Development and validation of a prognostic score to identify the optimal candidate for preemptive TIPS in patients with cirrhosis and acute variceal bleeding.

BACKGROUND AND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.

The arginine methyltransferase Prmt1 coordinates the germline arginine methylome essential for spermatogonial homeostasis and male fertility.

Arginine methylation, catalyzed by the protein arginine methyltransferases (PRMTs), is a common post-translational protein modification (PTM) that is engaged in a plethora of biological events. However, little is known about how the methylarginine-directed signaling functions in germline development. In this study, we discover that Prmt1 is predominantly distributed in the nuclei of spermatogonia but weakly in the spermatocytes throughout mouse spermatogenesis. By exploiting a combination of three Cre-mediated Prmt1 knockout mouse lines, we unravel that Prmt1 is essential for spermatogonial establishment and maintenance, and that Prmt1-catalyzed asymmetric methylarginine coordinates inherent transcriptional homeostasis within spermatogonial cells. In conjunction with high-throughput CUT&Tag profiling and modified mini-bulk Smart-seq2 analyses, we unveil that the Prmt1-deposited H4R3me2a mark is permissively enriched at promoter and exon/intron regions, and sculpts a distinctive transcriptomic landscape as well as the alternative splicing pattern, in the mouse spermatogonia. Collectively, our study provides the genetic and mechanistic evidence that connects the Prmt1-deposited methylarginine signaling to the establishment and maintenance of a high-fidelity transcriptomic identity in orchestrating spermatogonial development in the mammalian germline.

DNA-Programmed Four-Bit Quaternary Fluorescence Encoding (FLUCO) Enables 51-Colored Bioimaging Analysis.

Color encoding plays a crucial role in painting, digital photography, and spectral analysis. Achieving accurate, target-responsive color encoding at the molecular level has the potential to revolutionize scientific research and technological innovation, but significant challenges persist. Here, we propose a multibit DNA self-assembly system based on computer-aided design (CAD) technology, enabling accurate, target-responsive, amplified color encoding at the molecular level, termed fluorescence encoding (FLUCO). As a model, we establish a quaternary FLUCO system using four-bit DNA self-assembly, which can accurately encode 51 colors, presenting immense potential in applications such as spatial proteomic imaging and multitarget analysis. Notably, FLUCO enables the simultaneous imaging of multiple targets exceeding the limitations of channels using conventional imaging equipment, and marks the integration of computer science for molecular encoding and decoding. Overall, our work paves the way for target-responsive, controllable molecular encoding, facilitating spatial omics analysis, exfoliated cell analysis, and high-throughput liquid biopsy.

Small Transjugular Intrahepatic Portosystemic Shunt Plus Variceal Embolization for Gastric Varices: A Multicenter Cohort Study.

BACKGROUND & AIMS: The effect of transjugular intrahepatic portosystemic shunt (TIPS) plus variceal embolization for treating gastric varices (GVs) remains controversial. This nationwide multicenter cohort study aimed to evaluate whether adding variceal embolization to a small diameter (8-mm) TIPS could reduce the rebleeding incidence in patients with different types of GVs. METHODS: This retrospective cohort study involved 629 patients who underwent 8-mm TIPS for gastric varices at 7 medical centers. The primary endpoint was all-cause rebleeding, and the secondary endpoints included overt hepatic encephalopathy (OHE) and all-cause mortality. RESULTS: A total of 629 patients were included. Among them, 429 (68.2%) had gastroesophageal varices type 1 (GOV1), 145 (23.1%) had gastroesophageal varices type 2 (GOV2), and 55 (8.7%) had isolated gastric varices type 1 (IGV1). In the entire cohort, adjunctive embolization reduced rebleeding (6.2% vs 13.6%; P = .005) and OHE (31.0% vs 39.4%; P = .02) compared with TIPS alone. However, no significant differences were found in mortality (12.0% vs 9.7%; P = .42). In patients with GOV2 and IGV1, TIPS plus variceal embolization reduced both rebleeding (GOV2: 7.8% vs 25.1%; P = .01; IGV1: 5.6% vs 30.8%; P = .03) and OHE (GOV2: 31.8% vs 51.5%; P = .008; IGV1: 11.6% vs 38.5%; P = .04). However, in patients with GOV1, adjunctive embolization did not reduce rebleeding (5.9% vs 8.7%; P = .37) or OHE (33.1% vs 35.3%; P = .60). CONCLUSIONS: Compared with TIPS alone, 8-mm TIPS plus variceal embolization reduced rebleeding and OHE in patients with GOV2 and IGV1. These findings suggest that patients with GOV2 and IGV1, rather than GOV1, could benefit from embolization with TIPS.

