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Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified lecithin cholesterol acyltransferase (LCAT) as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth-promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and to dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC. Significance: Estrogen mediates the sex differences in hepatocellular carcinoma development by reducing cholesterol biosynthesis through activation of an LCAT/HDL-C axis, providing strategies for improving liver cancer prevention, prognosis, and treatment.
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Carcinoma Hepatocelular , Colesterol , Estrógenos , Homeostasis , Neoplasias Hepáticas , Fosfatidilcolina-Esterol O-Aciltransferasa , Animales , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Ratones , Estrógenos/metabolismo , Colesterol/metabolismo , Femenino , Masculino , Proliferación Celular/efectos de los fármacos , Pronóstico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , HDL-Colesterol/metabolismo , HDL-Colesterol/sangre , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genéticaRESUMEN
Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.
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The pooling layer in convolutional neural networks plays a crucial role in reducing spatial dimensions, and improving computational efficiency. However, standard pooling operations such as max pooling or average pooling are not suitable for all applications and data types. Therefore, developing custom pooling layers that can adaptively learn and extract relevant features from specific datasets is of great significance. In this paper, we propose a novel approach to design and implement customizable pooling layers to enhance feature extraction capabilities in CNNs. The proposed T-Max-Avg pooling layer incorporates a threshold parameter T, which selects the K highest interacting pixels as specified, allowing it to control whether the output features of the input data are based on the maximum values or weighted averages. By learning the optimal pooling strategy during training, our custom pooling layer can effectively capture and represent discriminative information in the input data, thereby improving classification performance. Experimental results show that the proposed T-Max-Avg pooling layer achieves good performance on three different datasets. When compared to LeNet-5 model with average pooling, max pooling, and Avg-TopK methods, the T-Max-Avg pooling method achieves the highest accuracy on CIFAR-10, CIFAR-100, and MNIST datasets.
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Reprogramming of lipid metabolism during hepatocarcinogenesis is not well elucidated. Here, we aimed to explore pivotal RNA-binding motif proteins (RBMs) in lipid metabolism and their therapeutic potential in hepatocellular carcinoma (HCC). Through bioinformatic analysis, we identified RBM45 as a critical gene of interest among differentially expressed RBMs in HCC, with significant prognostic relevance. RBM45 influenced the malignant biological phenotype and lipid metabolism of HCC cells. Mechanically, RBM45 promotes de novo lipogenesis in HCC by directly targeting two key enzymes involved in long-chain fatty acid synthesis, ACSL1 and ACSL4. RBM45 also targets Rictor, which has been demonstrated to modulate lipid metabolism profoundly. RBM45 also aided lipid degradation through activating a key fatty acid ß oxidation enzyme, CPT1A. Thus, RBM45 boosted lipid synthesis and decomposition, indicating an enhanced utility of lipid fuels in HCC. Clinically, body mass index was positively correlated with RBM45 in human HCCs. The combination of a PI3K/AKT/mTOR pathway inhibitor in vitro or Sorafenib in orthotopic liver cancer mouse models with shRBM45 has a more significant therapeutic effect on liver cancer than the drug alone. In summary, our findings highlight the versatile roles of RBM45 in lipid metabolism reprogramming and its therapeutic potential in HCC. Lipids induced RBM45 expression. In turn, RBM45 promoted the utility of lipid in HCCs through accelerating both de novo lipogenesis and fatty acid ß oxidation, which required the participation of Rictor, a core component of mTORC2 that has been demonstrated to modulate lipid metabolism potently, as well as ACSL1/ACSL4, two key enzymes of long-chain fatty acid synthesis. When the first-line chemotherapy drug sorafenib is combined with a PI3K/AKT/mTOR pathway inhibitor (MK2206 is an AKT inhibitor, rapamycin is a mTOR inhibitor, and inhibiting RBM45 can significantly inhibit Rictor), cell cycle, proliferation, lipid metabolism reprogramming, and hepatocarcinogenesis can be significantly inhibited, while apoptosis can be significantly enhanced.
