Exploring the causal relationship between interleukin-6 or C reactive protein and malignant melanoma using a two-sample Mendelian randomization approach.

The goal was to explore the effect of interleukin-6 (IL6) and C reactive protein (CRP) on malignant melanoma (MM) using two-sample Mendelian randomization. Methods: Data for this study were obtained from the IEU Open GWAS project website for genome-wide association study data (GWAS) on interleukin-6, C reactive protein levels and malignant melanoma. Inverse variance weighted (IVW) method was mainly used and supplemented with MR-Egger regression and weighted median. Finally, horizontal multivariate validity and heterogeneity tests were performed to assess the stability and reliability of the results. Results: The results of univariate two-sample MR analyses showed no significant effect of CRP on MM: inverse variance weighting method (OR=0.999, 95% CI: 0.998-1.001, P=0.343), MR-Egger regression (OR= 1.000, 95% CI: 0.998-1.001, P= 0.180), and weighted median method (OR= 0.999, 95% CI: 0.997 to 1.000, P= 0.583), and weighted model (OR= 0.999, 95% CI: 0.998 to 1.001, P= 0.328). Also,IL-6 had no significant effect on MM: inverse variance weighting method (OR= 1.001, 95% CI: 0.999 to 1.002, P=0.461), MR-Egger regression (OR= 1.000, 95% CI: 0.997 to 1.004, P= 0.910), weighted median method (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.749), and weighted mode (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.820). Conclusion: There was no causal relationship between C-reactive protein and IL-6 on the risk of malignant melanoma.

A multimodal physiological and psychological dataset for human with mental stress induced myocardial ischemia.

Accurate differentiation between angina with no obstructive coronary arteries (ANOCA) and mental stress-induced myocardial ischemia (MSIMI) is crucial for tailored treatment strategies, yet public data scarcity hampers understanding. Given the higher incidence of both conditions in women, this study prospectively enrolled 80 female ANOCA and 39 age-matched female controls, subjecting them to three types of mental stress tasks. ECGs were continuously monitored across Rest, Stress, and Recover stages of the mental stress tasks, with PET/CT imaging during the Stress stage to evaluate myocardial perfusion. With PET/CT serving as the gold standard for MSIMI diagnosis, 35 of the 80 ANOCA patients were diagnosed as MSIMI. Using ECG variables from different stages of mental stress tasks, we developed five machine learning models to diagnose MSIMI. The results showed that ECG data from different stages provide valuable information for MSIMI classification. Additionally, the dataset encompassed demographic details, physiological, and blood sample test results of the patients. We anticipate this new dataset will significantly push further progress in ANOCA and MSIMI research.

The Hepatic Nerves Regulated Inflammatory Effect in the Process of Liver Injury: Is Nerve the Key Treating Target for Liver Inflammation?

Liver injury is a common pathological basis for various liver diseases. Chronic liver injury is often an important initiating factor in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Currently, hepatitis A and E infections are the most common causes of acute liver injury worldwide, whereas drug toxicity (paracetamol overdose) in the USA and part of Western Europe. In recent years, chronic liver injury has become a common disease that harms human health. Meanwhile, the main causes of chronic liver injury are viral hepatitis (B, C) and long-term alcohol consumption worldwide. During the process of liver injury, massive inflammatory cytokines are stimulated by these hazardous factors, leading to a systemic inflammatory response syndrome, followed by a compensatory anti-inflammatory response, which causes immune cell dysfunction and sepsis, subsequent multi-organ failure. Cytokine release and immune cell infiltration-mediated aseptic inflammation are the most important features of the pathobiology of liver failure. From this perspective, diminishing the onset and progression of liver inflammation is of clinical importance in the treatment of liver injury. Although many studies have hinted at the critical role of nerves in regulating inflammation, there largely remains undetermined how hepatic nerves mediate immune inflammation and how the inflammatory factors released by these nerves are involved in the process of liver injury. Therefore, the purpose of this article is to summarize previous studies in the field related to hepatic nerve and inflammation as well as future perspectives on the aforementioned questions. Our findings were presented in three aspects: types of nerve distribution in the liver, how these nerves regulate immunity, and the role of liver nerves in hepatitis and liver failure.

Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for human non-small-cell lung cancer (NSCLC) treatment. However, acquired resistance to EGFR-TKIs is the major barrier of treatment success, and new resistance mechanism remains to be elucidated. In this study, we found that elevated NADPH oxidase 4 (NOX4) expression was associated with acquired EGFR-TKIs resistance. Gefitinib is the first-generation FDA-approved EGFR-TKI, and osimertinib is the third-generation FDA-approved EGFR-TKI. We demonstrated that NOX4 knockdown in the EGFR-TKI resistant cells enabled the cells to become sensitive to gefitinib and osimertinib treatment, while forced expression of NOX4 in the sensitive parental cells was sufficient to induce resistance to gefitinib and osimertinib in the cells. To elucidate the mechanism of NOX4 upregulation in increasing TKIs resistance, we found that knockdown of NOX4 significantly down-regulated the expression of transcription factor YY1. YY1 bound directly to the promoter region of IL-8 to transcriptionally activate IL-8 expression. Interestingly, knockdown of NOX4 and IL-8 decreased programmed death ligand 1 (PD-L1) expression, which provide new insight on TKIs resistance and immune escape. We found that patients with higher NOX4 and IL-8 expression levels showed a shorter survival time compared to those with lower NOX4 and IL-8 expression levels in response to the anti-PD-L1 therapy. Knockdown of NOX4, YY1 or IL-8 alone inhibited angiogenesis and tumor growth. Furthermore, the combination of NOX4 inhibitor GKT137831 and gefitinib had synergistic effect to inhibit cell proliferation and tumor growth and to increase cellular apoptosis. These findings demonstrated that NOX4 and YY1 were essential for mediating the acquired EGFR-TKIs resistance. IL-8 and PD-L1 are two downstream targets of NOX4 to regulate TKIs resistance and immunotherapy. These molecules may be used as potential new biomarkers and therapeutic targets for overcoming TKIs resistance in the future.

Relation extraction: advancements through deep learning and entity-related features.

Capturing semantics and structure surrounding the target entity pair is crucial for relation extraction. The task is challenging due to the limited semantic elements and structural features of the target entity pair within a sentence. To tackle this problem, this paper introduces an approach that fuses entity-related features under convolutional neural networks and graph convolution neural networks. Our approach combines the unit features of the target entity pair to generate corresponding fusion features and applies the deep learning framework to extract high-order abstract features for relation extraction. Experimental results from three public datasets (ACE05 English, ACE05 Chinese, and SanWen) indicate that the proposed approach achieves F1-scores of 77.70%, 90.12%, and 68.84%, respectively, highlighting its effectiveness and robustness. This paper provides a comprehensive description of the approach and experimental results.

Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.

Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.

Construction of a lipid metabolism-related and immune-associated prognostic score for gastric cancer.

BACKGROUND: The interaction between tumor cells and immune or non-immune stromal cells creates a unique tumor microenvironment, which plays an important role in the growth, invasion and metastasis of gastric cancer (GC). METHODS: The candidate genes were selected to construct risk-score by univariate and multivariate Cox regression analysis. Nomograms were constructed by combining clinical pathological factors, and the model performance was evaluated by receiver operating characteristic curve, decision curve analysis, net reclassification improvement and integrated discrimination improvement. The functional enrichment between high-risk group (HRisk) and low-risk group (LRisk) was explored through GO, KEGG, GSVA and ssGSEA. CIBERSORT, quanTIseq and xCell were used to explore the immune cell infiltration between HRisk and LRisk. The relevant EMT scores, macrophage infiltration scores and various metabolic scores were calculated through the "IOBR" package and analyzed visually. RESULTS: Through univariate and multivariate Cox regression analysis, we obtained the risk-score of fittings six lipid metabolism related genes (LMAGs). Through survival analysis, we found that risk-score has significant prognostic significance and can accurately reflect the metabolic level of patients. The AUCs of the nomogram model incorporating risk-score 1, 3 and 5 years were 0.725, 0.729 and 0.749 respectively. In addition, it was found that the inclusion of risk-score could significantly improve the prediction performance of the model. It was found that the arachidonic acid metabolism and prostaglandin synthesis were up-regulated in HRisk, and more tumor metastasis related markers and immune related pathways were also enriched. Further study found that HRisk had higher immune score and M2 macrophage infiltration. More importantly, the immune checkpoints of tumor associated macrophages involved in tumor antigen recognition disorders increased significantly. We also found that ST6GALNAC3 can promote arachidonic acid metabolism and up-regulate prostaglandin synthesis, increase M2 macrophage infiltration, induce epithelial mesenchymal transformation, and affect the prognosis of patients. CONCLUSIONS: Our research found a novel and powerful LMAGs signature. Six-LMAGs features can effectively evaluate the prognosis of GC patients and reflect the metabolic and immune status. ST6GALNAC3 may be a potential prognostic marker to improve the survival rate and prognostic accuracy of GC patients, and may even be a potential biomarker of GC patients, indicating the response to immunotherapy.

