Nanoplastics exposure simplifies the network structure of sea cucumber (Apostichopus japonicus) gut microbiota and improves cluster randomness.

Nanoplastics (NPs) are abundant in ocean environments, leading to environmental pollution and notable disruptions to the physiological functions of marine animals. To investigate the toxic effects of NPs on echinoderms, specifically sea cucumbers (Apostichopus japonicus), they were exposed to varying concentrations of NPs (0, 102, 104 particles/L) for 14 d. Subsequently, the 102 particles/L exposure group was purified for 35 d to elucidate the impact of both NPs exposure and purification on the intestinal bacteria structure and function. The results showed that the richness and variety of intestinal bacteria in sea cucumbers significantly reduced under NPs exposure, and then they could be restored to the pre-exposure treatment state after 35 d of purification. With the increase of NPs exposure concentration in the environment, the intestinal core bacteria gradually changed from Firmicutes and Proteobacteria to Pseudoalteromonas and Vibrio. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database annotated that the gut microbiota of sea cucumbers was significantly downregulated in the glycosylation, carbohydratic and amino acid metabolic pathways (P < 0. 05), exogenous substance biodegradation and metabolism, DNA replication and repair pathways were significantly up-regulated (P < 0.05) under the exposure of NPs. In addition, nanoplastics exposure simplified the symbiotic network relationships of the gut bacteria, reduced the selective effect of host on the intestinal bacteria, and increased stochasticity. In conclusion, waterborne NPs can adversely affect the structure and function of sea cucumber intestinal bacteria, with these effects persisting for a duration. However, as the purification time lengthens, these adverse effects gradually diminish. This study aims to provide some theoretical basis for the biotoxic effects of NPs.

Dexamethasone Use to Reduce Mechanical Ventilation and Bronchopulmonary Dysplasia in the Neonatal Intensive Care Unit.

Background: Ventilator-dependent neonates are at risk of bronchopulmonary dysplasia (BPD), a chronic lung disease. Dexamethasone may be used to facilitate extubation and reduce the incidence of BPD. Objectives: To determine the efficacy of dexamethasone in reducing the incidence of established BPD at 36 weeks postmenstrual age (PMA); to establish the rate of extubation success; to determine the factors affecting extubation success; and to describe complications associated with dexamethasone therapy. Methods: A chart review was conducted at Surrey Memorial Hospital, in Surrey, British Columbia, for neonates who received dexamethasone to reduce the development of BPD between July 1, 2016, and June 30, 2022. Results: A total of 47 neonates met the inclusion criteria. Of the 45 neonates still alive at 36 weeks PMA, all (100%) had BPD. Use of dexamethasone led to extubation success for 21 (47%) of these 45 neonates. The mean PMA at dexamethasone initiation was 30.7 weeks for neonates with extubation success, compared with 28.6 weeks for those with extubation failure (p = 0.001). Complications occurred in 43 (91%) of the 47 neonates. Conclusions: BPD occurred in all of the neonates, despite a 47% extubation success rate. The timing of dexamethasone initiation was associated with extubation success. Further research is required to determine the dose and timing of dexamethasone needed to reduce the incidence of BPD.