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Carcinoma Hepatocelular , Coenzima A Ligasas , Neoplasias Hepáticas , Proteínas del Tejido Nervioso , Proteínas de Unión al ARN , Ratones , Animales , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Metabolismo de los Lípidos/genética , Sorafenib/farmacología , Sorafenib/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/genética , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Lípidos , Ácidos Grasos , Proliferación Celular/genéticaRESUMEN
BACKGROUND: Mutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53wt) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53wt activity in the liver remains unclear. METHODS: Microarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo. RESULTS: Our study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53wt and subsequently blocking p53wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targeted by the liver-enriched microRNA miR-192, and the disruption of the miR-192-Rictor-p53-miR-192 signaling axis was consistently observed in both human and rat HCC models. Clinical analysis associated lower miR-192/higher Rictor with shorter overall survival and more advanced clinical stages (P < 0.05). In mice, xenograft tumors overexpressing miR-192 exhibited lower Rictor expression levels, leading to higher p53 activity, and these tumors displayed slower growth compared to untreated HCC cells. CONCLUSIONS: Rictor dynamically shuttles between the nucleus and cytoplasm during HCC development. Its pivotal oncogenic role involves binding and inhibiting p53wt activity within the nucleus in early hepatocarcinogenesis. Targeting Rictor presents a promising strategy for HCC based on p53 status.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Proteína Asociada al mTOR Insensible a la Rapamicina , Animales , Humanos , Ratones , Ratas , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Genes p53 , Hepatocitos/patología , Neoplasias Hepáticas/patología , Ratones Desnudos , MicroARNs/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismoRESUMEN
In this study, to establish the biomechanical characteristics of commercial vehicle drivers' muscles and bones while operating the three pedals, a driver pedal-operation simulator was built, and the real-life situation was reconstructed in OpenSim 3.3 software. We set up three seat heights to investigate the drivers' lower limbs, and the research proceeded in two parts: experiment and simulation. Chinese adult males in the 95th percentile were selected as the research participants. In the experiment, Delsys wireless surface electromyography (EMG) sensors were used to collect the EMG signals of the four main muscle groups of the lower limbs when the drivers operated the three pedals. Then, we analyzed the muscle activation and the degree of muscle fatigue. The simulation was based on OpenSim software to analyze the driver's lower limb joint angles and joint torque. The results show that the activation of the hamstrings, gastrocnemius, and rectus femoris muscles were higher in the four muscle groups. In respect of torque, in most cases, hip joint torque > knee joint torque > ankle joint torque. The knee joint angles were the largest, and the ankle joint angles changed the most. The experimental results provide a reference for improving drivers' handling comfort in commercial vehicles and provide theoretical bases for cab design and layout optimization.
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Extremidad Inferior , Músculo Esquelético , Masculino , Adulto , Humanos , Fenómenos Biomecánicos , Extremidad Inferior/fisiología , Músculo Esquelético/fisiología , Articulación de la Rodilla/fisiología , Electromiografía , TorqueRESUMEN
BACKGROUND: Enhanced de novo lipogenesis is essential for hepatocellular carcinoma (HCC). Abnormally high cullin-associated and neddylation-dissociated 1 (CAND1) expression is associated with poor clinical prognosis in HCC. The SKP1-Cullin-1-F-box (SCF) complex consists of the SKP1, Cullin-1 and F-box proteins (FBPs) and performs multiple functions including adipogenesis. SCF complex was modulated by CAND1, but Whether and how the CAND1 promotes HCC by regulating SCF complex and lipogenesis are unknown. METHODS: HCC samples were used to analyze the correlations between CAND1 expression and clinicopathological characteristics such as survival and prognosis. The in vitro functions of CAND1, FBXO11 and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) were measured by cell proliferation, colony formation and migration assays. The in vivo functions were tested in multiple mouse liver cancer models including patient-derived xenograft (PDX), cell line-derived xenograft and AKT/NRASV12-induced primary liver cancer models. Injections of adeno-associated virus targeting CAND1 (AAV-shCAND1) were performed to evaluate the therapeutic efficacy of targeting CAND1. RNA-Seq and lipidomic assays followed by serial biochemical experiments including mass spectrometry, immunoprecipitation and GST pull-down were performed to dissect the underlying mechanisms. RESULTS: CAND1 promoted the expression of lipid synthesis genes by disrupting SCF complex assembly and lipid accumulation. Furthermore, we identified hnRNPA2B1 as a novel F-box protein 11 (FBXO11)-binding partner. FBXO11 directly bound to hnRNPA2B1 and promoted hnRNPA2B1 ubiquitination and subsequent degradation. Our evaluations of the therapeutic efficacy of AAV-shCAND1 injections confirmed that targeting the CAND1-SCFFBXO11 -hnRNPA2B1A signalling axis was therapeutically effective. CAND1 downregulation significantly reduced the tumour burden in a primary mouse liver cancer model and a PDX model. CONCLUSIONS: Our results highlight that CAND1 is associated with poor prognosis in HCC and regulates lipid metabolic reprogramming by dissociating the SCF complex. Targeting the CAND1-SCFFBXO11 -hnRNPA2B1 axis may be a novel strategy for HCC treatment.
