Second Military Medical University

Clinical research is being contaminated by flawed or biased evidence, which negatively impacts daily evidence based clinical practice, write Fuchen Liuand colleagues.

Objective To investigate the impact of retracted trials on the production and use of healthcare evidence in the evidence ecosystem. Design Retrospective cohort study based on forward citation searching. Data sources Retraction Watch up to 5 November 2024. Study selection Randomised controlled trials in humans that were retracted for any reason. Methods Forward citation searching via Google Scholar and Scopus was used to identify evidence synthesis research (21 November 2024) that quantitatively incorporated retracted trials. Data were independently extracted by two groups of researchers. The results of meta-analyses were updated after exclusion of the retracted trials. The proportions of meta-analyses that changed direction of the pooled effect and/or the significance of the P value were estimated. A generalised linear mixed model was used to investigate the association between the number of included studies and the impact, measured by odds ratio and 95% confidence interval (CI). The impact of distorted evidence on clinical practice guidelines was also investigated on the basis of citation searching. Results The searches identified 1330 retracted trials and 847 systematic reviews that quantitatively synthesised retracted trials, with a total of 3902 meta-analyses that could be replicated. After the potential clustering effects were accounted for, the exclusion of the retracted trials led to a change in the direction of the pooled effect in 8.4% (95% CI 6.8% to 10.1%), in its statistical significance in 16.0% (14.2% to 17.9%), and in both direction and significance in 3.9% (2.5% to 5.2%) and a >50% change in the magnitude of the effect in 15.7% (13.5% to 17.9%). An obvious non-linear association existed between the number of included studies and the impact on the results, with a lower number of studies having higher impact (eg, for 10 studies versus ≥20 studies, change of direction: odds ratio 2.63, 95% CI 1.29 to 5.38; P<0.001). Evidence from 68 systematic reviews with conclusions distorted by retracted trials was used in 157 guideline documents. Conclusion Retracted trials have a substantial impact on the evidence ecosystem, including evidence synthesis, clinical practice guidelines, and evidence based clinical practice. Evidence generators, synthesisers, and users must pay attention to this problem, and feasible approaches that assist with easier identification and correction of such potential contamination are needed. Study registration Open Science Framework ( https://osf.io/7eazq/ ).

The plant hormone jasmonic acid (JA) can increase artemisinin content in Artemisia annua L., but the mechanism regulating artemisinin biosynthesis needs further study. Basic helix–loop–helix ( bHLH ) transcription factors play important roles in plant growth and development, defense responses, secondary metabolism, etc. However, the role of bHLH transcription factors in response to JA signaling in artemisinin biosynthesis has not been well reported. Therefore, it is of great significance to investigate whether potential bHLH transcription factors in A. annua can regulate artemisinin biosynthesis through the JA signaling pathway. In this study, transcriptome data of A. annua treated with MeJA (Methyl Jasmonate) were used to identify candidate bHLH transcription factors that respond to JA. Furthermore, AabHLH5 and two potential JASMONATE‐ZIM DOMAIN (JAZ) proteins interacting with AabHLH5 were identified through plant transformation, yeast two‐hybrid and bimolecular fluorescence complementarity assays. Furthermore, the molecular mechanism by which bHLH5 participates in the JA signaling pathway and negatively regulates artemisinin biosynthesis was verified.

Background Existing models to predict recurrence-free survival (RFS) after hepatectomy for hepatocellular carcinoma (HCC) rely on static preoperative factors such as alpha-fetoprotein (AFP) and tumor burden score (TBS). These models overlook dynamic postoperative AFP changes, which may reflect evolving recurrence risk. We sought to develop a dynamic, real-time model integrating time-updated AFP values with TBS for improved recurrence prediction. Patients and Methods Patients undergoing curative-intent hepatectomy for HCC (2000–2023) were identified from an international, multi-institutional database with RFS as the primary outcome. AFP trajectory was monitored from preoperative to 6- and 12-month postoperative values, using time-varying Cox regression with AFP as a time-dependent covariate. The predictive accuracy of this time-updated model was compared with a static preoperative Cox model excluding postoperative AFP. Results Among 1911 patients, AFP trajectories differed between recurrent and nonrecurrent cases. While preoperative AFP values were similar, recurrent cases exhibited higher AFP at 6 and 12 months. Multivariable analysis identified TBS (hazard ratio (HR):1.043 [95% confidence interval (CI): 1.002–1.086]; p = 0.039) and postoperative log AFP dynamics (HR:1.216 [CI 1.132–1.305]; p < 0.001) as predictors. Contour plots depicted TBS’s influence decreasing over time, while postoperative AFP became more predictive. The time-varying Cox model was created to update RFS predictions continuously on the basis of the latest AFP values. The preoperative Cox model, developed with age, AFP, TBS, and albumin-bilirubin score, had a baseline C-index of 0.61 [0.59–0.63]. At 6 months, the time-varying model’s C-index was 0.70 [0.67–0.73] versus 0.59 [0.56–0.61] for the static model; at 12 months, it was 0.70 [0.66–0.73] versus 0.56 [0.53–0.59]. The model was made available online ( https://nm49jf-miho-akabane.shinyapps.io/AFPHCC/ ). Conclusions Incorporating postoperative AFP dynamics into RFS prediction after HCC resection enhanced prediction accuracy over time, as TBS’s influence decreased. This adaptive, time-varying model provides refined RFS predictions throughout follow-up.

