Increased Expression of CD74 in Atherosclerosis Associated with Inflammatory Responses of Endothelial Cells and Macrophages.

To clarify the relationship between CD74 and atherosclerosis (AS) and the mechanisms in oxidized LDL (ox-LDL)-induced endothelial cell and macrophage injury. Datasets obtained from the Gene Expression Omnibus database are integrated. Differentially expressed genes (DEGs) were obtained using R software. Weighted gene co-expression network analysis (WGCNA) was performed to screen the target genes. The endothelial cell injury model and macrophage foaming model were established using ox-LDL, and CD74 expression was detected by Quantitative reverse transcription PCR (RT-qPCR) and Western blot (WB). Then, after silencing CD74, cell viability and ROS production were measured, and WB detected the expression of p-p38 MAPK and NF-κB. There were 268 DEGs associated with AS, of which CD74 was up-regulated. The turquoise module containing CD74 in WGCNA was positively associated with AS. Cell viability was significantly decreased in the endothelial cell injury and macrophage foaming models, while CD74, ROS production, NF-κB, and p-p38MAPK expression increased (P < 0.05). After silencing CD74, ROS production, NF-κB, and p-p38MAPK expression were decreased and cell viability was higher than the model group (P < 0.05). CD74 is up-regulated in endothelial cell injury and macrophage foaming models and is involved in AS progression via the NF-κB and MAPK signaling pathways.

Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice.

Polychlorinated biphenyls (PCBs) are environmental contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2',3,5',6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. Adipose tissue levels were significantly higher in wild-type (WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice. We also observed genotype-dependent differences in the enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were significantly lower in KI than in WT mice in blood and the liver, while the opposite trend was observed in female mice. In conclusion, the study highlights the differences in the atropselective disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.

Real-world efficacy and safety of TACE plus camrelizumab and apatinib in patients with HCC (CHANCE2211): a propensity score matching study.

OBJECTIVES: This study aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) plus camrelizumab, a monoclonal antibody targeting programmed death-1, and apatinib for patients with intermediate and advanced hepatocellular carcinoma (HCC) in a real-world setting. METHODS: A total of 586 HCC patients treated with either TACE plus camrelizumab and apatinib (combination group, n = 107) or TACE monotherapy (monotherapy group, n = 479) were included retrospectively. Propensity score matching analysis was used to match patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety in the combination group were described in comparison to monotherapy. RESULTS: After propensity score matching (1:2), 84 patients in the combination group were matched to 147 patients in the monotherapy group. The median age was 57 years and 71/84 (84.5%) patients were male in the combination group, while the median age was 57 years with 127/147 (86.4%) male in the monotherapy group. The median OS, PFS, and ORR in the combination group were significantly higher than those in the monotherapy group (median OS, 24.1 vs. 15.7 months, p = 0.008; median PFS, 13.5 vs. 7.7 months, p = 0.003; ORR, 59.5% [50/84] vs. 37.4% [55/147], p = 0.002). On multivariable Cox regression, combination therapy was associated with significantly better OS (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.26-0.64; p < 0.001) and PFS (adjusted HR, 0.52; 95% CI, 0.37-0.74; p < 0.001). Grade 3 or 4 adverse events occurred in 14/84 (16.7%) and 12/147 (8.2%) in the combination and monotherapy groups, respectively. CONCLUSIONS: TACE plus camrelizumab and apatinib showed significantly better OS, PFS, and ORR versus TACE monotherapy for predominantly advanced HCC. CLINICAL RELEVANCE STATEMENT: Compared with TACE monotherapy, TACE plus immunotherapy and molecular targeted therapy showed better clinical efficacy for predominantly advanced HCC patients, with a higher incidence of adverse events. KEY POINTS: • This propensity score-matched study demonstrates that TACE plus immunotherapy and molecular targeted therapy have a longer OS, PFS, and ORR compared with TACE monotherapy in HCC. • Grade 3 or 4 adverse events occurred in 14/84 (16.7%) patients treated with TACE plus immunotherapy and molecular targeted therapy compared with 12/147 (8.2%) patients in the monotherapy group, while no grade 5 adverse events were observed in all cohorts.

Machine Learning-Assisted Identification and Quantification of Hydroxylated Metabolites of Polychlorinated Biphenyls in Animal Samples.

