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OBJECTIVES: This study aimed to compare the safety and effectiveness of tunneled peripherally inserted central catheters (T-PICC) vs. conventional PICCs (C-PICC) in adult cancer patients. METHODS: A multicentre randomized controlled trial was conducted between April 2021 and January 2022 in seven hospitals in China. 564 participants were randomly assigned to T-PICC or C-PICC. These data were collected and compared: the baseline characteristics and catheterization-related characteristics, periprocedural complications, and long-term complications. RESULTS: Five-hundred fifty-three participants (aged, 52.6 ± 12.3 years; female, 39.1%) were ultimately analyzed. No significant differences in periprocedural complications were found between the T-PICC and C-PICC groups (all p > 0.05). Compared with C-PICC, T-PICC significantly reduced the incidence of long-term complications (26.4% vs. 39.9%, p < 0.001). Specifically, reduced complications were found in central line-associated bloodstream infection (1.8% vs. 5.1%, p = 0.04), thrombosis (1.1% vs. 4.0%, p = 0.03), catheter dislodgement (4.7% vs. 10.1%, p = 0.01), non-infectious oozing (17.3% vs. 28.6%, p = 0.002), local infection (3.6% vs. 7.6%, p = 0.04), skin irritation (6.1% vs. 10.9%, p = 0.046), and reduced unplanned catheter removal (2.2% vs. 7.2%, p = 0.005). No significant differences were found between T-PICC and C-PICC regarding catheter occlusion (6.5% vs. 5.8%, p = 0.73) or skin damage (2.2% vs. 2.9%, p = 0.58). CONCLUSION: T-PICC is safe and effectively reduces long-term complications. CLINICAL RELEVANCE STATEMENT: The tunneled technique is effective in reducing PICC-related long-term complications. Thus, it is recommended for cancer patients at high risk of PICC-related complications. TRIAL REGISTRATION: The registration number on https://www.chictr.org.cn/ is ChiCTR2100044632. The name of the trial registry is "A multicenter randomized controlled study of clinical use of tunneled vs. non-tunneled PICC". KEY POINTS: Cather-related complications are associated with the technique of catheterization. Compared with conventional PICC, tunneled PICC reduced catheter-related long-term complications. Tunneled PICC placement provides an alternative catheterization method for cancer patients.
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A Gram-staining-negative, facultative aerobic, motile strain, designated strain ZSDE20T, was isolated from the surface seawater of Qingdao offshore. Phylogenetic analysis of the 16S rRNA gene of strain ZSDE20T, affiliated it to the genus Photobacterium. It was closely related to Photobacterium lutimaris DF-42 T (98.92% 16S rRNA gene sequence similarity). Growth occurred at 4-28ºC (optimum 28ºC), pH 1.0-7.0 (optimum 7.0) and in the presence of 1-7% (w/v) NaCl (optimum 3%). The dominant fatty acids were summed feature 3 (C16:1 ω7c or/and C16:1 ω6c, 34.23%), summed feature 8 (C18:1 ω7c and C18:1 ω6c, 10.36%) and C16:0 (20.05%). The polar lipids of strain ZSDE20T comprised phosphatidylethanolamine, phosphatidylcholine, lyso-phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol dimannoside, phosphatidylinositol mannosides and two unknown lipids. The major respiratory quinone was ubiquinone-8 (Q-8). The DNA G + C content of strain ZSDE20T was 45.6 mol%. Average nucleotide identity (ANI) values between ZSDE20T and its reference species were lower than the threshold for species delineation (95-96%); in silico DNA-DNA hybridization further showed that strain ZSDE20T had less than 70% similarity to its relatives. Based on the polyphasic evidences, strain ZSDE20T is proposed as representing a novel species of the genus Photobacterium, for which the name Photobacterium pectinilyticum sp. nov. is proposed. The type strain is ZSDE20T (= MCCC 1K06283T = KCTC 82885 T).
