Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Mitochondria-localizing triphenylphosphine-8-hydroxyquinoline Ru complexes induce ferroptosis and their antitumor evaluation.

Ruthenium complexes are one of the most promising anticancer drugs and ferroptosis is a novel form of regulated cell death, the study on the effect of Ru complexes on ferroptosis is helpful to find more effective antitumor drugs. Here, the synthesis and characterization of two Ru complexes containing 8-hydroxylquinoline and triphenylphosphine as ligands, [Ru(L1) (PPh3)2Cl2] (Ru-1), [Ru(L2) (PPh3)2Cl2] (Ru-2), were reported. Complexes Ru-1 âˆ¼ Ru-2 showed good anticancer activity in Hep-G2 cells. Researches indicated that complexes Ru-1 âˆ¼ Ru-2 could be enriched and appear as red fluorescence in the mitochondria, arouse dysfunction of mitochondria, induce the accumulation of reactive oxygen species (ROS) and lipid peroxidation (LPO), while the morphology of nuclei and cell apoptosis had no significant change. Further experiments proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in Hep-G2 cells. Remarkably, Ru-1 showed high inhibitory activity against xenograft tumor growth in vivo (TGIR = 49%). This study shows that the complex Ru-1 could act as a novel drug candidate by triggering cell ferroptosis.

Ras-Targeting Stabilized Peptide Increases Radiation Sensitivity of Cancer Cells.

Radiation therapy is one of the most common treatments for cancer. However, enhancing tumors' radiation sensitivity and overcoming tolerance remain a challenge. Previous studies have shown that the Ras signaling pathway directly influences tumor radiation sensitivity. Herein, we designed a series of Ras-targeting stabilized peptides, with satisfactory binding affinity (KD = 0.13 µM with HRas) and good cellular uptake. Peptide H5 inhibited downstream phosphorylation of ERK and increased radio-sensitivity in HeLa cells, resulting in significantly reduced clonogenic survival. The stabilized peptides, designed with an N-terminal nucleation strategy, acted as potential radio-sensitizers and broadened the applications of this kind of molecule. This is the first report of using stabilized peptides as radio-sensitizers, broadening the applications of this kind of molecule.

[Effect and mechanism of Linggui Zhugan Decoction in regulating Sig1R on Angâ ¡-induced cardiomyocyte hypertrophy].

This study aims to explore the mechanism of Linggui Zhugan Decoction(LGZGD) in inhibiting Angiotensin Ⅱ(AngⅡ)-induced cardiomyocyte hypertrophy by regulating sigma-1 receptor(Sig1R). The model of H9c2 cardiomyocyte hypertrophy induced by AngⅡ in vitro was established by preparing LGZGD-containing serum and blank serum. H9c2 cells were divided into normal group, AngⅡ model group, 20% normal rat serum group(20% NSC), and 20% LGZGD-containing serum group. After the cells were incubated with AngⅡ(1 µmol·L~(-1)) or AngⅡ with serum for 72 h, the surface area of cardiomyocytes was detected by phalloidine staining, and the activities of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase were detected by micromethod. The mitochondrial Ca~(2+) levels were detected by flow cytometry, and the expression levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP), Sig1R, and inositol 1,4,5-triphosphate receptor type 2(IP_3R_2) were detected by Western blot. The expression of Sig1R was down-regulated by transfecting specific siRNA for investigating the efficacy of LGZGD-containing serum on cardiomyocyte surface area, Na~+-K~+-ATPase activity, Ca~(2+)-Mg~(2+)-ATPase activity, mitochondrial Ca~(2+), as well as ANP, BNP, and IP_3R_2 protein expressions. The results showed that compared with the normal group, AngⅡ could significantly increase the surface area of cardiomyocytes and the expression of ANP and BNP(P<0.01), and it could decrease the activities of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase, the concentration of mitochondrial Ca~(2+), and the expression of Sig1R(P<0.01). In addition, IP_3R_2 protein expression was significantly increased(P<0.01). LGZGD-containing serum could significantly decrease the surface area of cardiomyocytes and the expression of ANP and BNP(P<0.05, P<0.01), and it could increase the activities of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase, the concentration of mitochondrial Ca~(2+ )(P<0.01), and the expression of Sig1R(P<0.05). In addition, IP_3R_2 protein expression was significantly decreased(P<0.05). However, after Sig1R was down-regulated, the effects of LGZGD-containing serum were reversed(P<0.01). These results indicated that the LGZGD-containing serum could inhibit cardiomyocyte hypertrophy induced by AngⅡ, and its pharmacological effect was related to regulating Sig1R, promoting mitochondrial Ca~(2+ )inflow, restoring ATP synthesis, and protecting mitochondrial function.

