Objective To investigate the prognostic value of albumin-corrected anion gap (ACAG) in patients with advanced lung cancer receiving immune checkpoint inhibitors (ICIs). Methods A total of 637 patients with advanced lung cancer who received ICI treatment were enrolled. Baseline clinical data and laboratory parameters were collected, and ACAG was calculated. The optimal prognostic Cut-off value for ACAG (11.58 mmol/L) was determined using X-Tile software, and patients were divided into low (≤11.58 mmol/L) and high (>11.58 mmol/L) ACAG groups. Propensity score matching was performed to control for confounding factors. Survival curves were plotted using the Kaplan-Meier method. A Cox proportional hazards regression model was employed to analyze prognostic factors, and subgroup analyses were conducted. Results Among 637 patients, 440 patients remained in the matched cohort. Multivariate Cox analysis showed that after adjusting for clinical and laboratory parameters, ACAG >11.58 mmol/L was an independent risk factor for OS (HR=1.74, 95%CI: 1.02–2.98, P=0.044) but was not an independent predictor for PFS. After adjusting for different sets of covariates, stratified analysis further confirmed that ACAG >11.58 mmol/L was consistently associated with a significantly shortened OS. Survival curves demonstrated that the median OS in the high ACAG group (47.0 months) was significantly lower than that in the low ACAG group. Subgroup analysis indicated that the predictive value of ACAG for OS was more pronounced in males, patients aged <65 years, and patients with squamous cell carcinoma than in other patients. Conclusion In patients with advanced lung cancer treated with ICIs, a high baseline ACAG level (>11.58 mmol/L) is an independent risk factor for shortened OS but is not significantly associated with PFS. ACAG may serve as a simple and effective biological marker for assessing overall survival prognosis in patients with advanced lung cancer undergoing immunotherapy.

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with Primary ciliary dyskinesia (PCD). METHODS: A child who presented at the ENT Department of Zhengzhou University Children's Hospital in March 2024 due to secretory otitis media, chronic sinusitis, adenoid hypertrophy, dextrocardia, and bronchiectasis was selected as study subject. Relevant clinical data were collected. Peripheral blood samples from the child and her family members were collected. Following DNA extraction, whole exome sequencing was carried out. Candidate variants were validated by Sanger sequencing, and the correlation between the variants and phenotype was analyzed. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-K-135). RESULTS: The child and her elder siblings exhibited similar clinical manifestations including recurrent cough, secretory otitis media, chronic sinusitis, tracheobronchitis, and pneumonia. The child also presented with bronchiectasis and visceral situs inversus. Genetic testing results indicated that the child and her elder siblings had all harbored compound heterozygous variants of the DNAH11 gene, namely c.3000 1G>A and c.5775C>G (p.Tyr1925*), which were respectively inherited from their phenotypically normal parents. Both variants can affect mRNA splicing and protein translation integrity. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were classified as likely pathogenic. It was predicted that they may jointly lead to a functional defect in axonemal dynein, resulting in the phenotype of PCD, conforming to an autosomal recessive inheritance. CONCLUSION The compound heterozygous variants c.3000 1G>A and c.5775C>G (p.Tyr1925*) of the DNAH11 gene probably underlay the pathogenesis of PCD in this pedigree. The same variant in different individuals may lead to different clinical phenotypes, which has reflected significant heterogeneity in genetic background and clinical phenotype. Above findings have enriched the mutational spectrum of PCD gene and have important implications for the accurate diagnosis, treatment, prognosis, and genetic counseling.
Humans ; Pedigree ; Female ; Axonemal Dyneins/genetics* ; Male ; Child ; Asian People/genetics* ; Kartagener Syndrome/genetics* ; Mutation ; Phenotype ; China ; Adult ; East Asian People

