Reliability, Validity, Modification and Expansion of the Chinese Version of the Disease-Specific Anxiety Questionnaire for Chronic Obstructive Pulmonary Disease.

Purpose: To translate a disease-specific anxiety questionnaire on chronic obstructive pulmonary disease (COPD) and test its reliability and validity in China. Patients and Methods: The German version of the revised COPD Anxiety Questionnaire (CAF-R) was initially validated using step-by-step translation, back-translation, and cross-cultural adaptation. The reliability and validity of the Chinese version of the CAF-R (CAF-R-CN) were tested among 448 patients with COPD (mean age =71.42±9.33 years, 17.2% female) from four medical institutions in Suzhou, Jiangsu Province, using convenience sampling, from April 2022 to June 2023. Results: The CAF-R-CN included six dimensions with a total of 25 items. The item-level content validity index was 0.860-1.000; the scale-level content validity index was 0.920. The structural validity χ2/df was 2.326, the root mean square error of approximation was 0.077, the comparative fit index was 0.924, and the Tucker-Lewis index was 0.912. The six-dimensional internal consistency index Cronbach's α coefficient was 0.696-0.910, and the test-retest reliability was 0.949. An optimal cut-off score of 50.5 was selected with a sensitivity of 0.786 and specificity of 0.870. Conclusion: The CAF-R-CN had satisfactory reliability and validity and can be used to identify and assess anxiety in COPD patients with a Chinese cultural background.

In Vitro Stability and Pharmacokinetic Study of Pedunculoside and Its Beta-CD Polymer Inclusion Complex.

Pedunculoside, a triterpene saponin derived from various Ilex species, holds potential as a treatment for cardiovascular diseases. However, its clinical application is hindered by poor bioavailability, rapid elimination, and extensive intestinal metabolism to rotundic acid. To address these issues, a water-soluble inclusion complex of pedunculoside, namely, the beta-CD polymer inclusion complex of pedunculoside (pedunculoside-ßCDP), was prepared in this study, and a comparative in vitro stability and pharmacokinetic behavior study was performed between pedunculoside and pedunculoside-ßCDP. Both pedunculoside and pedunculoside-ßCDP exhibited the highest stability in simulated gastric fluid and simulated intestinal fluid but were readily metabolized when co-incubated with Bifidobacterium adolescentis and Bifidobacterium breve. An LC-MS/MS analytical method for the simultaneous determination of pedunculoside and rotundic acid in rat plasma was successfully established, validated, and applied to investigate the pharmacokinetic behavior after rats were intravenously administered with pedunculoside or pedunculoside-ßCDP. The results indicated that pedunculoside-ßCDP could significantly improve the pharmacokinetic profile of pedunculoside by increasing plasma exposure, retarding elimination, and reducing intestinal metabolism. This study enhances our understanding of pedunculoside-ßCDP's metabolic fate and pharmacokinetic properties and potentially advances its further research, development, and clinical application.

Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies.

Melanoma, renowned for its aggressive behavior and resistance to conventional treatments, stands as a formidable challenge in the oncology landscape. The dynamic and complex interplay between cancer cells and the tumor microenvironment has gained significant attention, revealing Melanoma-Associated Fibroblasts (MAFs) as central players in disease progression. The heterogeneity of MAFs endows them with a dual role in melanoma. This exhaustive review seeks to not only shed light on the multifaceted roles of MAFs in orchestrating tumor-promoting inflammation but also to explore their involvement in antitumor immunity. By unraveling novel mechanisms underlying MAF functions, this review aims to provide a comprehensive understanding of their impact on melanoma development. Additionally, it delves into the potential of leveraging MAFs for innovative immunotherapeutic strategies, offering new avenues for enhancing treatment outcomes in the challenging realm of melanoma therapeutics.

Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.

Acoustic emission features of granite from different rockburst areas in Sangzhuling Railway Tunnel.

