Survival benefit from adjuvant TACE combined with Lenvatinib for patients with hepatocellular carcinoma and microvascular invasion after curative hepatectomy.

BACKGROUND AND AIMS: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is unsatisfactory, especially for those with microvascular invasion (MVI). This study aimed to determine the impact of adjuvant transcatheter arterial chemoembolization (TACE) and Lenvatinib on the prognosis of patients with HCC and MVI after hepatectomy. METHODS: Patients diagnosed with HCC and MVI were reviewed, and stratified into four groups according to adjuvant TACE and/or Lenvatinib. Multivariate Cox regression analyses are used to determine independent risk factors. RESULTS: 346 patients were included, and divided into four groups (Group I, TACE+ Lenvatinib; Group II, Lenvatinib; Group III, TACE; Group IV, without adjuvant therapy). Multivariable analysis showed that compared to Group IV, Group I had the best effect on improving the overall survival (OS, HR 0.321, 95%CI 0.099-0.406, P = 0.001) and recurrence-free survival (RFS, HR 0.319, 95%CI 0.129-0.372, P = 0.001). Additionally, compared with Group II or Group III, Group I also can significantly improve the OS and RFS. There is no significant difference between Group II and Group III in OS and RFS. CONCLUSION: The combination of TACE and Lenvatinib should be considered for anti-recurrence therapy for patients with HCC and MVI after hepatectomy.

Precise planning based on 3D-printed dry-laboratory models can reduce perioperative complications of laparoscopic surgery for complex hepatobiliary diseases: a preoperative cohort study.

BACKGROUND & AIMS: Complications after laparoscopic liver resection (LLR) are important factors affecting the prognosis of patients, especially for complex hepatobiliary diseases. The present study aimed to evaluate the value of a three-dimensional (3D) printed dry-laboratory model in the precise planning of LLR for complex hepatobiliary diseases. METHODS: Patients with complex hepatobiliary diseases who underwent LLR were preoperatively enrolled, and divided into two groups according to whether using a 3D-printed dry-laboratory model (3D vs. control group). Clinical variables were assessed and complications were graded by the Clavien-Dindo classification. The Comprehensive Complication Index (CCI) scores were calculated and compared for each patient. Multivariable analysis was performed to determine the risk factors of postoperative complications. RESULTS: Sixty-two patients with complex hepatobiliary diseases underwent the precise planning of LLR. Among them, thirty-one patients acquired the guidance of a 3D-printed dry-laboratory model, and others were only guided by traditional enhanced CT or MRI. The results showed no significant differences between the two groups in baseline characters. However, compared to the control group, the 3D group had a lower incidence of intraoperative blood loss, as well as postoperative 30-day and major complications, especially bile leakage (all P < 0.05). The median score on the CCI was 20.9 (range 8.7-51.8) in the control group and 8.7 (range 8.7-43.4) in the 3D group (mean difference, -12.2, P = 0.004). Multivariable analysis showed the 3D model was an independent protective factor in decreasing postoperative complications. Subgroup analysis also showed that a 3D model could decrease postoperative complications, especially for bile leakage in patients with intrahepatic cholelithiasis. CONCLUSION: The 3D-printed models can help reduce postoperative complications. The 3D-printed models should be recommended for patients with complex hepatobiliary diseases undergoing precise planning LLR.

F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.

BACKGROUND: Diabetes is accompanied by a high prevalence of hyposalivation, causing severe damage to oral and systemic health. Mitochondrial dynamics play important roles in the pathogenesis of various diabetic complications; however, little is known about their roles in diabetic hyposalivation. MATERIALS AND METHODS: A diabetic mouse model and a high glucose (HG)-induced diabetic submandibular gland (SMG) cell model were employed. RESULTS: More mitochondria surrounded by autophagosomes and higher expression of mitophagy-related proteins were detected in the SMGs of diabetic mice and HG-treated SMG cells. In diabetic SMGs, dynamin-related protein 1 (DRP1) was upregulated, whereas mitofusin-2 was downregulated both in vivo and in vitro. Shortened mitochondria and impaired mitochondrial functions were observed in the HG group. A DRP1-specific inhibitor, mdivi-1, suppressed mitochondrial fission and mitophagy, as well as restored mitochondrial functions in the HG condition. Moreover, the interaction of F-actin and DRP1 was enhanced in the diabetic group. Inhibiting F-actin with cytochalasin D repaired the injured effects of HG on mitochondrial dynamics and functions. Conversely, the F-actin-polymerization-inducer jasplakinolide aggravated mitochondrial fission and dysfunction. CONCLUSIONS: F-actin contributes to HG-evoked mitochondrial fission by interacting with DRP1, which induces mitophagy and impairs mitochondrial function in SMG cells, ultimately damaging the SMG.

Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single-stranded DNA-binding protein 1 (SSBP1) promoter region.