Melittin is a natural antimicrobial peptide isolated from bee venom, the non-specific cytotoxicity and hemolytic activity severely limit its clinical application. Glycosylation of protein is very common in physiological and...

Antibody‐drug conjugates are a cutting‐edge biotechnology recently attracting wide attention in the medical field. Binding antibodies to drug molecules could deliver drugs precisely to the site of the lesion, which shows great potential in the treatment of tumors and immune diseases. In this paper, we outlined the current popular antibody‐coupling techniques and summarized various common antibody‐coupling techniques, including antibody‐coupled small toxic molecules, antibody‐coupled oligenucleotides, antibody‐coupled cells, and antibody‐coupled polymers. It provided a new therapeutic strategy and means for targeted drug delivery technology. Finally, we discussed the challenges and future development of the antibody‐drug conjugates.

Purpose We used bioinformatics methods and Mendelian randomization (MR) analysis to investigate the hub genes involved in acute myeloid leukemia (AML) and their causal relationship with hemolysis, to explore a new direction for molecular biology research of AML. Methods We first differentially analyzed peripheral blood samples from 62 healthy volunteers and 65 patients with AML from the Gene Expression Omnibus database to obtain differentially expressed genes (DEGs), and intersected them with genes sourced from weighted gene co-expression network analysis (WGCNA) and the GeneCards database to obtain target genes. Target genes were screened using protein–protein interaction (PPI) network analysis and ROC curves to identify genes associated with AML. Finally, we analyzed the correlation between genes and immune cells and the relationship between toll-like receptor 4 (TLR4) and AML using MR. Results We compared peripheral blood expression profiles using an array of 62 healthy volunteers (GSE164191) and 65 patients with AML (GSE89565) (M0:25; M1:11; M2:10; M3:1; M4:7; M4 eo t [16;16] ou inv [16]:4; M5:6; M6:1) and obtained 7,339 DEGs (3,733 upregulated and 3,606 downregulated). We intersected these DEGs with 4,724 genes from WGCNA and 1,330 genes related to hemolysis that were identified in the GeneCards database to obtain 190 target genes. After further screening these genes using the PPI network, we identified TLR4, PTPRC, FCGR3B, STAT1, and APOE, which are closely associated with hemolysis in patients with AML. Finally, we found a causal relationship between TLR4 and AML occurrence using MR analysis ( p < 0.05). Conclusion We constructed a WGCNA-based co-expression network and identified hemolysis-associated AML genes.

Iatrogenic blindness, a rare complication of hyaluronic acid (HA) injections for cosmetic purposes, often occurs during filler injections in the glabellar and nasolabial fold regions. Sudden vision loss during or immediately after HA injection is the primary sign of ophthalmic artery embolism. Enhancing awareness of this critical complication is of great significance, as early diagnosis and appropriate intervention can improve prognosis. This article presents a case reported by doctors at Weifang People’s Hospital, where ophthalmic artery embolism occurred after HA filler injection, followed by extensive cerebral infarction and severe complications, ultimately leading to the patient’s death due to cerebral herniation and multiple organ failure. The doctors explored the pathogenesis, treatment, and prognosis, and briefly reviewed relevant literature.

