Objective On the land battlefield,non-compressible torso hemorrhage is the leading cause of preventable death from combat injuries,yet frontline military physicians generally lack effective endovascular hemostatic skills.This study aims to develop a standardized training program for resuscitative endovascular balloon occlusion of the aorta(REBOA)by combining intelligent sensor-equipped simulation manikins with animal models,and to verify its efficacy in improving REBOA proficiency among frontline medical physicians with no prior interventional experience,with a goal of addressing the bottleneck in extending advanced combat casualty care to the frontline.Methods A self-controlled before-and-after study design was adopted.Twenty on-duty primary-level military physicians from the Army(representing 18 brigade-and regiment-level medical units)were enrolled in June 2023.The participants first completed 10 full-procedure practice sessions on an intelligent simulator to establish skill acquisition curves;subsequently underwent stepwise reinforcement training in femoral artery puncture and catheterization using 10 experimental pigs(weighing 30 to 40 kg);and finally,were assessed using 10 porcine hemorrhagic models(weighing 30 to 40 kg).Digital subtraction angiography(DSA)was applied to observe the accuracy of balloon position.Training effectiveness was evaluated by comparative analysis of trainees'procedural time at different stages of simulator practice,puncture time and procedural success rate during REBOA training on the porcine model,as well as puncture time,balloon positioning accuracy,procedural success rate,and complications during assessment on the porcine hemorrhagic model.Results All the 20 trainees successfully completed the training.① Skill acquisition efficiency:During the simulator training phase,the single-operator procedural time was decreased from 10.8±1.2 min at the first attempt to 5.3±0.4 min at the tenth attempt(P＜0.001);The goodness-of-fit of the single-phase decay model was R2=0.98,indicating that skill plateau was reached after the 7th practice session.② Real-world transfer capability:The trainees completed stepwise skill intensive practice on live experimental pigs,with a mean femoral artery puncture duration of 4.8±1.2 min and a success rate of 95％(19/20);Under DSA fluoroscopy guidance,the mean time for balloon positioning at aortic Zone Ⅰ(timed from balloon entry into the arterial sheath)was 3.8±0.9 min,with a success rate of 95％(19/20).In the assessment on the live porcine hemorrhagic model,the average total procedure time was 7.8±1.4 min(95％CI:7.2 to 8.4);19 out of 20 trainees(95％)achieved visual confirmation of successful hemostasis of the contralateral femoral artery.③ Safety:The complication rate during the assessment phase was 10％(2/20),and the overall pass rate in the final comprehensive evaluation reached 90％(18/20).Conclusion Junior military physicians with no prior interventional experience can acquire preliminary proficiency in REBOA technique through the training program of intelligent sensor-equipped simulator combined with animal model;This program provides a replicable training pathway for disseminating REBOA technology to grassroots units.

ABSTRACTObjectiveIschemia–reperfusion of the abdominal aorta often results in damage to distant organs, such as the heart and brain. This cellular heterogeneity within affected tissues complicates the roles of specific cell subsets in abdominal aorta occlusion model (AAO) injury. However, cell type–specific molecular pathology in the hippocampus after ischemia is poorly understood.AimsIn this study, we adopted a mouse AAO to investigate the single‐cell transcriptome in the hippocampi in AAO mice.MethodsMale C57BL/6 mice (8 weeks old) were used to create an AAO model, with animals divided into Sham and I/R groups. The I/R group was subjected to 2 h of ischemia followed by 24 h of reperfusion, after which hippocampal tissues were collected for single‐cell RNA sequencing and histological analysis. Behavioral tests, including the Rotarod, Y‐maze, and new object recognition tests, were performed daily for 28 days post‐surgery to evaluate neurological function. A total of 62,624 cells were corresponding 7 cell types with neuronal, glial, and vascular lineages. We next analyzed cell‐specific gene alterations in AAO mice and the function of these cell‐specific Genes.ResultsAAO injury upregulated astrocyte and oligodendrocyte precursor cell (OPC) proportions (p‐value < 0.05). Astrocytes showed unique gene expression related to neurogenesis and mRNA processing. Five distinct astrocyte subtypes emerged post‐injury. OPCs exhibited enhanced synapse organization. Microglia activation and the elevated expression level of the epithelial cell oxidative phosphorylation protein–protein interaction (PPI) module indicate an inflammatory response and metabolic changes in response to AAO injury.ConclusionsOur scRNA‐seq analysis provides insights into transcriptional changes at the single‐cell level in response to AAO‐induced hippocampal injury. This study illustrates how the hippocampal region responds to such injury and identifies potential therapeutic targets for intervention, thereby paving the way for future research and treatment strategies.