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Carcinoma Hepatocelular , Proteínas F-Box , Neoplasias Hepáticas , Animales , Ratones , Humanos , Proteínas Cullin/química , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Carcinoma Hepatocelular/genética , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Metabolismo de los Lípidos/genética , Neoplasias Hepáticas/genética , Ubiquitinación/genética , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Lípidos , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas F-Box/metabolismoRESUMEN
Although the plasma-induced receiving and radiating near-field cutoff phenomena in the subwavelength regime are found of crucial importance in electromagnetic (EM) signal transmissions and plasma property studies, their mechanisms to a large extent remain unclear and undistinguished. In this paper, in the perspective of field and energy transfer, it is demonstrated that the cutoff in the near-field regime is completely different from that in the geometric optical regime. Results show that, for the receiving mode, epsilon-near-zero (ENZ) plasmas can be treated as a nearly ideal EM fluid, and thus, EM waves are restricted into the plasma channel. For the radiating mode, on the other hand, it is the destructive interference between the electric dipole fields of the antenna and the ENZ plasma that results in vanishing far-field radiation. As an important supplement to the existing cutoff theories, our results not only offer clearer physical insights into the near-field cutoff effect but also provide a helpful reference for cutoff-related practical applications in various frequency bands.
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In the field of membrane separation, the environmental concerns caused by spent membranes are becoming increasingly serious, which contradicts the concept of sustainable development. Based on this, a biodegradable poly(butylene adipate-co-terephthalate) (PBAT) membrane was used for the first time in the pervaporation separation of phenol, a high boiling point organic compound (HBOC). By using the PBAT membrane, outstanding separation efficiency was achieved, and environmental pollution and disposal issues were also avoided. The separation process and mechanism of the PBAT membrane were systematically studied through the experiment together with molecular dynamics (MD) simulation. The swelling experiment and intermolecular interaction energy calculation demonstrated that the PBAT membrane had a strong affinity for phenol. Further simulation concluded that higher phenol concentration increased the number of hydrogen bonds so that the membrane was more greatly swollen. Meanwhile, the simulations on the adsorption, diffusion and permeation predicted that the PBAT membrane had excellent separation performance for phenol. Besides MD simulation, the influences of feed concentration and temperature on pervaporation performance were also investigated by experiment. The results showed that the flux of each component increased with the feed concentration. This phenomenon was attributed to the preferential adsorption of phenol by the PBAT membrane, which resulted in large free volumes and cavities within the membrane, accelerating the diffusion of molecules. In addition, it was found that the optimal operating temperature was 333 K with the best separation performance. This study confirms that the biodegradable PBAT membrane is valuable for the recovery of high boiling point organic compounds (HBOCs) such as phenol.