Contexte: Les nouveau-nés qui dépendent d'un ventilateur sont exposés à un risque de dysplasie broncho-pulmonaire (DBP), une maladie pulmonaire chronique. La dexaméthasone peut être utilisée pour faciliter l'extubation et réduire l'incidence de cette maladie. Objectifs: Déterminer l'efficacité de la dexaméthasone pour réduire l'incidence de la DBP établie à 36 semaines d'âge postmenstruel (APM); établir la réussite de l'extubation; déterminer les facteurs ayant une incidence sur cette dernière; et décrire les complications associées au traitement par la dexaméthasone. Méthodologie: Un examen des dossiers a été effectué à l'hôpital Surrey Memorial, à Surrey (Colombie-Britannique) pour les nouveau-nés ayant reçu de la dexaméthasone entre le 1er juillet 2016 et le 30 juin 2022 afin de réduire le risque de DBP. Résultats: Au total, 47 nouveau-nés répondaient aux critères d'inclusion. Sur les 45 nouveau-nés encore en vie à 36 semaines d'APM, tous (100 %) souffraient de DBP. L'utilisation de dexaméthasone a permis de réussir l'extubation chez 21 (47 %) de ces 45 nouveau-nés. L'APM moyen au début de l'administration de la dexaméthasone était de 30,7 semaines pour les nouveau-nés dont l'extubation avait été réussie, contre 28,6 semaines pour ceux chez qui ce n'était pas le cas (p = 0,001). Des complications sont survenues chez 43 (91 %) des 47 nouveau-nés. Conclusions: La DBP est survenue chez tous les nouveau-nés, malgré un taux de réussite d'extubation de 47 %. Le moment du début de l'administration de la dexaméthasone était associé à la réussite de l'extubation réussie. Des recherches supplémentaires sont nécessaires pour déterminer la dose de dexaméthasone requise et le moment opportun de l'administration pour réduire l'incidence de la BPD.

Glutathione-dependent degradation of SMARCA2/4 for targeted lung cancer therapy with improved selectivity.

SMARCA2 and SMARCA4 are the mutually exclusive catalytic subunits of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, and have recently been considered as attractive synthetic lethal targets for PROTAC-based cancer therapy. However, the potential off-tissue toxicity towards normal tissues remains a concern. Here, we optimize a GSH-inducible SMARCA2/4-based PROTAC precursor with selective antitumor activity towards lung cancer cells and negligible cytotoxicity towards normal cells in both in vitro and in vivo studies. The precursor is not bioactive or cytotoxic, but preferentially responds to endogenous GSH in GSH-rich lung cancer cells, releasing active PROTAC to degrade SMARCA2/4 via PROTAC-mediated proteasome pathway. Subsequent xenograft model study reveals that selective SMARCA2/4 degradation in lung tumors triggers DNA damage and apoptosis, which significantly inhibits lung cancer cell proliferation without obvious adverse events towards normal tissues. This study exemplifies the targeted degradation of SMARCA2/4 in lung cancer cells by the GSH-responsive PROTAC precursor, highlighting its potential as an encouraging cancer therapeutic strategy.

Redox-inducible Radiomimetic Photosensitizers Selectively Suppress Cancer Cell Proliferation by Damaging DNA through Radical Cation Chemistry.

Radiotherapy leverages ionizing radiation to kill cancer cells through direct and indirect effects, and direct effects are considered to play an equal or greater role. Several photosensitizers have been developed to mimic the direct effects of radiotherapy, generating radical cations in DNA models, but none has been applied in cellular studies. Here, we design a radiomimetic photosensitizer, producing DNA radical cations in cells for the first time. To reduce adverse effects, several redox-inducible precursors are prepared as cancer cells have elevated levels of GSH and H2O2. These precursors respond to GSH or H2O2, releasing the active photosensitizer that captures DNA abasic (AP) sites and generates DNA radical cations upon photolysis, without disrupting the redox state of cells. DNA radical cations migrate freely and are eventually trapped by H2O and O2 to yield DNA lesions, thus triggering DNA damage response. Our study suggests that direct effects of radiotherapy suppress cancer cell proliferation mainly by inducing G2/M phase cell cycle arrest, rather than promoting apoptosis. Synergistic effects of the precursor and chemotherapeutic agents are also observed in combination phototherapy. Beyond highlighting an alternative strategy for phototherapy, this proof-of-concept study affords a facile cellular platform to study the direct effects of radiotherapy.

Genome-wide identification and expression analysis of the CONSTANS-like family in potato (Solanum tuberosum L.).