Application value of intraoperative electrophysiological monitoring in cerebral eloquent area glioma surgery: a retrospective cohort study.

INTRODUCTION: Surgery for gliomas involving eloquent areas is a very challenging microsurgical procedure. Maximizing both the extent of resection (EOR) and preservation of neurological function have always been the focus of attention. Intraoperative neurophysiological monitoring (IONM) is widely used in this kind of surgery. The purpose of this study was to evaluate the efficacy of IONM in eloquent area glioma surgery. METHODS: Sixty-eight glioma patients who underwent surgical treatment from 2014 to 2019 were included in this retrospective cohort study, which focused on eloquent areas. Clinical indicators and IONM data were analysed preoperatively, two weeks after surgery, and at the final follow-up. Logistic regression, Cox regression, and Kaplan‒Meier analyses were performed, and nomograms were then established for predicting prognosis. The diagnostic value of the IONM indicator was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: IONM had no effect on the postoperative outcomes, including EOR, intraoperative bleeding volume, duration of surgery, length of hospital stay, and neurological function status. However, at the three-month follow-up, the percentage of patients who had deteriorated function in the monitored group was significantly lower than that in the unmonitored group (23.3% vs. 52.6%; P < 0.05). Logistic regression analysis showed that IONM was a significant factor in long-term neurological function (OR = 0.23, 95% CI (0.07-0.70). In the survival analysis, long-term neurological deterioration indicated worsened overall survival (OS) and progression-free survival (PFS). A prognostic nomogram was established through Cox regression model analysis, which could predict the probability 3-year survival rate. The concordance index was 0.761 (95% CI 0.734-0.788). The sensitivity and specificity of IONM evoked potential (SSEP and TCeMEP) were 0.875 and 0.909, respectively. In the ROC curve analysis, the area under the curve (AUC) for the SSEP and TCeMEP curves was 0.892 (P < 0.05). CONCLUSIONS: The application of IONM could improve long-term neurological function, which is closely related to prognosis and can be used as an independent prognostic factor. IONM is practical and widely available for predicting postoperative functional deficits in patients with eloquent area glioma.

Extracellular vesicles of Bifidobacterium longum reverse the acquired carboplatin resistance in ovarian cancer cells via p53 phosphorylation on Ser15.

We previously found that the relative abundance of Bifidobacterium was increased after chemotherapy; however, the role of Bifidobacterium longum in chemotherapeutic drug resistance in ovarian cancer (OVC) remains unclear. This study aimed to understand the potential effects and mechanism of B. longum extracellular vesicles (B. longum-EVs) on carboplatin (CBP) resistance in OVC. Eight normal and 11 ovarian tissues were collected and the expression of B. longum genomic DNA and its association with acquired CBP resistance in OVC patients was determined. After isolating EVs by ultracentrifugation from B. longum (ATCC 15707), CBP-resistant A2780 cells were treated with PBS, CBP, B. longum-EVs, or CBP + B. longum-EVs, and subsequently analyzed by CCK-8, Edu staining, Annexin V/PI double staining, wound healing, and Transwell assays to detect cell viability, proliferation, apoptosis, migration, and invasion, respectively. MRP1, ATP7A, ATP7B, and p53 expression as well as p53 phosphorylation were measured by western blot analysis. S15A mutation of p53 was assessed to examine the potential role of p53 Ser15 phosphorylation in CBP-resistant OVC. B. longum levels were elevated and positively associated with CBP resistance in OVC patients. Only high concentrations of B. longum-EVs attenuated A2780 cell proliferation, apoptosis, migration, and invasion. B. longum-EVs exposure significantly enhanced the sensitivity of CBP-resistant A2780 cells to CBP and decreased the expression of drug resistance-related proteins. The effect of B. longum-EVs on reversing CBP resistance was completely inhibited by S15A mutation of p53. B. longum-EVs enhanced the sensitivity of OVC cells to CBP through p53 phosphorylation on Ser15.

