KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Boosting Efficient Alkaline Hydrogen Evolution Reaction of CoFe-Layered Double Hydroxides Nanosheets via Co-Coordination Mechanism of W-Doping and Oxygen Defect Engineering.

While surface defects and heteroatom doping exhibit promising potential in augmenting the electrocatalytic hydrogen evolution reaction (HER), their performance remains unable to rival that of the costly Pt-based catalysts. Yet, the concurrent modification of catalysts by integrating both approaches stands as a promising strategy to effectively address the aforementioned limitation. In this work, tungsten dopants are introduced into self-supported CoFe-layered double hydroxides (LDH) on nickel foam using a hydrothermal method, and oxygen vacancies (Ov) are further introduced through calcination. The analysis results demonstrated that tungsten doping reduces the Ov formation energy of CoFeW-LDH. The Ov acted as oxophilic sites, facilitating water adsorption and dissociation, and reducing the barrier for cleaving HO─H bonds from 0.64 to 0.14 eV. Additionally, Ov regulated the electronic structure of CoFeW-LDH to endow optimized hydrogen binding ability on tungsten atoms, thereby accelerating alkaline Volmer and Heyrovsky reaction kinetics. Specifically, the abundance of Ov induced a transition of tungsten from a six-coordinated to highly active four-coordinated structure, which becomes the active site for HER. Consequently, an ultra-low overpotential of 41 mV at 10 mA cm-2 , and a low Tafel slope of 35 mV dec-1 are achieved. These findings offer crucial insights for the design of efficient HER electrocatalysts.

THBS1 promotes angiogenesis and accelerates ESCC malignant progression by the HIF-1/VEGF signaling pathway.

Previously, we demonstrated that the expression of THBS1 is increased in esophageal squamous cell carcinoma (ESCC) tissues and is correlated with lymph node metastasis and poor prognosis, indicating that THBS1 might be a candidate oncogene in ESCC. In this study, we future studied the specific role of THBS1 in ESCC and its molecular mechanism. Silencing THBS1 expression resulted in inhibition of cell migration and cell invasion of ESCC cells, the decrease of colony formation and proliferation. Tube formation of human umbilical vein endothelial cells (HUVECs) in vitro was decreased when cultured with conditioned medium from THBS1-silenced cells. The expression of CD31, a marker for blood vessel endothelial cells, was decreased in tumor tissues derived from THBS1-silenced tumors in vivo. Silencing THBS1 leaded the decreased of hypoxia-inducible factor-1α (HIF-1α), HIF-1ß, and VEGFA protein. The expression of p-ERK and p-AKT were declined in HUVECs following incubation with conditioned medium from THBS1-silenced ESCC cells compared conditioned medium from control cells. Furthermore, the treatment with bevacizumab boosted the decrease of the p-ERK and p-AKT levels in HUVECs incubated with the conditioned medium from THBS1-silenced ESCC cells. THBS1 silencing combined with bevacizumab blocked VEGF, inhibited to the tube formation, colony formation and migration of HUVECs, which were superior to that of bevacizumab alone. We presumed that THBS1 can enhance HIF-1/VEGF signaling and subsequently induce angiogenesis by activating the AKT and ERK pathways in HUVECs, resulting in bevacizumab resistance. THBS1 would be a potential target in tumor antiangiogenesis therapies.

MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.

Glioblastoma (GBM) is a WHO grade 4 tumor and is the most malignant form of glioma. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folate metabolism, has been reported to be highly expressed in several human tumors. However, little is known about the role of MTHFD2 in GBM. In this study, we aimed to explore the biological functions of MTHFD2 in GBM and identify the associated mechanisms. We performed experiments such as immunohistochemistry, Western blot, and transwell assays and found that MTHFD2 expression was lower in high-grade glioma than in low-grade glioma. Furthermore, a high expression of MTHFD2 was associated with a favorable prognosis, and MTHFD2 levels showed good prognostic accuracy for glioma patients. The overexpression of MTHFD2 could inhibit the migration, invasion, and proliferation of GBM cells, whereas its knockdown induced the opposite effect. Mechanistically, our findings revealed that MTHFD2 suppressed GBM progression independent of its enzymatic activity, likely by inducing cytoskeletal remodeling through the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, thereby influencing GBM malignance. Collectively, these findings uncover a potential tumor-suppressor role of MTHFD2 in GBM cells. MTHFD2 may act as a promising diagnostic and therapeutic target for GBM treatment.

