in untangling local adaptations.
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Picea , Picea/genética , Filogenia , Melhoramento Vegetal , Florestas , GenômicaRESUMO
MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.
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Resistência à Insulina , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Peptídeos/metabolismo , Envelhecimento , Homeostase , Resistência à Insulina/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Mitocondriais/genéticaRESUMO
BACKGROUND AND AIMS: Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the hypoxic TME of HCC remains to be elucidated. APPROACH AND RESULTS: We analyzed the immune landscapes of hypoxia-low and hypoxia-high tumor regions using cytometry by time of light, immunohistochemistry, and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including M2 macrophages and human leukocyte antigen-DR isotype (HLA-DRlo ) type 2 conventional dendritic cell (cDC2), were found to be significantly enriched in hypoxia-high tumor regions. On the other hand, the abundance of active granzyme Bhi PD-1lo CD8+ T cells in hypoxia-low tumor regions implied a relatively active immune landscape compared with hypoxia-high regions. The up-regulation of cancer-associated genes in the tumor tissues and immunosuppressive genes in the tumor-infiltrating leukocytes supported a highly pro-tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 (C-C motif chemokine ligand 20) and CXCL5 (C-X-C motif chemokine ligand 5) were associated with recruitment of both Tregs and HLA-DRlo cDC2 to hypoxia-high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen-presenting HLA-DR on cDC2. CONCLUSIONS: We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg-mediated immunosuppression through interaction with a cDC2 subset in HCC that could be exploited for immunotherapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Linfócitos T Reguladores , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Granzimas/metabolismo , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1/metabolismo , Ligantes , Microambiente Tumoral , Terapia de Imunossupressão , Hipóxia/metabolismo , Células Dendríticas/metabolismo , Antígenos HLARESUMO
Speciation among populations connected by gene flow is driven by adaptation to different environments, but underlying gene-environment associations remain largely unknown. Here, 162 individuals from 32 populations were sampled to obtain 191,648 independent single nucleotide polymorphisms (SNPs) across the genomes of two closely related spruce species, Picea asperata and Picea crassifolia, which occur on the Qinghai-Tibet Plateau and in surrounding regions. Using the SNP data set, genotype-environment associations and demographic modelling were used to examine local adaptation and genetic divergence between these two species. While morphologically similar, the two Picea species were genetically differentiated in multiple analyses. These species diverged despite continuous gene flow, and their initial divergence was dated back to the late Quaternary. The effective population sizes of both species have expanded since their divergence, as confirmed by niche distribution simulations. A total of 6365 genes were associated with the tested environmental variables; of these, 41 were positively selected in P. asperata and were mainly associated with temperature, while 83 were positively selected in P. crassifolia and were primarily associated with precipitation. These results deepen our understanding of the adaptive divergence and demographic histories of these two spruce species and highlight the importance of genomic data in deciphering the environmental selection underlying Quaternary interspecific divergence.