Immune checkpoint inhibitors (ICIs) have dramatically transformed cancer treatment; however, their impact on the male reproductive system remains poorly understood. This study aims to elucidate the incidence, risk factors, and molecular mechanisms underlying ICI‐associated prostatitis. We conducted an analysis of ICI‐associated prostatitis utilizing the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database and evaluated risk through the application of the reporting odds ratio. A mouse model of ICI treatment was developed, and subsequent transcriptomic changes in prostate tissue were investigated using high‐throughput sequencing. Hematoxylin and eosin staining, immunohistochemistry, Von Frey testing, and enzyme‐linked immunosorbent assay were employed to confirm ICI‐induced prostatitis and further delineate its underlying mechanisms. Additionally, we investigated the therapeutic potential of specifically targeting interleukin‐6 (IL‐6) and extracellular signal‐regulated kinase (ERK) signaling pathways. FAERS analysis demonstrated a statistically significant positive correlation between ICI treatment and prostatitis risk (p < .05). In the murine model, ICI treatment induced an elevated inflammatory response in prostate tissue, characterized by enhanced inflammatory cell infiltration and upregulated expression of IL‐6 and tumor necrosis factor‐alpha. Transcriptomic analysis revealed significant activation of multiple inflammation‐related signaling pathways in prostate tissue following ICI treatment (false discovery rate < 0.05). Targeted inhibition of IL‐6 or ERK signaling pathways significantly attenuated ICI‐induced prostatitis symptoms, resulting in improved tissue pathology and decreased inflammatory factor expression (p < .01). This study delineates the characteristics and potential molecular mechanisms underlying ICI‐associated prostatitis, thereby establishing a theoretical foundation for the development of prevention and treatment strategies. Targeted modulation of IL‐6 and ERK signaling pathways may present novel therapeutic interventions for ICI‐associated prostatitis, thus warranting further clinical validation.

Background Sepsis is a life-threatening condition with a high mortality rate in intensive care unit (ICU). However, rapid and accurate diagnostic criteria are still lacking. This pilot study explored the role of METRNL as a novel biomarker for sepsis by focusing on its diagnostic potential and rapid secretion mechanism. Methods METRNL levels were measured in cell and animal models of sepsis. Serum samples from 107 sepsis patients and 95 non-septic controls in ICU were collected. Diagnostic performance of METRNL, Procalcitonin (PCT) and C-reactive protein (CRP) were assessed using ROC analysis. Endothelial cell-specific Metrnl gene knockout mice (EC- Metrnl −/− mice) were used to identify the source of METRNL secretion. Chemical inhibitors and RNA interference were used to explore the secretion pathways. Results In lipopolysaccharide (LPS)-induced cell and mouse models of sepsis, METRNL levels significantly increased in a dose- and time-dependent manner. Similarly, in the cecal ligation and puncture mouse models, serum METRNL levels were elevated over time and correlated with sepsis severity. In animals, serum METRNL increased within 1 h post-modeling, preceding PCT and CRP. Clinically, sepsis patients had significantly higher serum METRNL levels. ROC analysis showed area under the curves [95% confidence intervals] of 0.943 [0.91–0.975] for METRNL, 0.955 [0.929–0.981] for PCT and 0.873 [0.825–0.921] for CRP. At the optimal cutoff value, METRNL (91.6%) exhibited relatively greater diagnostic specificity than PCT (88.4%) and CRP (69.5%). EC- Metrnl −/− reduced majority of serum Metrnl levels in sepsis mouse models. Inhibition of the endoplasmic reticulum-Golgi (ER-Golgi) pathway through chemical inhibitors or RNA interference significantly reduced METRNL levels in the supernatant of sepsis cell models compared to control groups. Similar results were obtained with Toll-like receptor 4 (TLR4) and ERK inhibitors. Conclusions This pilot study demonstrates that METRNL is a novel potential biomarker for sepsis with diagnostic capability comparable to that of PCT. Serum METRNL rapidly increased during the early phase of sepsis. Mechanistically, it mainly originates from the endothelium during sepsis, and TLR4-ERK signaling mediates the rapid secretion of METRNL via the classical ER-Golgi pathway in response to LPS stimulation.

Meteorin-like (Metrnl), also known as Subfatin, IL-41, or Cometin, is a secreted protein predominantly expressed in the intestinal epithelium. The intestinal barrier, primarily consisting of epithelial cells connected by tight junctions, is essential for maintaining gut homeostasis by preventing harmful substances from entering the body. Despite Metrnl’s high expression in the intestine, its role in barrier function remains unclear. In this study, we investigated Metrnl’s role in intestinal barrier function using both loss-of-function (using global and intestinal epithelium-specific knockout mice) and gain-of-function (using intestinal epithelium-specific overexpression mice) approaches. Our findings showed that Metrnl deficiency disrupted tight junctions between enterocytes and exacerbated endotoxin-induced barrier dysfunction. Mechanistically, Metrnl deficiency triggered activation of the IKKβ/IκBα/NFκB signaling pathway, leading to increased MLCK expression and MLC phosphorylation. The NFκB inhibitor PDTC reversed this effect both in vivo and in vitro. Macrophages played an essential role in Metrnl’s intestinal barrier protective effects during endotoxemia, but were not necessary in burn-induced barrier injury, suggesting potential differences in mechanism between these conditions. Notably, recombinant Metrnl protein administration protected against barrier dysfunction, and genetic overexpression of Metrnl in enterocytes preserved barrier function and alleviated DSS-induced colitis. These findings establish Metrnl as a key regulator of intestinal barrier integrity through the IKKβ/IκBα/NFκB/MLCK/MLC pathway, highlighting its potential therapeutic value in treating barrier dysfunction disorders.