Perylene-based molecular device: multifunctional spintronic and spin caloritronic applications.

Carbon-based magnetic molecular junctions are promising candidates for nanoscale spintronic applications because they are atomically thin and possess high stability and peculiar magnetism. Herein, based on first-principles and non-equilibrium Green's function, we designed a carbon-based molecular spintronic device composed of carbon atomic chains, zigzag-edged graphene nanoribbon (ZGNR), and a perylene molecule. Our results show that the device exhibits integrated spintronic and spin caloritronic functionalities, such as the bias-voltage driven spin filtering effect, negative differential resistance effect and giant magnetoresistance, temperature-gradient driven spin Seebeck effect, thermal spin filtering effect, high thermal magnetoresistance, and thermal colossal giant magnetoresistance. Furthermore, considering the phonon vibration effect, the spin and charge thermoelectric figure of merits (ZTsp and ZTch) can be enhanced and the peak of ZTsp is much larger than that of ZTch, indicating the excellent thermospin performance. The asymmetrical contact configuration between the carbon atomic chain and perylene/ZGNR inhibits the phonon thermal conductivity significantly, leading to the optimal ZTsp and ZTch of 2.4 and 0.5 at 300 K, respectively. These results suggest multifunctional spintronic and spin caloritronic applications for the perylene-based molecular device.

Downstaging and Conversation Strategy for Advanced Hepatocellular Carcinoma with Portal Vein Branch Tumor Thrombus: TACE, 125I Seed Implantation, and RFA for Hepatocellular Carcinoma with Portal Vein Branch Tumor Thrombus.

Background and Objectives: Trans-arterial chemoembolization (TACE) combined with 125I seed implantation is an effective treatment modality for hepatocellular carcinoma (HCC) with a portal vein tumor thrombus (PVTT). However, there are no reports on the effectiveness of radiofrequency ablation (RFA) after downstaging in such patients. This study aimed to investigate the efficacy and safety of TACE in combination with 125I seed implantation and RFA for the treatment of HCC complicated by PVTT. Methods: 49 patients diagnosed with HCC with PVTT between February 2015 and December 2016 were included. All patients were clinically or pathologically diagnosed with advanced HCC, intrahepatic lesions ≤3, and a single tumor diameter ≤70 mm, total diameter ≤100 mm. PVTT was limited to the unilateral portal vein branches. All the patients were treated with TACE combined with PVTT 125I seed implantation. The size and activity of intrahepatic lesions and PVTT were evaluated using enhanced magnetic resonance imaging 3 months after treatment, and other indicators were combined to determine the success of downstaging. Results: A total of 31 patients were successfully downstaged, while 18 patients did not achieve downstaging owing to the progression of intrahepatic lesions or PVTT activity/progression, the success rate of the downstaging was 63.27%. All 31 patients with successful downstaging underwent RFA for intrahepatic lesions. The 1-, 2-, and 3-year survival rates were 90.3%, 80.6%, and 48.4%, respectively. The median overall survival was 36 months (95% CI: 24.7-47.3). Conclusion: 125I seed implantation in combination with TACE can effectively inactivate PVTT and achieve downstaging. Furthermore, the addition of RFA can significantly improve patient survival.

