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Chemoresistance remains a major challenge in the current treatment of acute myeloid leukemia (AML). The bone marrow microenvironment (BMM) plays a complex role in protecting leukemia cells from chemotherapeutics, and the mechanisms involved are not fully understood. Antileukemia drugs kill AML cells directly but also damage the BMM. Here, we determined antileukemia drugs induce DNA damage in bone marrow stromal cells (BMSCs), resulting in resistance of AML cell lines to adriamycin and idarubicin killing. Damaged BMSCs induced an inflammatory microenvironment through NF-κB; suppressing NF-κB with small molecule inhibitor Bay11-7082 attenuated the prosurvival effects of BMSCs on AML cell lines. Furthermore, we used an ex vivo functional screen of 507 chemokines and cytokines to identify 44 proteins secreted from damaged BMSCs. Fibroblast growth factor-10 (FGF10) was most strongly associated with chemoresistance in AML cell lines. Additionally, expression of FGF10 and its receptors, FGFR1 and FGFR2, was increased in AML patients after chemotherapy. FGFR1 and FGFR2 were also widely expressed by AML cell lines. FGF10-induced FGFR2 activation in AML cell lines operates by increasing P38 MAPK, AKT, ERK1/2, and STAT3 phosphorylation. FGFR2 inhibition with small molecules or gene silencing of FGFR2 inhibited proliferation and reverses drug resistance of AML cells by inhibiting P38 MAPK, AKT, and ERK1/2 signaling pathways. Finally, release of FGF10 was mediated by ß-catenin signaling in damaged BMSCs. Our data indicate FGF10-FGFR2 signaling acts as an effector of damaged BMSC-mediated chemoresistance in AML cells, and FGFR2 inhibition can reverse stromal protection and AML cell chemoresistance in the BMM.
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Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Humanos , Células da Medula Óssea/metabolismo , Dano ao DNA , Fator 10 de Crescimento de Fibroblastos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral , Comunicação ParácrinaRESUMO
Oxidative stress triggered by aging, radiation, or inflammation impairs ovarian function by inducing granulosa cell (GC) apoptosis. However, the mechanism inducing GC apoptosis has not been characterized. Here, we found that ovarian GCs from aging patients showed increased oxidative stress, enhanced reactive oxygen species activity, and significantly decreased expression of the known antiapoptotic factor sphingosine-1-phosphate/sphingosine kinase 1 (SPHK1) in GCs. Interestingly, the expression of Krüppel-like factor 12 (KLF12) was significantly increased in the ovarian GCs of aging patients. Furthermore, we determined that KLF12 was significantly upregulated in hydrogen peroxide-treated GCs and a 3-nitropropionic acid-induced in vivo model of ovarian oxidative stress. This phenotype was further confirmed to result from inhibition of SPHK1 by KLF12. Interestingly, when endogenous KLF12 was knocked down, it rescued oxidative stress-induced apoptosis. Meanwhile, supplementation with SPHK1 partially reversed oxidative stress-induced apoptosis. However, this function was lost in SPHK1 with deletion of the binding region to the KLF12 promoter. SPHK1 reversed apoptosis caused by hydrogen peroxide-KLF12 overexpression, a result further confirmed in an in vitro ovarian culture model and an in vivo 3-nitropropionic acid-induced ovarian oxidative stress model. Overall, our study reveals that KLF12 is involved in regulating apoptosis induced by oxidative stress in aging ovarian GCs and that sphingosine-1-phosphate/SPHK1 can rescue GC apoptosis by interacting with KLF12 in negative feedback.