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The lithium-sulfur battery (Li-S) has been considered a promising energy storage system, however, in the practical application of Li-S batteries, considerable challenges remain. One challenge is the low kinetics involved in the conversion of Li2S4 to Li2S. Here, we reveal that highly dispersed Ni nanoparticles play a unique role in the reduction of Li2S4. Ni-porous carbon (Ni-PC) decorated in situ on a free-standing carbon nanotube sponge (CNTS/Ni-PC) enriches the current response of liquid phase Li2S4 and Li2S2 around the cathode more than 8.1 and 5.7 times higher than that of the CNTS blank sample, respectively, greatly boosting the kinetics and decreasing the reaction overpotential of Li2S4 reduction (lower Tafel slope and larger current response). Thus, with the same total overpotential, more space is provided for the concentration difference overpotential, allowing the more soluble polysulfide intermediates farther away from the surface of the conductive materials to be reduced based on the "wane and wax" strategy, and significantly improving the sulfur utilization. Consequently, S@CNTS/Ni-PC delivers excellent rate performance (812.4 mAh·g-1 at 2C) and a remarkable areal capacity of 10.1 mAh·cm-2. This work provides a viable strategy for designing a target catalyst to enhance the conversion kinetics in the Li2S4 reduction process.
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Lipopolysaccharide (LPS) from Gram-negative bacteria is a major contributor to cardiovascular failure, but the signaling mechanisms underlying its stress response are not fully understood. This study aimed to investigate the effect of the antioxidant enzyme catalase on LPS-induced cardiac abnormalities and the mechanisms involved, with particular focus on the interplay between autophagy, ferroptosis, and apoptosis. Cardiac-specific catalase (CAT) overexpression and wild-type (WT) mice were stimulated with LPS (6 mg/kg, intravenous injection), and cardiac morphology and function were evaluated. Oxidative stress, ferroptosis, apoptosis, and mitochondrial status were monitored, and survival curves were plotted based on the results of LPS stimulation. The results showed that, compared with WT mice, mice overexpressing catalase had a higher survival rate under LPS stimulation. Ultrasound echocardiography, cardiomyocyte characteristics, and Masson's trichrome staining showed that LPS inhibited cardiac function and caused cardiac fibrosis, while catalase alleviated these adverse effects. LPS increased apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), increased O2·- production, induced inflammation (TNF-α), autophagy, iron toxicity, and carbonyl damage, and significantly damaged mitochondria (mitochondrial membrane potential, mitochondrial proteins, and ultrastructure). These effects were significantly alleviated by catalase. Interestingly, the antioxidant N-acetylcysteine, autophagy inhibitor 3-methyladenine, and ferroptosis inhibitor lipostatin-1 all eliminated the LPS-induced contraction dysfunction and ferroptosis (using lipid peroxidation). Induction of ferroptosis could eliminate the cardioprotective effect of NAC. In conclusion, catalase rescues LPS-induced cardiac dysfunction by regulating oxidative stress, autophagy, ferroptosis, apoptosis, and mitochondrial damage in cardiomyocytes.
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Ferroptosis , Cardiopatías Congénitas , Ratones , Animales , Lipopolisacáridos/farmacología , Caspasa 3/metabolismo , Catalasa/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Miocitos Cardíacos/metabolismo , Cardiopatías Congénitas/metabolismo , AutofagiaRESUMEN
Based on the superior selectivity of bismuth oxybromide (BiOBr) for Br-, the excellent electrical conductivity of carbon nanotubes (CNTs), and the ion exchange capacity of quaternized chitosan (QCS), a three-dimensional network composite membrane electrode CNTs/QCS/BiOBr was constructed, in which BiOBr served as the storage space for Br-, CNTs provided the electron transfer pathway, and QCS cross-linked by glutaraldehyde (GA) was used for ion transfer. The CNTs/QCS/BiOBr composite membrane exhibits superior conductivity after the introduction of the polymer electrolyte, which is seven orders of magnitude higher than that of conventional ion-exchange membranes. Furthermore, the addition of the electroactive material BiOBr improved the adsorption capacity for Br- by a factor of 2.7 in electrochemically switched ion exchange (ESIX) system. Meanwhile, the CNTs/QCS/BiOBr composite membrane displays excellent Br- selectivity in mixed solutions of Br-, Cl-, SO42- and NO3-. Therein, the covalent bond cross-linking within the CNTs/QCS/BiOBr composite membrane endows it great electrochemical stability. The synergistic adsorption mechanism of the CNTs/QCS/BiOBr composite membrane provides a new direction for achieving more efficient ion separation.