BACKGROUND: Thoracic aortic ischemia-reperfusion (I/R) injury occurs in clinical scenarios and can lead to damage in organs such as the spinal cord, kidneys, and intestines. Hypoxic postconditioning (HyP) has shown promise in reducing organ I/R injury, suggesting its potential applicability in thoracic aortic I/R injury. However, the pathological damage caused by thoracic aorta occlusion (TAO) to the heart and brain is not yet well understood. This study aims to investigate the protective effects of hypoxic conditioning (HyP) treatment on brain and cardiac tissues following TAO-induced I/R injury. MATERIALS AND METHODS: Male C57BL/6 mice were used to construct the TAO model by blocking the thoracic aorta for 0.5 or 1 h, followed by 24 h of reperfusion. The mice were divided into five groups: sham, TAO (0.5 h), TAO (0.5 h) +HyP, TAO (1 h), and TAO (1 h) +HyP. Hematoxylin and eosin, Masson, and Sirius red staining were performed to assess morphological changes and collagen deposition in brain and heart tissues. Protein expression assays were conducted to quantify inflammation-related proteins in the serum. RESULTS: The results showed that TAO caused significant neuronal damage in the hippocampal regions (CA1, CA3, and DG) and myocardial cell damage with collagen deposition. HyP treatment significantly alleviated these damages, particularly with shorter ischemic durations (0.5 h). Specifically, in cardiac tissues, HyP treatment reduced myocardial injury and collagen deposition. In addition, HyP treatment modulated systemic inflammatory responses, as evidenced by the increased expression of anti-inflammatory proteins such as interleukin 13 (IL-13) and the decreased expression of pro-inflammatory proteins such as IL-6, IL-12p70, IL-17, and tumor necrosis factor-α. CONCLUSION: HyP treatment significantly mitigates brain and cardiac tissue damage caused by TAO, especially with shorter ischemic durations. These findings highlight the potential clinical application of HyP treatment in reducing TAO-induced tissue damage and inflammation, offering a novel therapeutic option for patients with thoracic aortic I/R injury. Future studies should further investigate the mechanisms and optimal implementation protocols of HyP treatment to maximize its clinical value.

Investigate the feasibility, efficacy, and safety of ventral caudal artery (VCA) approach for transarterial chemoembolization (TACE) in an orthotopic hepatocellular carcinoma (HCC) rat model. Sixteen orthotopically established tumor-bearing Sprague-Dawley rats were divided into two groups of eight each: drug-eluting bead transarterial chemoembolization (DEB-TACE) group and normal saline (NS) group. VCA was approached for transarterial procedures. Rats in DEB-TACE group and NS group received transarterial administration of doxorubicin-loaded microspheres and normal saline, respectively. In NS group, repeated transarterial procedures were attempted 3 days after initial procedures. The feasibility was evaluated based on success rate of VCA approach, proper hepatic artery catheterization, and transcatheter treatment. The efficacy was assessed according to tumor necrosis. Animal mortality and tail viability were observed for safety evaluation. In supplementary experiments, eight additional tumor-bearing rats were used to evaluate the repeatability of proper hepatic artery catheterization via VCA access at 14 days after initial transarterial procedures the same as the NS group. The safety during the 14 days was also evaluated. VCA was successfully approached in 16 rats at initial procedures. Catheterization of proper hepatic artery achieved success in 7 of 8 DEB-TACE group animals and 6 of 8 NS group animals at initial procedures. All 13 rats received subsequent DEB-TACE or NS injection. One animal in DEB-TACE group died within 24 h and no death was noted in NS group (14.29