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Composição de Bases , DNA Bacteriano , Ácidos Graxos , Photobacterium , Filogenia , RNA Ribossômico 16S , Água do Mar , Água do Mar/microbiologia , RNA Ribossômico 16S/genética , Photobacterium/genética , Photobacterium/classificação , Photobacterium/isolamento & purificação , Photobacterium/metabolismo , Photobacterium/fisiologia , DNA Bacteriano/genética , Ácidos Graxos/análise , Ácidos Graxos/química , China , Técnicas de Tipagem Bacteriana , Hibridização de Ácido Nucleico , Análise de Sequência de DNA , Quinonas/análise , Fosfolipídeos/análiseRESUMO
The capacity to anticipate and detect rewarding outcomes is fundamental for the development of adaptive decision-making and goal-oriented behavior. Delineating the neural correlates of different stages of reward processing is imperative for understanding the neurobiological mechanism underlying alcohol use disorder (AUD). To examine the neural correlates of monetary anticipation and outcome in AUD patients, we performed two separate voxel-wise meta-analyses of functional neuroimaging studies, including 12 studies investigating reward anticipation and 7 studies investigating reward outcome using the monetary incentive delay task. During the anticipation stage, AUD patients displayed decreased activation in response to monetary cues in mesocortical-limbic circuits and sensory areas, including the ventral striatum (VS), insula, hippocampus, inferior occipital gyrus, supramarginal gyrus, lingual gyrus and fusiform gyrus. During the outcome stage, AUD patients exhibited reduced activation in the dorsal striatum, VS and insula, and increased activation in the orbital frontal cortex and medial temporal area. Our findings suggest that different activation patterns are associated with nondrug rewards during different reward processing stages, potentially reflecting a changed sensitivity to monetary reward in AUD.
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Alcoolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Motivação , Recompensa , Córtex Pré-FrontalRESUMO
BACKGROUND: N6A methylation (m6A) is a significant epigenetic modification that critically impacts post-transcriptional regulation and tumor occurrence and development. While previous studies have identified a role for epigenetic regulation in hepatocellular carcinoma (HCC), the potential function of the m6A cluster in Hepatitis B virus (HBV)-related HCC remains unclear. METHODS: The related information was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Based on the expression of 20 m6A regulators, we comprehensively evaluated the m6A clusters and systematically explored the correlation between these clusters and immune cell infiltration characteristics of the tumor microenvironment (TME). The patients were divided into low- and high-m6A score groups. Then, the immune cell infiltration, chemokines, and cytokines levels, and drug sensitivity were further explored between the two groups. RESULTS: The m6A cluster predicted a better prognosis that was accompanied by increased immune cell infiltration. Using these results, an m6A score was established that could predict overall survival, immune checkpoints, and clinical treatments for patients with HBV-related HCC. This study demonstrated that m6A modifications affected tumorigenesis, TME, and the prognosis of patients with HBV-related HCC. CONCLUSION: A comprehensive assessment of m6A patterns could improve the current understanding of immune cell infiltration patterns and inform the development of individualized cancer treatments.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Vírus da Hepatite B/genética , Epigênese Genética , Neoplasias Hepáticas/genética , Carcinogênese , Microambiente Tumoral/genéticaRESUMO
p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.
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Tecido Adiposo/metabolismo , Imidazóis/uso terapêutico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Obesidade/metabolismo , Piridinas/uso terapêutico , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Reprogramação Celular , Temperatura Baixa , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Avaliação Pré-Clínica de Medicamentos , Imidazóis/farmacologia , Camundongos , Camundongos Knockout , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Obesidade/prevenção & controle , Fenótipo , Piridinas/farmacologia , TermogêneseRESUMO
The metabolic regulation of cell death is sophisticated. A growing body of evidence suggests the existence of multiple metabolic checkpoints that dictate cell fate in response to metabolic fluctuations. However, whether microRNAs (miRNAs) are able to respond to metabolic stress, reset the threshold of cell death, and attempt to reestablish homeostasis is largely unknown. Here, we show that miR-378/378* KO mice cannot maintain normal muscle weight and have poor running performance, which is accompanied by impaired autophagy, accumulation of abnormal mitochondria, and excessive apoptosis in skeletal muscle, whereas miR-378 overexpression is able to enhance autophagy and repress apoptosis in skeletal muscle of mice. Our in vitro data show that metabolic stress-responsive miR-378 promotes autophagy and inhibits apoptosis in a cell-autonomous manner. Mechanistically, miR-378 promotes autophagy initiation through the mammalian target of rapamycin (mTOR)/unc-51-like autophagy activating kinase 1 (ULK1) pathway and sustains autophagy via Forkhead box class O (FoxO)-mediated transcriptional reinforcement by targeting phosphoinositide-dependent protein kinase 1 (PDK1). Meanwhile, miR-378 suppresses intrinsic apoptosis initiation directly through targeting an initiator caspase-Caspase 9. Thus, we propose that miR-378 is a critical component of metabolic checkpoints, which integrates metabolic information into an adaptive response to reduce the propensity of myocytes to undergo apoptosis by enhancing the autophagic process and blocking apoptotic initiation. Lastly, our data suggest that inflammation-induced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy.