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Envelhecimento , Apoptose , Células da Granulosa , Peróxido de Hidrogênio , Fatores de Transcrição Kruppel-Like , Lisofosfolipídeos , Fosfotransferases (Aceptor do Grupo Álcool) , Esfingosina , Feminino , Humanos , Envelhecimento/metabolismo , Retroalimentação Fisiológica , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Peróxido de Hidrogênio/farmacologia , Técnicas In Vitro , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/biossíntese , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lisofosfolipídeos/biossíntese , Lisofosfolipídeos/metabolismo , Técnicas de Cultura de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Regiões Promotoras Genéticas , Esfingosina/biossíntese , Esfingosina/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The first asymmetric total synthesis of the hexacyclic veatchine-type C20-diterpenoid alkaloid (-)-garryine is presented. Key steps include a Pd-catalyzed enantioselective Heck reaction, a radical cyclization, and a photoinduced C-H activation/oxazolidine formation sequence. Of note, a highly enantioselective Heck reaction developed in this work provides efficient access to 6/6/6 tricyclic compounds, in particular, containing a C19-functionalitiy, which is useful for diverse transformations.
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OBJECTIVE: Designing physiologically adequate microvascular trees is of crucial relevance for bioengineering functional tissues and organs. Yet, currently available methods are poorly suited to replicate the morphological and topological heterogeneity of real microvascular trees because the parameters used to control tree generation are too simplistic to mimic results of the complex angiogenetic and structural adaptation processes in vivo. METHODS: We propose a method to overcome this limitation by integrating a conditional deep convolutional generative adversarial network (cDCGAN) with a local fractal dimension-oriented constrained constructive optimization (LFDO-CCO) strategy. The cDCGAN learns the patterns of real microvascular bifurcations allowing for their artificial replication. The LFDO-CCO strategy connects the generated bifurcations hierarchically to form microvascular trees with a vessel density corresponding to that observed in healthy tissues. RESULTS: The generated artificial microvascular trees are consistent with real microvascular trees regarding characteristics such as fractal dimension, vascular density, and coefficient of variation of diameter, length, and tortuosity. CONCLUSIONS: These results support the adoption of the proposed strategy for the generation of artificial microvascular trees in tissue engineering as well as for computational modeling and simulations of microcirculatory physiology.
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Simulação por Computador , Microcirculação , Microvasos , Microvasos/fisiologia , Microvasos/anatomia & histologia , Humanos , Microcirculação/fisiologia , Modelos Cardiovasculares , FractaisRESUMO
Charging LiCoO2 to high voltages yields alluring specific capacities, yet the deleterious phase-transitions lead to significant capacity degradation. Herein, this study demonstrates a novel strategy to stabilize LiCoO2 at 4.6 V by doping with Er and Mg at the Li-site and Co-site, respectively, which is different from the traditional method of doping foreign elements solely at the Co-site. Theoretical calculations and experiments jointly reveal that the inclusion of Mg2+-dopants at the Co-site curbs the hexagonal-monoclinic phase transitions ≈4.2 V. However, this unintentionally compromises the stability of lattice oxygen in LiCoO2, exacerbating the undesired phase transition (O3 to H1-3) above 4.45 V. Fascinatingly, the introduction of Er3+-dopants into Li-sites enhances the stability of lattice oxygen in LiCoO2, effectively mitigating phase transitions above 4.45 V. Therefore, the Er, Mg co-doped LiCoO2 exhibits high stability over 500 cycles when tested in a half-cell with a cut-off voltage of 4.6 V. Furthermore, the Er, Mg-doped LiCoO2//graphite pouch-type full cell demonstrates a high energy density of 310.8 Wh kg-1, preserving 91.3% of its energy over 100 cycles.
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Radiation therapy is one of the most common treatments for cancer. However, enhancing tumors' radiation sensitivity and overcoming tolerance remain a challenge. Previous studies have shown that the Ras signaling pathway directly influences tumor radiation sensitivity. Herein, we designed a series of Ras-targeting stabilized peptides, with satisfactory binding affinity (KD = 0.13 µM with HRas) and good cellular uptake. Peptide H5 inhibited downstream phosphorylation of ERK and increased radio-sensitivity in HeLa cells, resulting in significantly reduced clonogenic survival. The stabilized peptides, designed with an N-terminal nucleation strategy, acted as potential radio-sensitizers and broadened the applications of this kind of molecule. This is the first report of using stabilized peptides as radio-sensitizers, broadening the applications of this kind of molecule.