Valence-Inverted States of Nickel(II) Complexes Perform Facile C-H Bond Activation.

Valence-inverted reactivity (VIR) is discovered here through high-level computations of excited states of Ni(II) complexes that are generated by triplet energy transfer. For example, the so-generated 3[(Ar)(bpy)NiII(Br)] species possesses a valence-inverted occupancy, dxy1dxz1dx2-y22, wherein the uppermost dx2-y2 orbital is metal-ligand antibonding. This state promotes C-H bond activation of THF and its cross-coupling to the aryl ligand. Thus, due to the metal-ligand antibonding character of dx2-y2, the dxy1dx2-y22 subshell opens a Ni-coordination site by shifting the bidentate bipyridine ligand to monodentate plus a dangling pyridine. The tricoordinate Ni(II) intermediate inserts into a C-H bond of THF, transfers a proton to the dangling pyridine moiety, and eventually generates an arylated THF by reductive-coupling. The calculated high kinetic isotope effect is in accord with experiment, both revealing C-H activation. The VIR pattern is novel, its cross-coupling reaction is highly useful, and it is generally expected to occur in other d8 complexes.

Oxygen Vacancy-Mediated CuCoFe/Tartrate-LDH Catalyst Directly Activates Oxygen to Produce Superoxide Radicals: Transformation of Active Species and Implication for Nitrobenzene Degradation.

Oxygen vacancies play a vital role in the catalytic activity of layered double hydroxide (LDH) catalysts in wastewater treatment. However, the mechanism of oxygen vacancy-mediated LDH-activated oxygen to produce reactive oxygen species (ROS) still lacks a reasonable explanation. In this work, a tartrate-modified CuCoFe-LDH (CuCoFe/Tar-LDH) with abundant oxygen vacancies was designed, which can efficiently degrade nitrobenzene (NB) under room conditions. The technical energy consumption is 0.011 kW h L-1. According to the characterization and calculation results, it is proposed that oxygen vacancies are formed because of the oxygen deficiency which is caused by the reduction of the energy between the metal ion and oxygen, and the metal ion transitions to a lower state. Compared with CuCoFe-LDH, the oxygen vacancy formation energy of CuCoFe/Tar-LDH decreased from 1.98 to 1.13 eV. The O2 bond length adsorbed on the oxygen vacancy is 1.27 Å, close to the theoretical length of superoxide radicals (•O2-) (1.26 Å). Radical trapping experiments and electron spin-resonance spectroscopy spectrum prove that •O2- is an important precursor of •OH. This work is dedicated to the in-depth exploration of the oxygen vacancy-mediated CuCoFe/Tar-LDH catalyst activation mechanism for molecular oxygen and the conversion relationship between ROS.

Safety and effectiveness of laparoscopic intratumoral resection facilitated by coagulation of giant hepatic hemangioma: a matched case-control study and literature review.

BACKGROUND: To report the safety and effectiveness of laparoscopic intratumoral resection facilitated by coagulation (LIRC) compared with laparoscopic hepatectomy (LH) in treating giant hepatic hemangioma. METHODS: From 2017 to 2020, 19 consecutive patients with giant hepatic hemangioma (≥ 10 cm) received LIRC in one center. We selected a subgroup of 103 patients treated by LH in other four centers who well matched the 19 consecutive patients treated with LIRC, in a 1:1 fashion based on the tumor location, tumor size, and body mass index. Furthermore, the differences in technical success, operative time, operative blood loss, change of laboratory indexes, hospital stays, complication and clinical responds are compared between the two groups. RESULTS: Technical success was achieved in all 38 patients. Patients in the LIRC group had a relative shorter operative time (P < 0.001) and less operative blood loss (P = 0.003). The serum levels of C-reactive protein (CRP), total bilirubin (TBil), alanine aminotransferase (ALT), and aspartate transaminase (AST) were elevated significantly (P < 0.05) 1 day after the resection and returned to normal within 7 days in both groups; however, relatively lower serum levels of those indexes were observed in the LIRC group (P < 0.05). The total complication rate was relatively lower in the LIRC group compared with the LH group (P = 0.029). Patients in the LIRC group had shorter hospital stays than those in the LH group (P = 0.010). The clinical response was similar in the two groups. CONCLUSIONS: LIRC is safe and effective for treating giant hepatic hemangioma.