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MicroRNAs/fisiologia , Músculo Esquelético/fisiologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Caspase 9/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , Células Musculares/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Corrida , Transdução de Sinais , Estresse Fisiológico , Serina-Treonina Quinases TOR/metabolismoRESUMO
Bacterial biofilms, which are a group of bacteria attaching to and ultimately forming communities on reefs, perform essential ecological functions in coastal ecosystems. Particularly, they may attract or repulse the settling down of opportunistic algae. However, this phenomenon and the interaction mechanism are not fully understood. This study investigated reefs from the Changdao coastal zone to determine the structures and functions of bacterial biofilms symbiosing with various algae using high-throughput sequencing analysis. The Shannon diversity index of microbiota with algal symbiosis reached 5.34, which was higher than that of microbiota wherein algae were absent (4.80). The beta diversity results for 11 samples revealed that there existed a separation between bacterial communities on reefs with and without attached algae, while communities with similar algae clustered together. The taxa mostly associated with algae-symbiotic microbiota are the Actinobacteria phylum, and the Flavobacteriia and Gammaproteobacteria classes. The Cyanobacteria phylum was not associated with algae-symbiotic microbiota. As revealed by functional analysis, the bacteria mostly involved in the metabolism of sulfur were represented by brown and red algae in the biofilm symbiosis. Bacteria related to the metabolism of certain trace elements were observed only in specific groups. Moreover, phototrophy-related bacteria were less abundant in samples coexisting with algae. This study established the link between bacterial biofilms and algal settlements on costal reefs, and revealed the possible holobiont relationship between them. This may provide new technical directions toward realizing algal cultivation and management during the construction of artificial reef ecosystems.
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Antozoários , Microbiota , Animais , Biofilmes , Recifes de Corais , EcologiaRESUMO
Nuclear receptors (NRs) regulate gene transcription by recruiting coregulators, involved in chromatin remodeling and assembly of the basal transcription machinery. The NR-associated protein ligand-dependent corepressor (LCoR) has previously been shown to suppress hepatic lipogenesis by decreasing the binding of steroid receptor coactivators to thyroid hormone receptor. However, the role of LCoR in adipogenesis has not been established. Here, we show that LCoR expression is reduced in the early stage of adipogenesis in vitro LCoR overexpression inhibited 3T3-L1 adipocyte differentiation, whereas LCoR knockdown promoted it. Using an unbiased affinity purification approach, we identified CCAAT/enhancer-binding protein ß (C/EBPß), a key transcriptional regulator in early adipogenesis, and corepressor C-terminal binding proteins as potential components of an LCoR-containing complex in 3T3-L1 adipocytes. We found that LCoR directly interacts with C/EBPß through its C-terminal helix-turn-helix domain, required for LCoR's inhibitory effects on adipogenesis. LCoR overexpression also inhibited C/EBPß transcriptional activity, leading to inhibition of mitotic clonal expansion and transcriptional repression of C/EBPα and peroxisome proliferator-activated receptor γ2 (PPARγ2). However, LCoR overexpression did not affect the recruitment of C/EBPß to the promoters of C/EBPα and PPARγ2 in 3T3-L1 adipocytes. Of note, restoration of PPARγ2 or C/EBPα expression attenuated the inhibitory effect of LCoR on adipogenesis. Mechanistically, LCoR suppressed C/EBPß-mediated transcription by recruiting C-terminal binding proteins to the C/EBPα and PPARγ2 promoters and by modulating histone modifications. Taken together, our results indicate that LCoR negatively regulates early adipogenesis by repressing C/EBPß transcriptional activity and add LCoR to the growing list of transcriptional corepressors of adipogenesis.
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Adipócitos/citologia , Adipogenia , Proteína beta Intensificadora de Ligação a CCAAT/genética , Regulação da Expressão Gênica , Fatores de Transcrição/genética , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Técnicas de Silenciamento de Genes , Camundongos , Mapas de Interação de Proteínas , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
Theranostic nanomedicines that integrate diagnostic and therapeutic moieties into a single nanoscale platform are playing an increasingly important role in fighting cancer. Here, a facile and green synthetic strategy for hollow CoPt alloy nanoparticles (HCPA-NPs) using plant polyphenols as assisted agents is reported for the first time. This novel strategy enables size-controlled synthesis of HCPA-NPs through the control of the molecular sizes of polyphenols. It is also a versatile strategy for synthesizing other hollow alloy nanoparticles with various metal compositions due to the diverse metal-chelating ability of the polyphenols. Further studies show that HCPA-NPs have good biocompatibility and can be successfully implemented for magnetic resonance and photoacoustic dual-modal imaging guided photothermal therapy. This work brings new insights for the green synthesis of hollow nanoparticles and extends these biocompatible nanoparticles for theranostic applications.
