Objective:To explore the expressions of long noncoding RNA (lncRNA) homeobox A11 antisense RNA (HOXA11-AS) and lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) in hypopharyngeal carcinoma tissues and their relationships with prognosis.Methods:Prospectively, 80 patients with hypopharyngeal carcinoma who were treated in Handan Central Hospital from February 2019 to February 2021 were selected. The hypopharyngeal carcinoma tissues resected surgically and the adjacent normal tissues (more than 2 cm away from the edge of the cancer tissue) were obtained. The expressions of HOXA11-AS and LEF1-AS1 were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues and adjacent normal tissues were compared. The relationships between their expressions and clinicopathological features were analyzed. The Kaplan-Meier method was used to analyze the relationships between high/low expressions of HOXA11-AS and LEF1-AS1 and the prognosis of patients with hypopharyngeal carcinoma.Results:The expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues were higher than those in adjacent normal tissues (all P<0.05). The expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues were related to tumor node metastasis (TNM) stage, degree of differentiation, and lymph node metastasis (all P<0.05). The 3-year overall survival rates of patients with high expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues were lower than those of patients with low expressions (all P<0.05). Conclusions:The expressions of HOXA11-AS and LEF1-AS1 are increased in hypopharyngeal carcinoma tissues, which are related to poor prognosis of patients with hypopharyngeal carcinoma.

Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.

Objective:To explore the expressions of long noncoding RNA (lncRNA) homeobox A11 antisense RNA (HOXA11-AS) and lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) in hypopharyngeal carcinoma tissues and their relationships with prognosis.Methods:Prospectively, 80 patients with hypopharyngeal carcinoma who were treated in Handan Central Hospital from February 2019 to February 2021 were selected. The hypopharyngeal carcinoma tissues resected surgically and the adjacent normal tissues (more than 2 cm away from the edge of the cancer tissue) were obtained. The expressions of HOXA11-AS and LEF1-AS1 were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues and adjacent normal tissues were compared. The relationships between their expressions and clinicopathological features were analyzed. The Kaplan-Meier method was used to analyze the relationships between high/low expressions of HOXA11-AS and LEF1-AS1 and the prognosis of patients with hypopharyngeal carcinoma.Results:The expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues were higher than those in adjacent normal tissues (all P<0.05). The expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues were related to tumor node metastasis (TNM) stage, degree of differentiation, and lymph node metastasis (all P<0.05). The 3-year overall survival rates of patients with high expressions of HOXA11-AS and LEF1-AS1 in hypopharyngeal carcinoma tissues were lower than those of patients with low expressions (all P<0.05). Conclusions:The expressions of HOXA11-AS and LEF1-AS1 are increased in hypopharyngeal carcinoma tissues, which are related to poor prognosis of patients with hypopharyngeal carcinoma.

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.

Background::Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC.Methods::We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort ( n = 125), a validation cohort ( n = 82), and a control cohort ( n = 80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. Results::A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment.Conclusion::These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.
Humans ; NAD/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Nicotinamide Phosphoribosyltransferase/metabolism* ; Cytokines/metabolism* ; Quinones ; Oxidoreductases

AIM: To study the effect of intense pulsed light(IPL)combined with meibomian gland massage on postoperative dry eye in cataract patients with meibomian gland dysfunction(MGD).METHODS: A retrospective analysis was conducted on the general data of 100 patients(100 eyes)with cataract and postoperative dry eye syndrome accompanied by MGD treated in our hospital from June 2022 to June 2023. They were divided into a control group(n=50)and an observation group(n=50)according to different treatment methods, and received meibomian gland massage and meibomian gland massage combined with IPL treatment, respectively. The tear film break-up time(BUT), Schirmer I test(S I t), meibomian gland secretion score, ocular surface disease index(OSDI), ocular staining score(OSS), and treatment efficacy of the two groups of patients were compared before treatment and at 1 wk and 1 and 3 mo after treatment.RESULTS: The BUT and SIt in both groups after treatment were higher than those before treatment, while the secretion of meibomian gland, OSS score, and OSDI score were lower than those before treatment(all P<0.05); the observation group had higher levels of BUT and SIT at 1 wk, 1 and 3 mo compared to the control group(all P<0.05), and lower levels of meibomian gland secretion, OSS score, and OSDI score compared to the control group(all P<0.05); the effective rate of treatment in the observation group was 86.0%, which was higher than that in the control group(68.0%; P<0.05).CONCLUSION: IPL combined with meibomian gland massage for treating postoperative dry eye in cataract patients with MGD can promote the extension of BUT, increase tear secretion, and reduce OSS and OSDI scores.

Objective:To analyze the association between waist circumference (WC) and ischemic stroke (IS).Methods:The data for the present study were from the prospective cohort study of China Kadoorie Biobank in Qingdao. Using baseline information and IS events of the participants, the Cox proportional hazard regression model and restricted cubic spline (RCS) were used to analyze the association between WC and IS.Results:A total of 33 355 participants were included in the study, with 302 008.88 person-years of follow-up. A total of 1 093 new cases of IS were observed. Multivariate Cox proportional hazard regression model analysis showed that compared to the respondents with normal WC (male <85.0 cm, female <80.0 cm), respondents with excessive WC (male ≥85.0 cm, female ≥80.0 cm) had a 78% higher risk of IS incidence [hazard ratio( HR)=1.78, 95% CI: 1.51-2.10], and the risk increased by 72% ( HR=1.72, 95% CI: 1.40-2.12) and 83% ( HR=1.83, 95% CI: 1.40-2.39) in men and women. According to the RCS, the increase in WC and the risk of IS showed an "S" trend of nonlinear dose-response relationship. Conclusions:The risk of IS would increase with the WC. Keeping a normal WC is important for preventing IS.

Objective:To investigate the association between solid fuel use for heating, smoking, and respiratory diseases.Methods:This study is based on the Qingdao project of the China Kadoorie Biobank. After screening, 26 165 individuals were included in the study. We employed Cox proportional hazards regression models, stratified by risk age (in 5-year intervals) and sex while adjusting for confounding variables such as occupation and physical activity level to analyze the association between solid fuel use for heating, smoking, and increased risk of respiratory diseases.Results:Among the 26 165 participants, the average age of those using solid fuel for heating was (52.57±10.31) years, with females constituting 58.04% and former/current smokers accounting for 65.38%. The results indicated that both the solid fuel group and the former/current smoking group had a higher risk of respiratory diseases, with hazard ratios ( HR) (95% CI) of 1.21 (1.04-1.41) and 1.41 (1.16-1.71), respectively. For the duration of solid fuel use, the HR (95% CI) for 20 years or more, it was 1.27 (1.07-1.51). The multiplicative interaction term between solid fuel use and smoking was statistically significant. Conclusions:The use of solid fuel for heating and smoking significantly increases the risk of respiratory diseases, and there may be a multiplicative interaction between solid fuel use and smoking.

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.