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Peptídeos , Tolerância a Radiação , Proteínas ras , Humanos , Peptídeos/química , Peptídeos/farmacologia , Células HeLa , Tolerância a Radiação/efeitos dos fármacos , Proteínas ras/metabolismo , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Sobrevivência Celular/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/radioterapiaRESUMO
Nitrous oxide (N2O) emissions from livestock manure contribute significantly to the growth of atmospheric N2O, a powerful greenhouse gas and dominant ozone-depleting substance. Here, we estimate global N2O emissions from livestock manure during 1890-2020 using the tier 2 approach of the 2019 Refinement to the 2006 IPCC Guidelines. Global N2O emissions from livestock manure increased by ~350% from 451 [368-556] Gg N year-1 in 1890 to 2042 [1677-2514] Gg N year-1 in 2020. These emissions contributed ~30% to the global anthropogenic N2O emissions in the decade 2010-2019. Cattle contributed the most (60%) to the increase, followed by poultry (19%), pigs (15%), and sheep and goats (6%). Regionally, South Asia, Africa, and Latin America dominated the growth in global emissions since the 1990s. Nationally, the largest emissions were found in India (329 Gg N year-1), followed by China (267 Gg N year-1), the United States (163 Gg N year-1), Brazil (129 Gg N year-1) and Pakistan (102 Gg N year-1) in the 2010s. We found a substantial impact of livestock productivity, specifically animal body weight and milk yield, on the emission trends. Furthermore, a large spread existed among different methodologies in estimates of global N2O emission from livestock manure, with our results 20%-25% lower than those based on the 2006 IPCC Guidelines. This study highlights the need for robust time-variant model parameterization and continuous improvement of emissions factors to enhance the precision of emission inventories. Additionally, urgent mitigation is required, as all available inventories indicate a rapid increase in global N2O emissions from livestock manure in recent decades.
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Gado , Esterco , Óxido Nitroso , Óxido Nitroso/análise , Esterco/análise , Animais , Poluentes Atmosféricos/análiseRESUMO
BACKGROUND: Astragaloside IV (AS-IV) is one of the basic components of Astragali radix, that has been shown to have preventive effects against various diseases, including cancers. This study aimed to explore the role of AS-IV in hepatocellular carcinoma (HCC) and its underlying mechanism. METHODS: The cell viability, glucose consumption, lactate production, and extracellular acidification rate (ECAR) in SNU-182 and Huh7 cell lines were detected by specific commercial kits. Western blot was performed to analyze the succinylation level in SNU-182 and Huh7 cell lines. The interaction between lysine acetyltransferase (KAT) 2 A and phosphoglycerate mutase 1 (PGAM1) was evaluated by co-immunoprecipitation and immunofluorescence assays. The role of KAT2A in vivo was explored using a xenografted tumor model. RESULTS: The results indicated that AS-IV treatment downregulated the protein levels of succinylation and KAT2A in SNU-182 and Huh7 cell lines. The cell viability, glucose consumption, lactate production, ECAR, and succinylation levels were decreased in AS-IV-treated SNU-182 and Huh7 cell lines, and the results were reversed after KAT2A overexpression. KAT2A interacted with PGAM1 to promote the succinylation of PGAM1 at K161 site. KAT2A overexpression promoted the viability and glycolysis of SNU-182 and Huh7 cell lines, which were partly blocked following PGAM1 inhibition. In tumor-bearing mice, AS-IV suppressed tumor growth though inhibiting KAT2A-mediated succinylation of PGAM1. CONCLUSION: AS-IV inhibited cell viability and glycolysis in HCC by regulating KAT2A-mediated succinylation of PGAM1, suggesting that AS-IV might be a potential and suitable therapeutic agent for treating HCC.
