Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Objective:To investigate the distribution of pathological types of unilateral primary aldosteronism, and to explore the clinical characteristics and prognosis of patients with different pathological types.Methods:A total of 241 patients with unilateral primary aldosteronism who underwent adrenal surgery were included in this study. The clinical data and postoperative follow-up data were collected, and the postoperative tissue sections were stained with HE and aldosterone synthase. According to the staining results, pathological types of 241 patients were classified, and the clinical characteristics and surgical prognosis of patients with unilateral primary aldosteronism were compared.Results:According to the international histopathology consensus for unilateral primary aldosteronism, among 241 patients with unilateral primary aldosteronism, 223 were classical(92.5%), 17 were non-classical(7.1%), and 1 was aldosterone producing carcinoma(0.4%). Among classical cases, 189 were aldosterone producing adenoma and 34 were aldosterone producing nodule. In the non-classical cases, 8 cases were multiple aldosterone producing nodule and 9 cases were multiple aldosterone producing nodule. Compared with the classical group, the non-classical group had a longer duration of hypertension(9.0 vs 5.0 years, P=0.062) and a lower baseline plasma aldosterone concentration(273 vs 305 pg/mL, P=0.147), but the difference was not significant. There was no significant difference between the two groups in the proportion of patients who achieved a complete biochemical response after surgery(98% vs 92.3%, P=0.281), but the proportion of patients who achieved a complete clinical response was significantly lower in the non-classical group(23.1% vs 52.9%, P=0.046). Conclusion:The pathological types of unilateral primary aldosteronism are predominantly classical, with aldosterone-producing adenoma being the most common. There were no significant differences in the clinical characteristics and postoperative biochemical remission rates between classical and non-classical patients, but the clinical prognosis of the latter was inferior to the former.

Objective:To evaluate postoperative biochemical and clinical remission rates in patients with unilateral primary aldosteronism and analyze related influencing factors.Methods:A total of 406 patients of primary aldosteronism with confirmed subtyping, who underwent adrenalectomy and completed follow-up in the Department of Endocrinology of the First Affiliated Hospital of Chongqing Medical University from November 2013 to March 2022 were retrospectively enrolled. Clinical and biochemical data were recorded. Postoperative clinical and biochemical outcomes were assessed according to Primary Aldosteronism Surgery Outcome(PASO) consensus.Results:Complete biochemical success was achieved in 391(96.31%) of 406 primary aldosteronism patients, while partial and absent biochemical success in only 4(0.99%) and 11(2.71%) primary aldosteronism patients; Complete clinical success was seen in 217(53.45%) patients, and partial clinical success in 189(46.55%) patients. Compared to the partial clinical success group, the complete clinical success group was younger, had a greater proportion of women, a smaller body mass index, a shorter duration of hypertension, a smaller daily defined dose value for antihypertensive medication, a higher estimated glomerular filtration rate(eGFR), and a lower proportion of family history of hypertension and diabetes mellitus. Multifactorial logistic regression analysis further showed that gender( OR=2.49, 95% CI 1.42-4.35, P=0.001), body mass index( OR=1.16, 95% CI 1.05-1.28, P=0.003), antihypertensive drug daily defined dose( OR=1.83, 95% CI 1.37-2.44, P<0.001), family history of hypertension( OR=2.16, 95% CI 1.22-3.83, P=0.008), history of diabetes( OR=2.47, 95% CI 1.15-5.29, P=0.021), and eGFR( OR=0.98, 95% CI 0.97-0.99, P=0.001) were independent factors influencing clinical prognosis of primary aldosteronism. Conclusion:The postoperative complete biochemical success is higher in patients with unilateral primary aldosteronism, but only about half of all patients achieve complete clinical success.