In industrial and clinical applications, CT scanning is expected to be as fast as possible to improve the scanning efficiency in industrial CT or to reduce the radiation dose to patients in clinical CT. However, the kinematic constraints of the dual manipulators pose limits on shortening the scanning time. In addition, the X-ray tube and detector mounted on the end-effectors of the dual manipulators must be precisely aligned during the scanning motion, which imposes the synchronization motion constraint on the dual manipulators. In this letter, considering the kinematic constraints (velocity and acceleration constraints) in the task space of dual manipulators and the synchronization motion constraint, we propose a minimum-time trajectory planning algorithm for a dual robotic manipulator CT system. Specifically, the CT scanning paths of both the X-ray tube and detector are formulated as a parametric form. Then, a novel unified bound estimator is proposed to convert the task constraint and synchronization constraint into the parametric constraints. Finally, the minimum-time trajectory planning issue of the dual manipulators is solved in real time by a nonlinear filter in the parameter space. Comparative experiments are conducted on two UR20 manipulators. The experimental results confirm that the planned trajectories by the proposed approach are time-optimal and satisfy all the task and synchronization motion constraints as well.

The treatment of liver metastases is undergoing a transformation from single-modality therapy to multimodal combination therapy, with local interventional treatments playing an increasingly important role. This review explores the synergistic effects between local interventional therapy and systemic treatment, the reconstruction of interventional therapy indications driven by advances in systemic treatment, and the impact of local interventional therapy on systemic treatment “switching” strategies. Through multidisciplinary collaboration and innovative interventional materials and techniques, local interventional therapy has evolved from a traditional palliative approach to become an essential component in the comprehensive treatment system for liver metastases.

Liver ischemia-reperfusion (I/R) injury is a critical issue in clinical settings, particularly in liver transplantation and resection, leading to severe hepatocellular dysfunction and organ failure. This study investigates the role of fibrinogen and platelets in liver I/R injury, focusing on their distribution and pathophysiological impact within liver lobules. Using a mouse model, we examined the expression and localization of fibrinogen and platelets at various time points postreperfusion. In normal liver, fibrinogen is predominantly expressed in hepatic sinusoids near the portal vein, with sparse platelet distribution. Following I/R injury, fibrinogen expression significantly increases in hepatic sinusoids and hepatocytes, accompanied by substantial platelet aggregation and embolization, particularly in Zone 1 of the liver lobules. These findings highlight the zonal heterogeneity of fibrinogen distribution and its regulatory function in platelet adhesion and microthrombi formation. This study provides crucial insights for developing therapeutic strategies targeting fibrinogen and platelet interactions to mitigate liver I/R injury.

This study aimed to investigate the impact of abdominal aortic occlusion (AAO)-induced injury on the kidney, lower limb muscles, heart, and brain in mice, and the potential protective effects of hypoxic postconditioning (HyC). The experimental design employed an abdominal aortic occlusion (AAO) model, and involved three groups of mice: sham, AAO, and AAO+HyC. Ten minutes after the AAO model, mice were subjected to hypoxic treatment lowering oxygen concentration to 5% within 45 minutes, and then returned to a normal oxygen environment. Hematoxylin-eosin (HE) stain was used for Histopathological examinations, and Quantibody Mouse Array was used for detecting apoptosis and inflammation-related protein expression. Histopathological examinations showed that HyC mitigated pathological damage to proximal organs (kidneys and lower limb muscles), distal organs (heart and brain), and reduced inflammatory cell infiltration. Expression of apoptosis-and inflammation-related proteins in brain and heart tissues were also evaluated. HyC significantly increased cellular inhibitor of apoptosis 2 (cIAP2) in the brain and Bcl-2 and insulin-like growth factor 2 (IGF-2) in the heart. Additionally, HyC regulated the expression of several inflammation-related factors in both brain and heart tissues. Although further investigation is needed, particularly in human subjects, this study highlights the potential of HyC as a promising therapeutic strategy for reducing AAO-associated organ damage.

