Vascular endothelial growth factor (VEGF) inhibitors are drugs that target and inhibit tumor angiogenesis. By blocking the signaling pathway of VEGF and its receptor, they suppress tumor proliferation and play a crucial role in tumor treatment. However, their side effects, such as hypertension, proteinuria, hand-foot skin reactions, and myelosuppression, during treatment seriously affect patients' treatment compliance and quality of life. The development of intervention strategies for the side effects of VEGF inhibitors is of great importance for tumor treatment. This article reviews the clinical characteristics and toxic mechanisms of common side effects caused by VEGF inhibitors during tumor treatment and summarizes intervention strategies that combine traditional Chinese and Western medicines. Drug dosages were precisely monitored and adjusted to achieve antitumor treatment. Patients' discomfort symptoms are improved through prescriptions that act by tonifying qi and promoting blood circulation, strengthening the spleen, and tonifying the kidney. The combination of traditional Chinese and Western medicines is used to treat patients, thus providing a safe and effective treatment plan for patients with cancer.

Dysregulated RNA splicing is a well-recognized characteristic of colorectal cancer (CRC); however, its intricacies remain obscure, partly due to challenges in profiling full-length transcript variants at the single-cell level. Here, we employ high-depth long-read scRNA-seq to define the full-length transcriptome of colorectal epithelial cells in 12 CRC patients, revealing extensive isoform diversities and splicing alterations. Cancer cells exhibited increased transcript complexity, with widespread 3'-UTR shortening and reduced intron retention. Distinct splicing regulation patterns were observed between intrinsic-consensus molecular subtypes (iCMS), with iCMS3 displaying even higher splicing factor activities and more pronounced 3'-UTR shortening. Furthermore, we revealed substantial shifts in isoform usage that result in alterations of protein sequences from the same gene with distinct carcinogenic effects during tumorigenesis of CRC. Allele-specific expression analysis revealed dominant mutant allele expression in key oncogenes and tumor suppressors. Moreover, mutated PPIG was linked to widespread splicing dysregulation, and functional validation experiments confirmed its critical role in modulating RNA splicing and tumor-associated processes. Our findings highlight the transcriptomic plasticity in CRC and suggest novel candidate targets for splicing-based therapeutic strategies.
Humans ; Colorectal Neoplasms/metabolism* ; RNA Isoforms/metabolism* ; Single-Cell Analysis ; RNA Splicing ; Gene Expression Regulation, Neoplastic ; RNA, Neoplasm/metabolism* ; Transcriptome

Geminiviruses cause substantial crop yield losses worldwide. The replication initiator protein (Rep) encoded by geminiviruses is indispensable for geminiviral replication. The Rep protein encoded by beet severe curly top virus (BSCTV, genus Curtovirus, family Geminiviridae) induces VARIANT IN METHYLATION 5 (VIM5) expression in Arabidopsis leaves upon BSCTV infection. VIM5 functions as a ubiquitination-related E3 ligase to promote the proteasomal degradation of methyltransferases, resulting in reduction of methylation levels in the BSCTV C2-3 promoter. However, the specific domains of Rep responsible for VIM5 induction remain poorly characterized. Although Rep proteins from several geminiviruses act as viral suppressors of RNA silencing (VSRs), whether BSCTV Rep also possesses VSR activity remains to be illustrated. In this study, we employed a transient expression system in the 16c-GFP transgenic and the wild-type Nicotiana benthamiana plants to analyze the VSR and the VIM5-inducing activities of different truncated Rep proteins haboring distinct domains. We found that the N-terminal domain (amino acids 1-180) of Rep suppressed GFP silencing in 16c-GFP transgenic N. benthamiana leaves. The minimal N-terminal fragment (amino acids 1-104) induced VIM5 expression upon co-infiltration, while C-terminal truncations lacked VIM5-inducing activity. Our results indicate that the N-terminal domain of Rep encoded by BSCTV mediates the suppression of RNA silencing and induces VIM5 expression. Thus, our findings contribute to a better understanding of interactions between geminiviral Rep and plant hosts.
Geminiviridae/genetics* ; Nicotiana/metabolism* ; Arabidopsis/metabolism* ; RNA Interference ; Viral Proteins/metabolism* ; Arabidopsis Proteins/metabolism* ; Plants, Genetically Modified/metabolism* ; Protein Domains ; Plant Diseases/virology* ; Methyltransferases/metabolism* ; Ubiquitin-Protein Ligases/metabolism* ; DNA Helicases/genetics*