Laboratory studies of the disposition and toxicity of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites are challenging because authentic analytical standards for most unknown OH-PCBs are not available. To assist with the characterization of these OH-PCBs (as methylated derivatives), we developed machine learning-based models with multiple linear regression (MLR) or random forest regression (RFR) to predict the relative retention times (RRT) and MS/MS responses of methoxylated (MeO-)PCBs on a gas chromatograph-tandem mass spectrometry system. The final MLR model estimated the retention times of MeO-PCBs with a mean absolute error of 0.55 min (n = 121). The similarity coefficients cos θ between the predicted (by RFR model) and experimental MS/MS data of MeO-PCBs were >0.95 for 92% of observations (n = 96). The levels of MeO-PCBs quantified with the predicted MS/MS response factors approximated the experimental values within a 2-fold difference for 85% of observations and 3-fold differences for all observations (n = 89). Subsequently, these model predictions were used to assist with the identification of OH-PCB 95 or OH-PCB 28 metabolites in mouse feces or liver by suggesting candidate ranking information for identifying the metabolite isomers. Thus, predicted retention and MS/MS response data can assist in identifying unknown OH-PCBs.

Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway.

BACKGROUND: Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial. METHODS: The paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer. RESULTS: Here, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice. CONCLUSIONS: Together, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy.

Endovascular Repair of Spontaneous Iliac Vein Rupture.

Spontaneous iliac vein rupture is a relatively rare but fatal disease. Herein, 2 cases are reported. The two middle-aged and elderly females complaining of abdominal pain were admitted without any history of trauma. The computed tomography image both showed one huge hematoma in the lower abdominal cavity and the left external iliac venous thrombus. Venogram showed ruptures of the left external iliac vein and stenosis of the left common iliac vein after percutaneous mechanical thrombectomy. Stent grafts were implanted by endovascular technique. Favorable outcomes were achieved in both cases.

Evaluation of percutaneous transcatheter embolization for pulmonary arteriovenous malformations.

BACKGROUND: The purpose of this study was to assess the safety and efficacy of percutaneous transcatheter embolization (TCE) for the treatment of pulmonary arteriovenous malformations (PAVMs). METHODS: Forty-three consecutive patients (n = 17 males; n = 26 females) with 72 untreated PAVMs underwent coil and/or plug embolization between January 2010 and February 2018. The mean patient age was 42 ± 14 years (range 19-71 years). The median size of the feeding artery was 7.9 ± 2.9 mm (range 3.5-14.0 mm). The arterial blood gas level and cardiac function of all patients were analysed. The technical success rate, recanalization rate, and complications were evaluated. Computed tomography angiography (CTA) examinations were scheduled for 12 months after treatment and every 2-4 years thereafter. RESULTS: Twenty-five PAVMs were treated with coils alone, twenty-one were treated with plugs alone, and twenty-six were treated with both coils and plugs. The technical success rate was 100%. There were no complications during operation. However, one patient (2.3%) had pulmonary thrombosis and embolism post-operation. The patients' pre-operative and post-operative PaO2 and SaO2 levels were significantly different (p < 0.01). A comparison of the New York Heart Association (NYHA) grade before and after embolization in all patients showed a significant decrease in the post-operative grade (p < 0.01). The 72 PAVMs were divided into three groups (coils only group [n = 25], plugs only group [n = 21], and coils/plugs combined group [n = 26]). After 12 months of follow-up, there were seven reperfusion PAVMs in the coil group, seven reperfusion PAVMs in the plug group, and 1 reperfusion PAVM in the combined group. There were significant differences between the two groups and the combined group. CONCLUSION: Percutaneous TCE is safe and effective for the treatment of PAVMs. A combination of coils and vascular plugs may be useful for preventing recanalization after the embolization of PAVMs.

Theoretical search for heterogeneously architected 2D structures.

Architected 2D structures are of growing interest due to their unique mechanical and physical properties for applications in stretchable electronics, controllable phononic/photonic modulators, and switchable optical/electrical devices; however, the underpinning theory of understanding their elastic properties and enabling principles in search of emerging structures with well-defined arrangements and/or bonding connections of assembled elements has yet to be established. Here, we present two theoretical frameworks in mechanics-strain energy-based theory and displacement continuity-based theory-to predict the elastic properties of 2D structures and demonstrate their application in a search for novel architected 2D structures that are composed of heterogeneously arranged, arbitrarily shaped lattice cell structures with regulatory adjacent bonding connections of cells, referred to as heterogeneously architected 2D structures (HASs). By patterning lattice cell structures and tailoring their connections, the elastic properties of HASs can span a very broad range from nearly zero to beyond those of individual lattice cells by orders of magnitude. Interface indices that represent both the pattern arrangements of basic lattice cells and local bonding disconnections in HASs are also proposed and incorporated to intelligently design HASs with on-demand Young's modulus and geometric features. This study offers a theoretical foundation toward future architected structures by design with unprecedented properties and functions.

