Perilla frutescens leaf extracts alleviate acute lung injury in mice by inhibiting KAT2A.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) can lead to respiratory failure and even death. KAT2A is a key target to suppress the development of inflammation. A herb, perilla frutescens, is an effective treatment for pulmonary inflammatory diseases with anti-inflammatory effects; however, its mechanism of action remains unclear. AIM OF THE STUDY: The purpose of this study was to investigate the therapeutic effect and underlying mechanism of perilla frutescens leaf extracts (PLE), in the treatment of ALI by focusing on its ability to treat inflammation. MATERIALS AND METHODS: In vivo and in vitro models of ALI induced by LPS. Respiratory function, histopathological changes of lung, and BEAS-2B cells damage were assessed upon PLE. This effect is also tested under conditions of KAT2A over expression and KAT2A silencing. RESULTS: PLE significantly attenuated LPS-induced histopathological changes in the lungs, improved respiratory function, and increased survival rate from LPS stimuation background in mice. PLE remarkably suppressed the phosphorylation of STAT3, AKT, ERK (1/2) and the release of cytokines (IL-6, TNF-α, and IL-1ß) induced by LPS via inhibiting the expression of KAT2A. CONCLUSIONS: PLE has a dose-dependent anti-inflammatory effect by inhibiting KAT2A expression to suppress LPS-induced ALI n mice. Our study expands the clinical indications of the traditional medicine PLE and provide a theoretical basis for clinical use of acute lung injury.

Radiation-Emitting metallic stent for unresectable bismuth type III or IV perihilar cholangiocarcinoma: a multicenter randomized trial.

BACKGROUND AIMS: Self-expandable metallic stents (SEMSs) have been recommended for patients with unresectable malignant biliary obstruction while radiation-emitting metallic stents (REMSs) loaded with 125I seeds have recently been approved to provide longer patency and overall survival in malignant biliary tract obstruction. This trial is to evaluate the efficacy and safety of REMS plus hepatic arterial infusion chemotherapy (REMS-HAIC) versus SEMS plus HAIC (SEMS-HAIC) for unresectable perihilar cholangiocarcinoma (pCCA). METHODS: This multicenter randomized controlled trial recruited patients with unresectable Bismuth type III or IV pCCA between March 2021 and January 2023. Patients were randomly assigned (1:1 ratio) to receive either REMS-HAIC or SEMS-HAIC using permuted block randomization, with a block size of six. The primary endpoint was overall survival (OS). The secondary endpoints were time to symptomatic progression (TTSP), stent patency, relief of jaundice, quality of life, and safety. RESULTS: A total of 126 patients were included in the intent-to-treat population, with 63 in each group. The median OS was 10.2 months versus 6.7 months (P=0.002). The median TTSP was 8.6 months versus 5.4 months (P=0.003). The median stent patency was longer in the REMS-HAIC group than in the SEMS-HAIC group (P=0.001). The REMS-HAIC group showed better improvement in physical functioning scale (P<0.05) and fatigue symptoms (P<0.05) when compared to the SEMS-HAIC group. No significant differences were observed in relief of jaundice (85.7% vs. 84.1%; P=0.803) or the incidence of grade 3 or 4 adverse events (9.8% vs. 11.9%; P=0.721). CONCLUSION: REMS plus HAIC showed better OS, TTSP, and stent patency compared with SEMS plus HAIC in patients with unresectable Bismuth type III or IV pCCA with an acceptable safety profile.

Guidelines for permanent iodine-125 seed interstitial brachytherapy for pancreatic cancer (2023 edition): The Chinese expert consensus workshop report.

ABSTRACT: The incidence of pancreatic cancer is increasing worldwide. Approximately, 60% of patients with pancreatic cancer have distant metastases at the time of diagnosis, of which only 10% can be removed using standard resection. Further, patients derive limited benefits from chemotherapy or radiotherapy. As such, alternative methods to achieve local control have emerged, including permanent iodine-125 seed interstitial brachytherapy. In 2023, the Chinese College of Interventionalists, affiliated with the Chinese Medical Doctor Association, organized a group of multi-disciplinary experts to compose guidelines for this treatment modality. The aim of this conference was to standardize the procedure for permanent iodine-125 seed interstitial brachytherapy, including indications, contraindications, pre-procedural preparation, procedural operations, complications, efficacy evaluation, and follow-up.