Atmospheric occurrences and bioavailability health risk of PAHs and their derivatives surrounding a non-ferrous metal smelting plant.

Non-ferrous metal smelting emits large amounts of organic compounds into the atmosphere. Herein, 20 parent polycyclic aromatic hydrocarbons (PPAHs), 9 nitrated PAHs (NPAHs), 14 chlorinated PAHs (ClPAHs), and 6 alkylated PAHs (APAHs) in atmospheric samples from a typical non-ferrous metal smelting plant (NMSP) and residential areas were detected. In NMSP, benzo[a]pyrene, dibenz[a,h]anthracene, 6-nitrochrysene, 9-chlorofluorene, and 1-methylfluorene were the predominant compounds in the particulate phase, while phenanthrene constituted 57.3% in the gaseous phase. The concentration of PAHs in residential areas around NMSP was 1.8 times higher than that in the control area. Additionally, there was a significant negative correlation between the concentration and the distance from the NMSP. In terms of health risks, although the skin penetration coefficient of PM2.5 is smaller than that of the gaseous phase, dermal absorption of PM2.5 posed a greater threat to the population, the incremental lifetime cancer risk (ILCR) of NMSP was 1.8 × 10-4. After considering bioavailability, BILCR decreased by 1-2 orders of magnitude in different regions, and dermal absorption decreased more than inhalation intake. Nevertheless, the dermal absorption of PM2.5 in NMSP still presents a probable carcinogenic risk. This study provides a necessary reference for the subsequent control of NMSP contamination.

A prospective randomized trial comparing the pocket-creation method and conventional method of endoscopic submucosal dissection in early gastric cancers and precancerous lesions.

BACKGROUND: Endoscopic submucosal dissection (ESD) is widely used as a standard treatment regimen for early gastric cancers (EGCs). However, such an approach is time-consuming and has a high risk of perforation and bleeding in some corner-site lesions because of the obscured view and difficulty in submucosal lifting. The newly developed pocket-creation method (PCM) provides a clearer view and better traction of the submucosal layer than conventional ESD (c-ESD). Nevertheless, no prospective randomized study has evaluated the efficacy of the PCM in EGCs and precancerous lesions. METHODS: This was a prospective randomized controlled trial. Patients with superficial gastric neoplastic lesions≥20mm were randomly assigned to the PCM-ESD group or c-ESD group. The primary outcome was dissection speed. RESULTS: There were 28 patients in the PCM-ESD group and 27 in the c-ESD group. The median dissection speed was significantly higher in the PCM-ESD group than in the c-ESD group (21.5 mm2/min vs. 14.3 mm2/min, P<0.001). Meanwhile, the operation time in the PCM-ESD group was significantly shorter than that in the c-ESD group (30min vs. 40min，P=0.047). In multiple linear regression analysis, the treatment method was independently associated with the resection speed of ESD. CONCLUSIONS: PCM-ESD was an effective and safe treatment for EGCs and precancerous lesions.

[Mechanism of Kuntai Capsules in treatment of polycystic ovary syndrome rat models based on AGE-RAGE signal pathway].

