This study investigated the role of the nuclear factor of activated T cells c3 (NFATc3) in vascular smooth muscle cells (VSMCs) during aortic aneurysm and dissection (AAD) progression and the underlying molecular mechanisms. Cytoplasmic and nuclear NFATc3 levels were elevated in human and mouse AAD. VSMC-NFATc3 deletion reduced thoracic AAD (TAAD) and abdominal aortic aneurysm (AAA) progression in mice, contrary to VSMC-NFATc3 overexpression. VSMC-NFATc3 deletion reduced extracellular matrix (ECM) degradation and maintained the VSMC contractile phenotype. Nuclear NFATc3 targeted and transcriptionally upregulated matrix metalloproteinase 9 (MMP9) and MMP2, promoting ECM degradation and AAD development. NFATc3 promoted VSMC phenotypic switching by binding to eukaryotic elongation factor 2 (eEF2) and inhibiting its phosphorylation in the VSMC cytoplasm. Restoring eEF2 reversed the beneficial effects in VSMC-specific NFATc3-knockout mice. Cabamiquine-targets eEF2 and inhibits protein synthesis-inhibited AAD development and progression in VSMC-NFATc3-overexpressing mice. VSMC-NFATc3 promoted VSMC switch and ECM degradation while exacerbating AAD development, making it a novel potential therapeutic target for preventing and treating AAD.

Objective:To study the prognosis of congenital bile duct cysts following cyst resection, and to analyze the risk factors associated with the development of postoperative biliary calculus.Methods:Clinical data of 149 patients with congenital bile duct cysts undergoing surgery in the First Affiliated Hospital of Nanjing Medical University from May 2004 to January 2022 were retrospectively analyzed, including 59 males and 90 females, with a median age of 32 (21, 47) years old. Patients were divided into two groups: the stone group ( n=51, biliary calculus occurred during the follow-ups after surgery) and non-stone group ( n=98). Clinical data such as gender, age, medical history, cyst type, biliary calculus, anastomotic stenosis and occurrence of cancer were compared. All patients were followed up via telephone consultations. A logistic regression analysis was used to identify the risk factors associated with the occurrence of biliary calculus after surgery. Results:The duration of the follow-ups was 120 (24, 211) months. The observed incidence of postoperative biliary calculus, anastomotic stricture, and cancer in the patients were 34.2% (51/149), 8.7% (13/149), and 4.7% (7/149), respectively. The logistic regression analysis indicated that incomplete cyst resection ( OR=3.332, 95% CI: 1.221-9.094) and postoperative anastomotic stenosis ( OR=13.300, 95% CI: 2.586-68.401) were associated with a higher risk of biliary calculus formation after cystectomy (all P<0.05). Conclusion:Patients with congenital bile duct cysts suffer a high risk of biliary calculus formation after cystectomy. The residual cyst and postoperative anastomotic stenosis are independent risk factors for biliary calculus after surgery.

Objective:To examine the correlation between serum Klotho levels and frailty in elderly people.Methods:In this cross-sectional study, 150 community-dwelling elderly people aged 65 years and over were enrolled.Subjects were divided into a frail(n=50, 33.3%), a pre-frail(n=47, 31.3%)and a non-frail(n=53, 35.3%)group based on the Fried phenotype.General participant data, routine laboratory test results, short physical performance battery(SPPB)results and human body composition data were collected.Serum Klotho protein levels were measured by an enzyme-linked immunosorbent assay.The relationship between serum Klotho protein levels and frailty was analyzed by using Spearmen's correlation analysis and Logistic regression analysis.Results:Klotho protein levels were lower in the frail group than in the non-frail group( P=0.001), whereas differences between the frail group and the pre-frail group and between the pre-frail group and the non-frail group were not statistically significant(all P>0.05).When Klotho protein levels were classified into four quartiles, i.e., Q 1, Q 2, Q 3, and Q 4, using three cut-off vales(2.28, 3.52, and 5.09 mg/L), the prevalences of frailty were 51.4%(19/37), 39.5%(15/38), 24.3%(9/37)and 18.4%(7/38), respectively.The prevalence of frailty decreased with increasing Klotho protein levels( χ2=11.204, P=0.011).Spearman correlation analysis showed that the Klotho protein level was negatively correlated with frailty( r=-0.310, P<0.001).Multivariate Logistic regression analysis results showed that age( OR=1.109, 95% CI: 1.011-1.217, P=0.028)and sarcopenia( OR=6.511, 95% CI: 1.279-33.147, P=0.024)were risk factors for frailty, while walking( OR=0.104, 95% CI: 0.033-0.326, P<0.001), a high SPPB score( OR=0.780, 95% CI: 0.627-0.970, P=0.026), and a high Klotho protein level( OR=0.752, 95% CI: 0.581-0.974, P=0.031)were protective factors against frailty. Conclusions:The serum Klotho protein level may be used as a parameter for the assessment of frailty.It is negatively correlated with frailty, suggesting that elderly people with low serum Klotho protein levels are at high risk of developing frailty.