Clinical features and prognostic factors of patients with inoperable hepatocellular carcinoma treated with chemotherapy: a population-based study.

Background: In inoperable hepatocellular carcinoma (HCC), chemotherapy is a common treatment strategy. However, there is a lack of reliable methods to predict the prognosis of patients with inoperable HCC after chemotherapy. Therefore, the aim of this study was to identify the clinical characteristics of patients with inoperable HCC and to establish and validate nomogram models for predicting the survival outcomes in this patient group following chemotherapy. Methods: The data of patients diagnosed with HCC from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Logistic regression analyses were used to identify potential factors for inoperability in patients with HCC. Kaplan-Meier analyses were applied to evaluate the impact of chemotherapy on prognosis. Additionally, Cox regression analyses were performed to identify the potential risk factors associated with overall survival (OS) and cancer-specific survival (CSS) in patients with inoperable HCC treated with chemotherapy. Finally, we constructed prognostic nomograms for predicting the 1- and 3-year survival probabilities. Results: A total of 3,519 operable patients with HCC and 4,656 patients with inoperable HCC were ultimately included in this study. Logistic regression analyses revealed a significant association between patient age, gender, race, tumor, node, metastasis (TNM) stage, tumor size, pretreatment alpha fetoprotein (AFP) levels, and marital status with inoperability. Moreover, Kaplan-Meier analyses revealed a significant improvement in both OS and CSS with the administration of chemotherapy. Moreover, 1,456 patients with inoperable HCC were enrolled in the training group and 631 patients with inoperable HCC were enrolled in the validation group to develop and validate the prognostic models. Cox regression models indicated that TNM stage, tumor size, and pretreatment AFP were independent risk factors for predicting OS and CSS in patients with inoperable HCC receiving chemotherapy. These factors were subsequently integrated into the predictive nomograms. Conclusions: We preliminarily developed survival models with strong predictive capabilities for estimating survival probabilities in patients with HCC following chemotherapy. These models hold potential for clinical application and warrant further exploration through additional studies.

Exploring immune-related pathogenesis in lung injury: Providing new insights Into ALI/ARDS.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a significant global burden of morbidity and mortality, with lung injury being the primary cause of death in affected patients. The pathogenesis of lung injury, however, remains a complex issue. In recent years, the role of the immune system in lung injury has attracted extensive attention worldwide. Despite advancements in our understanding of various lung injury subtypes, significant limitations persist in both prevention and treatment. This review investigates the immunopathogenesis of ALI/ARDS, aiming to elucidate the pathological processes of lung injury mediated by dendritic cells (DCs), natural killer (NK) cells, phagocytes, and neutrophils. Furthermore, the article expounds on the critical contributions of gut microbiota, inflammatory pathways, and cytokine storms in the development of ALI/ARDS.

High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT.

OBJECTIVE: Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. DESIGN: Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77S and AKT1C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. RESULTS: By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. CONCLUSIONS: Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.

Polygonatum odoratum polysaccharide attenuates lipopolysaccharide-induced lung injury in mice by regulating gut microbiota.

Polygonatum odoratum is appreciated for its edible and medicinal benefits especially for lung protection. However, the contained active components have been understudied, and further research is required to fully exploit its potential application. We aimed to probe into the beneficial effects of Polygonatum odoratum polysaccharide (POP) in lipopolysaccharide-induced lung inflammatory injury mice. POP treatment could ameliorate the survival rate, pulmonary function, lung pathological lesions, and immune inflammatory response. POP treatment could repair intestinal barrier, and modulate the composition of gut microbiota, especially reducing the abundance of Klebsiella, which were closely associated with the therapeutic effects of POP. Investigation of the underlying anti-inflammatory mechanism showed that POP suppressed the generation of pro-inflammatory molecules in lung by inhibiting iNOS+ M1 macrophages. Collectively, POP is a promising multi-target microecological regulator to prevent and treat the immuno-inflammation and lung injury by modulating gut microbiota.