The Hedgehog (Hh) signaling pathway is a critical transduction system regulating cell proliferation, differentiation, and tissue homeostasis during embryonic development. Its aberrant activation is closely associated with the pathogenesis of malignancies such as basal cell carcinoma and medulloblastoma. Although Smoothened (SMO)-targeting inhibitors have received clinical approval, their therapeutic efficacy is limited by acquired resistance mutation and compensatory pathway activation. Glioma-associated oncogene homolog 1 (GLI1), the terminal effector transcription factor of the Hh pathway, has emerged as a promising therapeutic target due to its tumor-specific overexpression and lower propensity for resistance induction. However, GLI1 is classified as an "undruggable" target due to the absence of well-defined ligand-binding pockets, low inhibitory activity, and poor drug-like properties. Currently, no GLI1 inhibitor has entered clinical trials. This review systematically analyzes multidimensional modulation strategies (e.g., allosteric modulation, protein-protein interaction disruption, targeted protein degradation) for targeting transcription factors, based on the structural and functional features of GLI1-DNA interaction combined with recent advances in structural biology and chemical biology, offering new paradigms to overcome therapeutic barriers against undruggable targets.

Atrial fibrillation(AF)is one of the most common clinical arrhythmias and a significant risk factor for thromboembolism.The left atrial appendage(LAA)is the primary site of thrombus formation in AF patients.Recent studies have explored the mechanisms of LAA thrombosis from multiple dimensions,including anatomical structure(LAA morphology and architecture),functional indicators(hemodynamic alterations),pathophysiological mechanisms(endothelial injury,inflammatory activation),systemic diseases(renal dysfunction)and genetic factors(gene polymorphisms),providing critical evidence for precise clinical anticoagulation.This article systematically reviews the latest research advances in the mechanisms of LAA thrombosis in AF patients,aiming to offer theoretical support for the accurate assessment of thromboembolic risk and the formulation of individualized anticoagulation strategies.Additionally,it lays the foundation for exploring the intrinsic relationship and mechanisms between LAA hemodynamics and heart failure as well as thromboembolic events.

Objective:To investigate the impact of receptor-interacting protein kinase 3 (RIPK3) on major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), as well as the predictive performance of RIPK3 combined with traditional cardiovascular risk factors.Methods:This study was a single-center prospective cohort study. It included patients with AMI who underwent PCI at Peking Union Medical College Hospital between September 2017 and November 2017. Baseline clinical data were collected, and plasma samples were obtained 6 hours after PCI to measure RIPK3 levels. Follow-up was conducted via outpatient visits or phone calls to record the occurrence of MACE, including cardiovascular death, hospitalization for heart failure, and vascular events (recurrent AMI or stroke). The predictive performance of RIPK3, traditional cardiovascular risk factors and their combination for MACE was compared using receiver operating characteristic (ROC) curves. Patients were divided into low- and high-RIPK3 level groups based on the optimal cutoff value of RIPK3. Multivariate Cox proportional hazards regression analysis was used to assess the impact of RIPK3 levels on MACE after PCI in AMI patients. Kaplan-Meier survival curves were plotted, and the log-rank test was used to compare MACE incidence between the low-and high-RIPK3 groups.Results:A total of 103 AMI patients who underwent PCI were included, aged 63.0 (56.0, 69.0) years, and 83 (80.6%) were male. The follow-up time was 5.17 (2.81, 5.17) years, during which 44 patients (42.7%) experienced MACE. The ROC curve analysis showed that the area under the curve ( AUC) for traditional cardiovascular risk factors was 0.68 (95% CI: 0.58-0.78), while the AUC for plasma RIPK3 was 0.72 (95% CI: 0.62-0.82). The combined AUC for traditional risk factors and RIPK3 was 0.75 (95% CI: 0.65-0.85). Multivariate Cox proportional hazards regression analysis indicated that plasma RIPK3 level is greater than or equal to the optimal cutoff value of 440.9 μg/L ( HR=3.31, 95% CI: 1.53-8.30, P=0.005) was an independent risk factor for MACE in AMI patients after PCI. Kaplan-Meier survival analysis demonstrated that the high-RIPK3 group had a significantly higher risk of MACE after PCI compared to the low-RIPK3 group (log-rank P=0.006). Conclusions:Elevated plasma RIPK3 level is an independent risk factor for MACE in AMI patients after PCI. Plasma RIPK3 combined with traditional cardiovascular risk factors can more effectively predict the occurrence of MACE in AMI patients after PCI. AMI patients with RIPK3≥440.9 μg/L have a higher risk of MACE after PCI.