This study aims to investigate the impact of Kuntai Capsules(KTC) on polycystic ovarian syndrome(PCOS) rat models and explore the underlying mechanism. Fifty female SD rats were randomly divided into five groups(10 rats in each group), including control group, model group, low-, medium-, and high-dose KTC group. Except for the control group, the other groups were injected with dehydroepiandrosterone(DHEA) combined with a high-fat diet(HFD) to induce the PCOS rat model for 28 days. 0.315, 0.63, and 1.26 g·kg~(-1)·d~(-1) KTC was dissolved in the same amount of normal saline and given to low-, medium-, and high-dose KTC groups by gavage. Both control group and model group were given the same amount of normal saline for 15 days. After administration, fasting blood glucose(FBG) was measured by a glucose meter. Fasting insulin(FINS), luteinizing hormone(LH), testosterone(T), and follicle-stimulating hormone(FSH) were detected by enzyme-linked immunosorbent assay(ELISA), and LH/FSH ratio and insulin resistance index(HOMA-IR) were calculated. The pathological morphology of ovarian tissue was observed by hematoxylin-eosin(HE) staining. The expression levels of collagen α type Ⅲ 1 chain(COL3A1), apoptotic factors Bax, and Bcl-2 were detected using Western blot and immunofluorescence. The mRNA expressions of COL3A1, Bax, and Bcl-2 in ovarian tissue were performed by real-time PCR(RT-PCR). The results show that compared with the control group, the body weight, serum levels of FBG, FINS, LH, T, LH/FSH, and HOMA-IR are higher in model group(P<0.05 or P<0.01), and the level of FSH is lower(P<0.05). In model group, a large number of white blood cells are found in the vaginal exfoliated cells, mainly in the interictal phase. There are more cystic prominences on the surface of the ovary. The thickness of the granular cell layer is reduced, and oocytes are absent. COL3A1 and Bax protein expression levels are increased(P<0.01), while Bcl-2 protein expression levels are decreased(P<0.05) in the ovarian tissue COL3A1 and Bax mRNA expression levels are increased in ovarian tissue(P<0.05). Compared with the model group, the body weight, FBG, FINS, LH, T, LH/FSH, and HOMA-IR in low-, medium-, and high-dose KTC groups are decreased(P<0.05 or P<0.01), while the levels of FSH in medium-, and high-dose KTC groups are increased(P<0.05 or P<0.01). Low-, medium-, and high-dose KTC groups gradually show a stable interictal phase. The surface of the ovary is smooth. Oocytes and mature follicles can be seen in ovarian tissue, and the thickness of the granular cell layer is increased. The expression level of COL3A1 protein decreases in low-and medium-dose KTC groups(P<0.05 or P<0.01), and that of Bax protein decreases in low-dose KTC group(P<0.05 or P<0.01), and the expression level of Bcl-2 protein increases in low-dose KTC group(P<0.01). The expression levels of COL3A1 and Bax mRNA decreased in the low-dose KTC group(P<0.05), while the expression levels of Bcl-2 mRNA increased(P<0.05). In summary, KTC can inhibit ovarian granulosa cell apoptosis and reduce follicular atresia by regulating the AGE-RAGE signaling pathway. It can promote insulin secretion, reduce blood sugar and body weight, restore serum hormone levels, improve symptoms of PCOS, alleviate morphological damage of the ovary, and restore ovarian function, which is of great value in the treatment of PCOS.

Association between increased systemic immune-inflammation index and postoperative delirium in older intertrochanteric fracture patients.