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Ligas/química , Química Verde/métodos , Hipertermia Induzida , Nanopartículas Metálicas/química , Imagem Multimodal , Fototerapia , Polifenóis/química , Animais , Sobrevivência Celular , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Imageamento por Ressonância Magnética , Nanopartículas Metálicas/ultraestrutura , Camundongos , Polietilenoglicóis/química , Taninos/químicaRESUMO
A series of air-stable ferrocenylphosphines LB1-LB8 were designed and prepared in high yields. (R,SFc)-ferrocenylphosphine LB5 was found to efficiently promote the asymmetric [3 + 2] cycloaddition of Morita-Baylis-Hillman carbonates with maleimides to afford the corresponding bicyclic imides with 84-99% ee and 67-99% yield. Interestingly, the configuration of these products was contrary to those reported in the literature.
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Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration.
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Proteínas Quinases Ativadas por AMP/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Diferenciação Celular , Proliferação de Células , Músculo Esquelético/fisiologia , Mioblastos/citologia , Regeneração , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Camundongos , Mioblastos/metabolismo , Transdução de Sinais , Regulação para CimaRESUMO
Mariculture is one of the major seafood supplies worldwide and has caused serious environmental concerns on the coastal zone. Its rapid development has been shown to disrupt the sediment ecosystems and thus influence the benthic bacterial communities. Bacterial diversity and community structure within both adjacent farms and non-cultured zones intertidal sediments along the coasts of Qinhuangdao and Dalian, China, were investigated using full-length 16S rRNA gene-based T-RFLP analyses and clone library construction. Richness and Shannon-Wiener index were significantly increased at sites adjacent the mariculture farm with mean values of 29 and 2.97 from peak profiles of T-RFLP result. Clustering analyses suggested that impacts of mariculture on bacterial diversity of sediment were significantly larger than those resulted from temporal and spatial scales. Upon comparisons of RFLP patterns from 602 clones from libraries of the selected five samples, 137 OTUs were retrieved. Members of γ- and δ-Proteobacteria, Bacilli, Flavobacteria, and Actinobacteria were recorded in all libraries. In addition, γ-Proteobacteria were dominant in all samples (21.7~45.0 %). Redundancy analysis revealed that the distribution of bacterial composition seemed to be determined by the variables of salinity, PO4 (3-)-P, NH4 (+)-N, and Chlorophyll a content. The phyla of γ-Proteobacteria, Clostridia, Flavobacteria, Bacilli, and Planctomycetes were principal components to contribute to the bacterial differences of clone libraries. Our finding demonstrated that these phyla could display variations of bacterial composition linked to environmental disturbance resulted from mariculture.
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Bactérias/isolamento & purificação , Biodiversidade , Sedimentos Geológicos/microbiologia , Bactérias/classificação , Bactérias/genética , China , Ecossistema , Pesqueiros , Sedimentos Geológicos/análise , Dados de Sequência Molecular , Filogenia , Dióxido de Silício/análiseRESUMO
Background: Multiple studies have reported that the immune system is under the control of a circadian clock, especially in cancers, but how circadian clock genes shape tumor immune cell infiltration in hepatocellular carcinoma (HCC) remains unclear. Methods: The rhythmicity of circadian clock genes was investigated using the GETx database. The expression and methylation level of circadian clock genes in HCC and paracancerous was evaluated using the GETx and TCGA databases. The differential expression of circadian clock genes in HCC was analyzed using the "limma" package of the R 4.0.4 software. The prognosis of each circadian clock gene was accessed by Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. Quantitative real-time PCR and immunohistochemistry (IHC) was carried out to confirm the results. The relationship between circadian rhythm and immune infiltration in HCC was evaluated using the TIMER database and the CIBERSORT algorithm. Results: In addition to RORA, RORB, and ARNTL2, there was a rhythmic expression of other circadian clock genes in liver tissue. The correlation between the expression of circadian clock genes differed when comparing HCC and liver tissue. HCC patients who express low levels of PER-1and CRY2 had a poor overall survival (OS). In contrast, patients with higher expression of NPAS2 had a poor prognosis. In HCC, the expression of the PER-1, CRY2, and NPAS2 genes was closely related to immune infiltration. Conclusion: Our study indicated the disruption of the expression of circadian clock-regulated genes in HCC and identified PER-1, CRY2, and NPAS2 as independent predictors of survival. These genes may be applied as candidate molecular targets for diagnosis and therapy of HCC.