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Carcinoma Hepatocelular , Sobrevivência Celular , Glicólise , Neoplasias Hepáticas , Fosfoglicerato Mutase , Saponinas , Triterpenos , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Animais , Fosfoglicerato Mutase/metabolismo , Camundongos , Glicólise/efeitos dos fármacos , Triterpenos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Saponinas/farmacologia , Linhagem Celular Tumoral , Histona Acetiltransferases/metabolismo , Camundongos Nus , Proliferação de Células/efeitos dos fármacosRESUMO
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck. Vasculogenic mimicry (VM) is crucial for tumor growth and metastasis and refers to the formation of fluid channels by invasive tumor cells rather than endothelial cells. However, the regulatory mechanisms underlying VM during the malignant progression of LSCC remain largely unknown. METHODS: Gene expression and clinical data for LSCC were obtained from the TCGA and Gene GEO (GSE27020) databases. A risk prediction model associated with VM was established using LASSO and Cox regression analyses. Based on their risk scores, patients with LSCC were categorized into high- and low-risk groups. The disparities in immune infiltration, tumor mutational burden (TMB), and functional enrichment between these two groups were examined. The core genes in LSCC were identified using the machine learning (SVM-RFE) and WGCNA algorithms. Subsequently, the involvement of bone morphogenetic protein 2 (BMP2) in VM and metastasis was investigated both in vitro and in vivo. To elucidate the downstream signaling pathways regulated by BMP2, western blotting was performed. Additionally, ChIP experiments were employed to identify the key transcription factors responsible for modulating the expression of BMP2. RESULTS: We established a new precise prognostic model for LSCC related to VM based on three genes: BMP2, EPO, and AGPS. The ROC curves from both TCGA and GSE27020 validation cohorts demonstrated precision survival prediction capabilities, with the nomogram showing some net clinical benefit. Multiple algorithm analyses indicated BMP2 as a potential core gene. Further experiments suggested that BMP2 promotes VM and metastasis in LSCC. The malignant progression of LSCC is promoted by BMP2 via the activation of the PI3K-AKT signaling pathway, with the high expression of BMP2 in LSCC resulting from its transcriptional activation by runt-related transcription factor 1 (RUNX1). CONCLUSION: BMP2 predicts poor prognosis in LSCC, promotes LSCC VM and metastasis through the PI3K-AKT signaling pathway, and is transcriptionally regulated by RUNX1. BMP2 may be a novel, precise, diagnostic, and therapeutic biomarker of LSCC.
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Proteína Morfogenética Óssea 2 , Neoplasias de Cabeça e Pescoço , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core , Células Endoteliais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Transdução de SinaisRESUMO
The development of electrochemically inexpensive, durable, and active electrocatalysts for the oxygen evolution reaction (OER) is attracting considerable attention. The heterogeneous interfacing might regulate the electronic structure and further improve the electrochemical activity. Herein, a Ce(OH)3 nanoparticle-interfaced Fe-doped nickel sulfide (Ce(OH)3@Fe-Ni3S2) electrocatalyst was prepared to improve the OER performance. The fabricated electrocatalyst displayed excellent intrinsic activity and long-term stability in 1 M KOH for the OER. The catalyst shows an ultralow overpotential of 195 mV at a current density of 10 mA cm-2 and a Tafel slope of 52 mV dec-1, which are remarkably smaller than those of the control samples. This excellent electrocatalytic activity is attributed to the incorporation of Ce(OH)3 nanoparticles on the surface of the Fe-Ni3S2 nanosheet, which increases the electrochemical activity and enlarges the active surface area of the catalyst. In comparison to previous nonprecious OER electrocatalysts, the prepared Ce(OH)3@Fe-Ni3S2 exhibits greater electrocatalytic activity and longer durability, allowing for the selection of new electrocatalysts for practical applications.
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A new asymmetric synthesis of the A/E-ring fragment of C18-diterpenoid alkaloids is described. The crucial contiguous stereogenic centers at C4, C5, and C11 were established through an asymmetric Michael addition/allylation sequence. The unique azabicyclo[3.3.1]nonane motif (A/E rings) was assembled by employing ring-closing metathesis and Mitsunobu reaction as key strategies.