Enzyme Reaction-Assisted Programmable Transcriptional Switches for Bioactive Molecule Detection.

Bioactive molecules are highly worthwhile to recognize and explore the latent pathogenic mechanism. Conventional methods for bioactive molecule detection, including mass spectrometry and fluorescent probe imaging, are limited due to the complex processing and signal interference. Here, we designed enzyme-reaction-assisted programmable transcriptional switches for the detection of bioactive molecules. The approach is based on the use of programmable enzyme site-specific cleavage-assisted DNA triplex-based conformational switches that, upon responding to bioactive molecules, can trigger the transcription of fluorescent light-up aptamers. Thanks to the programmable nature of the sensing platform, the method can be adapted to different bioactive molecules, and we demonstrated the enzyme-small molecule catalytic reaction combination of myeloperoxidase (MPO)-hydrogen peroxide (H2O2) as a model that transcriptional switches was capable of detecting H2O2 and possessed the specificity and anti-interference ability in vitro. Furthermore, we successfully applied the switches into cells to observe the detection feasibility in vivo, and dynamically monitored changes of H2O2 in cellular oxidative stress levels. Therefore, we attempt to amalgamate the advantages of enzyme reaction with the pluripotency of programmable transcriptional switches, which can take both fields a step further, which may promote the research of biostimuli and the construction of DNA molecular devices.

Exploring the mechanism underlying the therapeutic effects of butein in colorectal cancer using network pharmacology and single-cell RNA sequencing data.

BACKGROUND: Butein has shown substantial potential as a cancer treatment, but its precise mechanism of action in colorectal cancer (CRC) remains unclear. This study aimed to uncover the underlying mechanisms through which butein operates in CRC and to identify potential biomarkers through a comprehensive investigation. METHODS: Target genes associated with butein were sourced from SwissTargetPrediction, CTD, BindingDB and TargetNet. Gene expression data from the GSE38026 dataset and the single-cell dataset (GSE222300) were retrieved from the Gene Expression Omnibus database. The activation of disease-related pathways was assessed using Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and differential gene analysis. Disease-associated genes were identified through differential analysis and weighted gene co-expression network analysis (WGCNA). The protein-protein interaction network was utilized to pinpoint potential drug targets. Molecular complex detection (MCODE) analysis was employed to uncover relevant genes influenced by butein within key subgroup networks. Machine learning techniques were applied for the screening of potential biomarkers, with receiver operating characteristic curves used to evaluate their clinical significance. Single-cell analysis was conducted to assess the pharmacological targets of butein in CRC, with validation performed using the external dataset GSE40967. RESULTS: A total of 232 target genes for butein were identified. Functional enrichment analysis revealed significant enrichment of signaling pathways, including mitogen-activated protein kinase, JAK-STAT and NF-κB, among these genes. Differential analysis, in conjunction with WGCNA, yielded 520 disease-related genes. Subsequently, a disease-drug-gene network consisting of 727 targets was established, and a subnetwork containing 56 crucial genes was extracted. Important pathways such as the FoxO signaling pathway exhibited significant enrichment within these key genes. Machine learning applied to the 56 important genes led to the identification of a potential biomarker, UBE2C. Receiver operating characteristic analysis demonstrated the excellent clinical predictive utility of UBE2C. Single-cell analysis suggested that butein's therapeutic effects might be linked to its influence on epithelial and T cells, with UBE2C expression associated with these cell types. Validation using the external dataset GSE40967 further confirmed the exceptional clinical predictive capability of UBE2C. CONCLUSION: This study combines network pharmacology with single-cell analysis to unravel the mechanisms underlying butein's effects in CRC. Notably, UBE2C emerged as a promising biomarker with superior clinical efficacy. These research findings contribute significantly to our understanding of specific molecular mechanisms, potentially shaping future clinical practices.

Tissue distribution of metabolites in Cordyceps cicadae determined by DESI-MSI analysis.