In order to investigate the acoustic emission (AE) features of rocks in different (medium and strong) rockburst areas, the Sangzhuling Railway Tunnel granite in China was taken as an example, the mineral composition of rocks in different rockburst areas was analyzed by using XRD (X-ray diffraction) method. The Original rock cores of different rockburst areas were processed into standard rock specimens (diameter 50 mm, height 100 mm) in different directions (transverse, oblique and longitudinal). AE feature parameters (event number, ringing count and energy) of standard rock specimens during indoor uniaxial compression test were obtained by using AE technique. The variation law of AE feature parameters of rocks in different rockburst grade areas was then analyzed. The AE features of failure precursor of rocks in different rockburst areas were therefore discussed. It shows that compared with rocks in medium rockburst area, the content of quartz and feldspar of rocks in strong rockburst area is high, while the content of biotite is low; the rock in the strong rock burst area released more energy during the failure process with about 2-3 times that of the rock in the medium rock burst area; the cumulative ringing curve of rock in medium burst area is a stepped type, while the cumulative ringing curve of rock in strong burst area is the smoothed type; the end of the second and first AE quiet period may be regarded as the failure precursor of rocks in medium and strong rockburst area, respectively. The results presented herein are important for understanding the mechanisms of rockburst.

Efficacy of traditional Chinese medicine combined with Silibinin on nonalcoholic fatty liver disease: A meta-analysis and systematic review.

BACKGROUND: The efficacy and safety of traditional Chinese medicine (TCM) combined with Silibinin in the treatment of nonalcoholic fatty liver disease (NAFLD) are still inconclusive. This meta-analysis intends to evaluation to explore the clinical efficacy and quality assessment of traditional Chinese medicine in combination with Silymarin in the treatment of NAFLD, aiming to aims to provide evidence-based data analysis for researchers and clinical practitioners involved in TCM research for NAFLD, with the hope of facilitating wider adoption and application. METHODS: In this meta-analysis, we searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, CQVIP and CBM databases from the establishment of the databases to Oct 2023. The study proposed to include studies that reported combination of TCM with Silibinin and Silibinin alone in the treatment of NAFLD, excluding studies for which full text was not available or for which data extraction was not possible; studies using animal studies; reviews and systematic reviews. All data were processed by STATA15.1 statistical software. RESULTS: 16 randomized controlled trials (RCTs) were included in this meta-analysis. The sample size ranged from 48 to 120, with a total of 1335 patients, including 669 in the Combined treatment group and 384 in the Silibinin group. The findings indicated that the total effective rate of combined treatment group was significantly higher than that of Silibinin alone. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), and gamma glutamyl transpeptidase (GGT) of combined treatment group were all significantly lower than that of western medicine alone. Additionally, after treating NAFLD with a combination of TCM and Silibinin, the TCM syndrome score were significantly lower than those observed with Silibinin alone. CONCLUSION: Traditional Chinese medicine in conjunction with Silibinin capsules has shown significant efficacy in the treatment of NAFLD, improving clinical symptoms, blood lipid levels, and liver function. Furthermore, it is essential to engage in multi-omics research, investigate iron death, and explore the gut microbiota as potential observational indicators for the diagnosis and inclusion criteria. Conducting more high-quality clinical experiments is necessary to further validate these findings.

A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs.

Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.

Cholesterol and low-density lipoprotein as a cause of psoriasis: Results from bidirectional Mendelian randomization.

BACKGROUND: Psoriasis is an inflammatory disease that affects many people. However, the causal effect of lipid metabolism on psoriasis has not yet been verified. This study aimed to identify the genetic relationship between serum lipid levels and psoriasis. METHODS: Bidirectional two-sample Mendelian randomization (MR) was used to analyse the causal relationship between cholesterol and psoriasis. The outcome of the forward causality test was psoriasis. In the analysis of reverse causality, psoriasis was exposed, and 79 single-nucleotide polymorphisms were detected in the genome-wide association study (GWASs) database from the IEU GWASs Project. MR-Egger regression, inverse variance-weighted, weighted median, weighted mode and simple mode were used for the MR analyses. RESULTS: The level of triglyceride, lipase member N, chylomicrons, extremely large very low-density lipoprotein (VLDL) particles, high-density lipoprotein (HDL) cholesterol levels, cholesterol esters in large HDL, cholesterol esters in medium HDL and cholesterol esters in medium VLDL have not affected the development of psoriasis. However, total cholesterol, total free cholesterol, low-density lipoprotein (LDL) cholesterol levels, cholesterol esters in large VLDL and cholesterol esters in medium LDL were unidirectional causal effects on psoriasis. CONCLUSION: Bidirectional two-sample MR analysis indicated that high levels of total cholesterol, total free cholesterol, LDL cholesterol, cholesterol esters in large VLDL and cholesterol esters in medium LDL are genetic risk factors for psoriasis.

Long-Read Sequencing Reveals Alternative Splicing-Driven, Shared Immunogenic Neoepitopes Regardless of SF3B1 Status in Uveal Melanoma.

Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNV), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent adult ocular malignancy, has poor clinical outcomes due to a lack of effective therapies. Recent studies have revealed the promise of harnessing tumor neoepitopes to treat UM. Previous studies have focused on neoepitope targets associated with mutations in splicing factor 3b subunit 1 (SF3B1), a key splicing factor; however, little is known about the neoepitopes that are commonly shared by patients independent of SF3B1 status. To identify the AS-derived neoepitopes regardless of SF3B1 status, we herein used a comprehensive nanopore long-read-sequencing approach to elucidate the landscape of AS and novel isoforms in UM. We also performed high-resolution mass spectrometry to further validate the presence of neoepitope candidates and analyzed their structures using the AlphaFold2 algorithm. We experimentally evaluated the antitumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN)γ production and activating T cell-based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.

Cement-augmented pedicle screw for thoracolumbar degenerative diseases with osteoporosis: a systematic review and meta-analysis.

BACKGROUND: Cement-augmentation pedicle screws have been widely used in spinal internal fixation surgery combined with osteoporosis in recent years, which can significantly improve the fixation strength, but compared with conventional methods, whether it has more advantages is still inconclusive of evidencebased medicine. To systematically evaluate the efficacy and safety of cement-augmented pedicle screw in the treatment of thoracolumbar degenerative diseases with osteoporosis. METHODS: We searched PubMed, Embase, and Cochrane Library for studies published from the establishment of the database up until June 2023. We included studies that concerning the cement-augmented pedicle screw and the traditional pedicle screw placement for thoracolumbar degenerative diseases with osteoporosis. We excluded repeated publication, researches without full text, incomplete information or inability to conduct data extraction and animal experiments, case report, reviews and systematic reviews. STATA 15.1 software was used to analyze the data. RESULTS: A total of 12 studies were included in this meta-analysis. The sample size of patients were totally 881, of which, 492 patients in cement-augmented screw group and 389 patients in conventional screw group. Meta-analysis results showed that Japanese Orthopaedic Association (JOA) score (WMD = 1.69, 95% CI 1.15 to 2.22), intervertebral space height (WMD = 1.66, 95% CI 1.03 to 2.29) and post-operation fusion rate (OR = 2.80, 95% CI 1.49 to 5.25) were higher in the cement-augmented screw group than those in the conventional screw group. Operation time was longer in the cement-augmented screw group than that in the conventional screw group (WMD = 15.47, 95% CI 1.25 to 29.70). Screw loosening rate was lower in the cement-augmented screw group than those in the conventional screw group (OR = 0.13, 95% CI 0.07 to 0.22). However, hospitalization time, intraoperative blood loss and Visual analog scale (VAS) score were not significantly different between the two groups (P > 0.05). CONCLUSION: Compared with conventional pedicle screw placement, cement-augmented pedicle screw is more effective in the treatment of osteoporotic thoracolumbar degenerative disease by improving fusion rate and interbody height, reducing the incidence of screw loosening, and elevating long-term efficacy.

microRNAs in parasite-induced liver fibrosis: from mechanisms to diagnostics and therapeutics.

Chronic parasite infections in the liver pose a global threat to human and animal health, often occurring with liver fibrosis that leads to cirrhosis, liver failure, and even cancer. Hepatic fibrogenesis is a complex yet reversible process of tissue repair and is associated with various factors, including immune cells, microenvironment, gut microbiome, and interactions of the different liver cells. As a profibrogenic or antifibrogenic driver, microRNAs (miRNAs) are closely involved in parasite-induced hepatic fibrosis. This article updates the current understanding of the roles of miRNAs in hepatic fibrogenesis by parasite infections and discusses the strategies using miRNAs as candidates for diagnostics and therapeutics.

Relative efficacy and safety of several regional analgesic techniques following thoracic surgery: a network meta-analysis of randomized controlled trials.

BACKGROUND: This network meta-analysis was performed to assess the relative efficacy and safety of various regional analgesic techniques used in thoracic surgery. MATERIALSAND METHODS: Randomized controlled trials evaluating different regional analgesic methods were retrieved from databases, including PubMed, Embase, Web of Science, and the Cochrane Library, from inception to March 2021. The surface under the cumulative ranking curve) was estimated to rank the therapies based on the Bayesian theorem. Moreover, sensitivity and subgroup analyses were performed on the primary outcomes to obtain more reliable conclusions. RESULTS: Fifty-four trials (3360 patients) containing six different methods were included. Thoracic paravertebral block and erector spinae plane block (ESPB) were ranked the highest in reducing postoperative pain. As for total adverse reactions and postoperative nausea and vomiting, postoperative complications, and duration of hospitalization, ESPB was found to be superior to other methods. It should be noted that there were few differences between various methods for all outcomes. CONCLUSIONS: Available evidence suggests that ESPB might be the most effective and safest method for relieving pain after thoracic surgery, shortening the length of hospital stay and reducing the incidence of postoperative complications.