Background::An evidence gap still exists regarding the efficacy and safety of tegoprazan in patients with erosive esophagitis (EE) in China. This study aimed to verify the efficacy and safety of tegoprazan vs. esomeprazole in patients with EE in China. Methods::This study was a multicenter, randomized, double-blind, parallel, active-controlled, non-inferiority phase III trial of patients with EE randomized 1:1 to tegoprazan 50 mg/day vs. esomeprazole 40 mg/day. This study was conducted in 32 sites between October 24, 2018 and October 18, 2019. The primary endpoint was the cumulative endoscopic healing rate at week 8. The secondary endpoint included endoscopic healing rate at week 4, changes in the reflux disease questionnaire (RDQ) and gastroesophageal reflux disease health-related quality of life (GERD-HRQL) scores, and symptom improvement. Results::A total of 261 patients were randomized: 132 to the tegoprazan group and 129 to the esomeprazole group. The cumulative endoscopic healing rate at 8 weeks in the tegoprazan group was non-inferior to that of the esomeprazole group (91.1% vs. 92.8%, difference: -1.7%, 95% confidence interval [CI]: -8.5%, 5.0%, P = 0.008). There were no statistically significant differences in the changes in RDQ (total, severity, and frequency) and GERD-HRQL scores between the two groups (all P >0.05). The percentages of days without symptoms, including daytime and nighttime symptoms based on patients' diaries, were similar between the two groups (all P >0.05). In the tegoprazan and esomeprazole groups, 71.5% (93/130) and 61.7% (79/128) of the participants reported adverse events (AEs), 2.3% and 0 experienced serious AEs, while 70.0% and 60.2% had treatment-emergent AEs, respectively. Conclusion::Tegoprazan 50 mg/day demonstrated non-inferior efficacy in healing EE, symptom improvement, and quality of life, and it has similar tolerability compared with esomeprazole 40 mg/day.

Objective To investigate the application value of conventional MRI combined with diffusion tensor imaging(DTI)in evaluating the correlation between the texture composition of benign prostatic hyperplasia(BPH)and the International Prostate Symptom Score(IPSS).Methods Seventy patients with BPH confirmed by pathology were retrospectively analyzed and all patients underwent conventional MRI,DTI and IPSS before surgery.Evaluation metrics included:the mean signal intensity of T2WI(mean-SI-T2WI),apparent diffusion coefficient(ADC)and fractional anisotropy(FA)values.Independent samples t-test,partial correlation analysis,and receiver operating characteristic(ROC)curve were used to assess the correlation between the texture parameters of the prostate transition zone and IPSS.Results The mean-SI-T2WI was significantly negatively correlated with IPSS(r=-0.683,P<0.001);the average ADC value was slightly negatively correlated with IPSS(r=-0.467,P<0.001);and the average FA value was slightly positively correlated with IPSS(r=0.419,P<0.001).The predictive value of MRI texture parameters for IPSS in BPH patients,ranked from high to low,mean-SI-T2WI[area under the curve(AUC)=0.734],average ADC value(AUC=0.673),and average FA value(AUC=0.635);However,the combination of mean-SI-T2WI+ADC+FA(AUC=0.791)did not significantly improve the diagnostic efficacy by DeLong's test(P>0.05).Conclusion Mean-SI-T2WI,DWI and DTI can be used to evaluate the composition of the prostate,among which mean-SI-T2WI is the best,and the com-bination of them can not improve the diagnostic efficacy.

