Objective To investigate the association between intraoperative dexamethasone administration and long-term survival outcomes.Methods A total of 1 629 NSCLC patients who underwent lung tumor resection between January 2008 and December 2014 were included in this study.A propensity score-matched cohort was generated at a ratio of 1∶2 to compare patients who received dexamethasone with those who did not.This matching process resulted in a cohort of 532 patients in the non-DEX group and 283 patients in the DEX group.Within this propensity score-matched cohort,disease-free survival(DFS)and overall survival(OS)were compared between the non-DEX and DEX groups using the Kaplan-Meier method.Additionally,Cox proportional hazards regression analysis was used to evaluate the associations between intraoperative administration of dexamethasone and high-risk factors for postoperative nausea and vomiting(PONV),as well as their impact on DFS and OS.Results After propensity score matching,intraoperative dexamethasone was significantly associated with worse OS(P=0.005),while no significant correlation was observed between intraoperative dexamethasone and DFS.Multivariate Cox regression analyses indicated that intraoperative dexamethasone was associated with poorer overall survival(HR=1.233,95%CI:1.002～1.516,P=0.048).In subgroup analyses,intraoperative dexamethasone was significantly associated with shorter OS in the female,video-assisted thoracoscopic surgery(VATS),prolonged anesthetic time,and inhalation anesthesia subgroups.Conclusions There was a significant correlation between intraopera-tive dexamethasone administration and overall survival in NSCLC patients following curative surgery.In high-risk subgroups for PONV,including females,those undergoing VATS,patients with prolonged anesthetic duration,and those under inhalation anesthesia,the administration of intraoperative dexamethasone was associated with a potentially poorer prognosis compared to patients who did not receive intraoperative dexamethasone.

Objective To review the research of safe injection protocols for peripheral norepinephrine(pNE),to make clear the main contents of safe injection protocols and the compliance of clinical implementation protocols,and to provide reference for clinical nurses to use drugs safely.Methods Systematic searches were conducted in the PubMed database,the Embase database from the Netherlands,the Web of Science,the Cochrane library,CNKI,Wanfang database,VIP,and the China biomedical literature database for studies related to safe injection protocols for pNE.The search period extended from the establishment of the databases to April 30,2024.Two researchers conducted data extraction and summary analysis of the included literature.Results A total of 10 articles were incorporated,including 2 guidelines,4 observational retrospective cohort studies,2 observational prospective cohort studies,2 ambispective cohort study.All documents provide a complete safe injection scheme of pNE,and its main contents were as follows:the drug concentration should be diluted to 8～64 mg/L;the injection dose should be small,and the maximum dose should not exceed 0.5 μg·kg-1·min-1 or 25 μg/min;a short infusion time was appropriate,among which 4 schemes require≤24 hours;intravenous catheters should be large-bore models,mainly 16,18 and 20 G;selection of infusion sites with favorable venous conditions of upper limb should be selected for injection;during infusion,regular and effective monitoring was required,and the frequency of monitoring should be once an hour,not exceeding a maximum of 2 hours;observation of the puncture site,and must assess whether there was blood return to the venous pathway,develop an emergency plan for drug extravasation.Several studies provided the compliance analysis of the protocol.The items with the highest compliance were using the drug concentration specified in the protocol,with the highest implementation rate of 100.0%.The items with low compliance were:using ultrasonic catheterization or evaluation,with minimum 26.6%;monitor according to the specified time frequency,with a minimum of 36.0%;selection of infusion sites,with a minimum of 65.0%.Conclusion The pNE is safe and feasible in emergency situations,but it comes with numerous risks and limitations.Norepinephrine(NE)should be administered at low concentrations and small doses,using large-caliber venous indwelling needles,and choosing optimal injection sites.Ultrasound assessment and localization can be used if conditions permit.Short-term infusion is preferred,and effective monitoring should be conducted at regular intervals during the infusion.Emergency plans for drug extravasation should be established.Developing safe injection protocols can reduce the incidence of adverse events such as extravasation.

Objective:To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia.Methods:A retrospective study was conducted on 7 patients diagnosed by Yangjiang People′s Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People′s Hospital of Yangjiang (Ethics No: 20240001).Results:For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A 2, whilst another had significantly decreased Hb A and Hb A 2, in addition with the appearance of a Hb H band. The content of Hb Bart′s in four neonates was ≥0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c. 2delT, HBA2: c. 1A>G, HBA2: c. 1A>T, and HBA1: c. 2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c. 427T>C (Hb CS) and HBA2: c. 2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c. 1A>G and Southeast Asian type deletion. Conclusion:Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c. 1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.

Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver disease(ALD),chronic alcohol consumption disrupts the expression and function of ncRNAs in the liver and circulation,contributing to the disease's pathogenesis and progression.Dysregulated ncRNAs influence key pathways involved in hepatocyte injury,lipid metabolism,inflam-mation,and hepatic stellate cell(HSC)activation,thereby exacerbating steatosis,inflammation,and fibrosis.Furthermore,extracellular vesicles play a pivotal role in mediating ncRNA-driven intercellular communication,amplifying liver damage and fibrosis.This review provides a comprehensive overview of the multifaceted roles of ncRNAs in ALD,with a focus on their mechanistic contributions to disease development and progression.Additionally,we discuss the potential of ncRNAs as diagnostic biomarkers and therapeutic targets,emphasizing their translational relevance in addressing the burden of ALD.

OBJECTIVE: To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia. METHODS: A retrospective study was conducted on 7 patients diagnosed by Yangjiang People's Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People's Hospital of Yangjiang (Ethics No: 20240001). RESULTS: For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A2, whilst another had significantly decreased Hb A and Hb A2, in addition with the appearance of a Hb H band. The content of Hb Bart's in four neonates was ≥ 0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c.2delT, HBA2: c.1A>G, HBA2: c.1A>T, and HBA1: c.2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c.427T>C (Hb CS) and HBA2: c.2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c.1A>G and Southeast Asian type deletion. CONCLUSION Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c.1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.
Humans ; Phenotype ; Codon, Initiator/genetics* ; Female ; Male ; Retrospective Studies ; alpha-Globins/genetics* ; alpha-Thalassemia/genetics* ; Hemoglobin A/genetics* ; Adult ; Mutation

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Hypoxic injury (HI) in the prenatal period often causes neonatal neurological disabilities. Due to the difficulty in obtaining clinical samples, the molecular and cellular mechanisms remain unclear. Here we use vascularized cerebral organoids to investigate the hypoxic injury phenotype and explore the intercellular interactions between vascular and neural tissues under hypoxic conditions. Our results indicate that fused vascularized cerebral organoids exhibit broader hypoxic responses and larger decreases in panels of neural development-related genes when exposed to low oxygen levels compared to single cerebral organoids. Interestingly, vessels also exhibit neural protective effects on T-box brain protein 2⁺ intermediate progenitors (IPs), which are markedly lost in HI cerebral organoids. Furthermore, we identify the role of bone morphogenic protein signaling in protecting IPs. Thus, this study has established an in vitro organoid system that can be used to study the contribution of vessels to brain injury under hypoxic conditions and provides a strategy for the identification of intervention targets.
Organoids/pathology* ; Animals ; Mice ; Hypoxia, Brain/metabolism* ; Brain/blood supply* ; Neurons/metabolism*