AIM:To explore the mechanism by which activation of α7 nicotinic acetylcholine receptor(nAChR)in combination with cold stimulation promotes the beiging of white adipose tissues in obese mice.METHODS:Male C57BL/6J mice,aged 8 weeks,were acclimated for 1 week before fed with high-fat diet(HFD)for 12 weeks to estab-lish an obese model.Fifty mice were randomly divided into 5 groups:control group(low-fat diet),HFD group,model group(HFD+cold stimulation),agonist group(HFD+cold stimulation+α7 nAChR agonist GTS-21),and inhibitor group(HFD+cold stimulation+α7 nAChR inhibitor α-bungarotoxin).Interventions lasted for 4 weeks.Serum levels of total cho-lesterol(TG),triglyceride(TC)and free fatty acid(FFA),and the levels of tumor necrosis factor-α(TNF-α),interleu-kin-1β(IL-1β),IL-10,Toll-like receptor 4(TLR4),nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),transforming growth factor-β(TGF-β),cyclic adenosine monophosphate(cAMP)and norepinephrine(NE)in while adipose tissues were measured using ELISA.Hematoxylin-eosin(HE)staining was performed to observe morpho-logical changes in white adipose tissues.The mRNA levels of nitric oxide synthase 2(NOS2),arginase 1(Arg1),uncou-pling protein 1(UCP1),peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α)and PR domain-containing 16(PRDM16)in white adipose tissues were determine by RT-qPCR.Immunohistochemistry was employed to examine the expression levels of CD86,CD206,C/EBP homologous protein(CHOP),immunoglobulin heavy-chain binding protein(BiP)and UCP1.Western blot analysis was conducted to detect the protein levels of CHOP,BiP,UCP1,α7 nAChR,nu-clear factor-κB(NF-κB)p65,phosphorylated Janus kinase 2(p-JAK2)and phosphorylated signal transducer and activa-tor of transcription 3(p-STAT3)in white adipose tissues.RESULTS:Activation of α7 nAChR with GTS-21,combined with cold-induced thermogenesis,led to decreased levels of TC,TG and FFA in peripheral blood and reduced lipid droplet area in white adipose tissues.Additionally,α7 nAChR activation resulted in decreased expression of TLR4 and NLRP3.In white adipose tissue,there was an increase in Arg1 mRNA level and CD206 expression,while NOS2 mRNA level and CD86 expression decreased.Phosphorylation of the JAK2/STAT3 pathway was up-regulated,and NF-κB p65 level de-creased.The levels of pro-inflammatory cytokines TNF-α and IL-1β were reduced,whereas the levels of anti-inflammatory factors TGF-β and IL-10 increased.Expression of CHOP and BiP also declined.Furthermore,α7 nAChR activation in-creased the mRNA levels of PRDM16 and PGC-1α,as well as UCP1 expression in white adipose tissues.CONCLUSION:Activation of α7 nAChR combined with cold stimulation not only promotes the beiging of white adipose tissue in obese mice,but also alliviates metabolic disorders,thereby enhancing the thermogenic efficiency of white adipose tissue beiging.

AIM:To explore the mechanism by which activation of α7 nicotinic acetylcholine receptor(nAChR)in combination with cold stimulation promotes the beiging of white adipose tissues in obese mice.METHODS:Male C57BL/6J mice,aged 8 weeks,were acclimated for 1 week before fed with high-fat diet(HFD)for 12 weeks to estab-lish an obese model.Fifty mice were randomly divided into 5 groups:control group(low-fat diet),HFD group,model group(HFD+cold stimulation),agonist group(HFD+cold stimulation+α7 nAChR agonist GTS-21),and inhibitor group(HFD+cold stimulation+α7 nAChR inhibitor α-bungarotoxin).Interventions lasted for 4 weeks.Serum levels of total cho-lesterol(TG),triglyceride(TC)and free fatty acid(FFA),and the levels of tumor necrosis factor-α(TNF-α),interleu-kin-1β(IL-1β),IL-10,Toll-like receptor 4(TLR4),nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),transforming growth factor-β(TGF-β),cyclic adenosine monophosphate(cAMP)and norepinephrine(NE)in while adipose tissues were measured using ELISA.Hematoxylin-eosin(HE)staining was performed to observe morpho-logical changes in white adipose tissues.The mRNA levels of nitric oxide synthase 2(NOS2),arginase 1(Arg1),uncou-pling protein 1(UCP1),peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α)and PR domain-containing 16(PRDM16)in white adipose tissues were determine by RT-qPCR.Immunohistochemistry was employed to examine the expression levels of CD86,CD206,C/EBP homologous protein(CHOP),immunoglobulin heavy-chain binding protein(BiP)and UCP1.Western blot analysis was conducted to detect the protein levels of CHOP,BiP,UCP1,α7 nAChR,nu-clear factor-κB(NF-κB)p65,phosphorylated Janus kinase 2(p-JAK2)and phosphorylated signal transducer and activa-tor of transcription 3(p-STAT3)in white adipose tissues.RESULTS:Activation of α7 nAChR with GTS-21,combined with cold-induced thermogenesis,led to decreased levels of TC,TG and FFA in peripheral blood and reduced lipid droplet area in white adipose tissues.Additionally,α7 nAChR activation resulted in decreased expression of TLR4 and NLRP3.In white adipose tissue,there was an increase in Arg1 mRNA level and CD206 expression,while NOS2 mRNA level and CD86 expression decreased.Phosphorylation of the JAK2/STAT3 pathway was up-regulated,and NF-κB p65 level de-creased.The levels of pro-inflammatory cytokines TNF-α and IL-1β were reduced,whereas the levels of anti-inflammatory factors TGF-β and IL-10 increased.Expression of CHOP and BiP also declined.Furthermore,α7 nAChR activation in-creased the mRNA levels of PRDM16 and PGC-1α,as well as UCP1 expression in white adipose tissues.CONCLUSION:Activation of α7 nAChR combined with cold stimulation not only promotes the beiging of white adipose tissue in obese mice,but also alliviates metabolic disorders,thereby enhancing the thermogenic efficiency of white adipose tissue beiging.