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Picea , Transcriptoma , Humanos , Tibet , Picea/genética , Deriva Genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC). METHODS: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples. RESULTS: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate. DISCUSSION/CONCLUSION: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Regulação Neoplásica da Expressão GênicaRESUMO
OBJECTIVES: To assess whether integrative radiomics and transcriptomics analyses could provide novel insights for radiomic features' molecular annotation and effective risk stratification in non-small cell lung cancer (NSCLC). METHODS: A total of 627 NSCLC patients from three datasets were included. Radiomics features were extracted from segmented 3-dimensional tumour volumes and were z-score normalized for further analysis. In transcriptomics level, 186 pathways and 28 types of immune cells were assessed by using the Gene Set Variation Analysis (GSVA) algorithm. NSCLC patients were categorized into subgroups based on their radiomic features and pathways enrichment scores using consensus clustering. Subgroup-specific radiomics features were used to validate clustering performance and prognostic value. Kaplan-Meier survival analysis with the log-rank test and univariable and multivariable Cox analyses were conducted to explore survival differences among the subgroups. RESULTS: Three radiotranscriptomics subtypes (RTSs) were identified based on the radiomics and pathways enrichment profiles. The three RTSs were characterized as having specific molecular hallmarks: RTS1 (proliferation subtype), RTS2 (metabolism subtype), and RTS3 (immune activation subtype). RTS3 showed increased infiltration of most immune cells. The RTS stratification strategy was validated in a validation cohort and showed significant prognostic value. Survival analysis demonstrated that the RTS strategy could stratify NSCLC patients according to prognosis (p = 0.009), and the RTS strategy remained an independent prognostic indicator after adjusting for other clinical parameters. CONCLUSIONS: This radiotranscriptomics study provides a stratification strategy for NSCLC that could provide information for radiomics feature molecular annotation and prognostic prediction. KEY POINTS: ⢠Radiotranscriptomics subtypes (RTSs) could be used to stratify molecularly heterogeneous patients. ⢠RTSs showed relationships between molecular phenotypes and radiomics features. ⢠The RTS algorithm could be used to identify patients with poor prognosis.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Transcriptoma , Prognóstico , Análise de SobrevidaRESUMO
Autophagy related 4B (ATG4B) which regulates autophagy by promoting the formation of autophagosome through reversible modification of LC3, is closely related to cancer cell growth and drug resistance, and therefore is an attractive therapeutic target. Recently, ATG4B inhibitors have been reported, yet with drawbacks including weak potency. To discover more promising ATG4B inhibitors, we developed a high-throughput screening (HTS) assay and identified a new ATG4B inhibitor named DC-ATG4in. DC-ATG4in directly binds to ATG4B and inhibits its enzyme activity with an IC50 of 3.08 ± 0.47 µM. We further confirmed that DC-ATG4in is an autophagy inhibitor and blocks autophagy induced by Sorafenib in Hepatocellular Carcinoma (HCC) cells. More importantly, combination of DC-ATG4in with Sorafenib synergized the cancer cell killing effect and proliferation inhibition activities on HCC cells. Our data suggested that inactivation of autophagy via ATG4B inhibition may be a viable strategy to sensitize existing targeted therapy such as Sorafenib in the future.
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Proteínas Relacionadas à Autofagia , Autofagia , Sorafenibe , Humanos , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/antagonistas & inibidores , Proteínas Relacionadas à Autofagia/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Cisteína Endopeptidases/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/farmacologia , Sorafenibe/uso terapêuticoRESUMO
BACKGROUND: Although exposure to ambient air pollution has been associated with mental disorder, little is known about its potential effects on children and adolescents, especially in Chinese population. We aimed to reveal the relationship of air pollutants with hospital outpatient visits for child and adolescence psychiatry (HOVCAP) in Shenzhen. METHODS: A case-crossover study based on time-series data was applied, and a distributed lag non-linear model (DLNM) was used to evaluate the non-linear and delayed effects of 4 major air pollutants (NO2, PM2.5, SO2 and O3) on HOVCAP. Least absolute shrinkage and selection operator (LASSO) regression was used to control the multicollinearity between covariates and to filter variables. RESULT: A total of 94,660 cases aged 3-18 were collected from 2014 to 2019 in the Mental Health Center of Shenzhen. Results of pollutants at mode value (M0) showed that in the single lag effect result, when the average daily concentration of NO2 at 24 µg/m3, there was a significant effect on HOVCAP over lag 1, lag 4 and lag 5, respectively. The cumulative RR of NO2 M0 value to the outpatient visits were 1.438 (1.137-1.818) over lag 0-2, 1.454 (1.120-1.887) over lag 0-3, 1.466 (1.084-1.982) over lag 0-4, 1.680 (1.199-2.354) over lag 0-5, 1.993 (1.369-2.903) over lag 0-6, and 2.069 (1.372-3.119) over lag 0-7. However, PM2.5, SO2, O3 were not associated with HOVCAP over neither single lag effects nor cumulative effects. The RR values both shown an increase either when NO2 increases by 10 units or when the maximum concentration of NO2 is reached. CONCLUSION: Our study suggests that exposure to the normal air quality of NO2 in Shenzhen may associated with the risk of HOVCAP. However, PM2.5, SO2, O3 were not associated with HOVCAP.