In this paper, we establish an in situ visualization analysis method to image the spatial distribution of metabolites in different parts (sclerotium, coremium) and different microregions of Cordyceps cicadae (C. cicadae) to achieve the in situ visual characterization of tissues for a variety of metabolites such as nucleosides, amino acids, polysaccharides, organic acids, fatty acids, and so on. The study included LC-MS chemical composition identification, preparation of C. cicadae tissue sections, DEDI-MSI analysis, DESI combined with Q-TOF/MS to obtain high-resolution imaging of mass-to-charge ratio and space, imaging of C. cicadae in positive-negative ion mode with a spatial resolution of 100 µm, and localizing and identifying its chemical compositions based on its precise mass. A total of 62 compounds were identified; nucleosides were mainly distributed in the coremium, L-threonine and DL-isoleucine, and other essential amino acids; peptides were mainly distributed in the sclerotium of C. cicadae; and the rest of the amino acids did not have a clear pattern; sugars and sugar alcohols were mainly distributed in the coremium of C. cicadae; organic acids and fatty acids were distributed in the nucleus of C. cicadae more than in the sclerotium, and the mass spectrometry imaging method is established in the research. The mass spectrometry imaging method established in this study is simple and fast and can visualize and analyse the spatial distribution of metabolites of C. cicadae, which is of great significance in characterizing the metabolic network of C. cicadae, and provides support for the quality evaluation of C. cicadae and the study of the temporal and spatial metabolic network of chemical compounds.

Cryoablation combined with dual immune checkpoint blockade enhances antitumor efficacy in hepatocellular carcinoma model mice.

BACKGROUND: Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response induced by Cryo in hepatocellular carcinoma (HCC) is poorly understood. PD-1 and CTLA-4 monoclonal antibodies are immune checkpoint inhibitors used in immunotherapy for tumors. The combined use of these antibodies with Cryo may enhance the immune effect. METHODS: A Balb/c mouse model of HCC was established and treated with Cryo, immune checkpoint blockade (ICB), or Cryo + ICB (combination therapy). The growth trend of right untreated tumors and survival time of mice were determined. The expression of apoptosis-related proteins was detected by Western blot (WB) assay. The percentages of immune cells and immunosuppressive cells were analyzed by flow cytometry. The numbers of infiltrating T lymphocytes were checked by immunohistochemistry, and the levels of T-cell-associated cytokines were detected by Quantitative real-time Polymerase Chain Reaction (qRT-PCR) assays and Enzyme-Linked Immunosorbent Assays (ELISA) assays. RESULTS: Cryo + ICB inhibited the growth of right untreated tumors, promoted tumor cell apoptosis, and prolonged the survival time of mice. Local T-cell infiltration in right tumor tissues increased after the combination therapy, while the number of immunosuppressive cells was significantly reduced. In addition, the combination therapy may induce the production of multiple Th1-type cytokines but reduce the production of Th2-type cytokines. CONCLUSIONS: Cryo can activate CD8+ and CD4+ T-cell immune responses. Cryo + ICB can relieve the immunosuppressive tumor microenvironment and shift the Th1/Th2 balance toward Th1 dominance, further enhancing the Cryo-induced T-cell immune response and resulting in a stronger antitumor immune response.

Protective Role of TRPC3 Gene Polymorphism (rs10518289) in Obstructive Sleep Apnea Hypopnea Syndrome Among Hypertensive Patients.

BACKGROUND Obstructive sleep apnea-hypopnea syndrome (OSAHS) presents a significant health concern, particularly among individuals with essential hypertension (EH). Understanding the genetic underpinnings of this association is crucial for effective management and intervention. We investigated the relationship between TRPC3 gene polymorphisms and susceptibility to OSAHS in patients with EH. MATERIAL AND METHODS We enrolled 373 patients with EH hospitalized at the First Affiliated Hospital of Xinjiang Medical University between April 2015 and November 2017. Patients were categorized into EH (n=74) and EH+OSAHS (n=299) groups according to the apnea-hypopnea index. Sequenom detection technology was used for TRPC3 gene single-nucleotide polymorphism genotyping, including genotypes at rs953691, rs10518289, rs2292232, rs4995894, rs951974, and rs4292355. RESULTS Sex, smoking history, alcohol history, hypertension duration, fasting blood glucose, urea, creatinine, total cholesterol, HDL-C, LDL-C, glycosylated hemoglobin, 24-h mean systolic BP, and 24-h mean diastolic BP were not significantly different between the 2 groups (P>0.05); however, age, BMI, triglyceride levels differed significantly (P<0.05). No significant difference was detected in distribution frequency of polymorphisms of TRPC3 gene between the 2 groups (P>0.05), while genotype, dominant genotype, and recessive genotype at rs10518289 and alleles at rs4292355 differed significantly (P<0.05). Logistic regression analysis showed age, BMI, and CG+GG genotypes at rs10518289 were risk factors for OSAHS in patients with EH. Interaction between TRPC3 (rs10518289) and obesity was not a risk of OSAHS with EH (P>0.05). CONCLUSIONS CC genotype of rs10518289 in the TRPC3 gene could be a protective genetic marker of OSAHS, and CG+GG genotype may be a risk genetic marker of OSAHS with EH.