Vancomycin (Van) is the preferred drug for clinically treating severe infections caused by Gram-positive bacteria, especially in intensive care unit (ICU). However, due to safety concerns, strict management and administration...

Ferroptosis is a novel form of programmed cell death characterized by iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation. The execution of ferroptosis is intricately linked to both iron and lipid metabolism. Intriguingly, iron and lipid metabolism are also pivotal for maintaining the physiological function of immune cells. Research has revealed that ferroptosis can potentiate the immunogenicity of tumor cells and engage in intricate interactions with immune cells. Certain ferroptosis inducers have the capacity to augment the efficacy of immunotherapy by modulating the tumor immune microenvironment. Ferroptosis holds immense potential in cancer immunotherapy and is anticipated to emerge as a novel therapeutic target in the future landscape of cancer treatment. In this review, we primarily delineate the ferroptosis signaling pathways and metabolic processes pertinent to immune cells, and further summarize the roles of ferroptosis in tumor-infiltrating immune cells. Ultimately, we anticipate further elucidation of the mechanisms of ferroptosis in immunotherapy and envision that strategies targeting ferroptosis and immunotherapy will be expeditiously applied in clinical oncology practice.

Objective The study evaluates the clinical value of the operating room nursing safety management model based on Heinrich’s law. Methods A quasi-experimental design with a historical control group was conducted at Changzheng Hospital. A total of 240 surgical patients (pre-intervention: n = 120, December 2021–2022; post-intervention: n = 120, January–December 2023) were recruited via convenience sampling. The intervention included standardized protocols, mobile nursing systems, electronic specimen labeling, and equipment management. Quantitative outcomes were analyzed using χ² tests (adverse events), independent t-tests (nursing competency scores), and logistic regression (risk factors). Patient satisfaction was assessed via a validated self-report questionnaire. Results The results showed a significant reduction in the incidence of operating room nursing safety accidents and a significant improvement in the specific nursing, identification, management of specimens, health education, safety awareness and operational skills of the nursing staff after the implementation of the operating room nursing safety management model based on Heinrich’s law (P < 0.05).The management model implemented in the operating room had a positive impact on nursing safety, as evidenced by the significant improvement in patient satisfaction (P < 0.05). Logistic multifactorial regression analysis identified several key factors that affect nursing care safety in the operating room, including the nursing staff’s business ability, legal awareness, the operating room environment, and the management system. Conclusion The Heinrich’s law-based model effectively enhances perioperative safety by reducing errors, improving nursing competency, and increasing patient satisfaction. Clinically, we recommend integrating standardized protocols with mobile alert systems, prioritizing staff training on legal and technical skills, and optimizing equipment workflows. Future studies should validate these findings in multicenter trials and assess long-term cost-effectiveness.

Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death in China. The rapid progress in systemic therapies has led to the approval of many therapeutic methods that have quickly changed clinical guidelines and practices. Because of the high heterogeneity of HCC, there are still some gaps between the guidelines and real‐world clinical practice. The present study surveyed experts in China to investigate the current treatment concepts and clinical practice regarding HCC. Methods A questionnaire survey on the treatment concepts and clinical practice of HCC was administered to 310 experts with senior professional titles in 2020 and 312 experts in 2021. The results were analyzed and compared. Results For treating patients with resectable HCC, 28% of hepatobiliary surgeons indicated neoadjuvant therapy, and 7% chose systemic therapy ± locoregional therapy as 1 L therapy in 2021 compared with 20% and 1% in 2020. More experts chose adjuvant treatment within 1 month in 2021 compared with 2020, and 6 months and 12 months were the leading choices for the duration of adjuvant treatment. In 2021, 79% of surgeons and 19% of interventionalists were willing to conduct downstaging/conversion therapy for patients with potentially resectable HCC, and 78% chose tyrosine kinase inhibitors (TKI) + immunotherapy (IO) + locoregional therapy for cases in which R0 resection could not be achieved. For completely unresectable HCC, more experts preferred TKI + IO‐based therapy as 1 L therapy in 2021 compared with 2020 (78% vs. 55%). The proportion of experts who indicated TKI + IO‐based therapy as 2 L therapy increased from 32% in 2020 to 40% in 2021. Conclusion The survey results indicated that in 2021, compared with 2020, more experts opted to administer IO + TKI for the treatment of liver cancer, and more experts and patients were willing to participate in clinical research.