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Here we report a multi-tissue gene expression resource that represents the genotypic and phenotypic diversity of modern inbred maize, and includes transcriptomes in an average of 255 lines in seven tissues. We mapped expression quantitative trait loci and characterized the contribution of rare genetic variants to extremes in gene expression. Some of the new mutations that arise in the maize genome can be deleterious; although selection acts to keep deleterious variants rare, their complete removal is impeded by genetic linkage to favourable loci and by finite population size. Modern maize breeders have systematically reduced the effects of this constant mutational pressure through artificial selection and self-fertilization, which have exposed rare recessive variants in elite inbred lines. However, the ongoing effect of these rare alleles on modern inbred maize is unknown. By analysing this gene expression resource and exploiting the extreme diversity and rapid linkage disequilibrium decay of maize, we characterize the effect of rare alleles and evolutionary history on the regulation of expression. Rare alleles are associated with the dysregulation of expression, and we correlate this dysregulation to seed-weight fitness. We find enrichment of ancestral rare variants among expression quantitative trait loci mapped in modern inbred lines, which suggests that historic bottlenecks have shaped regulation. Our results suggest that one path for further genetic improvement in agricultural species lies in purging the rare deleterious variants that have been associated with crop fitness.
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Alelos , Regulação da Expressão Gênica de Plantas/genética , Aptidão Genética/genética , Zea mays/genética , Produtos Agrícolas/genética , Variação Genética/genética , Genoma de Planta/genética , Genótipo , Desequilíbrio de Ligação , Fenótipo , Densidade Demográfica , Locos de Características Quantitativas/genética , RNA de Plantas/genética , Sementes/genética , Análise de Sequência de RNARESUMO
BACKGROUND: Large-scale outbreaks of scrub typhus combined with its emergence in new areas as a vector-borne rickettsiosis highlight the ongoing neglect of this disease. This study aims to explore the long-term changes and regional leading factors of scrub typhus in China, with the goal of providing valuable insights for disease prevention and control. METHODS: This study utilized a Bayesian space-time hierarchical model (BSTHM) to examine the spatiotemporal heterogeneity of scrub typhus and analyze the relationship between environmental factors and scrub typhus in southern and northern China from 2006 to 2018. Additionally, a GeoDetector model was employed to assess the predominant influences of geographical and socioeconomic factors in both regions. RESULTS: Scrub typhus exhibits a seasonal pattern, typically occurring during the summer and autumn months (June to November), with a peak in October. Geographically, the high-risk regions, or hot spots, are concentrated in the south, while the low-risk regions, or cold spots, are located in the north. Moreover, the distribution of scrub typhus is influenced by environment and socio-economic factors. In the north and south, the dominant factors are the monthly normalized vegetation index (NDVI) and temperature. An increase in NDVI per interquartile range (IQR) leads to a 7.580% decrease in scrub typhus risk in northern China, and a 19.180% increase in the southern. Similarly, of 1 IQR increase in temperature reduces the risk of scrub typhus by 10.720% in the north but increases it by 15.800% in the south. In terms of geographical and socio-economic factors, illiteracy rate and altitude are the key determinants in the respective areas, with q-values of 0.844 and 0.882. CONCLUSIONS: These results indicated that appropriate climate, environment, and social conditions would increase the risk of scrub typhus. This study provided helpful suggestions and a basis for reasonably allocating resources and controlling the occurrence of scrub typhus.