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A narrow linewidth Ti:sapphire laser is developed and characterized for the generation of an ultraviolet nanosecond laser pulses for the planar laser-induced fluorescence (PLIF) imaging of hydroxyl (OH). With a pump power of 11.4 W at 1 kHz, the Ti:sapphire laser produces 3.5 mJ at 849 nm with pulse duration of 17 ns and achieves a conversion efficiency of 28.2%. Accordingly, its third-harmonic generation outputs 0.56 mJ at 283 nm in BBO with type I phase match. An OH PLIF imaging system has been built; a 1 to 4 kHz fluorescent image of OH of a propane Bunsen burner has been captured based on this laser system.
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BACKGROUND: Near-infrared fluorescent cholangiography (NIRFC) with indocyanine green (ICG) as the developer yields clear visualization of the extrahepatic bile ducts and is effective in identifying key structures. Here, we analyzed and compared the surgical outcomes of fluorescent and conventional laparoscopy in cholecystectomy of various difficulties and then assessed the value of NIRFC. MATERIALS AND METHODS: This retrospective study collected clinical data from partial patients who underwent laparoscopic cholecystectomy (LC) at the Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University between 2020 and 2021. The study subjects were classified into ICG-assisted and white-light laparoscopy. Two cohorts with homogeneous baseline status were selected based on 1:1 ratio propensity score matching (PSM). Multivariate logistic regression analysis was performed to predict independent risk factors for LC difficulty. Thereafter, the matched cases were classified into difficult and easy subgroups by combining difficulty score and gallbladder disease type, and then the surgical outcomes of the two groups were compared. RESULTS: This study included a total of 624 patients. The patients were classified into the ICG group (n = 218) and the non-ICG group (n = 218) after a 1:1 ratio PSM. Our data showed significant differences between the groups in operative time (P = 0.020), blood loss (P = 0.016), length of stay (P = 0.036), and adverse reaction (P = 0.023). Stratified analysis demonstrated that ICG did not significantly improve the surgical outcomes in simple cases (n = 208). On the other hand, in difficult cases (n = 228), NIRFC shortened operative time (P = 0.003) and length of stay (P = 0.015), reduced blood loss (P = 0.028) and drain placement rate (P = 0.015), and had fewer adverse reactions (P = 0.023). The data showed that five cases were converted to laparotomy while two cases had minor bile leaks in the non-ICG group. There was no bile duct injury (BDI) in all the cases. Furthermore, high BMI, history of urgent admission and abdominal surgery, palpable gallbladder, thickened wall, and pericholecystic collection were risk factors for surgical difficulty. CONCLUSION: ICG-assisted NIRFC provides real-time biliary visualization. In complicated conditions such as acute severe inflammation, dense adhesions, and biliary variants, the navigating ability of fluorescence can enhance the operation progress, reduce the possibility of conversion or serious complications, and improve the efficiency and safety of difficult LC.