APOBEC3B coordinates R-loop to promote replication stress and sensitize cancer cells to ATR/Chk1 inhibitors.

The cytidine deaminase, Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B, herein termed A3B), is a critical mutation driver that induces genomic instability in cancer by catalyzing cytosine-to-thymine (C-to-T) conversion and promoting replication stress (RS). However, the detailed function of A3B in RS is not fully determined and it is not known whether the mechanism of A3B action can be exploited for cancer therapy. Here, we conducted an immunoprecipitation-mass spectrometry (IP-MS) study and identified A3B to be a novel binding component of R-loops, which are RNA:DNA hybrid structures. Mechanistically, overexpression of A3B exacerbated RS by promoting R-loop formation and altering the distribution of R-loops in the genome. This was rescued by the R-loop gatekeeper, Ribonuclease H1 (RNASEH1, herein termed RNH1). In addition, a high level of A3B conferred sensitivity to ATR/Chk1 inhibitors (ATRi/Chk1i) in melanoma cells, which was dependent on R-loop status. Together, our results provide novel insights into the mechanistic link between A3B and R-loops in the promotion of RS in cancer. This will inform the development of markers to predict the response of patients to ATRi/Chk1i.

Opportunistic colonoscopy in healthy individuals: A non-trivial risk of adenoma.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Opportunistic colonoscopy may be beneficial in reducing the incidence of CRC by detecting its precursors. AIM: To determine the risk of colorectal adenomas in a population who underwent opportunistic colonoscopy, and demonstrate the need for opportunistic colonoscopy. METHODS: A questionnaire was distributed to patients who underwent colonoscopy in the First Affiliated Hospital of Zhejiang Chinese Medical University from December 2021 to January 2022. The patients were divided into two groups, the opportunistic colonoscopy group who underwent a health examination including colonoscopy without intestinal symptoms due to other diseases, and the non-opportunistic group. The risk of adenomas and influence factors were analyzed. RESULTS: Patients who underwent opportunistic colonoscopy had a similar risk to the non-opportunistic group, in terms of overall polyps (40.8% vs. 40.5%, P = 0.919), adenomas (25.8% vs. 27.6%, P = 0.581), advanced adenomas (8.7% vs. 8.6%, P = 0.902) and CRC (0.6% vs. 1.2%, P = 0.473). Patients with colorectal polyps and adenomas in the opportunistic colonoscopy group were younger (P = 0.004). There was no difference in the detection rate of polyps between patients who underwent colonoscopy as part of a health examination and those who underwent colonoscopy for other reasons. In patients with intestinal symptoms, abnormal intestinal motility and changes in stool characteristics were frequent (P = 0.014). CONCLUSION: The risk of overall colonic polyps, advanced adenomas in healthy people undergoing opportunistic colonoscopy no less than that in the patients with intestinal symptoms, positive FOBT, abnormal tumor markers, and who accepted re-colonoscopy after polypectomy. Our study indicates that more attention should be paid to the population without intestinal symptoms, especially smokers and those older than 40 years.

Magnifying endoscopy is superior at detecting easy-missed neoplastic lesions on the upper gastrointestinal tract.

Magnifying endoscopy is advantageous in detecting precancerous lesions. Our study aimed to clarify its ability to detect easily missed neoplastic lesions on the upper gastrointestinal tract. A retrospective analysis of clinical, endoscopic, and pathological data of cases undergoing gastroscopy was performed using magnifying and routine endoscopy. The detection rates of overall lesions, the ability to identify flat-type neoplastic lesions, and the easily missed neoplastic lesions were compared between the two groups. Endoscopic data from 32,367 patients was analyzed in this study. The use of magnifying endoscopy was an independent factor in identifying flat lesions (OR 2.236, 95% CI 1.969-2.540, p < 0.001), particularly type IIb lesions (OR 3.117, 95% CI 2.333-4.165, p < 0.001). For neoplastic lesions, magnifying endoscopy was also identified as having better sensitivity than routine endoscopy (sensitivity, 90.4% vs. 78.9%, p < 0.001). Similarly, magnifying endoscopy was an independent factor for identifying flat lesions (OR 2.927, 95% CI 2.365-3.621, p < 0.001), especially type IIc lesions (OR 4.415, 95% CI 3.076-6.339, p < 0.001). Magnifying endoscopy was also identified as having superior sensitivity (44.7% vs. 13.3%, p = 0.034) for early cancerous lesions. Compared to routine endoscopy, magnification endoscopy is advantageous in detecting and identifying neoplastic lesions in the upper gastrointestinal tract, especially flat neoplastic lesions and early cancers.