The CONSTANS-like (COL) gene plays important roles in plant growth, development, and abiotic stress. A total of 15 COL genes are unevenly distributed on eight chromosomes in the potato genome. The amino acid length of the family members was 347-453 aa, the molecular weight was 38.65-49.92 kD, and the isoelectric point was 5.13-6.09. The StCOL family can be divided into three subfamilies by evolutionary tree analysis, with conserved motifs and similar gene structure positions in each subfamily. The analysis of promoter cis-acting elements showed 17 cis-acting elements related to plant hormones, stress, and light response. Collinearity analysis of COL genes of tomato, potato, and Arabidopsis showed that 13 StCOL genes in the different species may have a common ancestor. A total of 10 conserved motifs and six kinds of post-translational modifications in the 15 StCOL proteins were identified. The 15 StCOL genes exhibit a genomic structure consisting of exons and introns, typically ranging from two to four in number. The results showed that 10 genes displayed significant expression across all potato tissues, while the remaining five genes were down-expressed in potato transcriptome data. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis exhibited differential expression of 8 StCOL genes in the potato leaves and tubers at different growth stages, as well as 7 StCOL genes under 2°C treatment conditions. These results suggested that the StCOL gene family may play an important role in regulating potato tuberization and responding to cold stress.

FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator FTY720 in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying hematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary hemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analyzed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary hemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferators-activated receptors (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1A (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

OBJECTIVE: Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. DESIGN, PATIENTS AND MEASUREMENTS: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. RESULTS: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). CONCLUSIONS: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

Changes in monsoon precipitation in East Asia under a 2°C interglacial warming.

Past intervals of warming provide the unique opportunity to observe how the East Asia monsoon precipitation response happened in a warming world. However, the available evaluations are primarily limited to the last glacial-to-interglacial warming, which has fundamental differences from the current interglacial warming, particularly in changes in ice volume. Comparative paleoclimate studies of earlier warm interglacial periods can provide more realistic analogs. Here, we present high-resolution quantitative reconstructions of temperature and precipitation from north-central China over the past 800 thousand years. We found that the average precipitation increase, estimated by the interglacial data, was only around one-half of that estimated for the glacial-to-interglacial data, which is attributed to the amplification of climate change by ice volume variations. Analysis of the interglacial data suggests an increase in monsoon precipitation of ~100 mm for a warming level of 2°C on the Chinese Loess Plateau.

Liquid biopsy of oesophageal squamous cell carcinoma: implications in diagnosis, prognosis, and treatment monitoring.

Oesophageal squamous cell carcinoma (ESCC) is a common malignant tumour of the gastrointestinal tract. Early detection and access to appropriate treatment are crucial for the long-term survival of patients. However, limited diagnostic and monitoring methods are available for identifying early stage ESCC. Endoscopic screening and surgical resection are commonly used to diagnose and treat early ESCC. However, these methods have disadvantages, such as high recurrence, lethality, and mortality rates. Therefore, methods to improve early diagnosis of ESCC and reduce its mortality rate are urgently required. In 1961, Gary et al. proposed a novel liquid biopsy approach for clinical diagnosis. This involved examining exosomes, circulating tumour cells, circulating free DNA, and circulating free RNA in body fluids. The ability of liquid biopsy to obtain samples repeatedly, wide detection range, and fast detection speed make it a feasible option for non-invasive tumour detection. In clinical practice, liquid biopsy technology has gained popularity for early screening, diagnosis, treatment efficacy monitoring, and prognosis assessment. Thus, this is a highly promising examination method. However, there have been no comprehensive reviews on the four factors of liquid biopsy in the context of ESCC. This review aimed to analyse the progress of liquid biopsy research for ESCC, including its classification, components, and potential future applications.