BACKGROUND AND PURPOSE: Osteosarcoma, a primary malignant bone tumour prevalent among adolescents and young adults, remains a considerable challenge despite protracted progress made in enhancing patient survival rates over the last 40 years. Consequently, the development of novel therapeutic approaches for osteosarcoma is imperative. Sanguinarine (SNG), a compound with demonstrated potent anticancer properties against various malignancies, presents a promising avenue for exploration. Nevertheless, the intricate molecular mechanisms underpinning SNG's actions in osteosarcoma remain elusive, necessitating further elucidation. EXPERIMENTAL APPROACH: Single-stranded DNA-binding protein 1 (SSBP1) was screened out by differential proteomic analysis. Apoptosis, cell cycle, reactive oxygen species (ROS) and mitochondrial changes were assessed via flow cytometry. Western blotting and quantitative real-time reverse transcription PCR (qRT-PCR) were used to determine protein and gene levels. The antitumour mechanism of SNG was explored at a molecular level using chromatin immunoprecipitation (ChIP) and dual luciferase reporter plasmids. KEY RESULTS: Our investigation revealed that SNG exerted an up-regulated effect on SSBP1, disrupting mitochondrial function and inducing apoptosis. In-depth analysis uncovered a mechanism whereby SNG hindered the JAK/signal transducer and activator of transcription 3 (STAT3) signalling pathway, relieved the inhibitory effect of STAT3 on SSBP1 transcription, and inhibited the downstream PI3K/Akt/mTOR signalling axis, ultimately activating apoptosis. CONCLUSIONS AND IMPLICATIONS: The study delved further into elucidating the anticancer mechanism of SNG in osteosarcoma. Notably, we unravelled the previously undisclosed apoptotic potential of SSBP1 in osteosarcoma cells. This finding holds substantial promise in advancing the development of novel anticancer drugs and identification of therapeutic targets.

Discovery of a potent inhibitor of chaperone-mediated autophagy that targets the HSC70-LAMP2A interaction in non-small cell lung cancer cells.

BACKGROUND AND PURPOSE: Chaperone-mediated autophagy (CMA) is a selective type of autophagy targeting protein degradation and maintains high activity in many malignancies. Inhibition of the combination of HSC70 and LAMP2A can potently block CMA. At present, knockdown of LAMP2A remains the most specific method for inhibiting CMA and chemical inhibitors against CMA have not yet been discovered. EXPERIMENTAL APPROACH: Levels of CMA in non-small cell lung cancer (NSCLC) tissue samples were confirmed by tyramide signal amplification dual immunofluorescence assay. High-content screening was performed based on CMA activity, to identify potential inhibitors of CMA. Inhibitor targets were determined by drug affinity responsive target stability-mass spectrum and confirmed by protein mass spectrometry. CMA was inhibited and activated to elucidate the molecular mechanism of the CMA inhibitor. KEY RESULTS: Suppression of interactions between HSC70 and LAMP2A blocked CMA in NSCLC, restraining tumour growth. Polyphyllin D (PPD) was identified as a targeted CMA small-molecule inhibitor through disrupting HSC70-LAMP2A interactions. The binding sites for PPD were E129 and T278 at the nucleotide-binding domain of HSC70 and C-terminal of LAMP2A, respectively. PPD accelerated unfolded protein generation to induce reactive oxygen species (ROS) accumulation by inhibiting HSC70-LAMP2A-eIF2α signalling axis. Also, PPD prevented regulatory compensation of macroautophagy induced by CMA inhibition via blocking the STX17-SNAP29-VAMP8 signalling axis. CONCLUSIONS AND IMPLICATIONS: PPD is a targeted CMA inhibitor that blocked both HSC70-LAMP2A interactions and LAMP2A homo-multimerization. CMA suppression without increasing the regulatory compensation from macroautophagy is a good strategy for NSCLC therapy.

Publication trends of primary angle-closure disease during 1991-2022: a bibliometric analysis.

AIM: To perform a bibliometric analysis in the field of primary angle-closure disease (PACD) research to characterize current global trends and compare contributions from different countries, institutions, journals, and authors. METHODS: All PACD-related publications from 1991 to 2022 from the Web of Science Core Collection database were extracted. Microsoft Excel and VOSviewer were used to collect publication data, analyze publication trends, and visualize relevant results. RESULTS: A total of 1721 publications with 34 591 citations were identified. China produced the most publications (554) while ranking third in citations (8220 times). The United States contributed the most citations (12 315 times) with publications (362) ranking second. The Investigative Ophthalmology Visual Science was the most productive journal concerning PACD, and Aung Tin was the author with the highest number of publications in the field. Keywords were classified into three clusters, epidemiology and pathogenesis research, optical coherence tomography (OCT) and other imaging examinations, and glaucoma surgery treatment. Genome-wide association, susceptibility loci, OCT, and combined phacoemulsification have become new hot research topics in recent years since 2015. CONCLUSION: China, the United States, and Singapore make the most outstanding contributions in the field of PACD research. OCT, combined phacoemulsification, and gene mutation-related study, are considered the potential focus for future research.

Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis.