BACKGROUND:Intestinal ischemia-reperfusion (I/R) injury (II/RI) is a critical condition that results in oxidative stress, inflammation, and damage to multiple organs. Zinc, an essential trace element, offers protective benefits in several tissues during I/R injury, but its effects on intestinal II/RI remain unclear. AIM:To investigate the effects of zinc pretreatment on II/RI and associated multiorgan damage. METHODS:C57BL/6 mice were pretreated with zinc sulfate (ZnSO4, 10 mg/kg) daily for three days before I/R injury was induced via superior mesenteric artery occlusion (SMAO) and abdominal aortic occlusion (AAO) models. Tissue and serum samples were collected to evaluate intestinal, liver, and kidney damage using Chiu's score, Suzuki score, and histopathological analysis. Caco-2 cells and intestinal organoids were used for in vitro hypoxia-reoxygenation injury models to measure reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. RESULTS:Zinc pretreatment significantly reduced intestinal damage in the SMAO and AAO models (P < 0.001). The serum levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase) and kidney markers (creatinine and urea) were lower in the zinc-treated mice than in the control mice, indicating reduced hepatic and renal injury. In vitro, zinc decreased ROS levels and increased SOD activity in Caco-2 cells subject to hypoxia-reoxygenation injury. Intestinal organoids pretreated with zinc exhibited enhanced resilience to hypoxic injury compared to controls. CONCLUSION:Zinc pretreatment mitigates II/RI and reduces associated multiorgan damage. These findings suggest that zinc has potential clinical applications in protecting against I/R injuries.

Transcatheter Arterial Chemoembolization (TACE) is the first choice for the treatment of advanced-stage hepatocellular carcinoma (HCC). However, TACE suffers from a lack of specificity and rapid drug release. Herein, a targeted redox-responsive peptide (TRRP) was synthesized and used as a carrier of doxorubicin (DOX) to enhance the efficacy of TACE through tumor cells targeting and controlled drug release. TRRP has a high loading capacity of DOX and a sensitive drug release behavior at high glutathione (GSH) concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models. TRRP has a high loading capacity of DOX and a sensitive drug release behavior at GSH concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models. This study demonstrated that TRRP was a promising therapeutic agent for enhancing TACE therapy for HCC treatment.

BACKGROUND Hepatic ischemia-reperfusion injury (IRI) poses a great challenge in liver surgery and transplantation because of oxidative stress and inflammatory responses. The changes in glutamine synthetase (GS) expression during hepatic IRI remain unclear. AIM To investigate the dynamic expression of GS during hepatic IRI. METHODS Following hepatic ischemia for 1 h and reperfusion, liver tissue samples were collected at 0.5, 6, and 24 hours postreperfusion for fixation, embedding, sectioning. Hematoxylin and eosin staining and GS staining were performed. RESULTS GS expression rapidly decreases in hepatocytes around the central vein after IRI, reaching its lowest point at 6 hours postreperfusion, and then gradually recovers. CONCLUSION GS is highly sensitive to IRI, highlighting its potential role as an indicator of liver injury states and a target for therapeutic intervention.

BACKGROUND: Hemorrhagic shock (HS) causes severe organ damage, worsened by high-altitude conditions with lower oxygen and temperatures. Existing research lacks specific insights on brain and heart damage under these conditions. This study hypothesizes that high-altitude and cold (HAC) environments exacerbate HS-induced damage in the brain and heart, aiming to improve treatment strategies. MATERIALS AND METHODS: Twenty-four male Sprague-Dawley (SD) rats (200–250 g of weight) were randomly assigned into sham, HS + normal, HS + HAC (4,000 m), and HS + HAC (6,000 m). The HS model was established in SD rats (35% loss of total blood volume), and histopathological injuries of the brain and heart were detected using hematoxylin and eosin staining, Sirius red staining, and immunohistochemistry. Apoptosis of the brain and heart tissues was detected by terminal transferase-mediated dUTP nick end labeling (TUNEL) immunofluorescence staining. To determine the levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (Mcp-1), BCL2-associated X (BAX), and myeloid cell leukemia-1 (Mcl-1) protein, western blotting assay was used. RESULTS: The HAC environment induced pathological damage to the brain and heart and aggravated the degree of cardiac fibrosis in HS rats. However, it did not cause apoptosis of the brain and heart. In addition, it upregulated TNF-α, IFN-γ, Mcp-1, and BAX protein levels, but downregulated Mcl-1 protein levels (P < 0.05). CONCLUSIONS: The HAC environment aggravated the degree of brain and heart damage in HS rats, which may be related to neuron nucleus pyknosis, myocardial fibrosis, and inflammatory and apoptosis activation.