Increased intestinal barrier permeability, leaky gut, has been reported in patients with autism. However, its contribution to the development of autism has not been determined. We selected dextran sulfate sodium (DSS) to disrupt and metformin to repair the intestinal barrier in BTBR T⁺tf/J autistic mice to test this hypothesis. DSS treatment resulted in a decreased affinity for social proximity; however, autistic behaviors in mice were improved after the administration of metformin. We found an increased affinity for social proximity/social memory and decreased repetitive and anxiety-related behaviors. The concentration of lipopolysaccharides in blood decreased after the administration of metformin. The expression levels of the key molecules in the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa B (NF-κB) pathway and their downstream inflammatory cytokines in the cerebral cortex were both repressed. Thus, "leaky gut" could be a trigger for the development of autism via activation of the lipopolysaccharide-mediated TLR4-MyD88-NF-κB pathway.
Mice ; Animals ; NF-kappa B ; Myeloid Differentiation Factor 88/metabolism* ; Lipopolysaccharides/pharmacology* ; Toll-Like Receptor 4/metabolism* ; Autistic Disorder/metabolism* ; Signal Transduction/physiology*

Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types. Tumor-associated macrophages (TAMs) play a key role in promoting tumor malignant progression and therapy resistance. However, the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic. This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo. TAMs have been found to suppress cervical cancer cells ferroptosis. Mechanistically, macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells. In cancer cells, miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis. Moreover, the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway. Importantly, in clinical cervical cancer cases, ALOX15 is negatively associated with macrophages infiltration, which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer. Moreover, both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer. Altogether, this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

Objective:To construct a scientifically standardized and promotable pneumonia prevention and nursing plan for acute stroke patients to guide clinical nursing practice.Methods:According to the evidence-based retrieval strategy, we systematically searched the domestic and foreign clinical decision support system, guideline networks, professional association websites and relevant databases. All databases were searched from January 2012 to November 2022. A preliminary pneumonia prevention and nursing plan for acute stroke patients was formulated after literature quality evaluation, evidence extraction, evidence integration and evaluation. The plan was further revised and improved through three rounds of Delphi expert consultation.Results:In the three rounds of expert consultation, the enthusiasm of experts was 100.0%, 100.0%, 83.3%, the authority coefficient of experts were 0.967, 0.967, 0.937, the coefficient of variation were 0.048 to 0.363, 0 to 0.177, 0 to 0.144, and the Kendal harmony coefficient were 0.221, 0.139, 0.339 ( P<0.001) . The final nursing plan included 8 modules, including pneumonia risk prediction, general nursing, swallowing and dietary management, airway management, oral management, position and exercise, condition observation, and health education, with a total of 30 items. Conclusions:The evidence and Delphi method based pneumonia prevention and nursing plan for acute stroke patients is scientific, reliable and applicable, which can provide a basis for nursing practice.

Genome-wide association studies (GWASs) are the most widely used method to identify genetic risk loci associated with orofacial clefts (OFC). However, despite the increasing size of cohort, GWASs are still insufficient to detect all the heritability, suggesting there are more associations under the current stringent statistical threshold. In this study, we obtained an integrated epigenomic dataset based on the chromatin conformation of a human oral epithelial cell line (HIOEC) using RNA-seq, ATAC-seq, H3K27ac ChIP-seq, and DLO Hi-C. Presumably, this epigenomic dataset could reveal the missing functional variants located in the oral epithelial cell active enhancers/promoters along with their risk target genes, despite relatively less-stringent statistical association with OFC. Taken a non-syndromic cleft palate only (NSCPO) GWAS data of the Chinese Han population as an example, 3664 SNPs that cannot reach the strict significance threshold were subjected to this functional identification pipeline. In total, 254 potential risk SNPs residing in active cis-regulatory elements interacting with 1 718 promoters of oral epithelium-expressed genes were screened. Gapped k-mer machine learning based on enhancers interacting with epithelium-expressed genes along with in vivo and in vitro reporter assays were employed as functional validation. Among all the potential SNPs, we chose and confirmed that the risk alleles of rs560789 and rs174570 reduced the epithelial-specific enhancer activity by preventing the binding of transcription factors related to epithelial development. In summary, we established chromatin conformation datasets of human oral epithelial cells and provided a framework for testing and understanding how regulatory variants impart risk for clefts.
Chromatin ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Epithelium ; Genome-Wide Association Study ; Humans