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Colecistectomía Laparoscópica , Verde de Indocianina , Humanos , Colecistectomía Laparoscópica/efectos adversos , Estudios Retrospectivos , Colangiografía , ColorantesRESUMEN
BACKGROUND: Indocyanine green (ICG) fluorescence imaging technology is increasingly widely used in laparoscopic hepatectomy. However, whether it can provide long-term survival benefits to patients with liver malignancies remains unclear. This study investigated the clinical effect of laparoscopic hepatectomy for hepatocellular carcinoma (HCC) using ICG imaging technology. METHODS: We retrospectively analyzed HCC patients who underwent laparoscopic hepatectomy at Zhongnan Hospital of Wuhan University from January 2016 to December 2020. Propensity score matching (PSM) was used to match patients undergoing ICG fluorescence navigation laparoscopic hepatectomy (ICG-FNLH) with those undergoing conventional laparoscopic hepatectomy (CLH) in a 1:1 ratio to minimize the influence of confounding factors. We compared perioperative status and long-term prognosis between the two groups and performed multivariate analysis to identify risk factors associated with overall survival and recurrence-free survival. RESULTS: The original cohort consisted of 141 patients, with 50 patients in each group (100 patients in total) after PSM. The anatomical liver resection rate, R0 resection rate, and resection margin distance in the ICG-FNLH group were higher than those in the CLH group. The intraoperative blood loss was lower than that in the CLH group. The recurrence-free survival and overall survival of the ICG-FNLH group were better than those of the CLH group. ICG-FNLH improved the recurrence-free survival of HCC patients (hazard ratio [HR] = 2.165, 95% confidence interval [CI]: 1.136-4.127, P = 0.024). CONCLUSIONS: Compared with CLH, ICG-FNLH can improve the recurrence-free survival rate of patients with hepatocellular carcinoma and may help to improve the long-term prognosis of patients.
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Carcinoma Hepatocelular , Laparoscopía , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Verde de Indocianina , Estudios de Cohortes , Hepatectomía/métodos , Puntaje de Propensión , Laparoscopía/métodosRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect. METHODS: In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. RESULTS: We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice. CONCLUSIONS: These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Glucosa , Neoplasias Hepáticas/patología , Pronóstico , Proteasas Ubiquitina-EspecíficasRESUMEN
BACKGROUND & AIMS: Alterations of multiple metabolites characterize distinct features of metabolic reprograming in hepatocellular carcinoma (HCC). However, the role of most metabolites, including propionyl-CoA (Pro-CoA), in metabolic reprogramming and hepatocarcinogenesis remains elusive. In this study, we aimed to dissect how Pro-CoA metabolism affects these processes. METHODS: TCGA data and HCC samples were used to analyze ALDH6A1-mediated Pro-CoA metabolism and its correlation with HCC. Multiple metabolites were assayed by targeted mass spectrometry. The role of ALDH6A1-generated Pro-CoA in HCC was evaluated in HCC cell lines as well as xenograft nude mouse models and primary liver cancer mouse models. Non-targeted metabolomic and targeted energy metabolomic analyses, as well as multiple biochemical assays, were performed. RESULTS: Decreases in Pro-CoA and its derivative propionyl-L-carnitine due to ALDH6A1 downregulation were tightly associated with HCC. Functionally, ALDH6A1-mediated Pro-CoA metabolism suppressed HCC proliferation in vitro and impaired hepatocarcinogenesis in mice. The aldehyde dehydrogenase activity was indispensable for this function of ALDH6A1, while Pro-CoA carboxylases antagonized ALDH6A1 function by eliminating Pro-CoA. Mechanistically, ALDH6A1 caused a signature enrichment of central carbon metabolism in cancer and impaired energy metabolism: ALDH6A1-generated Pro-CoA suppressed citrate synthase activity, which subsequently reduced tricarboxylic acid cycle flux, impaired mitochondrial respiration and membrane potential, and decreased ATP production. Moreover, Pro-CoA metabolism generated 2-methylcitric acid, which mimicked the inhibitory effect of Pro-CoA on citrate synthase and dampened mitochondrial respiration and HCC proliferation. CONCLUSIONS: The decline of ALDH6A1-mediated Pro-CoA metabolism contributes to metabolic remodeling and facilitates hepatocarcinogenesis. Pro-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers for the diagnosis and treatment of HCC. Pro-CoA metabolism may provide potential targets for development of novel strategies against HCC. IMPACT AND IMPLICATIONS: Our study presents new insights on the role of propionyl-CoA metabolism in metabolic reprogramming and hepatocarcinogenesis. This work has uncovered potential diagnostic and predictive biomarkers, which could be used by physicians to improve clinical practice and may also serve as targets for the development of therapeutic strategies against HCC.