A novel catheter interaction simulating method for virtual reality interventional training systems.

Endovascular robotic systems have been applied in robot-assisted interventional surgery to improve surgical safety and reduce radiation to surgeons. However, this surgery requires surgeons to be highly skilled at operating vascular interventional surgical robot. Virtual reality (VR) interventional training systems for robot-assisted interventional surgical training have many advantages over traditional training methods. For virtual interventional radiology, simulation of the behaviors of surgical tools (here mainly refers to catheter and guidewire) is a challenging work. In this paper, we developed a novel virtual reality interventional training system. This system is an extension of the endovascular robotic system. Because the master side of this system can be used for both the endovascular robotic system and the VR interventional training system, the proposed system improves training and reduces the cost of education. Moreover, we proposed a novel method to solve catheterization modeling during the interventional simulation. Our method discretizes the catheter by the collision points. The catheter between two adjacent collision points is treated as thin torsion-free elastic rods. The deformation of the rod is mainly affected by the force applied at the collision points. Meanwhile, the virtual contact force is determined by the collision points. This simplification makes the model more stable and reduces the computational complexity, and the behavior of the surgical tools can be approximated. Therefore, we realized the catheter interaction simulation and virtual force feedback for the proposed VR interventional training system. The performance of our method is experimentally validated.

Effectiveness and safety of a newly designed self-assembling gel in the treatment of endoscopic submucosal dissection-induced gastric ulcer: A multicenter randomized controlled trial.

Objectives: To evaluate the effectiveness and safety of a newly designed self-assembling gel in treating ESD-induced gastric ulcers in patients. Methods: This open-label, multicenter, randomized controlled trial enrolled patients who underwent ESD between September 2020 and May 2021. Patients were randomized (1:1) to receive the gel (applied to cover the entire ulcer bed under endoscopic guidance immediately after ESD; gel group) or not (control group). The primary outcome was the ulcer healing rate at 28 days. And the secondary outcomes were the delayed bleeding, changes in the ulcer stage, and adverse events. Results: Finally, 125 patients (mean age, 63.7 years; 70 [56.0%] males) were enrolled. The ulcer healing rate was higher in the gel group than in the control group at 28 days (96.9 ± 4.1% vs. 94.7 ± 5.0%; p = 0.001). The ulcer reduction rate at 28 days differed significantly (p < 0.001) between ulcers with majority gel coverage (99.8%), ulcers with minority gel coverage (96.2%), and ulcers with no gel coverage (98.0%). Delayed bleeding was found in 1/63 gel-treated patients (1.6%) versus 5/62 controls (8.1%). A1-stage ulcers were found in 16/63 patients in the gel group versus 44/62 patients in the control group (25.4% vs. 71.0%, p < 0.001) at 3-5 days. Conclusion: The newly developed self-assembling gel was safe and effective in accelerating gastric ulcer healing in patients after ESD. Clinical Trial Registration: UMIN Clinical Trials Registry System (registration number, ChiCTR2100052935).

Improved pharmacokinetics of tenofovir ester prodrugs strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism in preclinical models.