Construction of a nomogram for predicting compensated cirrhosis with Wilson's disease based on non-invasive indicators.

BACKGROUND: Wilson's disease (WD) often leads to liver fibrosis and cirrhosis, and early diagnosis of WD cirrhosis is essential. Currently, there are few non-invasive prediction models for WD cirrhosis. The purpose of this study is to non-invasively predict the occurrence risk of compensated WD cirrhosis based on ultrasound imaging features and clinical characteristics. METHODS: A retrospective analysis of the clinical characteristics and ultrasound examination data of 102 WD patients from November 2018 to November 2020 was conducted. According to the staging system for WD liver involvement, the patients were divided into a cirrhosis group (n = 43) and a non-cirrhosis group (n = 59). Multivariable logistic regression analysis was used to identify independent influencing factors for WD cirrhosis. A nomogram for predicting WD cirrhosis was constructed using R analysis software, and validation of the model's discrimination, calibration, and clinical applicability was completed. Due to the low incidence of WD and the small sample size, bootstrap internal sampling with 500 iterations was adopted for validation to prevent overfitting of the model. RESULTS: Acoustic Radiation Force Impulse (ARFI), portal vein diameter (PVD), and serum albumin (ALB) are independent factors affecting WD cirrhosis. A nomogram for WD cirrhosis was constructed based on these factors. The area under the ROC curve (AUC) of the model's predictive ability is 0.927 (95% CI: 0.88-0.978). As demonstrated by 500 Bootstrap internal sampling validations, the model has high discrimination and calibration. Clinical decision curve analysis shows that the model has high clinical practical value. ROC curve analysis of the model's rationality indicates that the model's AUC is greater than the AUC of using ALB, ARFI, and PVD alone. CONCLUSION: The nomogram model constructed based on ARFI, PVD, and ALB can serve as a non-invasive tool to effectively predict the risk of developing WD cirrhosis.

Foot self-care behaviour in primary care patients with diabetic foot ulcers: Structural equation modelling of psychological predictors.

Diabetic foot ulcers (DFUs) are one of the most prevalent and costly diabetes complications, associated with diminished quality of life and poor prognosis. Management of DFUs relies heavily on patients' foot self-care behaviour. This study aims to explore psychological determinants of this important behaviour among primary care patients. A total of 186 patients with active DFUs self-reported their illness perception, diabetes distress, self-efficacy, and foot self-care behaviour. Structural equation modelling was performed to examine interrelationships among measured variables. The final model demonstrated satisfactory fit, CFI = 0.933, TLI = 0.913, RMSEA = 0.050, SRMR = 0.073, χ2(95) = 132.256 (p = 0.004), and explained 51.1% of the variance of foot self-care. Illness threat perceptions (i.e., consequence, timeline, identity, concern, and emotion) had a direct positive effect on foot self-care behaviours, but also indirectly decreased foot self-care through increasing diabetes distress. Control perceptions (i.e., personal control, treatment control, and coherence) were not directly associated with foot self-care behaviours, but indirectly improved foot self-care by reducing diabetes distress and increasing foot care confidence. These findings suggest illness perceptions, diabetes distress, and self-care confidence as modifiable predictors to be targeted in self-management interventions for patients with DFUs.

An Intelligent DNA Nanoreactor for Easy-to-Read In Vivo Tumor Imaging and Precise Therapy.