Automation in vitrification and thawing of mouse oocytes and embryos.

Vitrification is a common technique for cryopreserving oocytes or embryos. However, manual vitrification is tedious and labor-intensive, and can be subject to variations caused by human factors. To address these challenges, we developed an automated vitrification-thawing system (AVTS) based on a cryo-handle. Our study firstly assessed the efficiency of cryoprotectant exchange through comparing the osmolalities of fresh and collected solutions during automated vitrification and thawing, and evaluated the cooling and warming rates of the cryo-handle. We also compared mouse oocyte survival, fertilization and embryo development after thawing and ICSI, and the development of re-frozen cleavage embryos between manual operation and automated system. The results showed that the osmolalities of collected samples were within normal range and comparable to fresh solutions. Furthermore, the automated system could obtain the reliable cooling and warming rates. Particularly, there were no significant differences in oocyte survival rates, fertilization rates, and subsequent embryo development and its quality between two procedures. Our findings suggest that AVTS has no impact on osmolalities of vitrification and thawing solutions, ensuring the proper exchange of cryoprotectants. The cryo-handle also shows the ability to achieve reliable cooling and warming rates, which benefits for the cryopreservation and thawing process. Moreover, the results from mouse oocytes and embryos indicate that automated system has effectively maintained the survival and fertilization of frozen oocytes and supported subsequent embryo development. Therefore, the automated vitrification and thawing system will inevitably represent a superior alternative to manual operation.

Transarterial chemoembolization combined with apatinib with or without PD-1 inhibitors in BCLC stage C hepatocellular carcinoma: A multicenter retrospective study.

Objective: We evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib plus PD-1 inhibitors (TACE-AP) compared with TACE combined with apatinib (TACE-A) in patients with advanced hepatocellular carcinoma (HCC) and to explore the prognostic factors affecting patient survival. Methods: Data from patients with unresectable HCC who received TACE-AP or TACE-A from December 2018 to June 2021 were collected retrospectively. The main outcome of the study was overall survival (OS) and prognostic factors affecting survival, while the secondary outcomes were progression-free survival (PFS), the objective response rate (ORR), and treatment-related adverse events (TRAEs). Propensity score matching (PSM) analysis was used to reduce patient selection bias, and the random survival forest (RF) model was employed to explore prognostic factors affecting patient survival. Results: We enrolled 216 patients, including 148 and 68 patients in the TACE-A and TACE-AP groups, respectively. A total of 59 pairs of patients were matched using PSM analysis. Before and after PSM, the OS, PFS, and ORR in the TACE-AP group were significantly higher than in the TACE-A group (before, OS: 22.5 months vs. 12.8 months, P < 0.001; PFS: 6.7 months vs. 4.3 months, P < 0.001; ORR: 63.2% vs. 34.5%, P < 0.001; after, OS: 22.5 months vs. 12.0 months, P < 0.001; PFS: 6.7 months vs. 4.3 months, P < 0.001; ORR: 62.7% vs. 30.5%, P = 0.003). Multivariate Cox regression and RF models before and after PSM analysis revealed that the main prognostic factors affecting survival were tumor number, portal vein tumor thrombus (PVTT) invasion, alpha-fetoprotein (AFP) levels, total bilirubin (TBIL) level, and treatment. There was no significant difference in TRAEs between the two groups (P > 0.05). Conclusion: Compared with TACE-A, TACE-AP significantly improved OS, PFS, and ORR in patients with advanced HCC. The number of tumors, PVTT invasion, AFP levels, TBIL level, and treatment were significant prognostic factors associated with patient survival. All observed TRAEs were mild and controllable.

Comparison of methods of isolating extracellular vesicle microRNA from HepG2 cells for High-throughput sequencing.