A nationwide survey exploring physicians' and pharmacists' knowledge, awareness and perceptions regarding generic medicines in China.

BACKGROUND: Generic medicines substitution is an important means to control rapid growth of pharmaceutical expenditures for the healthcare system in China. Acceptance and utilization of generic medicines is highly influenced by healthcare providers' perceptions. This study aimed to compare the knowledge, awareness and perceptions of generic medicines between physicians and pharmacists in China. METHODS: We used an online, cross-sectional survey across China. The questionnaire explored four sections: demographic characteristics, assessment of the participants' knowledge and awareness of generic medicines, perceptions of generic medicines and generic substitution practices. Chi-square or Mann-Whitney-U tests were applied to compare differences between physicians and pharmacists. P-values < 0.05 were considered significant. RESULTS: A total of 1644 physicians and 4187 pharmacists participated. Most physicians (82.8%, n = 1362) and pharmacists (89.8%, n = 3760) correctly identified the definition of generic medicines. A similar percentage of physicians and pharmacists agreed that approved generic medicines are as effective (64.1% vs 68.2%) or safe (63.8% vs 69.1%) as brand-name medicines. Most physicians and pharmacists (67.6% vs 71.0%) supported the policy of generic substitution. In practice, 79.4% (n = 1305) of physicians reported that they had prescribed generic medicines. More than 78% of respondents reported an obvious increase in the number of generic medicines prescribed in their medical institutions. The majority of physicians and pharmacists identified lack of trust regarding efficacy and safety of generic medicines and the difficulty of changing patients' preference as top challenges in generic substitution. CONCLUSIONS: Both physicians and pharmacists surveyed had adequate knowledge of generic medicines, and hold positive attitude towards generics and generic substitution. Efficacy and safety are key factors related to prescribing or dispensing generic medicines. Various policies and regulations should be taken to encourage successful generic substitution.

[Research on gait recognition and prediction based on optimized machine learning algorithm].

Aiming at the problems of individual differences in the asynchrony process of human lower limbs and random changes in stride during walking, this paper proposes a method for gait recognition and prediction using motion posture signals. The research adopts an optimized gated recurrent unit (GRU) network algorithm based on immune particle swarm optimization (IPSO) to establish a network model that takes human body posture change data as the input, and the posture change data and accuracy of the next stage as the output, to realize the prediction of human body posture changes. This paper first clearly outlines the process of IPSO's optimization of the GRU algorithm. It collects human body posture change data of multiple subjects performing flat-land walking, squatting, and sitting leg flexion and extension movements. Then, through comparative analysis of IPSO optimized recurrent neural network (RNN), long short-term memory (LSTM) network, GRU network classification and prediction, the effectiveness of the built model is verified. The test results show that the optimized algorithm can better predict the changes in human posture. Among them, the root mean square error (RMSE) of flat-land walking and squatting can reach the accuracy of 10 -3, and the RMSE of sitting leg flexion and extension can reach the accuracy of 10 -2. The R 2 value of various actions can reach above 0.966. The above research results show that the optimized algorithm can be applied to realize human gait movement evaluation and gait trend prediction in rehabilitation treatment, as well as in the design of artificial limbs and lower limb rehabilitation equipment, which provide a reference for future research to improve patients' limb function, activity level, and life independence ability.

Long noncoding RNA HOTAIR promotes breast cancer development by targeting ZEB1 via sponging miR-601.