Objective To investigate the effect of tissue-resident memory T cells(TRM)on imiquimod-induced psoriatic-like skin lesions in mice,and to elucidate the underlying mechanisms of TRM involvement in this process.Methods Forty female BALB/c mice were procured and randomly allocated into four groups:ten in the blank control group,and thirty for the establishment of a psoriasis mouse model.Following successful modeling,the thirty mice were further randomized into three groups:the model control group,the methotrexate-treated group,and the imiquimod-treated group,with ten mice in each group.Mice in the blank control group and model control group were uniformly treated with Vaseline for intervention.The methotrexate group and the imiquimod group were treated with 62.5mg of 5％imiquimod cream.The methotrexate group was administered by gavage at a dose of 1 mg/kg,and the gavage volume of each group was 10 mL/kg.The model control group,blank group and imiquimod group were gavaged with the same volume of normal saline.Treatment was conducted over six consecutive days.Subsequently,comparisons were made across groups regarding the psoriasis area and severity index(PASI),histopathological findings,inflammatory cytokine levels,and TRM cell levels.Results(1)The imiquimod group exhibited signifi-cantly lower scores for erythema(2.54±0.32),skin thickening(2.59±0.25),and scaling(2.52±0.29)compared to the methotrexate group,model control group,and blank control group(P<0.05).Additionally,the methotrexate group demonstrated reduced scores for erythema,skin thickening,and scaling compared to the model control group(P<0.05).(2)Hematoxylin-eosin(HE)staining revealed that the epidermis in the methotrexate group became thin-ner,with fewer parakeratotic cells and increased hair follicles.Conversely,the imiquimod group displayed abnor-mal cell morphology and relatively thicker white skin after modeling.(3)The imiquimod group showed significantly lower levels of TNF-α(51.63±4.39 pg/mL),IL-1β(35.53±4.15 pg/mL),IFN-γ(23.43±3.41 pg/mL),and IL-23(15.24±2.95 pg/mL)compared to the methotrexate and model control groups(P<0.05).Similarly,the methotrexate group exhibited reduced levels of TNF-α,IL-1β,IFN-γ,and IL-23 compared to the model control group(P<0.05).(4)The imiquimod group had significantly lower levels of CD8+CD103+cells(15.39±2.31)than the methotrexate and model control groups(P<0.05).Furthermore,the methotrexate group demonstrated lower levels of CD8+CD103+cells compared to the model control group(P<0.05).Conclusion Miquimod induces heavier skin lesions,faster response,and more epidermal thickening in psoriasis like mice.CD8+CD103+TRM cells and inflammatory factors may be involved in the recurrence of psoriasis.

BACKGROUND: Owing to the high prevalence of antibiotic resistance in Helicobacter pylori ( H. pylori ) in China, bismuth-containing quadruple therapies have been recommended for H. pylori eradication. This study compared the efficacy and safety of quadruple regimens containing vonoprazan vs . esomeprazole for H. pylori eradication in a patient population in China. METHODS: This was a phase 3, multicenter, randomized, double-blind study. Patients with confirmed H. pylori infection were randomized 1:1 to receive quadruple therapy for 14 days: amoxicillin 1000 mg and clarithromycin 500 mg after meals, bismuth potassium citrate 600 mg before meals, plus either vonoprazan 20 mg or esomeprazole 20 mg before meals, all twice daily. The primary outcome was the eradication rate of H. pylori , evaluated using a 13 C urea breath test at 4 weeks after treatment. The non-inferiority margin was at 10%. RESULTS: The study included 510 patients, 506 of whom completed the follow-up assessment. The primary analysis revealed eradication rates of 86.8% (210/242) and 86.7% (208/240) for vonoprazan and esomeprazole therapy, respectively (treatment difference: 0.1%; 95% confidence interval [CI]: -5.95, 6.17; non-inferiority P  = 0.0009). Per-protocol analysis showed eradication rates of 87.4% for vonoprazan and 86.3% for esomeprazole (treatment difference: 1.2%; 95% CI: -5.03, 7.36; non-inferiority P  = 0.0004). Vonoprazan and esomeprazole were well tolerated, with similar safety profiles. CONCLUSION: Vonoprazan was found to be well-tolerated and non-inferior to esomeprazole for eradicating H. pylori in patients from China. TRIAL REGISTRATION ClinicalTrials.gov , NCT04198363.
Humans ; Esomeprazole/therapeutic use* ; Double-Blind Method ; Helicobacter Infections/drug therapy* ; Male ; Female ; Middle Aged ; Helicobacter pylori/pathogenicity* ; Pyrroles/therapeutic use* ; Sulfonamides/therapeutic use* ; Adult ; Clarithromycin/therapeutic use* ; Amoxicillin/therapeutic use* ; Aged ; Anti-Bacterial Agents/therapeutic use* ; Pyrrolidines/therapeutic use* ; Drug Therapy, Combination ; Proton Pump Inhibitors/therapeutic use*