BACKGROUND AND PURPOSE: The systemic immune-inflammation index (SII), a novel inflammation index derived from the counts of circulating platelets, neutrophils and lymphocytes, has been studied in the treatment of acute cancer and ischemic stroke (AIS). However, the clinical value of the SII in postoperative delirium patients has not been further investigated. The purpose of our research was to study the incidence and preoperative risk factors for postoperative delirium (POD) and verify whether the SII could serve as a potential marker for POD in older intertrochanteric fracture patients. Finally, we created a novel nomogram for predicting POD in older patients with intertrochanteric fractures. METHODS: We enrolled elderly patients with intertrochanteric fractures who underwent proximal femoral nail antirotation (PFNA) between February 2021 and April 2023. Univariate and multivariate logistic analyses were subsequently performed to confirm the risk factors and construct a nomogram model.Calibration curve and clinical decision curve analysis (DCA) were used to assess the model's fitting performance. The performance of the nomogram was evaluated for discrimination, calibration, and clinical utility. RESULTS: A total of 293 patients were eligible for inclusion in the study, 25.6% (75/293) of whom had POD. The POD patients had higher SII values than the non-POD patients. The SII was strongly correlated with POD in older intertrochanteric fracture patients, and the optimal cutoff value was 752.6 × 109. Multivariate analysis revealed that age, diabetes, total albumin, SII > 752.6 × 109 and a CRP > 20.25 mg/L were independent risk factors for POD patients. By incorporating these 5 factors, the model achieved a concordance index of 0.745 (95% CI, 0.683-0.808) and had a well-fitted calibration curve and good clinical application value. CONCLUSION: The SII is a simple and valuable biomarker for POD, and the new nomogram model can be used to accurately predict the occurrence of POD. They can be utilized in clinical practice to identify those at high risk of POD in older intertrochanteric fracture patients.

Prognostic significance of circulating tumor DNA in urothelial carcinoma: a systematic review and meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a non-invasive technique that provides valuable insights into molecular profiles and tumor disease management. This study aimed to evaluate the prognostic significance of circulating tumor DNA (ctDNA) in urothelial carcinoma (UC) through a systematic review and meta-analysis. METHODS: A comprehensive search was conducted in MEDLINE, EMBASE, and the Cochrane Library from the inception to December 2023. Studies investigating the prognostic value of ctDNA in UC were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted. Overall meta-analysis and subgroup exploration stratified by metastatic status, ctDNA sampling time, treatment type, and detection method was performed using the R software (version 4.2.2). RESULTS: A total of sixteen studies with 1725 patients were included. Fourteen studies assessed the association between baseline ctDNA status and patient outcomes. Patients with elevated ctDNA levels exhibited significantly worse DFS (HR=6.26; 95% CI, 3.71-10.58, P<0.001) and OS (HR=4.23; 95% CI, 2.72-6.57, P<0.001) regardless of metastatic status, ctDNA sampling time, treatment type and detection methods. Six studies evaluated the prognostic value of ctDNA dynamics in UC. Patients who showed a decrease or clearance in ctDNA levels during treatment or observation demonstrated more favorable DFS (HR=0.26, 95% CI, 0.17-0.41, P<0.001) and OS (HR=0.21, 95% CI, 0.11-0.38, P<0.001) compared to those who did not. The association remained consistent across the subgroup analysis based on metastatic status and detection methods. In the immune checkpoint inhibitor-treated setting, both lower baseline ctDNA level and ctDNA decrease during the treatment were significantly associated with more favorable oncologic outcomes. Furthermore, specific gene mutations such as FGFR3 identified in ctDNA also demonstrated predictive value in UC patients. CONCLUSION: This meta-analysis demonstrates a strong association of ctDNA status and its dynamic change with survival outcomes in UC, suggesting substantial clinical utility of ctDNA testing in prognosis prediction and decision making in this setting.

Investigation of temperature effects on wide steel box girder of suspension bridge based on long-term monitoring data.

The time-varying temperature distributions on bridge structures may remarkably change structural performance, which may result in differential strain/stress responses on structural members compared with the design conditions. Therefore, it is crucial to have a comprehensive understanding of temperature distributions and its effects on bridges. In this study, taking advantage of structural health monitoring technology, 1-year field monitoring data collected from a long-span suspension bridge were used to investigate the temperature distributions and their effects on the steel box girder. Specifically, the distributions and probability statistics of temperatures on the top and bottom plates were firstly analyzed. Based on which, the transverse and vertical temperature differences on the box girder were further examined, moreover, the representative values of temperature differences for various return periods were calculated by exceedance probability method. At end, a temperature prediction method was proposed to simulated the temperature field distributions during bridge life cycle, to provide substantial temperature data for estimating future operation condition. The results of this study were beneficial to structural evaluation of in-service bridges to ensure their serviceability and integrity in the life cycle.