Nephrotoxicity assessment of podophyllotoxin-induced rats by regulating PI3K/Akt/mTOR-Nrf2/HO1 pathway in view of toxicological evidence chain (TEC) concept.

Adverse reactions to traditional Chinese medicine have hindered the healthy development and internationalization process of the traditional Chinese medicine industry. The critical issue that needs to be solved urgently is to evaluate the safety of traditional Chinese medicine systematically and effectively. Podophyllotoxin (PPT) is a highly active compound extracted from plants of the genus Podophyllum such as Dysosma versipellis (DV). However, its high toxicity and toxicity to multiple target organs affect the clinical application, such as the liver and kidney. Based on the concurrent effects of PPT's medicinal activity and toxicity, it would be a good example to conduct a systematic review of its safety. Therefore, this study revolves around the Toxicological Evidence Chain (TEC) concept. Based on PPT as the main toxic constituent in DV, observe the objective toxicity impairment phenotype of animals. Evaluate the serum biochemical indicators and pathological tissue sections for substantial toxic damage results. Using metabolomics, lipidomics, and network toxicology to evaluate the nephrotoxicity of PPT from multiple perspectives systematically. The results showed that PPT-induced nephrotoxicity manifested as renal tubular damage, mainly affecting metabolic pathways such as glycerophospholipid metabolism and sphingolipid metabolism. PPT inhibits the autophagy process of kidney cells through the PI3K/Akt/mTOR and Nrf2/HO1 pathways and induces the activation of oxidative stress in the body, thereby causing nephrotoxic injury. This study fully verified the feasibility of the TEC concept for the safety and toxicity evaluation of traditional Chinese medicine. Provide a research template for systematically evaluating the safety of traditional Chinese medicine.

Endovascular brachytherapy with iodine-125 seed strand for extensive portal vein tumor thrombus in patients with hepatocellular carcinoma.

Objective: The aim of this study is to investigate the feasibility and effectiveness of endovascular brachytherapy with iodine-125 (I-125) seed strand for the treatment of extensive portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) patients. Methods: A total of 40 HCC patients complicated by extensive PVTT who received I-125 seed strand implantation from January 2015 to December 2022 in our center were analyzed retrospectively. Endpoints included technical success rate, concurrent therapies, overall survival time, and complications. Multivariate and subgroup analyses were conducted for overall survival. Results: The successful rate of operation was 100%, and there was no operation-related death. A total of 37 patients received single I-125 seed strand implantation, and three patients received double I-125 seed strand implantation. A total of 23 patients received a concurrent therapy: transarterial chemoembolization (TACE) combined with systematic treatment (n = 6), TACE alone (n = 10), and systematic treatment alone (n = 9). At a median follow-up of 3.5 (interquartile range (IQR), 2~8.5) months, the median overall survival (OS) of all patients was 92 days (95% confidence interval (CI): 77~108). In the subgroup analysis, the median OS was 128 days (95% CI: 101~155 days) in the I-125 seed strand implantation plus systematic treatment group and was longer than that (75 days (95% CI: 36~114) of the I-125 seed strand alone group (p = 0.037). Multivariate analysis revealed that no systematic treatment was an independent risk factor affecting the prognosis in this study. Six patients died of upper gastrointestinal bleeding: four patients in the I-125 seed strand alone group and two patients in the combination of I-125 seed strand with systematic treatment group. Conclusions: The study shows that endovascular brachytherapy with I-125 seed strand implantation is a safe and effective treatment method for extensive PVTT in HCC patients. The combination of I-125 seed strand implantation and systematic treatment can prolong the survival time.

Photonic Hyperthermia Synergizes with Immune-Activators to Augment Tumor-Localized Immunotherapy.