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AIM AND OBJECTIVE: To investigate the effect of Polyphyllin I (PPI) on HBV-related liver cancer through network pharmacology and in vitro experiments, and to explore its mechanism of action. MATERIALS AND METHODS: Use bioinformatics software to predict the active ingredient target of PPI and the disease target of liver cancer, and perform active ingredient-disease target analysis. The results of network pharmacology through molecular docking and in vitro experiments can be further verified. The HepG2 receptor cells (HepG2. 2. 15) were transfected with HBV plasmid for observation, with the human liver cancer HepG2 being used as the control. RESULTS: Bioinformatics analysis found that PPI had a total of 161 protein targets, and the predicted target and liver cancer targets were combined to obtain 13 intersection targets. The results of molecular docking demonstrated that PPI had a good affinity with STAT3, PTP1B, IL2, and BCL2L1. The results of the in vitro experiments indicated that the PPI inhibited cell proliferation and metastasis in a concentration-dependent manner (P<0.01). Compared with the vehicle group, the PPI group of 1.5, 3, and 6 µmol/L can promote the apoptosis of liver cancer to different degrees (P<0.01). CONCLUSION: The present study revealed the mechanism of PPI against liver cancer through network pharmacology and in vitro experiments. Its mechanism of action is related to the inhibition of PPI on the proliferation of HBV-related liver cancer through promoting the apoptosis of liver cancer cells. Additionally, in vitro experiments have also verified that PPI can promote the apoptosis of HepG2 and HepG2.2.15 cells.
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Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Diosgenina/análogos & derivados , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Medicina Tradicional Chinesa/métodos , Simulação de Acoplamento Molecular , Farmacologia em RedeRESUMO
The most efficient way to treat tumors is through surgery. However, many cancer patients have a poor prognosis even when they undergo radical excision at an early stage. Micrometastasis is one of the most critical factors that induced this situation. Undetected micrometastasis can lead to the failure of initial treatment. Therefore, preoperative and intraoperative detection of micrometastasis could have a significant clinical influence on the prognosis and optimal therapy for cancer patients. Additionally, to achieve this goal, researchers have aimed to create more effective detection technologies. Herein, we classify the currently reported micrometastasis detection technologies, introduce some representative samples for each technology, including the limitations, and provide future directions to overcome the limitations.
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Linfonodos , Micrometástase de Neoplasia , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Micrometástase de Neoplasia/diagnóstico , Micrometástase de Neoplasia/patologia , Estadiamento de Neoplasias , PrognósticoRESUMO
Background: Recent studies demonstrate that N6-methyladenosine (m6A) methylation plays a crucial role in colorectal cancer (CRC). Therefore, we conducted a comprehensive analysis to assess the m6A modification patterns and identify m6A-modified genes in patients with CRC recurrence. Methods: The m6A modification patterns were comprehensively evaluated by the NMF algorithm based on the levels of 27 m6A regulators, and tumor microenvironment (TME) cell-infiltrating characteristics of these modification patterns were systematically assessed by ssGSEA and CIBERSORT algorithms. The principal component analysis algorithm based on the m6A scoring scheme was used to explore the m6A modification patterns of individual tumors with immune responses. The weighted correlation network analysis and univariable and multivariable Cox regression analyses were applied to identify m6A-modified gene signatures. The single-cell expression dataset of CRC samples was used to explore the tumor microenvironment affected by these signatures. Results: Three distinct m6A modification patterns with significant recurrence-free survival (RFS) were identified in 804 CRC patients. The TME characterization revealed that the m6A modification pattern with longer RFS exhibited robust immune responses. CRC patients were divided into high- and low-score subgroups according to the m6A score individually, which was obtained from the m6A-related signature genes. The patients with low m6A scores had both longer RFS and overall survival (OS) with altered immune cell infiltration. Notably, m6A-modified genes showed significant differences related to the prognosis of CRC patients in the meta-GEO cohort and TCGA cohort. Single-cell expression indicated that ALVRL1 was centrally distributed in endothelial tip cells and stromal cells. Conclusion: The m6A modification plays an indispensable role in the formation of TME diversity and complexity. Importantly, the signatures (TOP2A, LRRC58, HAUS6, SMC4, ACVRL1, and KPNB1) were identified as m6A-modified genes associated with CRC recurrence, thereby serving as a promising predictive biomarker or therapeutic target for patients with CRC recurrence.