Effectiveness of azvudine in reducing mortality of COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: Azvudine has been approved for the treatment of coronavirus disease 2019 (COVID-19) patients in China, and this meta-analysis aims to illustrate the safety of azvudine and its effectiveness in reducing mortality. METHODS: PubMed, Embase, Web of science, Cochrane Library and the Epistemonikos COVID-19 Living Overview of Evidence database (L.OVE) were searched to aggregate currently published studies. Cochrane risk of bias tool and ROBINS-I tool were used to assess the risk of bias of randomized controlled study and cohort study respectively. Odds radios (ORs) with 95% confidence interval (CIs) were combined for dichotomous variables. Publication bias was assessed by Egger's test and funnel plots. RESULTS: A total of 184 articles were retrieved from the included databases and 17 studies were included into the final analysis. Pooled analysis showed that azvudine significantly reduced mortality risk in COVID-19 patients compared with controls (OR: 0.41, 95%CI 0.31-0.54, p < 0.001). Besides, either mild to moderate or severe COVID-19 patients could benefit from azvudine administration. There was no significant difference in the incidence of ICU admission (OR: 0.90, 95%CI 0.47-1.72, p = 0.74) and invasive ventilation (OR: 0.94, 95%CI 0.54-1.62, p = 0.82) between azvudine and control group. The incidence of adverse events was similar between azvudine and control (OR: 1.26, 95%CI 0.59-2.70, p = 0.56). CONCLUSIONS: This meta-analysis suggests that azvudine could reduce the mortality risk of COVID-19 patients, and the safety of administration is acceptable. TRIAL REGISTRATION: PROSPERO; No.: CRD42023462988; URL: https://www.crd.york.ac.uk/prospero/ .

Dendritic cell-cytokine killer combined with microwave ablation reduced recurrence for hepatocellular carcinoma compared to ablation alone.

BACKGROUND: Several international practice guidelines have recommended local ablation as the first-line treatment for early-stage hepatocellular carcinoma (HCC). OBJECTIVE: This study aims to investigate the synergetic anti-tumor impact of dendritic cell-cytokine killer (DC-CIK) combined with microwave ablation (MWA) for HCC. METHODS: This retrospective study included 1,141 patients from the American Joint Committee on Cancer stage I-II HCC, who were treated with therapeutic MWA. The immunotherapy group encompassing 40 patients received additional immunotherapy with DC-CIK, whereas the control group consisting of 1,101 patients was treated with MWA alone. Propensity score matching (PSM) with ratio of 1:3 was employed to balance selection bias. The oncological outcome and immune status were measured after combination therapy. RESULTS: The immunotherapy group patients exhibited significant longer disease-free survival (DFS, primary HCC: p= 0.036; recurrent HCC: p= 0.026). For patients with primary HCC, the recurrence frequency was reduced (p= 0.002), and recurrence interval (19 months vs. 9 months, p< 0.001) was prolonged in the immunotherapy group. Subgroup analysis revealed that patients ⩽ 60 years old, moderately-differentiated HCC, or co-infected with Hepatitis B Virus (HBV) had a significant benefit over DFS in the immunotherapy group. After combination therapy, the serum CD3+ (p= 0.049), CD8/CD28+ (p= 0.045) were elevated. CONCLUSION: Combination therapy with DC-CIK and MWA can significantly reduce the recurrence and prolong DFS, especially for patients ⩽ 60 years old or with moderately-differentiated HCC or co-infected with HBV.

Risk model based on genes regulating the response of tumor cells to T-cell-mediated killing in esophageal squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) represent a promising therapeutic approach for esophageal squamous cell carcinoma (ESCC). However, the subpopulations of ESCC patients expected to benefit from ICIs have not been clearly defined. The anti-tumor cytotoxic activity of T cells is an important pharmacological mechanism of ICIs. In this study, the prognostic value of the genes regulating tumor cells to T cell-mediated killing (referred to as GRTTKs) in ESCC was explored by using a comprehensive bioinformatics approach. Training and validation datasets were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. A prognostic risk scoring model was developed by integrating prognostic GRTTKs from TCGA and GEO datasets using a ridge regression algorithm. Patients with ESCC were divided into high- and low-risk groups based on eight GRTTKs (EIF4H, CDK2, TCEA1, SPTLC2, TMEM209, RGP1, EIF3D, and CAPZA3) to predict overall survival in the TCGA cohort. Using Kaplan-Meier curves, receiver operating characteristic curves, and C-index analysis, the high reliability of the prognostic risk-scoring model was certified. The model scores served as independent prognostic factors, and combining clinical staging with risk scoring improved the predictive value. Patients in the high-risk group exhibited abundant immune cell infiltration, including immune checkpoint expression, antigen presentation capability, immune cycle gene expression, and high tumor inflammation signature scores. The high-risk group exhibited a greater response to immunotherapy and neoadjuvant chemotherapy than the low-risk group. Drug sensitivity analysis demonstrated lower IC50 for AZD6244 and PD.0332991 in high-risk groups and lower IC50 for cisplatin, ATRA, QS11, and vinorelbine in the low-risk group. Furthermore, the differential expression of GRTTK-related signatures including CDK2, TCEA1, and TMEM209 were verified in ESCC tissues and paracancerous tissues. Overall, the novel GRTTK-based prognostic model can serve as indicators to predict the survival status and immunotherapy response of patients with ESCC, thereby providing guidance for the development of personalized treatment strategies.