Photothermal immunotherapy, the combination of photothermal hyperthermia and immunotherapy, is a noninvasive and desirable therapeutic strategy to address the deficiency of traditional photothermal ablation for tumor treatment. However, insufficient T-cell activation following photothermal treatment is a bottleneck to achieve satisfactory therapeutic effectiveness. In this work, a multifunctional nanoplatform is rationally designed and engineered on the basis of polypyrrole-based magnetic nanomedicine modified by T-cell activators of anti-CD3 and anti-CD28 monoclonal antibodies, which have achieved robust near infrared laser-triggered photothermal ablation and long-lasting T-cell activation, realizing diagnostic imaging-guided immunosuppressive tumor microenvironment regulation following photothermal hyperthermia by reinvigorating tumor-infiltrating lymphocytes. By virtue of high-efficient immunogenic cell death and dendritic cell maturation combined with T-cell activation, this nanosystem markedly restrains primary and abscopal tumors as well as metastatic tumors with negligible side effects in vivo, exerting the specific function for suppressing tumor recurrence and metastasis by establishing a long-term memory immune response.

A Novel Neutrophil-to-Lymphocyte Ratio and Sarcopenia Based TACE-Predict Model of Hepatocellular Carcinoma Patients.

Purpose: Transarterial chemoembolization (TACE) was commonly applied in hepatocellular carcinoma (HCC) patients across BCLC A-C stages with heterogeneous outcomes in real-world practice. We aimed to develop a neutrophil-to-lymphocyte ratio (NLR) and sarcopenia-based prognostic nomogram to estimate the prognosis of HCC patients after TACE treatment. Patients and Methods: Between June 2013 and December 2019, a total of 364 HCC patients who underwent TACE were included and randomly assigned to the training (n=255) and the validation cohort (n=109). Sarcopenia was diagnosed based on the third lumbar vertebra skeletal muscle mass index (L3-SMI). The multivariate Cox proportional risk model was used to generate a nomogram. Results: NLR ≥4.0, sarcopenia, alpha-fetoprotein (AFP) ≥200 ng/mL, albumin-bilirubin (ALBI) grade 2 or 3, number of lesions (≥2), and maximum size of the lesion (≥5 cm) were independent predictors for overall survival (OS) (P < 0.05). The calibration curve shows that the predicted results agree well with the observed results. The time-dependent areas under the receiver-operating characteristic curves for OS at 1, 2, and 3 years predicted by the nomogram were 0.818/0.827, 0.742/0.823, and 0.748/0.836 in both training and validation cohorts. Nomogram can divide patients into low-, medium- and high-risk groups based on predictor factors. The C-indexes of the nomogram for OS were 0.782/0.728 in the training and validation cohorts, outperforming other currently available models. Conclusion: A novel nomogram based on NLR and sarcopenia may be useful to predict the prognosis of HCC patients who underwent TACE across BCLC A-C stage patients.

Irradiation stent with 125 I plus TACE versus sorafenib plus TACE for hepatocellular carcinoma with major portal vein tumor thrombosis: a multicenter randomized trial.

BACKGROUND AND AIM: Treatment strategy for hepatocellular carcinoma (HCC) and Vp4 [main trunk] portal vein tumor thrombosis (PVTT) remains limited due to posttreatment liver failure. We aimed to assess the efficacy of irradiation stent placement with 125 I plus transcatheter arterial chemoembolization (TACE) (ISP-TACE) compared to sorafenib plus TACE (Sora-TACE) in these patients. METHODS: In this multicenter randomized controlled trial, participants with HCC and Vp4 PVTT without extrahepatic metastases were enrolled from November 2018 to July 2021 at 16 medical centers. The primary endpoint was overall survival (OS). The secondary endpoints were hepatic function, time to symptomatic progression, patency of portal vein, disease control rate, and treatment safety. RESULTS: Of 105 randomized participants, 51 were assigned to the ISP-TACE group, and 54 were assigned to the Sora-TACE group. The median OS was 9.9 months versus 6.3 months (95% CI: 0.27-0.82; P =0.01). Incidence of acute hepatic decompensation was 16% (8 of 51) versus 33% (18 of 54) ( P =0.036). The time to symptomatic progression was 6.6 months versus 4.2 months (95% CI: 0.38-0.93; P =0.037). The median stent patency was 7.2 months (interquartile range, 4.7-9.3) in the ISP-TACE group. The disease control rate was 86% (44 of 51) versus 67% (36 of 54) ( P =0.018). Incidences of adverse events at least grade 3 were comparable between the safety populations of the two groups: 16 of 49 (33%) versus 18 of 50 (36%) ( P =0.73). CONCLUSION: Irradiation stent placement plus TACE showed superior results compared with sorafenib plus TACE in prolonging OS in patients with HCC and Vp4 PVTT.

