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Sorafenib (SFN) is a multi-kinase inhibitor drug for the treatment of advanced hepatocellular carcinoma (HCC), but its limited efficacy is a major obstacle to the clinical outcomes of patients with HCC. We aimed to explore a novel molecular mechanism underlying the chemosensitivity of HCC to SFN, and to identify a promising therapeutic target for HCC treatment. In this study, bioinformatic analysis revealed that DDX24 was associated with poor survival in HCC cases, and significantly related to the pathways modulating tumor development. DDX24 regulated HCC cell proliferation and migration potentials. Moreover, reduction of DDX24 promoted the sorafenib-mediated inhibition of HCC cell growth and migration, the elevation of sorafenib-induced HCC cell apoptosis. DDX24 overexpression suppressed the inhibitory effect of SFN on cell proliferation and migration and reduced the apoptosis induced by SFN. Further, DDX24, combined with SFN treatment, presented a synergistic enhancement of the sensitivity of SFN to the growth and migration of HCC cells via AKT/ERK and the epithelial-mesenchymal transition (EMT) pathways, and that it modulated apoptosis via the caspase/PARP pathway. Mechanistically, SNORA18 served as a target gene for DDX24, regulating the chemosensitivity of sorafenib-treated HCC cells. Furthermore, SNORA18 knockdown or overexpression could partially reverse the inhibition or elevation of cell viability, colony formation and migration induced by DDX24 in sorafenib-treated HCC cells, respectively. Collectively, our results suggest that DDX24 regulates the chemosensitivity of HCC to SFN by mediating the expression of SNORA18, which may act as an effective therapeutic target for improving SFN efficiency in HCC treatment.

Abstract Background To evaluate the effectiveness of enhanced check to the duration of the central venous catheters associated bloodstream infections (CABSIs), and the impact on infection rates. Methods A before-after, real-world study in six adult intensive care units was conducted. All adult patients who had only one central venous catheter were included during two consecutive periods. The intervention period, added cross-check that all patients with central venous catheter (CVC) need to be performed, and included nurses' checks for insertion practices and doctors' checks for maintenance practices. Propensity scores matching were used to account for potential confounding, and restricted cubic spline was served as visualizing the CABSI risk. Results A total of 2906 patients with 26,157 CVC-days were analyzed. After intervention, the density incidence of CABSI decreased from 10.24 to 6.33/1,000 CVC-days (P

Abstract Purpose Non‐small cell lung cancer (NSCLC) is a leading cause of cancer death, and metastasis is a crucial determinant of increased cancer mortality. DDX24 has garnered increased attention due to its correlation with tumorigenesis and malignant progression. However, the correlation between DDX24 and NSCLC remains unclear. Methods DDX24 expression in NSCLC tissues and survival rate of patients was analyzed using bioinformatic analysis. Transwell assays, wound‐healing assays, and tail vein lung colonization models were employed to determine the role of DDX24 in migration and invasion in vitro and in vivo. We searched for DDX24‐interacting proteins using co‐immunoprecipitation followed by mass spectroscopy and verified the interaction. The influence of DDX24 on RPL5 expression and ubiquitination was examined using protein stability assays. Results DDX24 expression was upregulated in NSCLC cell lines and tumors of patients, particularly those with high tumor grades. A high DDX24 level was also correlated with a poor prognosis. DDX24 upregulation enhanced the migration and invasion ability of NSCLC cells, whereas its downregulation had the opposite effects. In vivo xenograft experiments confirmed that tumors with high DDX24 expression had higher metastatic abilities. The interaction between DDX24 and RPL5 promoted its ubiquitination and destabilized it. Conclusions DDX24 acted as a pro‐tumorigenic factor and promoted metastasis in NSCLC. DDX24 interacted with RPL5 to promote its ubiquitination and degradation. As a result, targeting DDX24/RPL5 axis may provide a novel potential therapeutic strategy for NSCLC.

Summary: Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction, posing life-threatening risks in severe cases. Reported risk factors include inherited and acquired hypercoagulable states or other predisposing factors. However, many patients have no identifiable etiology, and causes of BCS differ between the West and East. This study recruited 500 BCS patients and 696 normal individuals for whole-exome sequencing and developed a polygenic risk scoring (PRS) model using PLINK, LASSOSUM, BLUP, and BayesA methods. Risk factors for venous thromboembolism and vascular malformations were also assessed for BCS risk prediction. Ultimately, we discovered potential BCS risk mutations, such as rs1042331, and the optimal BayesA-generated PRS model presented an AUC >0.9 in the external replication cohort. This model provides particular insights into genetic risk differences between China and the West and suggests shared genetic risks among BCS, venous thromboembolism, and vascular malformations, offering different perspectives on BCS pathogenesis.