Hippocampal atrophy and functional connectivity disruption in cirrhotic patients with minimal hepatic encephalopathy.

The hippocampus is a crucial pathological node for minimal hepatic encephalopathy (MHE) and it is associated with various cognitive impairments. Investigations on alterations involving hippocampal morphology and functional connectivity (FC) in MHE are limited. This study aimed to simultaneously evaluate hippocampal volume and FC alterations and their association with cognitive decline in MHE. Twenty-two cirrhotic patients with MHE, 31 cirrhotic patients without MHE (NHE), and 43 healthy controls underwent high-resolution T1-weighted imaging, resting-state functional magnetic resonance imaging, and cognition assessment based on Psychometric Hepatic Encephalopathy Score (PHES). The structural images were preprocessed using a voxel-based morphometry method, during which hippocampal volume was measured. The hippocampal connectivity network was identified using seed-based correlation analysis. Hippocampal volume and FC strength were compared across the three groups and correlated against the PHES results of the cirrhotic patients. Compared to the controls, MHE patients exhibited a significantly lower bilateral hippocampal volume. A slight decrease in hippocampal volume was obtained from NHE to MHE, but it did not reach statistically significance. In addition, the average FC strength of the bilateral hippocampal connectivity network was significantly lower in the MHE patients. In particular, the MHE patients showed a decrease in FC involving the left hippocampus to bilateral posterior cingulate gyrus and left angular gyrus. The MHE patients also showed FC reduction between the right hippocampus and bilateral medial frontal cortex. A progressive reduction in hippocampal FC from NHE to MHE was also observed. The bilateral hippocampal FC strength (but not hippocampal volume) was positively correlated with the PHES results of the cirrhotic patients. Our assessment of MHE patients revealed decreased hippocampal volume, which suggests regional atrophy, and reduced hippocampal connectivity with regions that are primarily involved in the default-mode network, thereby suggesting a functional disconnection syndrome. These alterations reveal the mechanisms underlying cognitive deterioration with disease progression.

Is Multilayer Bare Stent Safe or Effective for the Treatment of Aortic Aneurysms? A Meta-analysis with Early and Mid-term Outcomes.

BACKGROUND: As a novel endovascular treatment, multilayer bare stent implantation remains controversial. This study evaluated the safety and efficacy of multilayer bare stent-based endovascular treatment applied in aortic aneurysms in the reported literature. METHODS: Articles regarding multilayer bare stent-based endovascular treatment published before and during February 2016 were obtained by searching PubMed, EMBASE, Wiley Online Library, and Web of Science. R software was employed for a meta-analysis. RESULTS: Five studies including 154 patients satisfied the inclusion criteria. The mean follow-up was 12.7 (8-22.1) months. The rate of aneurysm exclusion was 76.1%. The rate of aneurysm shrinkage and enlargement was 14.1% and 12.5%, respectively. The patency rate of branch vessels was 98.4%. The overall rate of aneurysm rupture was almost 0%. The 30-day postoperative and 1-year aneurysm-related mortality were 0% and 1.7%, respectively. Technical success was achieved in all patients. Only 6.7% of the patients needed reintervention. About 1.9% of the patients suffered endoleak. CONCLUSIONS: Our study indicates that treatment of aneurysms with multilayer bare stents is safe with high technical success rates and low incidence of complications. However, the low rates of aneurysm exclusion are not negligible. Due to the limitations of the existing studies, we only suggest its use for aortic aneurysms with branch vessels if the standard techniques are contraindicated.