Existing studies reported that Long non-coding RNA (lncRNA) modulates the stemness of CSCs. Here, we found that LncRNA DBH-antisense RNA 1(AS1) is upregulated in liver CSCs. Forced LncRNA DBH-AS1 promotes tumorigenesis and liver CSCs self-renewal. On the other hand, LncRNA DBH-AS1 expression knockdown prevents liver CSCs from self-renewing. Mechanistically, LncRNA DBH-AS1 mediated regulation of SRY-box transcription factor 4 (SOX4), acting as a ceRNA to sponge miR-612 in liver CSCs. LncRNA DBH-AS1 enhanced liver CSCs self-renew and tumorigenesis via upregulating SOX4. Furthermore, liver cells with LncRNA DBH-AS1 knockdown are susceptible to apoptosis caused by Lenvatinib. Furthermore, the sensitivity of HCC cells with LncRNA DBH-AS1 knockdown to lenvatinib-induced cell death could be reversed by adding SOX4. In conclusion, experimental evidence revealed that METTL3-dependent m6A methylation was the mechanism mediating the elevated lncRNADBH-AS1 in HCC. This study demonstrated the critical role that LncRNA DBH-AS1 plays in the carcinogenesis and self-renewal of liver CSCs, which renders it the perfect target for HCC therapy.

Background Liver cirrhosis seriously harms human health and fibrosis is the essential pathological process of cirrhosis. Recently, circular RNAs (circRNAs) were found to play critical roles in liver fibrosis, but the key circRNAs and precise mechanisms remained unclear. This study aimed to investigate the effect of circ_0098181 in fibrogenesis and explore its mechanism. Methods RNA sequencing was conducted to identify circRNA signatures in human liver cirrhotic tissues. Hepatic stellate cells (HSCs) (including primary rat HSCs, LX2, HSC-T6) and carbon tetrachloride (CCl 4 ) induced liver cirrhosis model were used to explore the role of circ_0098181 on HSC activation and liver fibrogenesis in vitro and in vivo . RNA sequencing, RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) experiments were performed to elucidate the mechanism. Results Circ_0098181 was obviously reduced in human fibrotic liver tissues and activated HSCs. Exogenous administration of circ_0098181 blocked the activation, proliferation, and migration of HSCs in vitro and mitigated the progression of CCl 4 -induced liver fibrosis in vivo . Mechanistically, adenosine deaminase acting on RNA1 (ADAR1) combined with the intronic complementary sequences (ICSs) in the flanking regions, thereby regulating the biogenesis of circ_0098181. RNA sequencing and qRT-PCR revealed the suppression of circ_0098181 on pro-inflammation cytokines expression (TNFα, Fas, Cxcl11, etc.). RNA pull-down, mass spectrometry, and RIP experiments indicated that pyruvate kinase M2 (PKM2) was the direct target of circ_0098181. Circ_0098181 bound to PKM2, restrained its nuclear translocation and phosphorylation. Conclusion In conclusion, circ_0098181 exerts a significant anti-fibrotic effect by binding PKM2 to repress its nuclear translocation and inhibiting hepatic inflammation, suggesting the promising therapeutic merit in liver cirrhosis.

We previously found that intravenous injection of extracellular vesicles (EVs) from human adipose tissue–derived stem cells (hADSC) could ameliorate allergic rhinitis (AR) in mice through immunomodulatory effects. In clinical trials, nasal delivery has been an attractive treatment for AR. We sought to determine whether there are differences in the therapeutic effects between caudal injection and their combination. We treated AR mice with ADSC-EVs via caudal vein, nasal cavity, or both. After treatment, the mice were re-sensitized and the indices of behavior, nasal mucosa morphology, and cytokine secretion of the mice under different modes of administration were calculated. The resultes show that tail vein, nasal, and combined administration could effectively relieve the inflammatory infiltration of the nasal mucosa of mice, reduce the secretion of IgE, IL-4, and other inflammatory factors, and alleviate the Th1/Th2 imbalance. Injection and nasal delivery, as well as their combination, effectively alleviated the symptoms of rhinitis in mice. Nasal administration has a better therapeutic effect when the inflammatory response is mild. It could be speculated that ADSC-EVs have excellent properties in the treatment of AR, and modes of administration can be selected for different stages of treatment in clinical therapy.