Objective:To investigate the appropriate cut-off for diagnosis of primary aldosteronism (PA) by seated saline suppression test (SSST) based on liquid chromatography with tandem mass spectrometry (LC-MS/MS).Methods:In this cross-sectional study, patients who underwent SSST for suspected PA in the First Affiliated Hospital of Chongqing Medical University from January 2018 to March 2022 were evaluated. Briefly, 300 patients with PA and 119 with essential hypertension (EH) were included. Plasma aldosterone concentration (PAC) after SSST was determined by LC-MS/MS. Primary aldosteronism confirmatory testing (PACT) score was used as the reference standard for diagnosis of PA, and receiver operating characteristic (ROC) curve was used to explore the cut-off value.Results:The average age of the PA group was (50.8±10.5) years, and males accounted for 53.00% ( n=159); the average age of the EH group was (49.4±11.2) years, and males accounted for 26.89% ( n=32). The area under the ROC curve of PAC post-SSST was 0.819 (95% CI 0.775-0.862). When 40 pg/ml (110.8 pmol/L) was selected as the appropriate cut-off for diagnosis of PA, the sensitivity was 83.67% (95% CI 78.88%-87.56%) and specificity was 60.50% (95% CI 51.10%-69.21%). Thus, 95.09% (155/163) of patients with unilateral PA could be identified. Conclusion:PAC after SSST determined by LC-MS/MS has high efficacy for diagnosis of PA, and 40 pg/ml is recommended as the appropriate cut-off value.

Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe complications.Despite surgery being the primary treatment,the recurrence rate remains high.Therefore,exploring the molecular mechanisms underlying cholesteatoma is crucial for discovering new therapeutic approaches.This study aims to explore the involvement of N6-methyladenosine(m6A)methylation in long non-coding RNAs(lncRNAs)in the biological functions and related pathways of middle ear cholesteatoma. Methods:The m6A modification patterns of lncRNA in middle ear cholesteatoma tissues(n=5)and normal post-auricular skin tissues(n=5)were analyzed using an lncRNA m6A transcriptome microarray.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to identify potential biological functions and signaling pathways involved in the pathogenesis of middle ear cholesteatoma.Methylated RNA immunoprecipitation(MeRIP)-PCR was used to validate the m6A modifications in cholesteatoma and normal skin tissues. Results:Compared with normal skin tissues,1 525 lncRNAs were differentially methylated in middle ear cholesteatoma tissues,with 1 048 showing hypermethylation and 477 showing hypomethylation[fold change(FC)≥3 or<1/3,P<0.05].GO enrichment analysis indicated that hypermethylated lncRNAs were involved in protein phosphatase inhibitor activity,neuron-neuron synapse,and regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor activity.Hypomethylated lncRNAs were associated with mRNA methyltransferase activity,secretory granule membrane,and mRNA methylation.KEGG analysis revealed that hypermethylated lncRNAs were mainly associated with 5 pathways:the Hedgehog signaling pathway,viral protein interaction with cytokines and cytokine receptors,mitogen-activated protein kinase(MAPK)signaling pathway,cytokine-cytokine receptor interaction,and adrenergic signaling in cardiomyocytes.Hypomethylated lncRNAs were mainly involved in 4 pathways:Renal cell carcinoma,tumor necrosis factor signaling pathway,transcriptional misregulation in cancer,and cytokine-cytokine receptor interaction.Additionally,MeRIP-PCR confirmed the changes in m6A methylation levels in NR_033339,NR_122111,NR_130744,and NR_026800,consistent with microarray analysis.Real-time PCR also confirmed the significant upregulation of MAPK1 and NF-κB,key genes in the MAPK signaling pathway. Conclusion:This study reveals the m6A modification patterns of lncRNAs in middle ear cholesteatoma,suggests a direction for further research into the role of lncRNA m6A modification in the etiology of cholesteatoma.The findings provide potential therapeutic targets for the treatment of middle ear cholesteatoma.