BACKGROUND: Breast cancer (BC) is a common malignancy worldwide. It has been reported that long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) is abnormally expressed in BC. However, the role of HOTAIR in the malignancy of BC is worth further discussion. This study aims to clarify the function and molecular mechanism of HOTAIR in BC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expression of HOTAIR, microRNA (miR)-601 and zinc finger E-box binding homeobox 1 (ZEB1). Cell counting kit-8 (CCK-8) and transwell assay were used to detect the proliferation, migration and invasion of cells. Further, the protein levels of AKT, phosphorylated-AKT (p-AKT), ZEB1 and Ki-67 were confirmed by western blot (WB) assay. Moreover, dual-luciferase reporter assay was applied to examine the targeting relationship between HOTAIR and miR-601 or miR-601 and ZEB1. In addition, animal experiments were conducted to verify the effect of HOTAIR on BC tumor growth in vivo. RESULTS: HOTAIR was upregulated in BC tissues and cells, and its knockdown suppressed the proliferation, migration, invasion and the activity of AKT signaling pathway of BC cells. HOTAIR could serve as a sponge of miR-601. Further experiments revealed that miR-601 inhibitor could reverse the inhibition effect of HOTAIR silencing on the progression of BC. Meanwhile, ZEB1 was a target of miR-601, and its overexpression could invert the suppression effect of miR-601 overexpression on the progression of BC. Additionally, ZEB1 expression was regulated by HOTAIR and miR-601. Furthermore, interference of HOTAIR could attenuate BC tumor growth in vivo. CONCLUSION: In short, this study demonstrated that HOTAIR promoted the proliferation, migration, invasion of BC through regulating the miR-601/ZEB1 axis, which provided a theoretical basis for the research on lncRNA-directed therapeutics in BC.

Downregulation of serum exosomal miR-320d predicts poor prognosis in hepatocellular carcinoma.

BACKGROUND: MicroRNAs (miRNAs) is a class of functional regulator of tumorigenesis of human cancer including hepatocellular carcinoma (HCC). However, the potential clinical significance of serum exosomal miR-320d in HCC has not been elucidated. METHODS: Real-time reverse transcription PCR was used to detect the expression pattern of serum exosomal miR-320d in patients with HCC, and the correlation between the deregulation of serum exosomal miR-320d and the clinical outcome of HCC was explored. The biological function of exosomal miR-320d in HCC was also investigated. RESULTS: Our results showed that the expression levels of exosomal miR-320d were remarkably reduced in the serum samples of HCC patients and the culture medium of HCC cell lines compared with their respective controls. Serum exosomal miR-320d could differentiate the HCC patients from healthy controls with high accuracy. In addition, its level was remarkably increased in the HCC patients who had received surgical treatment. Moreover, reduced serum exosomal miR-320d was associated with advanced tumor stage, positive lymph node metastasis, and poorly differentiated tumors. HCC patients with lower serum exosomal miR-320d had shorter overall and disease-free survival. Low serum exosomal miR-320d was identified to be an independent unfavorable prognostic factor for HCC. Finally, overexpression of miR-320d inhibited the proliferation and invasion of HCC cells, and BMI1 was demonstrated to be a direct target of miR-320d. CONCLUSION: Taken together, serum exosomal miR-320d could be a potential non-invasive biomarker for the diagnosis and prognosis of HCC.

Endothelial pyroptosis underlies systemic inflammatory response following radiofrequency ablation of hepatic hemangiomas.

This study investigated the relationship between endothelial pyroptosis and the occurrence of systemic inflammatory response (SIR) after radiofrequency (RF) ablation of hepatic hemangiomas. Thirty-two patients with hepatic hemangiomas were treated with RF ablation and blood samples of the patients were collected at different time points. Immunohistochemistry staining was performed to evaluate the expression of caspase-1, gasdermin D (GSDMD), IL-1ß and IL-18 in hepatic hemangioma and subablated hemangioma tissue. In vitro experiments, human umbilical vein endothelial cells (HUVECs) were treated with sub-ablative hyperthermia with or without the addition of caspase-1 inhibitor, Ac-YVAD-CMK in the medium. Lactate dehydrogenase (LDH), IL-18, IL-1ß, caspase-1 and GSDMD were measured by enzyme-linked immunosorbent assay, real-time PCR and Western blot methods. An elevation of general SIR parameters (CRP and WBC), pyroptosis-related inflammatory cytokines (IL-1ß and IL-18) and LDH were observed 1-day post-RF ablation and their peak values were significantly correlated with ablated volume (p < .001) and ablation time (p < .001). Moreover, levels of pyroptosis-related inflammatory cytokines correlated well with general SIR parameters, respectively (p < .001). Immunohistochemical analysis showed the increased expression of caspase-1, GSDMD, IL-18 and IL-1ß in the endothelial cells of subablated hemangioma. In vitro experiments showed that subablative hyperthermia induced the caspase-1-associated endothelial pyroptosis and Ac-YVAD-CMK attenuated pyroptosis. In conclusion, SIR in patients treated by RF ablation for hepatic hemangiomas was significantly associated with the ablated volume and ablation time and endothelial pyroptosis may involve in the occurrence of SIR following RF ablation of hepatic hemangiomas.