Background: Extracellular vesicles (EVs) were reported to participate in various cellular processes based on the biomolecules, particularly microRNAs. Numerous commercial EVs isolation reagents are available. However, whether these reagents are suitable for separating EVs from the culture medium supernatant supernatant of model cell lines, such as HepG2, and whether the isolated products are suitable for High-throughput sequencing remains unclear. Methods: We examined three commonly used EVs isolation kits: the ExoQuick-TC exosome precipitation solution (EQ), Total Exosome Isolation from cell culture medium (EI), and exoEasy Maxi Kit (EM), to isolate EVs from HepG2 cell culture medium supernatants. EVs were identified based on marker proteins, particle size measurements, and electron microscopy analysis. The total amounts of microRNA and microRNA High-throughput sequencing data quality from EVs isolated by each kit were compared. Results: The total amount of EVs' microRNA isolated from the EI and EM groups were higher than that obtained from the EQ group (EQ/EI: p = 0.036, EI/EM: p = 0.024). High-throughput sequencing data quality evaluation showed that the EI group possessed higher quality than those in the EM group. Conclusion: For the cell culture medium from HepG2, EVs' microRNA isolated by EI reagents might be more suitable for High-throughput sequencing applications.

Prospective study of TACE combined with sorafenib vs TACE combined with 125I seed implantation in the treatment of hepatocellular carcinoma with portal vein tumor thrombus and arterioportal fistulas.

Purpose: To compare the efficacy of TACE combined with sorafenib and TACE combined with 125I seed implantation in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) combined with arterioportal fistulas (APFs), and discuss the efficacy and safety of TACE combined with 125I seed implantation. Patients and methods: Between January 2017 and December 2018, the clinical data of patients with HCC complicated with PVTT and APFs who were admitted to the Affiliated Cancer Hospital of Zhengzhou University, First Affiliated Hospital of Zhengzhou University, and Henan Provincial People's Hospital were prospectively collected. The patients were divided into the TACE+sorafenib (TACE-S) group based on their treatment willingness. There were 26 and 32 patients in the TACE-S and TACE-125I groups, respectively. Both groups of patients underwent APFs occlusion during TACE therapy. The embolization effect of APFs was observed and recorded in the two groups, the efficacy of intrahepatic lesions and PVTT was evaluated, and the effects of different treatment methods on the efficacy were analysed. Results: All patients completed the 3 months follow-up. The improvement rates of APFs in TACE-S and TACE-125I groups were 30.77% (8/26) and 68.75% (22/32), respectively, and difference was statistically significant (χ2 = 8.287, P=0.004). The median survival time of TACE-S and TACE-125I groups was 8.00 months and 12.8 months, respectively (χ2 = 7.106, P=0.008). Multivariate analysis showed that the PVTT subtype (IIa/IIb) and treatment method (TACE-S or TACE-125I) were independent factors affecting the recanalization of APFs in patients (P<0.05). Conclusion: For patients with HCC with PVTT and APFs, TACE combined with 125I seed implantation can effectively treat portal vein tumor thrombus, thereby reducing the recanalization of APFs and prolonging the survival time of patients.

Plasma arginase-1 as a predictive marker for early transarterial chemoembolization refractoriness in unresectable hepatocellular carcinoma.

Objective: To explore the relationship between plasma arginase-1 (ARG1) and early transarterial chemoembolization (TACE) refractoriness in patients with hepatocellular carcinoma (HCC) and develop nomograms for predicting early TACE refractoriness. Methods: A total of 200 patients with HCC, treated with TACE, were included in the study, including 120 in the training set and 80 in the validation set. Pre-treatment enzyme-linked immunosorbent assay was used to detected the plasma ARG1 levels of the patient, and independent predictors of early TACE refractoriness were determined using a multivariate logistic regression model, based on which a predictive model was developed using a nomogram. Results: Risk of early TACE refractoriness was negatively correlated with plasma ARG1 levels, and multivariate logistic analysis showed tumour size (OR = 1.138, 95% CI = 1.006-1.288, P = 0.041), multiple tumors (OR=4.374, 95% CI = 1.189-16.089, P = 0.026), platelet count (OR = 0.990, 95% CI = 0.980-0.999, P = 0.036), and plasma ARG1 levels (OR = 0.209, 95% CI = 0.079-0.551, P = 0.002) to be independent prognostic factors for early TACE refractoriness.The AUC value for the nomogram of the training cohort was 0.786 (95% CI = 0.702-0.870), and the validation set AUC value was 0.833 (95% CI = 0.791-0.875).The decision curve analysis suggested that the nomogram had good clinical utility. Conclusion: High plasma ARG1 expression was associated with a lower incidence of early TACE refractoriness. The nomogram constructed based on four independent prognostic factors could facilitate an individualised prediction of the incidence of early TACE refractoriness.