Objective:To investigate the impact of body mass index (BMI) on delayed extubation of patients with acute Stanford type A aortic dissection (ATAAD).Methods:A total of 400 ATAAD patients who were admitted to our hospital from October 2021 to October 2023 and underwent surgical treatment were selected as the research objects. According to BMI, they were divided into obese group (BMI≥28 kg/m 2, 119 cases) and non-obese group (BMI<28 kg/m 2, 281 cases). The differences of preoperative clinical characteristics, intraoperative and postoperative data between the two groups were compared. Starting from transferring to the ICU and ending with the first successful extubation, The risk factors of postoperative invasive mechanical ventilation time ≥ 48 h in ATAAD patients were analyzed, and the predictive efficacy of related factors for postoperative invasive mechanical ventilation time ≥ 48 h in ATAAD patients was evaluated. Results:Compared with the non-obese group, the proportion of hypertension, diabetes, admission heart rate, admission systolic blood pressure, admission diastolic blood pressure and preoperative white blood cell count in the obese group were significantly increased, and the differences were statistically significant ( P<0.05). The cardiopulmonary bypass time, aortic cross-clamp time, operation time, red blood cell transfusion volume, invasive mechanical ventilation time, secondary operation rate and total hospitalization cost in the obese group were significantly higher than those in the non-obese group, and the differences were statistically significant ( P<0.05). Univariate logistic regression analysis showed that BMI, cardiopulmonary bypass time, ascending aortic cross-clamp time, operation time, age, hypertension, and red blood cell transfusion were related factors for postoperative invasive mechanical ventilation time ≥48 h in ATAAD patients ( P<0.05). Logistic multivariate regression analysis showed that increased BMI ( OR=1.213, P<0.05) and increased age ( OR=1.020, P<0.05) were independent risk predictors of postoperative invasive mechanical ventilation time≥48 h in ATAAD patients. Receiver operating characteristic curve ( ROC) analysis showed that the area under the ROC curve ( AUC) of BMI for predicting the duration of postoperative invasive mechanical ventilation in ATAAD patients≥48 h was 0.682 ( P<0.05), and the best predictive cut-off value was 25.64 kg/m 2. Conclusion:BMI≥28kg/m 2 increases the difficulty of surgery and the duration of invasive mechanical ventilation in ATAAD patients. BMI has a high predictive value for the duration of invasive mechanical ventilation in ATAAD patients after surgery ≥48 h, and effective intervention measures can be formulated to improve the treatment effect of patients.

Neuroglia ; Brain ; Biology

Objective: To analyze the spatial temporal distribution characteristics of tuberculosis among high school students at county levels in Gansu Province from 2018 to 2022,so as to provide a scientific basis for tuberculosis prevention and control in schools. Methods: Tuberculosis data from high school students in counties (districts) reported in Gansu Province from 2018 to 2022 was collected from the Tuberculosis Information Management System and Infectious Disease Information Reporting System of the Chinese Disease Prevention and Control Information Management System. Demographic data of high school students in counties (districts) came from the General Management System of the Chinese Disease Prevention and Control Information Management System, and the spatial clustering of the reported incidence rate of pulmonary tuberculosis among high school students in Gansu Province in the past five years was analyzed using the methods of global spatial autocorrelation (Moran s I) and local indicators of spatial audocorrelation(LISA). Results: A total of 41 885 pulmonary tuberculosis cases were reported in various counties of Gansu Province From 2018 to 2022, with an average reported incidence rate of 32.81/100 000. During the same period, 1 170 high school students cases were reported, with an average reported incidence rate of 13.72/100 000. With the exception of 2020, the reported incidence rate of pulmonary tuberculosis among high school students was non random distribution in other 4 years, showed a moderate intensity of spatial clustering. From 2018 to 2022, most counties in Gansu Province reported that the incidence rate of pulmonary tuberculosis among high school students was 10.00/100 000 or below, the counties with reported incidence rate >40.00/100 000 were mainly distributed in Luqu County, Maqu County, Diebu County, Hezuo City, Xiahe County of Gannan Prefecture, Gangu County and Wushan County of Tianshui Prefecture, Wenxian County and Kangxian County of Longnan Prefecture, Huachi County of Pingliang Prefecture, Huanxian County of Qingyang Prefecture. The number of counties where the reported incidence rate of tuberculosis among high school students more than 30.00/100 000 gradually decreased from 2018 to 2022. In the past five years, the reported incidence rate of tuberculosis among high school students in all counties of Gannan Prefecture remained above 40.00/ 100 000 . The LISA analysis results showed that the high incidence areas were mainly concentrated in Gannan Prefecture. Conclusions The epidemic situation of pulmonary tuberculosis among high school students in Gansu province from 2018 to 2022 is still a serious condition, showing the characteristics of unbalanced regional distribution. The reported incidence rate shows a strong spatial clustering, and the hot spots are concentrated in the counties (districts) of Gannan prefecture in Gansu Province.