Objective To investigate the clinical application value of 3D printing technology in the treatment of complex posterior lateral tibial plateau fractures using the suprafibular approach. Methods A retrospective analysis was conducted on the clinical data of 67 patients with complex posterior lateral tibial plateau fractures treated with the suprafibular approach. Patients were divided into 3D printing group (35 cases) and conventional group (32 cases) based on whether 3D printing simulation surgery was used preoperatively. The operation time, intraoperative blood loss, and intraoperative fluoroscopy frequency were compared between the two groups. Postoperative complications such as incision infection, popliteal vessel injury, and common peroneal nerve injury were observed. Fracture healing time was recorded during follow-up, and Rasmussen scores were evaluated at 6 months postoperatively. The Hospital for Special Surgery (HSS) knee function score was assessed during the final follow-up. Results The follow-up duration for 67 patients was 14 to 22 months. One patient in each group developed postoperative incision infection, and no complications such as popliteal vessel injury, common peroneal nerve injury, or deep venous thrombosis of the lower extremity occurred. The operation time, intraoperative blood loss, and intraoperative fluoroscopy frequency were significantly lower in the 3D printing group than in the conventional group (P < 0.05). There were no significant differences in fracture healing time, Rasmussen scores at 6 months postoperatively, and HSS scores during the final follow-up between the two groups (P>0.05). Conclusion The application of 3D printing technology in the treatment of complex posterior lateral tibial plateau fractures using the suprafibular approach can optimize surgical plans, shorten operation time, and reduce intraoperative blood loss and fluoroscopy frequency.

Objective To construct the medical risk comprehensive assessment system based on big data,and to evaluate its consistency and efficiency.Methods Aiming at the current situation of risk assessment of inpatients,based on the means of big data,the medical natural language processing was used to design a medi-cal risk comprehensive assessment system.The system can automatically capture various data of patients,au-tomatically generate the scores by data mining and machine learning technology and send the risk data to med-ical staff,so as to realize the automation and intellectualization.The randomized controlled analysis was used to conduct the manual scoring and machine scoring for included the score scale.The visual risk matrix diagram was automatically generated by comparing the scoring.Results The Kappa values of the scoring system in the included study of the system were as follows:the Kappa value in Caprini scale(surgery)and Padua scale(internal medicine)was 1.00,NNIS Kappa value was 1.00,Nomogram Kappa value was 0.87,Kappa value in the Morse assessment scale/Hendrich model was 0.83,Braden Kappa value was 0.80,ASA 2023 Kappa was 1.00 and NRS 2002 Kappa value was 0.90.The taking time in the machine scoring all were shorter than those in the manual scoring,and the difference was statistically significant(P＜0.05).Conclusion The risk matrix graph constructed by this system could sharply increase the evaluation efficiency and accuracy,which not only provide the accuracy diagnosis and treatment regimen,but also shorten the hospitalization duration and reduce the medical costs.

Objective To explore the prognostic impact and clinical application value of therapeutic plasma exchange(TPE)intervention timing and liver injury periodization in patients with exertional heat stroke(EHS).Methods Data of 127 EHS patients from the First Medical Center of the General Hospital of the People′s Liberation Army from January 2011 to December 2023 were collected,then divided into the death group and the survival group based on therapeutic outcomes and into 5 stages according to the dynamic changes of ALT,AST,TBIL and DBIL.According to propensity score matching analysis,11 patients in the survival group and 12 patients in the death group were included in the statistical analysis,and 20 of them were treated with TPE.The changes in indicators and clinical outcomes before and after TPE were observed,in order to evaluate the impact of intervention timing on prognosis.Results Among the 23 patients,14 had no liver injury or could progress to the repair phase,resulting in 3 deaths(with the mortality rate of 21.43%),while 9 patients failed to pro-gress to the repair phase,resulting in 9 deaths(with the mortality rate of 100%),with significant differences(P＜0.05).The mortality rate of the first TPE intervention before the third stage of liver injury was 23.08%(3/13),while that of interven-tion after reaching or exceeding the third stage was 85.71%(6/7),and the difference was statistically significant(P＜0.05).Conclusion TPE should be executed actively in EHS patients combined with liver injury before the third phase to lock its pathological and physiological processes,thereby improving prognosis and reducing mortality.