Role of CYP2A13 in the bioactivation and lung tumorigenicity of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: in vivo studies using a CYP2A13-humanized mouse model.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is abundant in tobacco smoke, is a potent lung procarcinogen. The present study was aimed to prove that transgenic expression of human cytochrome P450 2A13 (CYP2A13), known to be selectively expressed in the respiratory tract and be the most efficient enzyme for NNK bioactivation in vitro, will enhance NNK bioactivation and NNK-induced tumorigenesis in the mouse lung. Kinetic parameters of NNK bioactivation in vitro and incidence of NNK-induced lung tumors in vivo were determined for wild-type, Cyp2a5-null and CYP2A13-humanized (CYP2A13-transgenic/Cyp2a5-null) mice. As expected, in both liver and lung microsomes, the loss of CYP2A5 resulted in significant increases in Michaelis constant (K m) values for the formation of 4-oxo-4-(3-pyridyl)-butanal, representing the reactive intermediate that can lead to the formation of O(6)-methylguanine (O(6)-mG) DNA adducts; however, the gain of CYP2A13 at a fraction of the level of mouse lung CYP2A5 led to recovery of the activity in the lung, but not in the liver. The levels of O(6)-mG, the DNA adduct highly correlated with lung tumorigenesis, were significantly higher in the lungs of CYP2A13-humanized mice than in Cyp2a5-null mice. Moreover, incidences of lung tumorigenesis were significantly greater in CYP2A13-humanized mice than in Cyp2a5-null mice, and the magnitude of the differences in incidence was greater at low (30mg/kg) than at high (200mg/kg) NNK doses. These results indicate that CYP2A13 is a low K m enzyme in catalyzing NNK bioactivation in vivo and support the notion that genetic polymorphisms of CYP2A13 can influence the risks of tobacco-induced lung tumorigenesis in humans.

MiR-140-3p Normalizes Vascular Smooth Muscle Cell Behavior by Inhibiting the RhoA/ROCK Signaling Pathway in Lower-extremity Arteriosclerosis Obliterans.

BACKGROUND: Excessive vascular smooth muscle cell (VSMC) proliferation and migration are the main contributors to the symptoms of lower-extremity arteriosclerosis obliterans (ASO). Previous studies suggested that microRNAs (miRNAs) regulate VSMC activity. Nevertheless, the molecular mechanisms by which they do so are unclear. OBJECTIVE: The present study aimed to identify the biological processes accounting for the effects of miR-140-3p on VSMCs in ASO. METHODS: The expression levels of miR-140-3p in clinical samples were analyzed by real-time polymerase chain reaction. An ASO cell model was established to investigate the expression of miR-140-3p on VSMCs. The transwell® assays and MTT assays were used to assess migration and proliferation. The interaction between RhoA and miR-140-3p was verified using the Dualluciferase reporter assay. Western blot technique was used to identify RhoA, RhoA-associated protein kinase 1 (ROCK1), and ROCK2. RESULTS: We discovered that miR-140-3p inhibited the proliferation, migration, and invasion but promoted the apoptosis of VSMCs, and RhoA was its downstream target gene. RhoA, ROCK1, and ROCK2 were upregulated in vascular tissues damaged by ASO compared to normal, healthy arteries. MiR-140-3p also decreased RhoA, ROCK1, and ROCK2 mRNA and protein expression. CONCLUSION: Overall, the present work partially elucidated the mechanism by which miR-140-3p regulates VSMC function and offered novel insights into potential therapeutic approaches for patients with lower-extremity arteriosclerosis obliterans.

Three-dimensional treatment-planning-based prediction of seed migration to chest after 125I seed brachytherapy for hepatic malignancy.

PURPOSE: To develop and validate risk models incorporating clinical and/or imaging parameters based on three-dimensional treatment-planning systems (3D-TPS) to predict the occurrence of 125I seed migration and the number of migrated seeds <2/≥2 to the chest after brachytherapy for patients with malignant hepatic tumors. METHODS AND MATERIALS: A total of 480 patients diagnosed with malignant liver tumors receiving 125I seed brachytherapy from July 2010 to May 2020 were retrospectively enrolled. Variables included 3D-TPS-based CT parameters, that is, the distance from the seed to the inferior vena cava (DSI), the distance from the seed to the second hepatic portal (DSP) and the angle from the seed to the second hepatic portal (ASP), and patients' clinical characteristics, that is, the number of seed implantation procedures (NSP), the maximum number of implanted seeds one time (MAX) and laboratory parameters within 1 week before treatment. Two sets of logistic regression models incorporating clinical and/or imaging variables were developed to predict the occurrence of seed migration and the number of migrated seeds <2/≥2. Model performance was assessed by ROC analysis and decision curve analysis. RESULTS: Compared with the clinical models, the combined model showed a higher discriminative ability for both the prediction of migration occurrence and number of migrated seeds ≥ 2/<2 to the chest (AUC, 0.879 vs. 0.668, p < 0.05; 0.895 vs. 0.701, p < 0.05). The decision curve analysis results indicated higher net benefits of combined models than clinical models. Variables, including DSI, NSP and pretreatment lymphocyte-to-neutrophil ratio, acted as the most important predictors in combined models. CONCLUSIONS: The proposed combined models based on 3D-TPS improved discriminative abilities for predicting 125I seed migration and number of migrated seeds <2/≥2 to the chest after hepatic brachytherapy, being promising to aid clinical decision-making.