Background and aim:Hepatic ischemia-reperfusion injury (IRI) is a significant challenge in liver transplantation, trauma, hypovolemic shock, and hepatectomy, with limited effective interventions available. This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2 (LECT2) in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA (shRNA) delivered through adeno-associated virus (AAV) vectors. Materials and methods:This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver. Lect2-knockout and C57BL/6J mice were used. Hepatic IRI was induced by clamping the hepatic pedicle. Treatments included recombinant human LECT2 (rLECT2) and AAV-Lect2-shRNA. LECT2 expression levels and serum biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) were measured. Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed. Results:Serum and liver LECT2 levels were elevated during hepatic IRI. Serum LECT2 protein and mRNA levels increased post reperfusion. Lect2-knockout mice had reduced weight loss; hepatic necrosis; and serum ALT, AST, creatinine, and BUN levels. rLECT2 treatment exacerbated weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN). AAV-Lect2-shRNA treatment significantly reduced weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN), indicating therapeutic potential. Conclusions:Elevated LECT2 levels during hepatic IRI increased liver damage. Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage, indicating its therapeutic potential. AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI, offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.

Resusciative endovascular balloon aortic occlusion (REBOA) can be used in various surgical operations, especially in patients with hypotension and shock caused by traumatic main vascular rupture and massive haemorrhage. However, the hydrodynamic effects of surgery on aortic haemodynamics and organ perfusion are still unclear. Herein, computational fluid dynamic methods were used to evaluate the effect of balloon expansion and that of balloon-occluded aortic ratios on haemodynamics. The simulation shows that the balloon reduces the flow rate from the heart to the ruptured aorta. While reducing the flow rate of the aortic branches downstream of the balloon under conditions with fixed cardiac output, the balloon will increase the flow rate of the aortic branches upstream of the balloon. And the flow in the diastolic phase is more complicated than that of the systolic phase, and the vortex generated upstream of the balloon is more evident than that of the formed downstream. Moreover, when the inflation rate of the balloon changes rapidly, the flow rate of blood at the balloon changes suddenly accordingly, which generates a large additional pressure on the balloon. The pressure will spread upstream, thereby generating a blood hammer effect on the blood vessel wall.

Background. Abdominal aortic occlusion (AAO) occurs frequently and causes ischemia/reperfusion (I/R) injury to distant organs. In this study, we aimed to investigate whether AAO induced I/R injury and subsequent damage in cardiac and neurologic tissue. We also aimed to investigate the how length of ischemic time in AAO influences reactive oxygen species (ROS) production and inflammatory marker levels in the heart, brain, and serum. Methods. Sixty male C57BL/6 mice were used in this study. The mice were randomly divided into either sham group or AAO group. The AAO group was further subdivided into 1–4 hr groups of aortic occlusion times. The infrarenal abdominal aorta was clamped for 1–4 hr depending on the AAO group and was then reperfused for 24 hr after clamp removal. Serum, hippocampus, and left ventricle tissue samples were then subjected to biochemical and histopathological analyses. Results. AAO-induced I/R injury had no effect on cell necrosis, cell apoptosis, or ROS production. However, serum and hippocampus levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH) increased in AAO groups when compared to sham group. Superoxide dismutase and total antioxidant capacity decreased in the serum, hippocampus, and left ventricle. In the serum, AAO increased the level of inducible nitric oxide synthase (iNOS) and decreased the levels of anti-inflammatory factors (such as arginase-1), transforming growth factor- β1 (TGF-β1), interleukin 4 (IL-4), and interleukin 10 (IL-10). In the hippocampus, AAO increased the levels of tumor necrosis factor (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), IL-4, and IL-6, and decreased the level of TGF-β1. In the left ventricle, AAO increased the level of iNOS and decreased the levels of TGF-β1, IL-4, and IL-10. Conclusions. AAO did not induce cell necrosis or apoptosis in cardiac or neurologic tissue, but it can cause inflammation in the serum, brain, and heart.