Imaging, pathology, and diagnosis of solitary fibrous tumor of the pancreas: A case report and review of literature.

BACKGROUND: A solitary fibrous tumor (SFT) is often located in the pleura, while SFT of the pancreas is extremely rare. Here, we report a case of SFT of the pancreas and discuss imaging, histopathology, and immunohistochemistry for accurate diagnosis and treatment. CASE SUMMARY: A 54-year-old man presented to our hospital with pancreatic occupancy for over a month. There were no previous complaints of discomfort. His blood pressure was normal. Blood glucose, tumor markers, and enhanced computed tomography (CT) suggested a malignant tumor. Because the CT appearance of pancreatic cancer varies, we could not confirm the diagnosis; therefore, we performed endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Pathology and immunohistochemistry were consistent with SFT of the pancreas. The postoperative pathology and immunohistochemistry were consistent with the puncture results. The patient presented for a follow-up examination one month after discharge with no adverse effects. CONCLUSION: Other diseases must be excluded in patients with a pancreatic mass that cannot be diagnosed. CT and pathological histology have diagnostic value for pancreatic tumors. Endoscopic puncture biopsy under ultrasound can help diagnose pancreatic masses that cannot be diagnosed preoperatively. Surgery is an effective treatment for SFT of the pancreas; however, long-term follow-up is strongly recommended because of the possibility of malignant transformation of the tumor.

Sulfamethoxazole stress endangers the gut health of sea cucumber (Apostichopus japonicus) and affects host metabolism.

Sulfamethoxazole (SMZ) is a frequently detected antibiotic in the environment, and there is a growing concern about its potential toxic effects on aquatic organisms. sea cucumber (Apostichopus japonicas) is a benthic invertebrate whose gut acts as a primary immune defense and serves critical protective barrier. In this study, growth performance, histology, gut microbiota, and metabolomics analyses were performed to investigate the toxic response in the intestine of sea cucumber effects caused by SMZ stress for 56 d by evaluating with different concentrations of SMZ (0, 1.2×10-3, and 1.2 mg/L). The weight gain rate of sea cucumbers under SMZ stress showed significant decrease, indicating that the growth of sea cucumbers was hindered. Analysis of the intestinal morphological features indicated that SMZ stimulation resulted in atrophy of the sea cucumber gut. In the 1.2×10-3 mg/L concentration, the thickness of muscle and mucosal layers was reduced by 12.40% and 21.39%, while in the 1.2 mg/L concentration, the reductions were 35.08% and 26.98%. The abundance and diversity of sea cucumber intestinal bacteria decreased significantly (P < 0.05) under the influence of SMZ. Notably, the intestinal bacteria of sea cucumber became homogenized with the increase in SMZ concentration, and the relative abundance of Ralstonia reached 81.64% under the stress of 1.2 mg/L concentration. The SMZ stress significantly impacted host metabolism and disrupted balance, particularly in L-threonine, L-tyrosine, neuronic acid, piperine, and docosapentaenoic acid. SMZ leads to dysregulation of metabolites, resulting in growth inhibition and potential inflammatory responses that could adversely affect the normal activities of aquatic organisms. Further metabolic pathway enrichment analyses demonstrated that impaired biosynthesis of unsaturated fatty acids and aminoacyl-tRNA biosynthesis metabolic pathway were major reasons for SMZ stress-induced intestinal bacteria dysbiosis. This research aims to provide some theoretical evidence for the ecological hazard assessment of antibiotics in water.