Comparison of ICG-Guided Near-Infrared Fluorescence Imaging and Modified Inflation-Deflation Method in Identifying the Intersegmental Plane During Lung Segmentectomy of Infants.

BACKGROUND: The identification of the intersegmental plane (ISP) is a crucial step in segmentectomy for children with congenital pulmonary airway malformation (CPAM) due to complex anatomical variations. However, there is very limited literature available on this aspect specifically for infant. In this study, we compared the intravenous indocyanine green (ICG)-guided near-infrared fluorescence (NIRF) imaging method with the modified inflation-deflation method in terms of their perioperative characteristics and summarized our experience. METHODS: From June 2021 to November 2022, the data of 83 patients with CPAM who underwent segmentectomy by video-assisted thoracoscopic surgery were retrospectively reviewed. Twenty-eight patients underwent ICG-guided NIRF method, and 56 patients underwent the modified inflation-deflation method, characteristics and clinical outcomes were compared. RESULTS: The median age of the patients was 4.99 months (4.99 ± 1.51) with a mean body weight of 7.54 kg (7.54 ± 1.99). Both methods could accurately identify the ISP. The time taken to clearly display the ISP was shorter in ICG group than in the modified inflation-deflation group (0.18 ± 0.08 vs. 6.49 ± 1.67 min; P < 0.001), and the surgical duration (61.32 ± 14.28 vs. 88.18 ± 8.03 min; P < 0.001) were significantly shorter in the ICG group too. The two groups exhibited differences in the length of chest tube drainage (1.75 ± 1.24 vs. 2.36 ± 1.54 days; P = 0.072) and the length of hospital stay (4.61 ± 1.75 vs. 5.20 ± 3.07 days; P = 0.078), however, the differences were not statistically significant. There were no significant differences between the two groups in the blood lost and postoperative complications. At a follow-up of more than 1 year after operation, all patients had recovered well without recurrence. CONCLUSIONS: According to our experience, the ICG-guided NIRF method was safe and feasible for infants during thoracoscopic segmentectomy, it can quickly display the ISP and shorten the surgical duration compared with the modified inflation-deflation method.

Assessing the application of barbed sutures in comparison to conventional sutures for surgical applications: a global systematic review and meta-analysis of preclinical animal studies.

BACKGROUND: Following an initiative published by Lancet in 2002 and an IDEAL-D framework, the value of preclinical animal studies has garnered increasing attention in recent research. Numerous preclinical animal experiments tried to generate evidence to guide the development of barbed sutures. However, discernible drawbacks and incongruities in outcomes have emerged between clinical and preclinical animal studies. Therefore, this meta-analysis aimed to review the preclinical animal experiments comparing barbed sutures with conventional sutures. The authors hope to facilitate clinical translation of barbed sutures by evaluating effectiveness, safety, and physical properties/reliability. MATERIALS AND METHODS: A systematic search of PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov was conducted to identify controlled preclinical animal experiments comparing barbed sutures with conventional sutures. The risk of bias was assessed using SYRCLE. GRADE approach was used to evaluate evidence quality. Revman was applied to analyze all the data. Subgroup, sensitivity, and meta-regression analyses were also performed. RESULTS: A total of 62 articles were eligible with low to moderate quality, including 2158 samples from 10 different animal species across 27 surgical procedures. Barbed suture exhibited a significant reduction in suture time, limited change in Cross-Sectional Area (CSA), and decreased instances of tissue disruption (all P <0.05). Subgroup analyses, considering both clinical and research significance, indicated that barbed sutures might cause more specific adverse events and demonstrate suboptimal performance of physical properties/reliability. Meta-regression suggested that heterogeneity resulted from variations in studies and animal models. CONCLUSION: Although barbed suture demonstrated superiority in numerous surgeries for time efficiency, its safety and physical properties/reliability might be influenced by diverse preclinical models, sutures' brand, surgeries, and anatomical sites. Further evaluation, based on standardized and well-designed animal experiments, is essential for medical device development and applications in human beings.