BACKGROUNDIschemic stroke (IS) is a cerebrovascular disease with high incidence and mortality. White matter repair plays an important role in the long-term recovery of neurological function after cerebral ischemia. Neuroprotective microglial responses can promote white matter repair and protect ischemic brain tissue.AIMSThe aim of this study was to investigate whether hypoxic postconditioning (HPC) can promote white matter repair after IS, and the role and mechanism of microglial polarization in white matter repair after HPC treatment.MATERIALS & METHODSAdult male C57/BL6 mice were randomly divided into three groups: Sham group (Sham), MCAO group (MCAO), and hypoxic postconditioning group (HPC). HPC group were subjected to 45 min of transient middle cerebral artery occlusion (MCAO) immediately followed by 40 min of HPC.RESULTSThe results showed that HPC reduced the proinflammatory level of immune cells. Furthermore, HPC promoted the transformation of microglia to anti-inflammatory phenotype on the third day after the procedure. HPC promoted the proliferation of oligodendrocyte progenitors and increased the expression of myelination-related proteins on the 14th day. On the 28th day, HPC increased the expression of mature oligodendrocytes, which enhanced myelination. At the same time, the motor neurological function of mice was restored.DISCUSSIONDuring the acute phase of cerebral ischemia, the function of proinflammatory immune cells was enhanced, long-term white matter damage was aggravated, and motor sensory function was decreased.CONCLUSIONHPC promotes protective microglial responses and white matter repair after MCAO, which may be related to the proliferation and differentiation of oligodendrocytes.

Background: To identify the incidence, manifestation and risk factors of transarterial chemoem-bolization (TACE) failure defined as untreatable progression (UP) in patients with hepatocellular carcinoma (HCC) on short-term observation. Methods: Patients from two hospitals with HCC treated with TACE were considered. According to the definition of UP, TACE failure was considered to be present in at least one of the following sit-uations: situation I, failure to achieve objective response in the targeted tumor after at least two initial TACE treatments; situation II, failure to achieve objective response in local tumor pro-gression or new intrahepatic tumor after another TACE session; situation III, presence of major progression; and situation IV, presence of impaired liver function or performance status that con-traindicates TACE treatment. Patients were assessed for TACE failure on follow-up visits after two or three TACE sessions. Risk factors for TACE failure were evaluated with logistic regression analysis. Results: A total of 206 patients were included. TACE failure occurred in 42 (42/206, 20.4%) patients, of whom 21, 1, 4, 0 and 16 patients manifested as situation I, II, III, IV alone, and combi -nation of situation I with the others, respectively. Multivariate analysis showed that tumor without complete capsule (P <.001) and non-smooth margin (P = .004) were independent predictors of the presence of TACE failure. Conclusions: TACE failure was uncommon in patients with HCC, which manifested predominantly as failure of treatment response of the initial intrahepatic tumor. Non-smooth tumor margin and tumors without complete capsule were associated with the presence of TACE failure.(c) 2022 Elsevier Masson SAS. All rights reserved.