Alkali metal-modified crystalline carbon nitride for photocatalytic nitrogen fixation.

Alkali metal chlorides have been used as molten salts for further preparing crystalline carbon nitride, but the effect of alkali metal types on the properties of crystalline carbon nitride has not been systematically studied. Therefore, in this paper, a series of crystalline carbon nitride samples doped with different alkali metals were successfully prepared using LiCl-KCl, KCl-NaCl, LiCl-KCl-NaCl and LiCl-NaCl as molten salts: LK-HTCN (Li-K co-doping), KN-HCN (K-Na co-doping), LKN-HTCN (Li-K-Na co-doping) and LN-HTCN (Li-Na co-doping). The experimental results show that KN-HCN contains only the heptazine unit structure, while the other samples contain heptazine and triazine unit structures. Meanwhile, the concentration of the cyano group in the KN-HCN sample structure is significantly higher than that of other samples, which may be related to the fact that there is only a heptazine unit in the structure of the KN-HCN sample. In addition, the loading mode of K and Na ions in the KN-HCN structure is favorable for the migration and separation of photogenerated charges. Thanks to these characteristics, KN-HCN showed excellent photocatalytic ammonia production activity. This study can provide theoretical insight for the development of crystallized carbon nitride.

Local ablation of pulmonary malignancies abutting pleura: Evaluation of midterm local efficacy and safety.

Objective: To retrospectively evaluate the efficacy and safety of local ablation treatment for adjacent pleural lung tumors. Materials and methods: Sixty-two patients who underwent pulmonary nodule ablation at the Affiliated Cancer Hospital of Zhengzhou University were enrolled between January 2016 and December 2020. All patients were followed up with enhanced computed tomography or magnetic resonance imaging within 48 h after treatment and 2, 4, 6, 9, and 12 months after treatment. All patients were followed for at least 12 months. Results: A total of 84 targeted tumors (62 patients) underwent 94 ablations. In the 12-month follow-up images, 69 of the 84 targeted tumors were completely ablated, 15 had incomplete ablation, and the 12-month incomplete ablation rate was 17.8% (15/84). Of the 15 incompletely ablated tumors, six had partial responses, five had stable disease, and four had progressive disease. The most common adverse event was pneumothorax, with an incidence of 54.8% (34/62). The second most common complication was pleural effusion, with an incidence rate of 41.9% (26/62). The incidence of needle-tract bleeding was 21% (13/62) and all patients were cured using hemostatic drugs. Serious complications were bronchopleural fistula in four patients (6.5%, 4/62) and needle tract metastasis in one patient. Four cases of bronchopleural fistula were found in the early stages and were cured after symptomatic treatment. Conclusion: Local ablation is effective for the treatment of adjacent pleural lung tumors, and its operation is safe and controllable.

Preclinical safety of a bionic tiger bone capsule in Sprague-Dawley rats and beagle dogs.