Objective:To observe the effect of early exercise intervention on the corticospinal tract of rats with cerebral infarction.Methods:Eighteen male Sprague-Dawley rats were randomly divided into a sedentary group (SED), a 1 day later exercise group (1D) and a 1 week later exercise group (1W), each of 6. A modified Longa′s method was used to occlude the middle cerebral artery to model a stroke. Rats in the 1D and 1W groups started exercising 1 day and 1 week after the modeling, while those in the sedentary group were placed on a stationary treadmill for 30 minutes every day. Modified neurological severity scores (mNSSs) were used to quantify neurological functioning after 1, 4 and 8 weeks. Magnetic resonance imaging was used to calculate the infarct volume ratio, and diffusion tensor imaging was used to detect the fractional anisotropy ratio (rFA) of the corticospinal tract for correlation with the mNSS scores. The corticospinal cord′s morphology was observed using DTT.Results:After 1 week the average mNSS score of the 1D group was significantly lower than the other two groups′ averages. At 4 weeks the average mNSS scores of both the 1D and the 1W group were significantly lower than the sedentary group′s average. At 8 weeks the 1D group′s average mNSS score was significantly lower than those of the other two groups, while that of the 1W group was significantly lower than the sedentary group′s average. At 1 and 4 weeks after modeling the average infarct volume ratio in the 1D group was significantly lower than those of the other groups. By 4 weeks the average infarct volume ratio of the 1W group was significantly lower than that of the sedentary group, and by 8 weeks the average infarct volume ratios of both the 1D and 1W groups was significantly lower than that of the sedentary group. After 1 week the average rFA of the 1D group was significantly lower than that of the sedentary group, but by 4 weeks the averages of the 1D group and the 1W group were both significantly higher than the sedentary group′s average. At 8 weeks the 1D group′s average rFA was significantly above that of the 1W group and of the sedentary group, and that of the 1W group was significantly higher than that of the sedentary group. After 8 weeks the corticospinal tracts in the 1D group appeared to be more symmetrical than those of the other 2 groups. The rFA results correlated strongly with the mNSS scores ( r=-0.707). Conclusions:Exercise can promote corticospinal cord remodeling and improve neurological function after cerebral infarction, at least in rats. It should be started as early as possible.

Objective To analyze the clinical manifestations and gene mutations of rare causes of primary adrenal insufficiency (PAI) in childhood.Methods The clinical features,laboratory tests and gene mutation of 13 patients with PAI in our hospital from September 2010 to August 2017 were analyzed retrospectively.Patients with congenital adrenal hyperplasia,X-linked adrenoleukodystrophy with neurological onset or a clear family history,and autoimmune adrenal insufficiency were excluded.Results The median age of 13 cases (12 males,1 female) was 3 years and 10 months.Medical history or clinical manifestations on the first visit included hyperpigmentation,electrolyte imbalance/salt-wasting crisis,gastrointestinal symptoms,and fatigue,etc.All developments of external genitalia were normal.All cases presented with decreased serum cortisol and increased ACTH levels.Some of the cases showed decreased aldosterone level and plasma renin activity,while 17α-hydroxyprogesterone,testosterone,and androstenedione were in the normal range.Part of cases revealed delayed bone age and adrenal atrophy.Three gene mutations were detected in 13 patients,including NR0B 1 gene (9/13),ABCD 1 gene (3/13),and CYP 11A 1 gene (1/13).NR0B1,and ABCD1 gene mutations were pathogenic mutations,consistent with clinical characteristics.CYP11A1 gene mutation was heterozygote,which cannot fully explain the clinical features.Conclusion PAI in childhood presents common clinical manifestations of adrenal insufficiency,e.g.hyperpigmentation and electrolyte imbalance/sah-wasting crisis,but without specificity.Gene mutational analysis is necessary for precise diagnosis and prognosis estimation.NR0B1 and ABCD1 gene mutations were common in childhood with rare causes of PAI.