MASAN: a novel staging system for prognosis of patients with oesophageal squamous cell carcinoma.

BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers worldwide. Treatment of ESCC is in progress through accurate staging and risk assessment of patients. The emergence of potential molecular markers inspired us to construct novel staging systems with better accuracy by incorporating molecular markers. METHODS: We measured H scores of 23 protein markers and analysed eight clinical factors of 77 ESCC patients in a training set, from which we identified an optimal MASAN (MYC, ANO1, SLC52A3, Age and N-stage) signature. We constructed MASAN models using Cox PH models, and created MASAN-staging systems based on k-means clustering and minimum-distance classifier. MASAN was validated in a test set (n = 77) and an independent validation set (n = 150). RESULTS: MASAN possessed high predictive accuracies and stratified ESCC patients into three prognostic groups that were more accurate than the current pTNM-staging system for both overall survival and disease-free survival. To facilitate clinical utilisation, we also constructed MASAN-SI staging systems based on staining indices (SI) of protein markers, which possessed similar prognostic performance as MASAN. CONCLUSION: MASAN provides a good alternative staging system for ESCC prognosis with a high precision using a simple model.

Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold.

The free fatty acid receptor 1 (FFA1) plays an important role in amplifying insulin secretion in a glucose dependent manner. We have previously reported a series of FFA1 agonists with thiazole scaffold exemplified by compound 1, and identified a small hydrophobic subpocket partially occupied by the methyl group of compound 1. Herein, we describe further structure optimization to better fit the small hydrophobic subpocket by replacing the small methyl group with other hydrophobic substituents. All of these efforts resulted in the identification of compound 6, a potent FFA1 agonist (EC50 = 39.7 nM) with desired ligand efficiency (0.24) and ligand lipophilicity efficiency (4.7). Moreover, lead compound 6 exhibited a greater potential for decreasing the hyperglycemia levels than compound 1 during an oral glucose tolerance test. In summary, compound 6 is a promising FFA1 agonist for further investigation, and the structure-based study promoted our understanding for the binding pocket of FFA1.

A three-gene signature and clinical outcome in esophageal squamous cell carcinoma.

It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications. GASC1, member of the histone demethylases affecting heterochromatin formation and transcriptional repression, has been found to be dysregulation in many types of cancers including breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia. In this study, we examined the expression of GASC1 and certain GASC1-targeted genes (KLF4, MYC, SOX2, PPARG, MDM2, and NANOG) and identified a three-gene prognostic signature (PPARG, MDM2, and NANOG), using risk scores based on immunohistochemical analyses of 149 tumor specimens from patients with esophageal squamous cell carcinoma (ESCC). The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients. We validated the predictive value of the three-gene signature in a second independent cohort of 101 patients with ESCC in order to determine whether it had predictive value. The results were similar to those in 149 patients. According to multivariate Cox proportional hazards analyses, the predictive model of a three-gene signature was an independent predictor for OS (p = 0.005 in cohort 1, p = 0.025 in cohort 2). In addition, ROC analysis indicated that the predictive ability of the three-gene model was more robust than that of a single biomarker. Therefore, our three-gene signature is closely associated with OS among patients with ESCC and may serve as a predictor for the poor prognosis of ESCC patients.

Autoantibodies as potential biomarkers for the early detection of esophageal squamous cell carcinoma.

OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent causes of cancer death worldwide and effective diagnosis is needed. We assessed the diagnostic potential of an autoantibody panel that may benefit early diagnosis. METHODS: We analyzed data for patients with ESCC and normal controls in a test cohort and a validation cohort. Autoantibody levels were measured against a panel of six tumor-associated antigens (p53, NY-ESO-1, matrix metalloproteinase-7 (MMP-7), heat shock protein 70 (Hsp70), peroxiredoxin VI (Prx VI), and BMI1 polycomb ring finger oncogene (Bmi-1)) by enzyme-linked immunosorbent assay. RESULTS: We assessed serum autoantibodies in 513 participants: 388 with ESCC and 125 normal controls. The validation cohort comprised 371 participants: 237 with ESCC, and 134 normal controls. Autoantibodies to at least 1 of 6 antigens demonstrated a sensitivity/specificity of 57% (95% confidence interval (CI): 52-62%)/95% (95% CI: 89-98%) and 51% (95% CI: 45-57%)/96% (95% CI: 91-99%) in the test and validation cohorts, respectively. Measurement of the autoantibody panel could differentiate early-stage ESCC patients from normal controls (sensitivity 45% (95% CI: 32-59%) and specificity 95% (95% CI: 89-98%) in the test cohort; 46% (95% CI: 35-58%) and 96% (95% CI: 91-99%) in the validation cohort). In either cohort, no significant differences were seen when patients were subdivided by age, gender, smoking status, size of tumor, site of tumor, depth of tumor invasion, histological grade, lymph node status, TNM stage, or early-stage and late-stage groups. CONCLUSIONS: Measurement of an autoantibody response to multiple tumor-associated antigens in an optimized panel assay, to help discriminate early-stage ESCC patients from normal controls, may aid in early detection of ESCC.

Heme-Inducing Endothelial Pyroptosis Plays a Key Role in Radiofrequency Ablation of Hepatic Hemangioma Leading to Systemic Inflammatory Response Syndrome.

Purpose: Systemic inflammatory response syndrome (SIRS) is a common complication of radiofrequency ablation (RFA) for hepatic hemangiomas. RFA can cause hemolytic reactions during hepatic hemangioma ablation. However, the mechanisms underlying RFA-induced SIRS remain unclear. Methods: We established an orthotopic liver hemangioma model and performed radiofrequency ablation. The levels of interleukin (IL)-1ß and IL-18 and the production of ROS were measured. The wet-to-dry lung ratio, inflammation score, and in vivo endothelial cell permeability were examined. GSDMD-/- mice were used to investigate the effect of heme-inducing SIRS. RNA sequencing (RNA-seq) was performed to identify the main pathways underlying heme-induced SIRS. Western blotting and immunoprecipitation were used to determine the changes and interactions of associated proteins. Results: The levels of heme, IL-1ß, and IL-18 were significantly increased after RFA. The wet-to-dry lung ratio increased in hepatic hemangiomas after RFA, indicating that SIRS occurred. Heme induced increased levels of IL-1ß and IL-18, cell death, wet-to-dry lung radio, and inflammation score in vitro and in vivo, indicating that heme induced SIRS and pyroptosis. Furthermore, GSDMD participates in heme-induced SIRS in mice, and GSDMD deletion in mice reverses the effect of heme. Heme regulates NLRP3 activation through the NOX4/ROS/TXNIP-TRX pathway, and an N-acetyl-L-cysteine (NAC) or NOX4 inhibitor (GLX351322) reverses heme-induced SIRS. Conclusion: Our findings suggest that heme induces endothelial cell pyroptosis and SIRS in mice and decreasing heme levels and ROS scavengers may prevent SIRS in hepatic hemangioma after RFA.

Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways.