Objective:To investigate the mechanism of cyclic AMP receptor protein (CRP) in regulating the siderophore enterobactin-related gene entC of carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods:A mutant strain with crp gene deletion strain (Δ crp) and a complementary strain (c-Δ crp) were constructed using CRKP-27 as the wild-type strain. The influence of CRP on the secretion of siderophore by CRKP was analyzed by chrome azurol sulfonate (CAS) quantitative assay. RT-qPCR and lacZ reporter gene fusion assay were used to detect the regulatory effect of CRP on entC gene expression and its promoter. Electric mobility shift assay (EMSA) was performed to detect the binding of CRP to the entC promoter region and the binding sequence was analyzed by DNase Ⅰ footprinting assay. Results:The Δ crp and c-Δ crp strains were successfully constructed. Compared with the wild-type and c-Δ crp strains, the Δ crp strain could secrete more siderophore under both normal and iron-deficient conditions, but the difference was statistically significant only under normal condition ( P<0.05). The relative expression of entC gene at mRNA level was significantly lower in the Δ crp strain than that in the wild-type and c-Δ crp strains under both normal and iron-deficient conditions (both P<0.05). The promoter of entC gene in the Δ crp strain was less active than that in the wild-type and c-Δ crp strains under both normal and iron-deficient conditions (both P<0.05). EMSA showed that with the increase of CRP protein, the distance of entC probe from the positive pole was shortened and blocked. DNase Ⅰ footprinting assay further identified the specific binding site of the entC promoter region to CRP as 5′-AAGGTGATAAATGCGTCTCATTTTCAA-3′. Conclusions:The CRP protein in CRKP could specifically bind to the entC promoter region and directly promote its expression at transcriptional level.

Objective:To discuss the value of pubo-femoral distance(PFD) in the diagnosis of infants with developmental dysplasia of the hip(DDH).Methods:Nine hundred and thirty-one infants with DDH and normal infants diagnosed by clinical examination and ultrasonography were involved from February 2022 to June 2023 in Beijing Jishuitan Hospital. The ultrasonographic examination included Graf method and pubo-femoral distance measurement. Statistical analysis was made on the measurements of PFD of different types of hips.Results:Among all the hips, 1 359 hips were Graf type Ⅰ, 274 hips were Graf type Ⅱa, 166 hips were Graf type Ⅱb, 31 hips were Graf type Ⅱc, 7 hips were Graf type D, 13 hips were Graf type Ⅲ, and 12 hips were Graf type Ⅳ. The PFD of these hips were (0.34±0.07)cm, (0.35±0.08)cm, (0.35±0.08)cm, (0.51±0.11)cm, (0.67±0.09)cm, (0.95±0.26)cm, (1.27±0.30)cm, respectively. There was no significant difference in PFD between hips of Graf Ⅰ, Graf Ⅱa and Graf Ⅱb ( P>0.05), but there was significant difference in PFD between hips of the other Graf types ( P<0.05). The area under curve(AUC) of the PFD for the diagnosis of stability of the hips in infants was 0.959 with the cut-off value of 0.435 cm, the sensitivity and specificity were 88.9% and 90.4%, respectively. Conclusions:The PFD has great value in the evaluation of the stability of hip joint, and the cut-off value is 0.435 cm.