Background and Aims Stem cell transplantation is a potential treatment option for liver cirrhosis (LC). Accurately and noninvasively monitoring the distribution, migration, and prognosis of transplanted stem cells using imaging methods is important for in-depth study of the treatment mechanisms. Our study aimed to develop Au-Fe3O4 silica nanoparticles (NPs) as tracking nanoplatforms for dual-modal stem cell imaging. Methods Au-Fe3O4 silica NPs were synthesized by seed-mediated growth method and co-precipitation. The efficiency and cytotoxicity of the NPs-labeled bone marrow-derived mesenchymal stem cells (BM-MSCs) were evaluated by Cell Counting Kit-8 assays, ICP-MS, phenotypic characterization, and histological staining. The biodistribution of labeled BM-MSCs injected through different routes (the hepatic artery or tail vein) into rats with LC was detected by magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and Prussian blue staining. Results Synthesized Au-Fe3O4 silica NPs consisted of a core (star-shaped Au NPs) and an outside silica layer doped with Fe3O4 NPs. After 24 h coincubation with 2.0 OD concentration of NPs, the viability of BM-MSCs was 77.91%±5.86% and the uptake of Au and Fe were (22.65±1.82) µg/mL and (234.03±11.47) µg/mL, respectively. The surface markers of labeled BM-MSCs unchanged significantly. Labeled BM-MSCs have osteogenic and adipogenic differentiation potential. Post injection in vivo, rat livers were hypointense on MRI and hyperintense on PAI. Prussian blue staining showed that more labeled BM-MSCs accumulated in the liver of the hepatic artery group. The severity of LC of the rats in the hepatic artery group was significantly alleviated. Conclusions Au-Fe3O4 silica NPs were suitable MRI/PAI dual-modal imaging nanoplatforms for stem cell tracking in regenerative medicine. Transhepatic arterial infusion of BM-MSCs was the optimal route for the treatment of LC.

BACKGROUND Immune cells, including neutrophils, natural killer (NK) cells, T cells, NKT cells and macrophages, participate in the progression of acute liver injury and hepatic recovery. To date, there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery. AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time, and to study the relationship between the changes in leukocyte cell-derived chemotaxin 2 (LECT2) and the infiltration of several immune cells. METHODS Carbon tetrachloride- and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively. The quantitative changes in various immune cells were monitored at different time points. Serum samples were collected, and liver tissues were harvested. Ly6G, CD161, CD4, CD8 and F4/80 staining were used to indicate neutrophils, NK/NKT cells, CD4(+ )T cells, CD8(+ )T cells and macrophages, respectively. Lect2-KO mice were used to detect the function of LECT2. RESULTS During the injury and repair process, different types of immune cells began to increase, reached their peaks and fell into decline at different time points. Furthermore, when the serum alanine transaminase (ALT) and aspartate transaminase (AST) indices reverted to normal levels 7 d after the injury, the infiltration of immune cells still existed even 14 d after the injury, showing an obvious lag effect. We found that the expression of LECT2 was upregulated in acute liver injury mouse models, and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice. Compared with wild-type mice, Lect2-KO mice had different immune cell infiltration. CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair. LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.

ObjectivesTo compare the safety and efficacy of lenvatinib (LEN) combined with camrelizumab plus transcatheter arterial chemoembolization (TACE-LEN-C) and TACE combined with LEN (TACE-LEN) in patients with unresectable hepatocellular carcinoma (uHCC).MethodsEighty-three patients with uHCC treated with TACE-LEN-C or TACE-LEN from September 2018 to May 2021 were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), local tumor response, and adverse events (AEs) were evaluated. Univariate and multivariate analyses were used to determine the factors affecting survival.ResultsThere were 31 patients in the TACE-LEN-C group and 52 patients in the TACE-LEN group. The median follow-up period was 14.2 months (range 7.2–25.2 months) in the whole study. The combination of triple therapy was found to significantly prolong the PFS (12.5 months vs. 6.6 months, P<0.001) and OS (18.9 months vs. 13.9 months, P<0.001. In terms of tumor response, the combination demonstrated a higher objective response rate (71% vs. 42.3% by the modified Response Evaluation Criteria in Solid Tumors, P=0.023) without a statistically significant difference in the disease control rate (93.5% in TACE-LEN-C, 80.8% in TACE-LEN, P=0.195). In the multivariate analysis, two independent factors affecting PFS were identified: number of tumors and treatment. Three independent factors affected OS: number of tumors, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment. All the AEs were tolerable.ConclusionTACE-LEN-C is a safe and effective treatment for patients with uHCC, and could be a potential treatment option.