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Tifo por Ácaros , Humanos , Tifo por Ácaros/epidemiologia , Teorema de Bayes , China/epidemiologia , Estações do Ano , Fatores Econômicos , IncidênciaRESUMO
OBJECTIVE: Achieving textbook outcome (TO) implies a smooth recovery post-operation without specified composite complications. This study aimed to evaluate TO in laparoscopic pancreaticoduodenectomy (LPD) and identify independent risk factors associated with achieving TO. METHODS: We conducted a retrospective analysis of data from a randomized controlled trial on LPD at West China Hospital (ChiCTR1900026653). Patients were categorized into the TO and non-TO groups. Perioperative variables were compared between these groups. Multivariate logistic regression was utilized to identify the risk factors. RESULTS: A total of 200 consecutive patients undergoing LPD were included in this study. TO was achieved in 82.5% (n = 165) of the patients. Female patients (OR: 2.877, 95% CI: 1.219-6.790; P = 0.016) and those with a hard pancreatic texture (OR: 2.435, 95% CI: 1.018-5.827; P = 0.046) were associated with an increased likelihood of achieving TO. CONCLUSIONS: TO can be achieved in more than 80% of patients in a high-volume LPD center. Independent risk factors associated with achieving TO included gender (male) and pancreatic texture (soft).
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Laparoscopia , Pancreaticoduodenectomia , Humanos , Pancreaticoduodenectomia/métodos , Pancreaticoduodenectomia/efeitos adversos , Feminino , Masculino , Laparoscopia/métodos , Pessoa de Meia-Idade , Fatores de Risco , Estudos Retrospectivos , Idoso , Resultado do Tratamento , Estudos Prospectivos , China/epidemiologia , Adulto , Hospitais com Alto Volume de Atendimentos , Complicações Pós-Operatórias/epidemiologiaRESUMO
The railway fastener, as a crucial component of railway tracks, directly influences the safety and stability of a railway system. However, in practical operation, fasteners are often in low-light conditions, such as at nighttime or within tunnels, posing significant challenges to defect detection equipment and limiting its effectiveness in real-world scenarios. To address this issue, this study proposes an unsupervised low-light image enhancement algorithm, CES-GAN, which achieves the model's generalization and adaptability under different environmental conditions. The CES-GAN network architecture adopts a U-Net model with five layers of downsampling and upsampling structures as the generator, incorporating both global and local discriminators to help the generator to preserve image details and textures during the reconstruction process, thus enhancing the realism and intricacy of the enhanced images. The combination of the feature-consistency loss, contrastive learning loss, and illumination loss functions in the generator structure, along with the discriminator loss function in the discriminator structure, collectively promotes the clarity, realism, and illumination consistency of the images, thereby improving the quality and usability of low-light images. Through the CES-GAN algorithm, this study provides reliable visual support for railway construction sites and ensures the stable operation and accurate operation of fastener identification equipment in complex environments.
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OBJECTIVE: To investigate the reliability and validity of the Chinese version of simplified nutritional appetite questionnaire (SNAQ). METHODS: The SNAQ was translated and back-translated for the study population. We surveyed 122 community-dwelling residents aged ≥60 years in Beijing's residential communities. Participants underwent face-to-face surveys including the SNAQ, mini-nutritional assessment short-form (MNA-SF), FRAIL scale, Sarcopenia-Five (SCAR-F), 15-item Geriatric Depression Scale (GDS-15), 7-item Generalized Anxiety Disorder (GAD-7), 8-item Oral Frailty Index (OFI-8), 10-item Eating Assessment Tool (EAT-10), and Mini-Mental State Examination (MMSE). Cronbach's alpha was used to measure the internal consistency and the relationship between individual items. The construct validity was verified using the KMO-Bartlett. Concurrent validity was established to validate measures of the same constructs. RESULTS: Cronbach's alpha measured the internal consistency of the questionnaire at 0.694. The split-half reliability stood at 0.725. The construct validity of the SNAQ was confirmed using a KMO-Bartlett value of 0.648 (P <0.001). The MNA-SF, as validation benchmark, has a correlation coefficient of 0.345 (P =0.001). CONCLUSION: The Chinese version of the SNAQ has good reliability and validity for older adults in community settings.