Efficacy and safety of a novel vena cava filter on pulmonary embolism prophylaxis: a prospective, multicenter, randomized, parallel, positive-controlled, noninferiority clinical trial.

Background: There are different types of vena cava filter (VCF) available in clinical practice. However, limited data exist to determine whether one type is superior to another, and no single VCF is universally recommended in clinical guidelines. The objective of this study was to investigate the safety and efficacy of a novel VCF, Octoparms, for the prevention of pulmonary embolism (PE) and to compare it with the Celect filter. Methods: This multicenter, randomized, open-label, parallel, positive-controlled, noninferiority trial was conducted in 10 centers across 6 provinces in China from October 2017 to March 2019. Patients who had confirmed lower extremity deep vein thrombosis or PE or who were at risk of PE with a clinical indication for VCF placement due to contraindication to or failure of anticoagulant therapy were included in the trial. The sample size for this trial was based on the assumption that the clinical success rate would be 95% and the noninferiority margin would be 10% for both filters. Each patient underwent baseline testing and was randomized using a web-based central system. Any additional interventions or standard treatments patients received along with the VCF placement were recorded. The primary endpoint was the overall clinical success rate, including technical and clinical success of filter placement and retrieval. The secondary endpoint was the safety of filter placement and retrieval, encompassing procedure-related and filter-related complications. Results: A total of 188 patients were included and were divided into two groups: the Octoparms group (n=94) and the Celect group (n=94). Baseline characteristics and demographics were comparable between the two groups (P>0.05). Technical and clinical success rates for filter placement were achieved in 100% (188/188) of patients. The median dwelling time was 12.0 days (range, 4-190 days). Ten VCFs were left in situ as permanent devices. Of the remaining 178 patients, technical success and clinical success rates for filter retrieval were both achieved in 100% of cases (178/178). Clinical success rates were 92.6% (87/94) for the Octoparms group and 96.8% (91/94) for the Celect group, with a difference of -4.2% (hazard ratio 2.441, 95% confidence interval 0.612-9.741; P=0.206). The lower limit was greater than the noninferiority margin of -10%. Eight patients experienced a total of eight procedure-related complications. No filter-related complications, such as migration, deformation, inferior vena cava (IVC) penetration, peripheral organ damage, or IVC stenosis/occlusion, were observed (P>0.05). Conclusions: The Octoparms filter exhibited a high rate of clinical success and a low rate of complications during placement and retrieval, demonstrating noninferiority to the Celect filter.

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.

Generation and characterization of a novel Cyp2a(4/5)bgs-null mouse model.

Knockout mouse models targeting various cytochrome P450 (P450 or CYP) genes are valuable for determining P450's biologic functions, including roles in drug metabolism and chemical toxicity. In this study, a novel Cyp2a(4/5)bgs-null mouse model was generated, in which a 1.2-megabase pair genomic fragment containing nine Cyp genes in mouse chromosome 7 (including, sequentially, Cyp2a5, 2g1, 2b19, 2b23, 2a4, 2b9, 2b13, 2b10, and 2s1) are deleted, through Cre-mediated recombination in vivo. The resultant mouse strain was viable and fertile, without any developmental deficits or morphologic abnormalities. Deletion of the constitutive genes in the cluster was confirmed by polymerase chain reaction analysis of the genes and the mRNAs in tissues known to express each gene. The loss of this gene cluster led to significant decreases in microsomal activities toward testosterone hydroxylation in various tissues examined, including olfactory mucosa (OM), lung, liver, and brain. In addition, systemic clearance of pentobarbital was decreased in Cyp2a(4/5)bgs-null mice, as indicated by >60% increases in pentobarbital-induced sleeping time, compared with wild-type (WT) mice. This novel Cyp2a(4/5)bgs-null mouse model will be valuable for in vivo studies of drug metabolism and chemical toxicities in various tissues, including the liver, lung, brain, intestine, kidney, skin, and OM, where one or more of the targeted Cyp genes are known to be expressed in WT mice. The model will also be valuable for preparation of humanized mice that express human CYP2A6, CYP2A13, CYP2B6, or CYP2S1, and as a knockout mouse model for five non-P450 genes (Vmn1r184, Nalp9c, Nalp4a, Nalp9a, and Vmn1r185) that were also deleted.