Nanomaterial-based in vivo tumor imaging and therapy have attracted extensive attention; however, they suffer from the unintelligent "always ON" or single-parameter responsive signal output, substantial off-target effects, and high cost. Therefore, achieving in vivo easy-to-read tumor imaging and precise therapy in a multi-parameter responsive and intelligent manner remains challenging. Herein, an intelligent DNA nanoreactor (iDNR) was constructed following the "AND" Boolean logic algorithm to address these issues. iDNR-mediated in situ deposition of photothermal substance polydopamine (PDA) can only be satisfied in tumor tissues with abundant membrane protein biomarkers "AND" hydrogen peroxide (H2 O2 ). Therefore, intelligent temperature-based in vivo easy-to-read tumor imaging is realized without expensive instrumentation, and its diagnostic performance matches with that of flow cytometry, and photoacoustic imaging. Moreover, precise photothermal therapy (PTT) of tumors could be achieved via intelligent heating of tumor tissues. The precise PTT of primary tumors in combination with immune checkpoint blockade (ICB) therapy suppresses the growth of distant tumors and inhibits tumor recurrence. Therefore, highly programmable iDNR is a powerful tool for intelligent biomedical applications.

Proximity-Enhanced Functional Imaging Analysis of Engineered Tumors.

Functional imaging (FI) techniques have revolutionized tumor imaging by providing information on specific tumor functions, such as glycometabolism. However, tumor cells lack unique molecular characteristics at the molecular level and metabolic pathways, resulting in limited metabolic differences compared to normal cells and increased background signals from FI. To address this limitation, we developed a novel imaging technique termed proximity-enhanced functional imaging (PEFI) for accurate visualization of tumors. By using "two adjacent chemically labeled glycoproteins" as output signals, we significantly enhance the metabolic differences between tumor and normal cells by PEFI, thereby reducing the background signals for analysis and improving the accuracy of tumor functional imaging. Our results demonstrate that PEFI can accurately identify tumors at the cellular, tissue, and animal level, and has potential value in clinical identification and analysis of tumor cells and tissues, as well as in the guidance of clinical tumor resection surgery.

Comprehensive analysis of cancer of unknown primary and recommendation of a histological and immunohistochemical diagnostic strategy from China.

BACKGROUND: Previous studies on cancer of unknown primary (CUP) mainly focus on treatment and prognosis in western populations and lacked clinical evaluation of different IHC markers, so this study aimed to evaluate characteristics of CUP and recommend a diagnostic strategy from a single center in China. METHODS AND RESULTS: Data of 625 patients with CUP were retrospectively collected and reviewed. The patients ranged in age from 20 to 91 years, with a female-to-male ratio of 1.3:1. The predominant histological type was poor or undifferentiated adenocarcinomas (308; 49.3%). The results of Canhelp-Origin molecular testing for the identification of the tissue of origin in 262 of 369 patients (71.0%) were considered predictable (similarity score > 45), with the most common predicted primary tumor site being the breast (57, 21.8%). Unpredictable molecular results correlated with more aggressive clinical parameters and poor survival. Thee positivity rates of several targeted antibodies (GATA3, GCDFP15, TTF1, Napsin A, and PAX8), based on the clinically predicted site, were lower than those reported for the corresponding primary tumors. Nonetheless, TRPS1 and INSM1 were reliable markers of predicted breast carcinoma (75.0%) and neuroendocrine tumors (83.3%), respectively. P16 expression, as well as HPV and EBER testing contributed significantly to the diagnosis of squamous cell carcinomas. Survival analysis revealed that older ages (> 57), ≥ 3 metastatic sites, non-squamous cell carcinomas, bone/liver/lung metastases, unpredictable molecular results, and palliative treatment correlated with poor overall survival. CONCLUSIONS: We recommend a CUP diagnostic strategy involving the use of targeted antibody panels as per histological findings that is potentially applicable in clinical practice. The markers TRPS1, INSM1, and P16 expression, as well as HPV and EBER testing are particularly valuable in this aspect. Molecular testing is also predictive of survival rates.