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Visualization of mechanochemical damages, especially for those in the molecular-scale (e.g., bond scission in polymeric materials), is of great industrial and academic significance. Herein, we report a novel strategy for in situ and real-time visualization of mechanochemical damages in hydrogels by utilizing prefluorescent probes via oxygen-relayed free-radical trapping. Double-network (DN) hydrogels that generate numerous mechanoradicals by homolytic bond scission of the brittle first network at large deformation are used as model materials. Theoretical calculation suggests that mechanoradicals generated by the damage of the first network undergo an oxygen-relayed radical-transfer process which can be detected by the prefluorescent probe through the radical-radical coupling reaction. Such an oxygen-relayed radical-trapping process of the prefluorescent probe exhibits a dramatically enhanced emission, which enables the real-time sensing and visualization of mechanochemical damages in DN hydrogels made from brittle networks of varied chemical structures. To the best of authors' knowledge, this work is the first report utilizing oxygen as a radical-relaying molecule for visualizing mechanoradical damages in polymer materials. Moreover, this new method based on the probe post-loading is simple and does not introduce any chemical structural changes in the materials, outperforming most previous methods that require chemical incorporation of mechanophores into polymer networks.
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To investigate the potential of the gut microbiome as a biomarker for predicting the early recurrence of HBV-related hepatocellular carcinoma (HCC), we enrolled 124 patients diagnosed with HBV-associated HCC and 82 HBV-related hepatitis, and 86 healthy volunteers in our study, collecting 292 stool samples for 16S rRNA sequencing and 35 tumor tissue samples for targeted metabolomics. We performed an integrated bioinformatics analysis of gut microbiome and tissue metabolome data to explore the gut microbial-liver metabolite axis associated with the early recurrence of HCC. We constructed a predictive model based on the gut microbiota and validated its efficacy in the temporal validation cohort. Dialister, Veillonella, the Eubacterium coprostanoligenes group, and Lactobacillus genera, as well as the Streptococcus pneumoniae and Bifidobacterium faecale species, were associated with an early recurrence of HCC. We also found that 23 metabolites, including acetic acid, glutamate, and arachidonic acid, were associated with the early recurrence of HCC. A comprehensive analysis of the gut microbiome and tissue metabolome revealed that the entry of gut microbe-derived acetic acid into the liver to supply energy for tumor growth and proliferation may be a potential mechanism for the recurrence of HCC mediated by gut microbe. We constructed a nomogram to predict early recurrence by combining differential microbial species and clinical indicators, achieving an AUC of 78.0%. Our study suggested that gut microbes may serve as effective biomarkers for predicting early recurrence of HCC, and the gut microbial-tumor metabolite axis may explain the potential mechanism by which gut microbes promote the early recurrence of HCC.
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Carcinoma Hepatocelular , Microbioma Gastrointestinal , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Microbioma Gastrointestinal/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/patologia , RNA Ribossômico 16S/genética , Biomarcadores , AcetatosRESUMO
Hepatocellular carcinoma (HCC) is the most common primary human liver malignancy with high mortality. Liver cancer stem cells (CSCs) have been demonstrated to contribute to the recurrence, metastasis and drug resistance of liver cancer. Human HCC cohort analysis indicated that the epigenetic regulator polycomb chromobox homologue 4 (CBX4) was overexpressed in human HCC. Moreover, we found that CBX4 expression was significantly higher in CD44+ CD133+ Hep3B CSCs. Functionally, we demonstrated that CBX4 regulated cell proliferation, self-renewal, and metastasis ability of Hep3B CSCs. Bioinformatics analysis predicted that CBX4 was a direct target of microRNA-6838-5p (miR-6838-5p), which was further confirmed by luciferase reporter assay. MiR-6838-6p was down-regulated in HCC tumors and overexpression of miR-6838-5p attenuated the malignant traits of human liver CSCs in vitro. In addition, we found that miR-6838-5p/CBX4 axis modulates the biological properties of human liver CSCs via regulating ERK signaling. Overexpression of miR-6838-5p suppressed Hep3B xenograft tumor growth in vivo, while CBX4 overexpression abrogated the suppression effect, restored the angiogenesis, epithelial-to-mesenchymal transition (EMT), and ERK signaling in Hep3B tumor. In summary, our findings suggest that miR-6838-5p/CBX4 axis regulates liver tumor development and metastasis, which could be utilized as potential therapeutic target for HCC treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/patologia , Proliferação de Células , Ligases/metabolismo , Proteínas do Grupo Polycomb/metabolismoRESUMO