Application of Guglielmi detachable coils in embolization of iatrogenic renal hemorrhage.

BACKGROUND: This study aims to evaluate the application value of Guglielmi detachable coils (GDCs) in the embolization of iatrogenic renal hemorrhage. METHODS: Twelve iatrogenic renal hemorrhage patients who failed conservative treatment were randomly treated by superselective transcatheter arterial embolization (TAE) with GDCs, gelatin sponge, and microcoil embolization, respectively. The efficacy of treatment, damage to renal function, and renal infarct size were observed. RESULTS: Embolizations were successful in all patients on the first attempt. Hematuria disappeared completely after the surgery; no recurrence of hemorrhage and no abnormal renal function were observed during the follow-up period. Postoperative angiography revealed that patients treated with GDC embolization had minimum renal infarcts. CONCLUSIONS: In summary, while superselective TAE provides a safe and effective therapy in patients with iatrogenic renal hemorrhage, the application of GDCs can better prevent the loss of normal renal tissue after embolization.

Transthyretin promotes the invasion of combined hepatocellular cholangiocarcinoma by tumor-associated macrophages.

BACKGROUND: Patients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) have limited treatment options and poor prognosis. Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment and promote tumor stemness, proliferation, invasion and metastasis. Evidence suggested that transthyretin (TTR) influenced the prolifetation and invasion functions of different tumors and play an essential role in the tumor microenvironment. AIMS: To investigate the involvement of TTR in TAMs affecting the invasion of cHCC-CCA. METHODS AND RESULTS: Data sets obtained from the Gene Expression Omnibus database were integrated. Differentially expressed genes (DEGs) were obtained using R software, and modules associated with cHCC-CCA were screened by weighted gene co-expression network analysis (WGCNA). Human THP-1 cells were induced to differentiate into macrophages and then co-cultured with HCCC9810 cells and tumor necrosis factor-α (TNF-α) to simulate the inflammatory microenvironment of cHCC-CAA. In addition, small interfering RNA against TTR was transfected into HCCC9810 cells, and recombinant TTR and ERK and AKT-specific inhibitors were added to HCCC9810 cells, respectively; after that, the levels of NF-κB protein and phosphorylated ERK and AKT were measured. The invasive abilities of HCCC9810 cells were also tested. One hundred forty-five DEGs were associated with cHCC-CCA, of which TTR was up-regulated. Turquoise modules containing TTR in WGCNA were most significantly associated with cHCC-CCA. TTR was highly expressed in HCCC9810 compared to Huh-28. HCCC9810 showed enhanced invasive capacity after co-culture with TNF-α + macrophages (p < .05). After interfering with TTR, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB, p-ERK1/2, and p-AKT (p < .05). After treating HCCC9810 with ERK and AKT-specific inhibitors, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB and TTR (p < .05). CONCLUSION: TTR can promote the invasive ability of cHCC-CCA by regulating AKT/NF-κB and ERK pathways with the assistance of TAMs.

Mechanical Janus Structures by Soft-Hard Material Integration.

Engineering Janus structures that possess anisotropic features in functions have attracted growing attention for a wide range of applications in sensors, catalysis, and biomedicine, and are yet usually designed at the nanoscale with distinct physical or chemical functionalities in their opposite sides. Inspired by the seamless integration of soft and hard materials in biological structures, here a mechanical Janus structure composed of soft and hard materials with a dramatic difference in mechanical properties at an additively manufacturable macroscale is presented. In the combination of extensive experimental, theoretical, and computational studies, the design principle of soft-hard materials integrated mechanical Janus structures is established and their unique rotation mechanism is addressed. The systematic studies of assembling the Janus structure units into superstructures with well-ordered organizations by programming the local rotations are further shown, providing a direct route of designing superstructures by leveraging mechanical Janus structures with unique soft-hard material integration. Applications are conducted to demonstrate the features and functionalities of assembled superstructures with local ordered organizations in regulating and filtering acoustic wave propagations, thereby providing exemplification applications of mechanical Janus design in functional structures and devices.