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Applying Chinese medicine (CM) is an important strategy for malignant tumor treatment in China. One of the significant characteristics of CM is to treat diseases based on syndrome differentiation. For Western medicine, it is of important clinical significance to formulate guidelines for the diagnosis and treatment of cancer patients based on the characteristics of disease differentiation. In Chinese clinical practice, the combination of disease differentiation and syndrome differentiation is an important feature for cancer treatment in the past. Currently, molecular profiling and genomic analysis-based precision medicine optimizes the anticancer drug design and holds the greatest success in treating cancer patients. Therefore, we want to know which populations of cancer patients can benefit more from CM treatment if the theory of precision medicine is applied to CM clinical practice. So, we developed a novel diagnostic and therapeutic strategy "disease-syndrome differentiation-genomic profiling-prescriptions" for cancer patients by CM syndrome differentiation and precision medicine. As a result, this strategy has greatly enhanced the anti-tumor efficacy of CM and improved clinical outcomes for cancer patients with some gene mutations. Our idea will hopefully establish a novel approach for the inheritance and innovation of CM.
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Antineoplásicos , Medicamentos de Ervas Chinesas , Neoplasias , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão , SíndromeRESUMO
Background: Colorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy. Methods: CRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene. Results: Nine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7High) and chemotherapy sensitive (RBP7Low) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells. Conclusions: Immune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients.
Assuntos
Neoplasias Colorretais , Fluoruracila , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Microambiente Tumoral/genéticaRESUMO
Macropinocytosis, a unique endocytosis pathway characterized by nonspecific internalization, has a vital role in the uptake of extracellular substances and antigen presentation. It is known to have dual effects on cancer cells, depending on cancer type and certain microenvironmental conditions. It helps cancer cells survive in nutrient-deficient environments, enhances resistance to anticancer drugs, and promotes invasion and metastasis. Conversely, overexpression of the RAS gene alongside drug treatment can lead to methuosis, a novel mode of cell death. The survival and proliferation of cancer cells is closely related to macropinocytosis in the tumor microenvironment (TME), but identifying how these cells interface with the TME is crucial for creating drugs that can limit cancer progression and metastasis. Substantial progress has been made in recent years on designing anticancer therapies that utilize the effects of macropinocytosis. Both the induction and inhibition of macropinocytosis are useful strategies for combating cancer cells. This article systematically reviews the general mechanisms of macropinocytosis, its specific functions in tumor cells, its occurrence in nontumor cells in the TME, and its application in tumor therapies. The aim is to elucidate the role and therapeutic potential of macropinocytosis in cancer treatment.
RESUMO
Sialic acid binding lectin (SABL) is a member of immunoglobulin-like lectins family that are thought to promote cell-cell interactions and regulate the functions of cells in the innate and adaptive immune systems through glycan recognition. In the present study, the full-length cDNA of SABL was identified from Manila clam Venerupis philippinarum (denoted as VpSABL) by cDNA library and RACE approaches. The cDNA of VpSABL consisted of a 5'terminal untranslated region (UTR) of 62 bp, a 3' UTR of 354 bp with a poly (A) tail, and an open reading frame (ORF) of 588 bp encoding a polypeptide of 195 amino acids with a typical C1q domain in the C-terminus. Multiple alignment analysis indicated that the deduced amino acid of VpSABL shared higher positive to other SABLs and C1q-contained proteins and should be adopted typical 10 ß-strand jelly-roll folding topology common to all C1q-TNF family. Spatial expression analysis indicated that mRNA transcript of VpSABL was predominantly detectable in tissues of mantle, hepatopancreas and gill, and to a lesser degree in the tissues of muscle and haemocytes. After challenged by Vibrio anguillarum, the mRNA level of VpSABL in overall haemocytes population was recorded by quantitative real-time RT-PCR. VpSABL mRNA was down-regulated in the first 24 h post-infection. Then, the expression level increased to the peak at 72 h and recovered to the original level at 96 h. All these results indicated that VpSABL was involved in the immune response against microbe infection and might be contributed to the recognition of bacterial pathogens.