Tumor necrosis factor α1 decreases mucosal immune and antioxidant response in the midgut of hybrid fish (white crucian carp ♀ × red crucian carp ♂).

Tumor necrosis factor α1 (TNFα) is a pleiotropic cytokine involved in immune regulation and cellular homeostasis, but the crucial role of TNFα in fish gut remained unclear. The current study aimed to evaluate the immunoregulatory function of TNFα1 on gut barrier in a novel hybrid fish (WR), which was produced by crossing white crucian carp (Carassius cuvieri, ♀) with red crucian carp (Carassius auratus red var, ♂). In this study, WR-tnfα1 sequence was identified, and a high-level expression was detected in the intestine. Elevated levels of WR-tnfα1 expressions were detected in immune-related tissues and cultured fish cells on stimulation. The appearance of vacuolization and submucosal rupture was observed in TNFα1-treated midgut of WR, along with elevated levels of goblet cell atrophy, whereas no significant changes were detected in most expressions of tight-junction genes and mucin genes. In contrast, WR receiving gut perfusion with WR-TNFα1 showed a remarkable decrease in antioxidant status in midgut, whereas the expression levels of apoptotic genes and redox responsive genes increased sharply. These results suggested that TNFα1 could exhibit a detrimental effect on antioxidant defense and immune regulation in the midgut of WR.

Ca-doping interfacial engineering and glycolysis enable rapid charge separation for efficient phototherapy of MRSA-infected wounds.

Methicillin-resistant Staphylococcus aureus (MRSA) is the primary pathogenic agent responsible for epidermal wound infection and suppuration, seriously threatening the life and health of human beings. To address this fundamental challenge, we propose a heterojunction nanocomposite (Ca-CN/MnS) comprised of Ca-doped g-C3N4 and MnS for the therapy of MRSA-accompanied wounds. The Ca doping leads to a reduction in both the bandgap and the singlet state S1-triplet state T2 energy gap (ΔEST). The Ca doping also facilitates the two-photon excitation, thus remarkably promoting the separation and transfer of 808 nm near-infrared (NIR) light-triggered electron-hole pairs together with the built-in electric field. Thereby, the production of reactive oxygen species and heat are substantially augmented nearby the nanocomposite under 808 nm NIR light irradiation. Consequently, an impressive photocatalytic MRSA bactericidal efficiency of 99.98 ± 0.02 % is achieved following exposure to NIR light for 20 min. The introduction of biologically functional elements (Ca and Mn) can up-regulate proteins such as pyruvate kinase (PKM), L-lactate dehydrogenase (LDHA), and calcium/calmodulin-dependent protein kinase (CAMKII), trigger the glycolysis and calcium signaling pathway, promote cell proliferation, cellular metabolism, and angiogenesis, thereby expediting the wound-healing process. This heterojunction nanocomposite, with its precise charge-transfer pathway, represents a highly effective bactericidal and bioactive system for treating multidrug-resistant bacterial infections and accelerating tissue repair. STATEMENT OF SIGNIFICANCE: Due to the bacterial resistance, developing an antibiotic-free and highly effective bactericidal strategy to treat bacteria-infected wounds is critical. We have designed a heterojunction consisting of calcium doped g-C3N4 and MnS (Ca-CN/MnS) that can rapidly kill methicillin-resistant Staphylococcus aureus (MRSA) without damaging normal tissue through a synergistic effect of two-photon stimulated photothermal and photodynamic therapy. In addition, the release of trace amounts of biofunctional elements Mn and Ca triggers glycolysis and calcium signaling pathways that promote cellular metabolism and cell proliferation, contributing to tissue repair and wound healing.