BACKGROUND: Jintiange capsule is composed of bionic tiger bone powder and has similar ingredients to natural tiger bone. OBJECTIVE: To characterize the subacute toxicities of Jintiange capsule in rats and beagle dogs for preclinical safety assessment. METHODS: Suspensions of Jintiange capsule were given via gastric lavage over a 26-week period at low (500 mg/kg), mid (1500 mg/kg) and high doses (4000 mg/kg) in SD rats. Beagles were given by gastric lavage of suspensions of Jintiange capsule once daily for 6 days per week for 39 weeks at low (300 mg/kg), mid (900 mg/kg) or high dose (2000 mg/kg). RESULTS: Repeated gastric lavages of suspensions of Jintiange capsule at doses from 500 to 4000 mg/kg over 26 weeks caused no significant toxicity (No Observed Adverse Effect Level, NOAEL) in rats. In addition, repeated gastric lavages of suspensions of Jintiange capsule at doses from 300 to 2000 mg/kg over 39 weeks caused NOAEL in beagles. CONCLUSIONS: Jintiange capsule was safe in rats at a dose 66.7 times the clinically recommended dose and in beagles at 33.3 times the clinically recommended dose. Our subacute toxicity studies in rats and beagles demonstrated no apparent overall toxicities including haematotoxicities, hepatotoxicities and renal toxicities.

Self-healing, injectable hydrogel based on dual dynamic covalent cross-linking against postoperative abdominal cavity adhesion.

Clinically, increasing the peritoneal barrier is an effective adjunct to reducing postoperative peritoneal adhesion. This study presents a facile template for preparing a supramolecular hybrid hydrogel through dynamic covalent cross-linking between carboxymethyl chitosan (CMCS), 2-formylphenylboronic acid (2-FPBA), and quercetin (Que). The as-prepared complex CMCS/2-FPBA/Que (CFQ) hydrogel exhibited favorable antibacterial, anti-inflammatory, and antioxidant effects. A L929 cytotoxicity evaluation confirmed the favorable cytocompatibility of the CFQ hydrogel. The postoperative anti-adhesion ability of the CFQ hydrogel was further evaluated in rats with lateral wall defects and cecal abrasions. Compared with control groups, the tissue adhesion rate was significantly reduced by increasing the Que concentration in all the hydrogel-treated groups. Additionally, the sustained-release time of the C3F0.8Q0.08 hydrogel can exceed 14 days, which is highly desirable for clinical wound treatment. STATEMENT OF SIGNIFICANCE: Postoperative adhesions are a very common postoperative complication that seriously affects the quality of life of patients. The currently commonly used methods for preventing adhesion mainly use degradable barrier materials for physical separation. In this study, we prepared a dual dynamic covalently cross-linked CFQ hydrogel, which is not only degradable and injectable, but also has multiple properties such as antibacterial, antioxidant and anti-inflammatory, which can effectively prevent postoperative adhesion and promote wound healing.

Metallothionein 2A (MT2A) controls cell proliferation and liver metastasis by controlling the MST1/LATS2/YAP1 signaling pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the three major cancers in the world and is the cancer with the most liver metastasis. The present study aimed to investigate the role of metallothionein 2A (MT2A) in the modulation of CRC cell proliferation and liver metastasis, as well as its molecular mechanisms. METHODS: The expression profile of metallothionein 2A (MT2A) in colorectal cancer retrieved from TCGA, GEO and Oncomine database. The biological effect of MT2A overexpression was investigated mainly involving cell proliferation and migration in CRC cells as well as growth and metastasis in CRC animal models. To explore the specific mechanism of MT2A metastasis in CRC, transcriptome sequencing was used to compare the overall expression difference between the control group and the MT2A overexpression group. RESULTS: Metallothionein 2A (MT2A) was downregulated in the tumor tissues of patients with CRC compared to adjacent normal tissues and was related to the tumor M stage of patients. MT2A overexpression inhibited CRC cell proliferation and migration in cells, as well as growth and metastasis in CRC animal models. While knockdown of MT2A had the opposite effect in cells. Western blotting confirmed that MT2A overexpression promoted the phosphorylation of MST1, LAST2 and YAP1, thereby inhibiting the Hippo signaling pathway. Additionally, specific inhibitors of MST1/2 inhibited MT2A overexpression-mediated phosphorylation and relieved the inhibition of the Hippo signaling pathway, thus promoting cell proliferation. Immunohistochemistry in subcutaneous grafts and liver metastases further confirmed this result. CONCLUSIONS: Our results suggested that MT2A is involved in CRC growth and liver metastasis. Therefore, MT2A and MST1 may be potential therapeutic targets for patients with CRC, especially those with liver metastases.