BACKGROUND: Residual tumor progression after insufficient radiofrequency ablation (RFA) has been recently reported. However, whether epithelial-mesenchymal transition (EMT), which is a key process that drives cancer metastasis, is involved in the tumor progression after insufficient RFA is not well understood. METHODS: Human hepatocellular carcinoma (HCC) cell lines SMMC7721 and Huh7 were used. Insufficient RFA was simulated using a water bath (47°C 5 min, 10 min, 15 min, 20 min and 25 min gradually). MTT assay was used to evaluate the proliferation of HCC cells in vitro. Migration and invasion of HCC cells were determined by transwell assay. The molecular changes in HCC cells after insufficient RFA were evaluated by western blot. LY294002 and PD98059 were used to treat HCC cells. An ectopic nude mice model and a tail vein metastatic assay were used to evaluate the growth and metastatic potential of SMMC7721 cells in vivo after insufficient RFA. RESULTS: SMMC7721 and Huh7 cells after insufficient RFA (named as SMMC7721-H and Huh7-H respectively) exhibited enhanced proliferation, migration and invasion (6.4% and 23.6%, 33.2% and 66.1%, and 44.1% and 57.4% increase respectively) in vitro. Molecular changes of EMT were observed in SMMC7721-H and Huh7-H cells. LY294002 and PD98059 inhibited the EMT of SMMC7721-H and Huh7-H cells. SMMC7721-H cells also exhibited larger tumor size (1440.8±250.3 mm3 versus 1048.56±227.6 mm3) and more lung metastasis (97.4% increase) than SMMC7721 cells in vivo. Higher expression of PCNA, N-cadherin and MMP-2 and MMP-9, was also observed in SMMC7721-H tumors. CONCLUSIONS: Insufficient RFA could directly promote the invasiveness and metastasis of HCC cells. Insufficient RFA may promote the EMT of HCC cells through Akt and ERK signaling pathways.

Dynamic System Stability Modeling Approach with Sparrow-Inspired Meta-Heuristic Optimization Algorithm.

Aiming at the accurate prediction of the inception of instability in a compressor, a dynamic system stability model is proposed based on a sparrow-inspired meta-heuristic optimization algorithm in this article. To achieve this goal, a spatial mode is employed for flow field feature extraction and modeling object acquisition. The nonlinear characteristic presented in the system is addressed using fuzzy entropy as the identification strategy to provide a basis for instability determination. Using Sparrow Search Algorithm (SSA) optimization, a Radial Basis Function Neural Network (RBFNN) is achieved for the performance prediction of system status. A Logistic SSA solution is first established to seek the optimal parameters of the RBFNN to enhance prediction accuracy and stability. On the basis of the RBFNN-LSSA hybrid model, the stall inception is detected about 35.8 revolutions in advance using fuzzy entropy identification. To further improve the multi-step network model, a Tent SSA is introduced to promote the accuracy and robustness of the model. A wider range of potential solutions within the TSSA are explored by incorporating the Tent mapping function. The TSSA-based optimization method proves a suitable adaptation for complex nonlinear dynamic modeling. And this method demonstrates superior performance, achieving 42 revolutions of advance warning with multi-step prediction. This RBFNN-TSSA model represents a novel and promising approach to the application of system modeling. These findings contribute to enhancing the abnormal warning capability of dynamic systems in compressors.

Aerodynamic System Machine Learning Modeling with Gray Wolf Optimization Support Vector Regression and Instability Identification Strategy of Wavelet Singular Spectrum.

The prediction of a stall precursor in an axial compressor is the basic guarantee to the stable operation of an aeroengine. How to predict and intelligently identify the instability of the system in advance is of great significance to the safety performance and active control of the aeroengine. In this paper, an aerodynamic system modeling method combination with the wavelet transform and gray wolf algorithm optimized support vector regression (WT-GWO-SVR) is proposed, which breaks through the fusion technology based on the feature correlation of chaotic data. Because of the chaotic characteristic represented by the sequence, the correlation-correlation (C-C) algorithm is adopted to reconstruct the phase space of the spatial modal. On the premise of finding out the local law of the dynamic system variety, the machine learning method is applied to model the reconstructed low-frequency components and high-frequency components, respectively. As the key part, the parameters of the SVR model are optimized by the gray wolf optimization algorithm (GWO) from the biological view inspired by the predatory behavior of gray wolves. In the definition of the hunting behaviors of gray wolves by mathematical equations, it is superior to algorithms such as differential evolution and particle swarm optimization. In order to further improve the prediction accuracy of the model, the multi-resolution and equivalent frequency distribution of the wavelet transform (WT) are used to train support vector regression. It is shown that the proposed WT-GWO-SVR hybrid model has a better prediction accuracy and reliability with the wavelet reconstruction coefficients as the inputs. In order to effectively identify the sign of the instability in the modeling system, a wavelet singular information entropy algorithm is proposed to detect the stall inception. By using the three sigma criteria as the identification strategy, the instability early warning can be given about 102r in advance, which is helpful for the active control.