HSV: The scout and assault for digestive system tumors.

More than 25% of all malignant tumors are digestive system tumors (DSTs), which mostly include esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, gallbladder cancer and cholangiocarcinoma, and colorectal cancer. DSTs have emerged as one of the prominent reasons of morbidity and death in many nations and areas around the world, posing a serious threat to human life and health. General treatments such as radiotherapy, chemotherapy, and surgical resection can poorly cure the patients and have a bad prognosis. A type of immunotherapy known as oncolytic virus therapy, have recently shown extraordinary anti-tumor effectiveness. One of the viruses that has been the subject of the greatest research in this field, the herpes simplex virus (HSV), has shown excellent potential in DSTs. With a discussion of HSV-1 based on recent studies, we outline the therapeutic effects of HSV on a number of DSTs in this review. Additionally, the critical function of HSV in the detection of cancers is discussed, and some HSV future possibilities are shown.

Chlorogenic acid reduces inflammation by inhibiting the elevated expression of KAT2A to ameliorate lipopolysaccharide-induced acute lung injury.

BACKGROUND AND PURPOSE: Respiratory diseases have become a global health problem and may lead to acute lung injury (ALI) in severe cases. ALI progression is associated with complex pathological changes; however, there are currently no effective therapeutic drugs. Excessive activation and recruitment of immunocytes in the lungs and the release of large amounts of cytokines are considered the primary causes of ALI, but the cellular mechanisms involved remain unknown. Therefore, new therapeutic strategies need to be developed to control the inflammatory response and prevent the further aggravation of ALI. EXPERIMENTAL APPROACH: Lipopolysaccharide was administered to mice via tail vein injection to establish an ALI model. Key genes regulating lung injury in mice were screened by RNA sequencing (RNA-seq), and their regulatory effects on inflammation and lung injury were assessed in in vivo and in vitro experiments. KEY RESULTS: The key regulatory gene KAT2A up-regulated the expression of inflammatory cytokines and induced lung epithelial injury. Chlorogenic acid, a small natural molecule and KAT2A inhibitor, inhibited the inflammatory response and significantly improved the decreased respiratory function caused by lipopolysaccharide administration in mice by inhibiting the expression of KAT2A. CONCLUSION AND IMPLICATIONS: Targeted inhibition of KAT2A suppressed the release of inflammatory cytokines and improved respiratory function in this murine model of ALI. Chlorogenic acid, a specific KAT2A-targeting inhibitor, was effective in treating ALI. In conclusion, our results provide a reference for the clinical treatment of ALI and contribute to the development of novel therapeutic drugs for lung injury.

AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.

The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth in response to amino acid and glucose levels. However, how mTORC1 senses glucose availability to regulate various downstream signalling pathways remains largely elusive. Here we report that AMP-activated protein kinase (AMPK)-mediated phosphorylation of WDR24, a core component of the GATOR2 complex, has a role in the glucose-sensing capability of mTORC1. Mechanistically, glucose deprivation activates AMPK, which directly phosphorylates WDR24 on S155, subsequently disrupting the integrity of the GATOR2 complex to suppress mTORC1 activation. Phosphomimetic Wdr24S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity. On the other hand, compared to wild-type littermates, phospho-deficient Wdr24S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity. Our findings reveal that AMPK-mediated phosphorylation of WDR24 modulates glucose-induced mTORC1 activation, thereby providing a rationale for targeting AMPK-WDR24 signalling to fine-tune mTORC1 activation as a potential therapeutic means to combat human diseases with aberrant activation of mTORC1 signalling including cancer.