Efficacy and safety of azvudine in symptomatic adult COVID-19 participants who are at increased risk of progressing to critical illness: a study protocol for a multicentre randomized double-blind placebo-controlled phase III trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 will coexist with humans for a long time, and it is therefore important to develop effective treatments for coronavirus disease 2019 (COVID-19). Recent studies have demonstrated that antiviral therapy is a key factor in preventing patients from progressing to severe disease, even death. Effective and affordable antiviral medications are essential for disease treatment and are urgently needed. Azvudine, a nucleoside analogue, is a potential low-cost candidate with few drug interactions. However, validation of high-quality clinical studies is still limited. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled phase III clinical trial involving 1096 adult patients with mild-to-moderate symptoms of COVID-19 who are at high risk for progression to severe COVID-19. Patients will be randomized to (1) receive azvudine tablets 5 mg daily for a maximum of 7 days or (2) receive placebo five tablets daily. All participants will be permitted to use a standard treatment strategy except antiviral therapy beyond the investigational medications. The primary outcome will be the ratio of COVID-19-related critical illness and all-cause mortality among the two groups within 28 days. DISCUSSION: The purpose of this clinical trial is to determine whether azvudine can prevent patients at risk of severe disease from progressing to critical illness and death, and the results will identify whether azvudine is an effective and affordable antiviral treatment option for COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT05689034. Registered on 18 January 2023.

Hypomethylation-Mediated Upregulation of NFE2L3 Promotes Malignant Phenotypes of Clear Cell Renal Cell Carcinoma Cells.

This work aimed to study the effect of NFE2 like bZIP transcription factor 3 (NFE2L3) on clear cell renal cell carcinoma (ccRCC) cells and whether NFE2L3 expression was mediated by DNA methylation. Twenty-one ccRCC patients were collected. The gene methylation and expression data of TCGA-KIRC were accessed from TCGA. Candidate methylation driver genes were identified by "MethylMix" package, and finally, NFE2L3 was selected as the target gene. The methylation of NFE2L3 was assayed by Ms PCR and QMSP. mRNA level of NFE2L3 was analyzed by qRT-PCR. Protein level of NFE2L3 was measured by Western blot. Demethylation was performed with methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR). Proliferative, migratory, and invasive abilities of ccRCC cells were assayed via cell colony formation assay, scratch healing assay, and transwell assay, respectively. Analysis of TCGA database presented that DNA hypomethylation occurred in the NFE2L3 promoter region in ccRCC tissues. NFE2L3 was significantly upregulated in ccRCC tissues and cells. Its expression in cells treated with 5-Aza-CdR was proportional to the concentration of methylation inhibitor. In cell function experiments, overexpressing NFE2L3 or demethylation could stimulate proliferation, migration, and invasion abilities of ccRCC and normal cells. 5-Aza-CdR treatment rescued repressive impact of knockdown NFE2L3 on malignant phenotypes of ccRCC and normal cells. DNA hypomethylation could induce high expression of NFE2L3 and facilitate malignant phenotypes of ccRCC cells. These results may generate insights into ccRCC therapy.

Burnout among radiology residents: a systematic review and meta-analysis.