Human telomerase reverse transcriptase (hTERT) is highly expressed in many tumors and is essential for tumorigenesis and metastasis in multiple cancers. However, the molecular mechanisms underlying its high expression level in hepatocellular carcinoma (HCC) remain unclear. In this study, we identified X-ray repair cross-complementing 5 (XRCC5), a novel hTERT promoter-binding protein in HCC cells, using biotin-streptavidin-agarose pull-down assay. We found that XRCC5 was highly expressed in HCC cells, in which it transcriptionally upregulated hTERT. Functionally, the transgenic expression of XRCC5 promoted HCC progression and 5-fluorouracil resistance, whereas short hairpin RNA knockdown of XRCC5 had converse effects in vitro and in vivo. Moreover, hTERT overexpression reversed XRCC5 knockdown- or 5-fluorouracil (5-Fu)-mediated HCC inhibition. Mechanistically, nuclear-factor-erythroid-2-related factor 2 (NRF2) interacted with XRCC5, which in turn upregulated hTERT. However, the upregulation was insignificant when NRF2 was reduced, suggesting that the XRCC5-mediated hTERT expression was NRF2 dependent. The HCC patients with high expression levels of XRCC5 and hTERT had shorter overall survival times compared with those with low XRCC5 and hTERT levels in their tumor tissues. Collectively, our study demonstrates the molecular mechanisms of the XRCC5/NRF2/hTERT signaling in HCC metastasis, which will aid in the identification of novel strategies for the diagnosis and treatment of HCC.

Abstract Background The prevention of peripherally inserted central catheters (PICC)-associated BSI and central venous catheters (CVC)-associated BSI have been a topic of national importance in China. Therefore, we aimed to explore the epidemiological characteristics of central line-associated bloodstream infection (CLABSI), and to evaluate whether PICCs were associated with a protective effect for CLABSI. Methods A retrospective cohort study was conducted in teaching hospital in Western China. All adult patients received a CVC or PICC during their hospital stay were included from January 2017 to December 2020. Primary endpoint was CLABSI up to 30 days after CVC or PICC placement. Propensity scores with a 2:1 match was used to account for potential confounders, and restricted cubic spline was used to visualize the risk of CLABSI at different time points during the catheterization. Results A total of 224687 devices (180522 PICCs and 45965 CVCs) in 24879 patients were included. The overall incidence was 1.8 CLABSIs per 1000 catheter-days. The odds ratio (OR) value increased day by day after PICC insertion, reached a relatively high point on the 4th day, and decreased from days 5 through 8. From the 9th day of intubation the OR value began to gradually increase day by day again. After covariate adjustment using propensity scores, CVCs were associated with higher risk of CLABSI (adjHR = 3.27, 95% CI 2.38–4.49) compared with PICCs. Conclusions PICCs have a protective role and the effect of fluctuation curve feature in CLABSI when compared to CVCs, and the first 8 calendar days after CVC insertion are the acute stage of CVC-associated BSI.

The high morbidity of patients with coronavirus disease 2019 (COVID-19) brings on a panic around the world. COVID-19 is associated with sex bias, immune system, and preexisting chronic diseases. We analyzed the gene expression in patients with COVID-19 and in their microbiota in order to identify potential biomarkers to aid in disease management. A total of 129 RNA samples from nasopharyngeal, oropharyngeal, and anal swabs were collected and sequenced in a high-throughput manner. Several microbial strains differed in abundance between patients with mild or severe COVID-19. Microbial genera were more abundant in oropharyngeal swabs than in nasopharyngeal or anal swabs. Oropharyngeal swabs allowed more sensitive detection of the causative SARS-CoV-2. Microbial and human transcriptomes in swabs from patients with mild disease showed enrichment of genes involved in amino acid metabolism, or protein modification via small protein removal, and antibacterial defense responses, respectively, whereas swabs from patients with severe disease showed enrichment of genes involved in drug metabolism, or negative regulation of apoptosis execution, spermatogenesis, and immune system, respectively. Microbial abundance and diversity did not differ significantly between males and females. The expression of several host genes on the X chromosome correlated negatively with disease severity. In this way, our analyses identify host genes whose differential expression could aid in the diagnosis of COVID-19 and prediction of its severity via non-invasive assay.