Nomogram Estimating Vessels Encapsulating Tumor Clusters in Hepatocellular Carcinoma From Preoperative Gadoxetate Disodium-Enhanced MRI.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) pattern is a novel microvascular pattern associated with poor outcomes of hepatocellular carcinoma (HCC). Preoperative estimation of VETC has potential to improve treatment decisions. PURPOSE: To develop and validate a nomogram based on gadoxetate disodium-enhanced MRI for estimating VETC in HCC and to evaluate whether the estimations are associated with recurrence after hepatic resection. STUDY TYPE: Retrospective. POPULATION: A total of 320 patients with HCC and histopathologic VETC pattern assessment from three centers (development cohort:validation cohort = 173:147). FIELD STRENGTH/SEQUENCE: A3.0  T/turbo spin-echo T2-weighted, spin-echo echo-planar diffusion-weighted, and 3D T1-weighted gradient-echo sequences. ASSESSMENT: A set of previously reported VETC- and/or prognosis-correlated qualitative and quantitative imaging features were assessed. Clinical and imaging variables were compared based on histopathologic VETC status to investigate factors indicating VETC pattern. A regression-based nomogram was then constructed using the significant factors for VETC pattern. The nomogram-estimated VETC stratification was assessed for its association with recurrence. STATISTICAL TESTS: Fisher exact test, t-test or Mann-Whitney test, logistic regression analyses, Harrell's concordance index (C-index), nomogram, Kaplan-Meier curves and log-rank tests. P value < 0.05 was considered statistically significant. RESULTS: Pathological VETC pattern presence was identified in 156 patients (development cohort:validation cohort = 83:73). Tumor size, presence of heterogeneous enhancement with septations or with irregular ring-like structures, and necrosis were significant factors for estimating VETC pattern. The nomogram incorporating these indicators showed good discrimination with a C-index of 0.870 (development cohort) and 0.862 (validation cohort). Significant differences in recurrence rates between the nomogram-estimated high-risk VETC group and low-risk VETC group were found (2-year recurrence rates, 50.7% vs. 30.3% and 49.6% vs. 31.8% in the development and validation cohorts, respectively). DATA CONCLUSION: The nomogram integrating gadoxetate disodium-enhanced MRI features was associated with VETC pattern preoperatively and with postoperative recurrence in patients with HCC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

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.

Circular RNA hsa_circ_0005239 contributes to hepatocellular carcinoma cell migration, invasion, and angiogenesis by targeting the miR-34a-5p/PD-L1 axis.

Circular RNAs (circRNAs) may be involved in tumorigenesis. Recently, the role of circRNAs in hepatocellular carcinoma (HCC) has drawn wide attention. Herein, we aimed to explore the regulation and function of hsa_circ_0005239 in the malignant biological behavior and angiogenesis of HCC, as well as the link between hsa_circ_0005239 and programmed cell death ligand 1 (PD-L1) in HCC. Quantitative real-time polymerase chain reaction (qRT-PCR) assays revealed that hsa_circ_0005239 was upregulated in HCC tumor samples and cell lines. Furthermore, a series of in vitro and in vivo assays explored the effects of hsa_circ_0005239 on biological processes involved in the development of HCC. Knockdown of hsa_circ_0005239 significantly inhibited cell migration, cell invasion, and angiogenesis in HCC, while overexpression showed the opposite effect. In the in vivo assays, hsa_circ_0005239 downregulation suppressed the growth of xenograft tumors in nude mice, which supported that hsa_circ_0005239 is a tumor promoter in HCC. Mechanistically, hsa_circ_0005239 binds to miR-34a-5p and functions as a competing endogenous RNA to modulate the expression of PD-L1. Further experiments revealed that the hsa_circ_0005239/PD-L1 axis regulates the malignant phenotypes of HCC cells through the phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) signaling pathway. These results revealed the role of hsa_circ_0005239 and the hsa_circ_0005239/miR-34a-5p/PD-L1 axis in HCC, providing a potential diagnostic biomarker and therapeutic target for HCC.

Emergent Transjugular Intrahepatic Portosystemic Shunt as a First-Line Therapy in Patients with Cirrhosis with Acute Gastroesophageal Variceal Hemorrhage.