X-ray-guided and ultrasound-guided percutaneous transluminal angioplasty to treat arteriovenous fistula dysfunction in hemodialysis patients: A retrospective controlled study.

PURPOSE: To compare the safety and efficacy of X-ray-guided and ultrasound-guided percutaneous transluminal angioplasty in treating arteriovenous fistula dysfunction. MATERIALS AND METHODS: Data for 219 patients with arteriovenous fistula dysfunction between January 2016 and December 2018 were retrospectively analyzed. The primary endpoints were technical success, clinical success, and primary patency rates. The secondary endpoints were complications and secondary patency rates. Procedure outcomes and both endpoints were evaluated by propensity score analysis. RESULTS: After the propensity score matching, 73 matched pairs of cases were created with 34 pairs of autogenous arteriovenous fistula cases and 39 pairs of prosthetic arteriovenous graft cases. There was no significant difference between the X-ray-guided and ultrasound-guided group, respectively, regarding the technical success rate (84.9% vs 87.7%, p = 0.630), clinical success rate (98.6% vs 97.3%, p = 0.999), and complications (10.9% vs 5.5%, p = 0.228). Although the 6- and 12-month secondary patency rates for the dialysis access between the two groups had significant difference (p < 0.05), there was no significant difference in primary and secondary patency curves between the two groups (p > 0.05). CONCLUSION: The overall efficacy of ultrasound-guided versus X-ray-guided percutaneous transluminal angioplasty in treating arteriovenous fistula dysfunction might be comparable.

Establishment and validation of a prediction model for the first recurrence of Budd-Chiari syndrome after endovascular treatment: a large sample size, single-center retrospective study.

OBJECTIVE: To investigate the independent risk factors for the first recurrence after endovascular management in patients with Budd-Chiari syndrome (BCS), and to establish a prediction model for predicting recurrence in target patients. METHODS: BCS patients who underwent endovascular treatment in the Affiliated Hospital of Xuzhou Medical University from January 2010 to December 2015 were retrospectively examined, with their clinical, laboratory test, and imaging data collected and analyzed. Independent risk factors for recurrence were identified, and a prediction model was established and validated. RESULTS: A total of 450 patients met the filtering criteria, and 102 recurred during the follow-up. The median follow-up time was 87 months, ranging from 1 to 137 months. The 1-, 3-, 5- and 10-year cumulative recurrence rate was 9.11% (6.41-11.73%), 17.35% (13.77-20.78%), 20.10% (16.30-23.72%), and 23.06% (18.86-27.04%), respectively. Liver cirrhosis, ascites, thrombosis, and all the main intrahepatic drainage veins obstructed (obstructed HV + AHV) are independent risk factors, while age is an independent protective factor. The prediction model was named MRBET. Based on the model, the risk score of each patient equals (-0.385981 * Age/10) + (0.0404184 * PT) + (0.0943423 * CRE/10) + (0.0157053 * LDH/10) + (0.592179 * LC) + (0.896034 * Ascites) + (0.691346 * Thrombosis) + (0.886741 * obstructed HV + AHV), and those in the high-risk group (risk score ≥ 1.57) were more likely to recur than those in the low-risk group (HR = 6.911, p < 0.001). The MRBET model is also available as a web tool at https://mrbet.shinyapps.io/dynnomapp . CONCLUSION: Liver cirrhosis, ascites, thrombosis, and obstructed HV + AHV are independent risk factors for the first recurrence; age is an independent protective factor. The prediction model can effectively and conveniently predict the risk of recurrence and screen out patients at a high recurrence risk.

Sarcopenia increases the risk of early biliary infection after percutaneous transhepatic biliary stent placement.