Purpose: To measure the choroidal circulatory parameters Han Chinese children aged 4–14 years from Southwest China, and to explore the relationships between these parameters and age, axial length (AL), and choroidal thickness (ChT). Methods: 284 eyes from 142 subjects were included in this cross-sectional study. All participants underwent cycloplegic refraction and IOLMaster500 examination. Swept-source optical coherence tomography (SS-OCT) was used to measure submacular choroidal thickness, choroidal vascular volume (CVV), choroidal stromal volume (CSV), choroidal vascularity index (CVI), and CVV/CSV ratio. Results: In this population, the mean CVV was 2.92 ± 0.55 mm3, CSV was 4.69 ± 0.68 mm3, CVI was 38.22 ± 2.46 %, and CVV/CSV ratio was 62.11 ± 6.44 %. Multivariable regression analyses showed that both CVV and CSV were negatively correlated with AL (both P < 0.001) and positively correlated with ChT (both P < 0.001), while age showed no significant correlation with them (both P > 0.05). However, the correlations between CVI and age were not uniform rectilinear. Among participants aged ≤8 years, CVI showed no correlation with age (P > 0.05), while among those aged >8 years, it was positively correlated with age (P < 0.01). CVV/CSV ratio was positively correlated with ChT and age (both P < 0.01). Conclusion: After the age of 8, age was positively correlated with CVI. ChT was well correlated with CVI. Longer AL and thinner ChT were associated with reduced CVV and CSV, with CVV decreasing more rapidly than CSV.

Background Gliomas are characterized by high mortality rates and resistance. Even with conventional chemotherapy the prognosis of glioblastoma remains poor. Many medications are not optimally effective due to limited bioavailability. The bioavailability of medicine can be enhanced by borneol, a monoterpenoid substance. In this study, we investigated the effect of borneol, a commonly used Chinese medicine, on chemosensitivity in C6 glioma and U251 human glioma cell lines and elucidated its therapeutic molecular targets. Methods The chemosensitivity-inducing effects of borneol in C6 and U251 cells were examined using CCK8 and clonal formation assays. The mechanism underlying the effect of borneol was evaluated through immunohistochemistry and western blotting assays. Further, the number of autophagosomes was determined via transmission electron microscopy. Finally, the chemical sensitization effect of borneol was evaluated in SD rats after C6 orthotopic tumor transplantation. Results Borneol increased cytotoxicity in C6 and U251 cells in response to temozolomide (TMZ). In addition, through transmission electron microscopy, western blotting, and immunohistochemical tests, we found that borneol combined with TMZ significantly increased the level of autophagy and that hypoxia inducible factor-1(HIF-1α) is a candidate target through which borneol enhances the cytotoxic effect of TMZ. Borneol’s ability to enhance HIF-1α degradation was counteracted following the administration of autophagy inhibitors. In vivo, borneol treatment was found to enhance the anticancer effect of TMZ and delay tumor progression, and this effect was closely related to its ability to promote the autophagic degradation of HIF-1α. Conclusions HIF-1α might be a valid therapeutic target of borneol, which can be potentially applied as a chemosensitizing drug used for glioma treatment.

Multidrug-resistant tuberculosis (MDR-TB) remains a main global health concern as there is no comprehensive therapeutic intervention yet and numerous adverse effects follow the therapeutic process. In recent years, linezolid has been frequently used for treating MDR-TB. However, peripheral neuropathy associated with linezolid has reduced patient compliance. The current study explored the mechanism underlying linezolid-induced peripheral neuropathy in MDR-TB. Autophagy plays a neuroprotective role against peripheral nerve injury. We hypothesized that autophagy might also play a neuroprotective role against linezolid-induced peripheral neuropathy. In this study, we collected 12 questionnaires from MDR-TB patients in our hospital, and 10 of them developed linezolid-induced pain. The pain is mainly concentrated in the feet and accompanied by numbness. Subsequently, we used Sprague-Dawley (SD) rats and Schwann cells (SCs) to explore the mechanism. We found that linezolid causes a sparse arrangement of sciatic nerve tissue with associated loss of neurons, myelin sheaths, and down-regulation of LC3B expression. These results were also confirmed by in vitro experiments, showing that linezolid inhibited the proliferation of SCs. And the expression of P-AKT and P62 was elevated, and the expression of LC3B declined compared with the control group. Moreover, chloroquine (CQ), an autophagy inhibitor, also exhibited experimental results similar to linezolid. In summary, we conclude that linezolid-induced peripheral neuropathy is associated with the inhibition of autophagy flux.