PURPOSE: To investigate the safety and effectiveness of emergent transjugular intrahepatic portosystemic shunt (TIPS) as first-line therapy in patients with advanced cirrhosis with acute variceal hemorrhage. MATERIALS AND METHODS: From July 2016 to June 2019, 76 patients with advanced cirrhosis and acute variceal hemorrhage were included in this retrospective study. All patients underwent emergent TIPS as first-line therapy within 24 hours. Gastroesophageal varices in patients with cirrhosis were diagnosed with contrast-enhanced computed tomography because emergent endoscopy has not been routinely performed in this center. The primary outcomes were the control rate of bleeding and the rate of rebleeding. Secondary outcomes were the technical success rate of procedure, transplantation-free survival, the mean hospitalization time, the time of stay in the intensive care unit, and adverse events. RESULTS: All patients underwent TIPS creation successfully and were transferred to general wards. The median follow-up time was 21.7 months (interquartile range, 12.6-28.1 months). The control rate of bleeding (≤5 days) was 100%. The rates of early (>5 days to 6 weeks) and late (>6 weeks to 2 years) rebleeding were 6.6% and 1.3%, respectively. The 6-week, 1-year, and 2-year transplantation-free survival rates were 94.7%, 93.4%, and 84.6%, respectively. The incidences of acute liver failure, hepatic encephalopathy, and shunt dysfunction were 5.3%, 25%, and 5.3%, respectively. CONCLUSIONS: Emergent TIPS as a first-line therapy in patients with advanced cirrhosis with acute variceal hemorrhage is safe and effective. This study provides an alternative approach for medical centers without emergent endoscopy facility to manage the condition.

Prevalence and risk factors of oral human papillomavirus infection among 4212 healthy adults in Hebei, China.

BACKGROUND: Human papillomavirus (HPV) infection is an essential cause of oropharyngeal squamous cell carcinoma that is increasing in incidence worldwide. However, little is known about the epidemiology of oral HPV infection among healthy adults in China. METHODS: A study in northern China was conducted in 2021 as baseline data of Diverse Life-Course Cohort (DLCC). Residents who aged above 20 were eligible to participate. Oral swab specimens and questionnaires were collected from 4226 participants. HPV DNA in oral exfoliated cells was tested by Nested Polymerase Chain Reaction approach and sequencing. Univariate and multivariate analyses were performed to assess the associations between exposure factors and oral HPV infection. RESULTS: Overall prevalence of oral HPV infection was 4.08% (95%CI, 3.69%-4.68%). The most prevalent HPV type detected was HPV-81 (1.35%; 95% CI, 1.00%-1.70%), followed by HPV-16 (0.64%; 95% CI, 0.40%-0.88%). Oral HPV infection presented a bimodal pattern with respect to age in male and female participants. Oral HPV prevalence of male participants was significantly higher than prevalence of female participants (5.0% versus 3.6%, P = 0.041). Prevalence of oral HPV was higher among current smokers (OR = 1.59; 95% CI, 1.11-2.29; P = 0.039) and current drinkers (OR = 1.60; 95% CI, 1.14-2.25; P = 0.023). Current alcohol consumption was independently associated with oral HPV infection (OR = 1.74; 95% CI, 1.22-2.50; P = 0.010). CONCLUSIONS: Among healthy adults aged above 20 in Hebei, China, the prevalence of high-risk HPV infection was 1.92% (95%CI, 1.51%-2.34%). Oral HPV prevalence was independently associated with alcohol consumption. More tailored prevention strategies are needed to prevent oral HPV infection through smoking cessation, reduction of alcohol consumption, and HPV vaccination.

Discovery of urea-based pleuromutilin derivatives as potent gram-positive antibacterial agents.

There is an urgent need to discover new antibacterial drugs and provide new treatment options for clinical antimicrobial resistance (AMR) pathogen infections. Inspired by the structural insights from analyzing the co-crystal structure of lefamulin with the ribosomes of S. aureus, a series of novel pleuromutilin derivatives of phenylene sulfide incorporated with urea moiety were designed and synthesized. The structure-activity relationship (SAR) study revealed that derivatives with urea in the meta position of phenylene sulfide had optimal antibacterial activities in vitro. Among them, 21h was the most potent one against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical AMR Gram-positive bacteria with minimum inhibitory concentrations (MICs) in the range of 0.00195-0.250 µg/mL. And it possessed low resistance frequency, prolonged Post-Antibiotic Effect and the capability to overcome lefamulin-induced resistance. Furthermore, 21h exhibited potent antibacterial activity in vivo in both the thigh infection model and trauma infection model, representing a promising lead for the development of new antibiotics against Gram-positive pathogens, especially for AMR bacteria.