Tenofovir (TFV) ester prodrugs, a class of nucleotide analogs (NAs), are the first-line clinical anti-hepatitis B virus (HBV) drugs with potent antiviral efficacy, low resistance rate and high safety. In this work, three marketed TFV ester drugs, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide fumarate (TMF), were used as probes to investigate the relationships among prodrug structures, pharmacokinetic characteristics, metabolic activations, pharmacological responses and to reveal the key factors of TFV ester prodrug design. The results indicated that TMF and TAF exhibited significantly stronger inhibition of HBV DNA replication than did TDF in HBV-positive HepG2.2.15 cells. The anti-HBV activity of TMF was slightly stronger than TAF after 9 days of treatment (EC50 7.29 ± 0.71 nM vs. 12.17 ± 0.56 nM). Similar results were observed in the HBV decline period post drug administration to the HBV transgenic mouse model, although these three TFV prodrugs finally achieved the same anti-HBV effect after 42 days treatments. Furthermore, TFV ester prodrugs showed a correcting effect on disordered host hepatic biochemical metabolism, including TCA cycle, glycolysis, pentose phosphate pathway, purine/pyrimidine metabolism, amino acid metabolism, ketone body metabolism and phospholipid metabolism. The callback effects of the three TFV ester prodrugs were ranked as TMF > TAF > TDF. These advantages of TMF were believed to be attributed to its greater bioavailability in preclinical animals (SD rats, C57BL/6 mice and beagle dogs) and better target loading, especially in terms of the higher hepatic level of the pharmacologically active metabolite TFV-DP, which was tightly related to anti-HBV efficacy. Further analysis indicated that stability in intestinal fluid determined the actual amount of TFV prodrug at the absorption site, and hepatic/intestinal stability determined the maintenance amount of prodrug in circulation, both of which influenced the oral bioavailability of TFV prodrugs. In conclusion, our research revealed that improved pharmacokinetics of TFV ester prodrugs (especially intestinal stability) strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism, which provides new insights and a basis for the design, modification and evaluation of new TFV prodrugs in the future.

Risk of progression in patients with chronic atrophic gastritis: A retrospective study.

Background: Chronic atrophic gastritis (CAG) can progress to gastric cancer (GC) thus requiring endoscopic surveillance. Here, we analyze various aspects of CAG progression, time, and mucosal background, to guide reasonable surveillance. Methods: CAG patients with three or more endoscopies from 2010-2021 were included. All cases were analyzed for rate and time of progression, and cases with operative link on gastritis assessment (OLGA) staging, operative link on gastric intestinal metaplasia assessment (OLGIM) staging, and Kimura-Takemoto classification were further analyzed. Additional investigation of guideline-defined low-risk patients by reviewing endoscopy in the short-term (1-2 years) after baseline identified several patients as high-risk. Results: Ninety-seven (10.4%) of the 929 CAG patients progressed to low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), or GC, during the observation period of 36-129 months (median 53, IQR=24), including 75 (8.1%) cases of LGIN, eight (0.9%) of HGIN, and 14 (1.5%) of GC. Among 170 patients with OLGA/OLGIM at baseline, two (2/2, 100%) GC cases occurred in patients with OLGA/OLGIM III and IV. Of the 236 patients with Kimura-Takemoto classification at baseline, 5/7 (71.4%) cases of GC occurred in patients with C3-O3. Ten, 11, and 25 patients classified as low-risk on the European, British, and Chinese Guidelines, underwent additional endoscopy within 1-2 years, resulting in three (30.0%), four (36.4%), and eight (32.0%) patients being classified as high-risk on these guidelines, respectively. Conclusion: A minority of CAG patients can progress to GC. OLGA/OLGIM III and IV staging are closely associated with progression. Disease-associated risk may be underestimated in one-third of patients classified as low-risk by initial endoscopy.

LIN28B inhibition sensitizes cells to p53-restoring PPI therapy through unleashed translational suppression.

p53 is the most highly mutated tumor suppressor across multiple types of human cancers. The level and function of p53 are fine-tuned through multifaced mechanisms in which the protein-protein interaction between p53 and MDM2 is considered as a major circuit. Recent studies suggest therapeutic strategy attempts to restore p53 function by small molecule inhibitors targeting p53-MDM2 interaction can be a promising direction in treating cancers with wild-type or functional p53. Currently, clinical tests of the p53-MDM2 protein-protein interaction inhibitors (PPIs) are underway. However, it remains elusive about the biomarkers that may predict the therapeutic responses to those inhibitors. Here we report that RNA-binding protein LIN28B directly regulates p53 through binding to the 5'΄ untranslated region of p53 mRNA and blocks its translation by competing with a translation enhancer protein, ribosomal protein L26 (RPL26). This regulatory mechanism of LIN28B does not involve let-7 maturation or the canonical protein turnover pathway of p53. Furthermore, we show that inhibition of LIN28B unleashes the translational suppression of p53 through RPL26, and leads to enhanced sensitivities of cancer cells to inhibitors of p53-MDM2 interaction. Together, we demonstrate a competitive regulatory mechanism of p53 by LIN28B, which has important implications in developing biomarkers to the therapies aiming to reinstate p53 function.