BACKGROUND: The procedure of choice for the resection of ampullary tumors comprises transduodenal ampullectomy (TDA), endoscopic papillectomy (EP), and pancreaticoduodenectomy (PD).1 For neoplasms with low-grade dysplasia, TDA and EP have equivalent efficacies and lower morbidities than PD1. Compared with EP, also as an organ-preserving procedure, TDA could be applicable for tumors involving the pancreatic ducts or common bile ducts.2 Because TDA has a lower incidence of postoperative gastrointestinal bleeding and a higher R0 resection rate, its use could avoid the need to use multiple endoscopic procedures for larger lesions.3 Furthermore, during TDA, surgeons could convert to PD as necessary. However, TDA has rarely been performed using a minimally invasive approach that addresses the shortcomings of both the endoscopic and open surgical techniques without adding significant morbidity or compromising outcomes.2,4 Conventional laparoscopic TDA (LTDA) remains limited due to the complexity of the surgical anatomy of the ampulla and the reconstruction required compared with robot-assisted procedures.2-5 However, robot-assisted surgery is less popular and much more expensive than laparoscopic surgery. This report with a video describes the LTDA approach to standardize and simplify the surgical processes. METHODS: A 48-year-old man was admitted to the hospital with epigastric pain. He had a history of cholecystolithiasis with chronic cholecystitis. A tumor approximately 2.2 cm in diameter located in the duodenal papilla was diagnosed by an enhanced computed tomography (CT) scan. The endoscopic biopsy result indicated a villous adenoma with moderate dysplasia. Laparoscopic TDA and cholecystectomy were planned. However, if the frozen sample analysis showed adenocarcinoma, laparoscopic PD (LPD) would be applied. The patient was placed in the supine position with both legs apart. Trocars were distributed in the same manner as in the authors' previous study to facilitate conversion to LPD.6 The procedure began with kocherization and dissection of the gastrocolic ligament to explore the second and third portions of the duodenum. A figure-eight suture was made using 4-0 prolene in the seromuscular layer, and then the duodenum was retracted to the left side of the patient. A longitudinal duodenotomy was made, and the ampulla of Vater was identified. A transfixing suture was placed through the tumor. Submucosal injection of norepinephrine (1:500) was performed to divide the mucosa from the muscular planes. Ampullectomy was performed by first dissecting in the submucosal plane with a harmonic scalpel at the 6 o'clock position until the pancreatic duct was reached. A 6-Fr plastic catheter was inserted into the pancreatic duct for subsequent reconstruction. Continued dissection around the tumor identified the bile duct. Another 6-Fr plastic catheter was inserted into the bile duct. The dissection was completed in the submucosal plane, and the specimen was retrieved for frozen sectioning. After confirmation of villous adenoma with moderate dysplasia and the proximal margin without residual tumor on frozen biopsy, reconstruction was performed. The septum between the ducts was plastered, and the bile and pancreatic ducts were reconstructed on the duodenal wall with 5-0 PDS-II interrupted sutures to ensure that these ducts remained patent and connected. After reconstruction, the plastic catheter was kept in the pancreatic duct but removed from the bile duct. Then, cholecystectomy was applied. Finally, the duodenum was closed obliquely in two layers, and two drains were routinely placed. RESULTS: The operation time was 139 min, and the estimated blood loss was 50 ml. Final pathology confirmed villous adenoma with mild to moderate dysplasia. The postoperative course was uneventful, with a hospital stay of 9 days. There was no evidence of recurrence or patency of the reimplanted ducts 5 months after surgery. From February 2022 to May 2022, four cases of LTDA with the same surgical processes were managed by the authors, and all the patients recovered quickly without any postoperative complications. CONCLUSION: After standardization of the surgical processes, laparoscopic TDA was safe for highly selected patients. However, long-term follow-up is required to observe the quality of life and survival of patients.