Purpose: To assess the association between sarcopenia and the risk of early biliary infection (EBI) after percutaneous transhepatic biliary stent (PTBS) placement in patients with inoperable biliary tract cancer (BTC). Patients and methods: In this single center, retrospective observational study, patients diagnosed with inoperable BTC undergoing PTBS placement between January 2013 and July 2021 were enrolled. Preoperative sarcopenia was defined based on skeletal muscle mass measured by computed tomography images on the level of third lumbar vertebra within one month before PTBS placement. Patients were divided into two groups in accordance with the status of sarcopenia. Univariate and further multivariate logistic analyses were performed to determine predictors for EBI. Stratified and interactive analyses were conducted to investigate the stability of results. Further receiver operating characteristic curve was performed to determine the predictive value of sarcopenia on EBI after PTBS placement. Results: Totally, 134 patients were included in this retrospective study, with 45 (33.6%) patients characterized as sarcopenia. The incidence rate of EBI was 26.9% (36/134). Multivariate analyses demonstrated that sarcopenia [Odds ratio (OR), 2.75; 95%CI: 1.11-6.77; P=0.028], obstruction length (OR, 1.04; 95%CI: 1.00-1.08; P=0.030) and diabetes (OR, 2.46; 95%CI: 1.01-5.96; P=0.047) were significant predictors of EBI. There were no significant interactions in different subgroups (P for interaction > 0.05). Moreover, the areas under the curves (AUC) revealed that the combined index containing sarcopenia, obstruction length, and diabetes showed the better predictive value (AUC= 0.723) than either one alone. Conclusion: Sarcopenia increased the risk of EBI in patients with inoperable BTC after PTBS placement. Preoperative assessment of sarcopenia may aid in risk stratification. Patients with sarcopenia should be given intensive monitoring.

Tumor oxygenation nanoliposome synergistic hypoxia-inducible-factor-1 inhibitor enhanced Iodine-125 seed brachytherapy for esophageal cancer.

Iodine-125 (125I) brachytherapy has become one of the most effective palliative treatment options for advanced esophageal cancer. However, resistance toward 125I brachytherapy caused by pre-existing tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) signaling pathway activation represents a significant limitation in esophageal cancer treatment. To circumvent these problems, herein, we proposed an innovative strategy to alleviate radioresistance of brachytherapy by co-encapsulating catalase (CAT) and HIF-1 inhibitor-acriflavine (ACF) into the hydrophilic cavities of liposome, termed as "ACF-CAT@Lipo". Under overexpressed H2O2 stimulation in the tumor region, the fabricated ACF-CAT@Lipo can generate an amount of O2 and alleviate tumor hypoxia in vitro and in vivo. Furthermore, cooperating with ACF, the expression of hypoxia-related protein (e.g. HIF-1α, VEGF, MMP-2) are obviously decreased. Importantly, the copious oxygenation and the significant inhibition expression of HIF-1α can further improve the radiosensitivity of 125I brachytherapy and finally realize the eradication of esophageal cancer in vivo. The oxygen enrichment and HIF-1 inhibition function of ACF-CAT@Lipo provides a new strategy to overcome the brachytherapy resistance of esophageal cancer therapy.

Microorganism-enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy.

Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) generation has been envisioned as a distinct modality for efficient cancer treatment. However, insufficient ROS generation and partial ROS consumption frequently limit the theraputic effect and outcome of NDT owing to the low oxygen (O2) tension and high glutathione (GSH) level in tumor microenvironment (TME). To circumvent these critical issues, we herein proposed and engineered the biodegradable GSH-depletion Mn(III)-riched manganese oxide nanospikes (MnOx NSs) with the photosynthetic bacterial cyanobacteria (Cyan) as a high-efficient and synergistic platform to reshape TME by simultaneously increasing oxygen content and decreasing GSH level. Specifically, under the trigger of acidity, MnOx NSs reacted with photosynthetic oxygen can generate toxic singlet oxygen (1O2). Moreover, MnOx NSs significantly reduced intracellular GSH, resulting in decreased GPX4 activity, which induced tumor cell non-apoptotic ferroptosis. Consequently, this combined strategy based on coadministration with Cyan and MnOx NSs demonstrated the superior antitumor efficacy via amplification of oxidative stress in 4T1 tumor-bearing mice for the synergetic oxygen-augmented nanodynamic/ferroptosis therapy. This work highlights a facile synergistic micro-/nano-system with the specific capability of reshaping TME to augment the sensitivity and therapeutic efficacy of NDT in solid hypoxic tumor therapy.