Length-controlled hydrophobic CF3-COF as a highly efficient absorbent coating for dual-mode solid-phase microextraction of sixteen polycyclic aromatic hydrocarbons in water samples.

Polycyclic aromatic hydrocarbons (PAHs), a group of seriously hazardous environmental contaminants, have attracted extensive attention due to their carcinogenicity, genotoxicity, mutagenicity, and ubiquity. In this work, the excellent hydrophobic trifluoromethyl-enriched covalent organic framework (CF3-COF) was designed and synthesized as coating of solid-phase microextraction (SPME). The CF3-COF offered a high adsorption selectivity for PAHs, which could be attributed to the multiple interactions between the CF3-COF and PAHs, including hydrophobicity interaction, π-π and H bond interactions. Furthermore, headspace (HS) and direct immersion (DI) dual-mode solid-phase microextraction (HS/DI-SPME) were innovatively integrated as a dual-mode extraction by varying the length of SPME coating on stainless-steel, which could simultaneously and efficiently extract 16 PAHs with different volatile. Amazingly, the proposed strategy achieved fast adsorption for PAHs and shortened the adsorption equilibrium time to 15 min. By further integrating with gas chromatography tandem mass spectrometry (GC-MS/MS), PAHs could be detected in the range of 0.008-0.16 ng mL-1 with a quantitative limit of 0.029-0.47 ng mL-1, respectively. The recoveries of PAHs in water samples ranged from 80.84 to 117.67 %. This work indicates that the dual-mode CF3-COF-SPME is a promising candidate for the enrichment of multiple hazardous substances in complicated samples.

[Seasonal dynamics in photosynthetic characteristics and growth of Cunninghamia lanceolata saplings and their response to soil warming]. / æ‰æœ¨å¹¼æ ‘å ‰åˆç‰¹æ€§ä¸Žç”Ÿé•¿çš„å­£èŠ‚å˜åŒ–åŠå ¶å¯¹åœŸå£¤å¢žæ¸©çš„å“åº”.

In order to understand the response and adaptation mechanisms of photosynthetic characteristics and growth for Cunninghamia lanceolata saplings in the subtropical region to global warming, we conducted the root-box warming experiment (ambient, ambient+4 ℃) at the Sanming Forest Ecosystem National Observation and Research Station in Fujian Province to investigate the effects of soil warming on the photosynthetic characteristics and growth of C. lanceolata saplings in different seasons. The results showed that the net photosynthetic rate (Pn) and stomatal conductance (gs) of C. lanceolata significantly decreased in summer compared with in spring and autumn. Soil warming had no effect on the Pn and gs of C. lanceolata. However, the interaction between warming and season significantly impacted the leaf water use efficiency (WUE). The tree height and ground diameter growth of C. lanceolata significantly increased in spring compared with in summer and autumn. Warming significantly reduced ground diameter growth, and it diminished the net diameter growth by 48.1% in autumn. However, warming had no impact on the tree height growth of C. lanceolata in each season. The specific leaf area, soluble sugar, and non-structural carbohydrates contents of C. lanceolata significantly improved in summer and autumn compared with in spring. Warming had rarely influence on leaf functional traits in each season. In conclusion, the response of photosynthesis for C. lanceolata to soil warming was insignificant. The photosynthesis of C. lanceolata exhibited significant seasonal dynamics, primarily controlled by gs. C. lanceolata adapted to soil warming by adjusting WUE, and it adjusted to high temperatures and drought stress in summer by increasing soluble sugar content and specific leaf area. The effect of warming on ground diameter growth of C. lanceolata was primarily driven by soil moisture. The seasonal difference in the growth of C. lanceolata was influenced by the photosynthesis of C. lanceolata and the trade-off between the utilization and storage of photosynthetic products.

FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti-PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. SIGNIFICANCE: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.