OBJECTIVE: To analyze the prevalence of burnout among radiology residents. METHOD: Five databases (PubMed, Web of Science, Embase, PsycINFO, and Scopus) were searched for studies reporting burnout in radiology residents for the period up to November 7, 2022. RESULTS: A total of 423 studies were identified, and eventually, 16 studies were selected for the qualitative analysis, of which 11 studies were used in the meta-analysis. There was a total of 2164 radiology residents. Six studies reported the prevalence of burnout but the data could not be pooled due to their inconsistent definitions of burnout. The mean scores of three burnout subscales indicated a moderate to high degree of severity: emotional exhaustion = 25.2 (95% CI, 22.1-28.3; I2 = 94.4%), depersonalization = 10.2 (95% CI, 8.5-11.9; I2 = 93.0%), and low perception of personal accomplishment = 32.9 (95% CI, 30.5-35.4; I2 = 94.4%). The pooled prevalence of high-degree emotional exhaustion was 49.9% (95% CI, 43.6-56.1%; I2 = 55.7%), high-degree depersonalization was 45.1% (95% CI, 38.3-52.0%; I2 = 63.2%), and high-degree diminished personal accomplishment was 58.2% (95% CI, 36.0-77.6%; I2 = 84.9%). The impact of the COVID-19 pandemic on radiology residents was not investigated. In addition, there are inconsistent findings on the effects of female sex, seniority, and social support on burnout. CONCLUSIONS: About half of the radiology residents showed at least one of the three burnout manifestations (emotional exhaustion, depersonalization, and personal accomplishment), with a moderate to high degree of severity. CLINICAL RELEVANCE STATEMENT: Such a high prevalence and severity of burnout among radiology residents warrant the attention of residency program directors. KEY POINTS: • Burnout, not uncommon among radiology residents, has not been effectively analyzed. • Nearly half of the radiology residents experience at least one of the three manifestations of burnout to a moderate to high degree. • The high prevalence and severe degree of burnout among radiology residents warrant the attention of residency program directors.

UHPLC-MS/MS metabolomics analysis of sea cucumber (Apostichopus japonicus) processed using different methods.

The effects of different processing methods on the nutritional components of sea cucumber (Apostichopus japonicus) are of concern to consumers who select sea cucumber products. This study employed liquid chromatography tandem mass spectrometry to examine the metabolites in fresh, unsoaked salted, soaked salted, and instant sea cucumber body wall samples sourced from Dalian, China. Metabolites were evaluated utilizing partial least squares discriminant analysis (PLS-DA) and subsequently subjected to KEGG metabolic pathway analysis for further investigation. PLS-DA effectively discriminated the body wall metabolites of sea cucumbers obtained via various processing techniques. The differential metabolites identified predominantly encompassed amino acids, lipids, and carbohydrates. Subsequent KEGG metabolic pathway analysis demonstrated a significant association between lipid, carbohydrate, and amino acid metabolism and the specific processing methods employed. The assessment of nutritional differences corresponding to the various A. japonicus processing methods was conducted. The findings of this study can assist in the choice of sea cucumber products and the selection of suitable processing methods.

MethylRAD Sequencing Technology Reveals DNA Methylation Characteristics of Apostichopus japonicus of Different Ages.

The A. japonicus industry has expanded significantly, but no research has focused on determining the age of A. japonicus during farming. Correctly estimating the age of A. japonicus can provide a decision-making basis for the breeding process and data for the protection of A. japonicus aquatic germplasm resources. DNA methylation levels in the body wall of Apostichopus japonicus at 4 months, 1 year, 2 years, and 3 years old were determined using MethylRAD-Seq, and differentially methylated genes were screened. A total of 441 and 966 differentially methylated genes were detected at the CCGG and CCWGG sites, respectively. Aspartate aminotransferase, succinate semialdehyde dehydrogenase, isocitrate dehydrogenase, the histone H2AX, heat shock protein Hsp90, aminopeptidase N, cell division cycle CDC6, Ras GTPase activating protein (RasGAP), slit guidance ligand slit1, integrin-linked kinase ILK, mechanistic target of rapamycin kinase Mtor, protein kinase A Pka, and autophagy-related 3 atg3 genes may play key roles in the growth and aging process of A. japonicus. This study provides valuable information regarding age-related genes for future research, and these candidate genes can be used to create an "epigenetic clock".

Dual-responsive probe and DNA interstrand crosslink precursor target the unique redox status of cancer cells.

Elevated GSH and H2O2 in cancer cells is sometimes doubted due to their contrary reactivities. Here, we construct a dual-responsive fluorescent probe to confirm the conclusion, and employ this to exploit a redox-inducible DNA interstrand crosslink (ICL) precursor. It crosslinks DNA upon activation by GSH and H2O2, affording an alternative dual-responsive strategy.