OBJECTIVES: Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA. METHODS: Screening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of digoxin in vitro; Assays for defining the therapeutic effects of digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; identification and characterisation of the binding of digoxin to low-density lipoprotein receptor-related protein 4 (LRP4); various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of digoxin regulation of chondrocytes. RESULTS: Serial screenings led to the identification of ouabain and digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and digoxin protected against OA and relieved OA-associated pain. The cohort study of 56 794 patients revealed that digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin's regulations of chondrocytes. CONCLUSIONS: These findings not only provide new insights into the understanding of digoxin's chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for OA.

[Application characteristics of abdominal acupuncture based on data mining technique].

OBJECTIVE: To investigate the disease spectrum and predominant diseases treated by abdominal acupuncture by data mining and analysis of journal articles on abdominal acupuncture, and to provide a reference for clinical diagnosis and treatment. METHODS: Based on the database of abdominal acupuncture established by the research group, the data mining technique was used for the analysis and extraction of the articles on abdominal acupuncture included in this study. RESULTS: A total of 788 original journal articles were included. Six departments and 96 disease categories, among which there were 45 internal diseases (46.84%) and 18 surgical diseases (18.75%) were involved. As for the diseases involved, cervical spondylosis had the highest frequency of 84, followed by low back and leg pain with a frequency of 77 and stroke sequela with a frequency of 67. Of all 788 studies, 519 (65.86%) used abdominal acupuncture combined with other therapies with a total frequency of 552, among which acupuncture had the highest frequency of 135 (24.46%), followed by oral administration of traditional Chinese medicine with a frequency of 81 (14.67%) and moxibustion with a frequency of 80 (14.49%). Abdominal acupuncture had a marked clinical effect in the treatment of various diseases, with the highest effective rate of 95.10% in surgical diseases. CONCLUSION: Abdominal acupuncture has a wide disease spectrum and is most frequently used for the treatment of cervical spondylosis, with a marked clinical effect. Abdominal acupuncture has unique therapeutic characteristics and advantages, but it can achieve a better clinical effect when combined with other therapies.

Nitrate effects on chromate reduction in a methane-based biofilm.

The effects of nitrate (NO3-) on chromate (Cr(VI)) reduction in a membrane biofilm reactor (MBfR) were studied when CH4 was the sole electron donor supplied with a non-limiting delivery capacity. A high surface loading of NO3- gave significant and irreversible inhibition of Cr(VI) reduction. At a surface loading of 500 mg Cr/m2-d, the Cr(VI)-removal percentage was 100% when NO3- was absent (Stage 1), but was dramatically lowered to < 25% with introduction of 280 mg N m-2-d NO3- (Stage 2). After ∼50 days operation in Stage 2, the Cr(VI) reduction recovered to only ∼70% in Stage 3, when NO3- was removed from the influent; thus, NO3- had a significant long-term inhibition effect on Cr(VI) reduction. Weighted PCoA and UniFrac analyses proved that the introduction of NO3- had a strong impact on the microbial community in the biofilms, and the changes possibly were linked to the irreversible inhibition of Cr(VI) reduction. For example, Meiothermus, the main genus involved in Cr(VI) reduction at first, declined with introduction of NO3-. The denitrifier Chitinophagaceae was enriched after the addition of NO3-, while Pelomonas became important when nitrate was removed, suggesting its potential role as a Cr(VI) reducer. Moreover, introducing NO3- led to a decrease in the number of genes predicted (by PICRUSt) to be related to chromate reduction, but genes predicted to be related to denitrification, methane oxidation, and fermentation increased.

[Corneal permeability of topically applied pirenzepine solution].

OBJECTIVE: To study the corneal permeability of three different pirenzepine eye-drop solutions and provide reference for further clinical use. METHODS: Sixty-three New Zealand white rabbits were divided into three groups. Each group of rabbits received 2% pirenzepine (pirenzepine group), 2% pirenzepine with 0.1% hyaluronic acid (hyaluronic acid group), or 2% pirenzepine with 0.1% azone (azone group). One drop eye-drops was applied to conjunctive sac every 5 min for six times. Aqueous samples were obtained from each group at 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 h after the last drop, respectively. Concentration of pirenzepine in these samples was determined by the HPLC (high pressure liquid chromatography). Stimulation symptom of rabbit eyes was also observed. RESULTS: The concentrations of pirenzepine in aqueous humor were (0.40 +/- 0.06) microg/ml at 0.5 h, (0.53 +/- 0.03) microg/ml at 1.0 h, (1.52 +/- 0.33) microg/ml at 2.0 h and (0.15 +/- 0.02) microg/ml at 4.0 h in pirenzepine group. Aqueous humor concentration of pirenzepine in both 2% pirenzepine with 0.1% azone and 2% pirenzepine with 0.1% hyaluronic acid were significantly higher than that of single pirenzepine application, and their bioavailability in the groups with combinations of pirenzepine with 0.1% azone or 0.1% hyaluronic acid were 23.0 times and 3.4 times higher than that of single pirenzepine usage. No obvious irritate symptom was found in rabbit of all three groups after eye-drop applying. CONCLUSIONS: The combination application of pirenzepine with azone or hyaluronic acid has higher corneal permeability compared with pirenzepine alone. This result indicates that azone and hyaluronic acid could be used in pirenzepine eye-drop solution to increase corneal permeability.