Objective:To explore the curative effect of surgical treatment for Crohn′s disease (CD), to investigate the timing of surgical intervention and the choice of surgical methods.Methods:From January 1, 2016 to August 31, 2020, at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, the clinical data of 123 patients with CD and receiving surgical treatment were retrospectively analyzed, which included the type of lesion, the location of lesion, clinical manifestation, surgical method, preoperative inflammatory and nutritional indicators, postoperative recovery of digestive tract function, and the development and treatment of postoperative complications. CD was diagnosed according to Consensus opinion on diagnosis and treatment of inflammatory bowel disease ( Beijing 2018). Patient was classitied according to the Montreal Classification. Postoperative complications were graded according to the Clavien-Dindo Criteria. Mann-Whitney U test was used for statistical analysis. Results:Among 123 patients, according to the Montreal classification, two cases (1.6%) were diagnosed at ≤16 years old (type A1), 66 cases (53.7%) were diagnosed at 17 to 40 years old (type A2), and 55 cases (44.7%) were diagnosed at >40 years old (type A3). The lesions were 52 cases (42.3%) of terminal ileum (L1) type, 20 cases (16.3%) of colon (L2) type, and 51 cases (41.5%) of ileocolon (L3) type. Four cases (3.2%) were non-stenosis and non-penetrating (B1) type, 87 cases (70.7%) were stenosis (B2) type, and 32 cases (26.0%) were penetrating (B3) type. Eighteen patients (14.6%) underwent emergency surgery due to complete intestinal obstruction (10 cases), gastrointestinal perforation (five cases), gastrointestinal bleeding (two cases), and rectovesical fistula complicated with septic shock (one case). One hundred and five patients (85.4%) received selective surgery due to poor conservative treatment effects. 51 cases (41.5%) underwent traditional open surgery and 72 cases (58.5%) underwent laparoscopic surgery. Nineteen patients (15.4%) received temporary or permanent ostomy. The preoperative C reactive protein level of patients with emergency surgery was higher than that of patients undergoing selective surgery ((39.23±24.13) mg/L vs. (11.48±2.68) mg/L), while the levels of plasma albumin (ALB) and pre-ALB were lower than those of patients receiving selective surgery ((29.90±10.60) g/L vs. (38.38±8.30) g/L, (146.00±125.49) mg/L vs. (209.06±61.19) mg/L), and the differences were statistically significant ( Z=9.603, 8.754 and 7.111, all P<0.01). During the follow-up, a total of 23 cases (18.7%) developed postoperative complications, including one case of postoperative intra-abdominal hemorrhage and underwent re-operation (Clavien-Dindo grade Ⅲ complication); four cases of anastomotic leakage after operation; six cases of postoperative paralytic ileus; 11 cases of surgical site infection, all of which were Clavien-Dindo grade Ⅱ complications, and one case of deep venous thrombosis of lower extremity. No patient with severe intraoperative complication was observed, and no patients died during the operation or hospitalization. The postoperative exhaust time of patients was (3.2±1.4) d, the time of open fluid diet was (5.8±0.8) d, the length of hospital stay was (18.0±14.1) d, and the length of postoperative hospital stay was (11.2±8.8) d. Conclusions:The concept of multidisciplinary collaboration should be emphasized in the treatment of CD. Surgical treatment can effectively control the complications and improve the quality of life of patients, but the timing of operation and the choice of surgical methods should be decided prudently after perioperative treatment, multi-disciplinary participated and regulation of the internal environment. The standardized and targeted treatments for the surgical difficulties of inflammatory bowel disease should be conducted.

Objective:To investigate the status of monotherapy for newly diagnosed tic disorders and its comorbidity in children, so as to provide a reference for clinical medication.Methods:A questionnaire survey was conducted to collect the application experience of monotherapy for newly diagnosed tic disorders and comorbidities in 110 pediatric neurologists and psychiatrists from Chinese Tic Disorders Study Consortium from February to August in 2019. Doctors were asked to rate treatment options based on a rank 5-point scale with "1" least appropriate and "5" most appropriate. The drug evaluation index was based on the comparison of the median score of a single drug with the overall scores of all drugs in this disease ( M( Q1, Q3)), single drug M≥ overall Q3 was recommended as preferred drugs; overall Q1≤ single drug M< overall Q3 was considered as secondary drugs; single drug M< overall Q1 was considered as unsuitable drugs. Results:Among 110 electronic questionnaires, 94 (86%) were availably responded, responding doctors included 37 (39%) males and 57 (61%) females, the age of responding doctors was (48±10) years, and their working year was (17±10) years. In the investigation of the first and second monotherapy for newly diagnosed tic disorders in children without comorbidities, there were no preferred drugs for mild transient tic disorders. The scores of clonidine, aripiprazole and tiapride were 4 (3, 4), 4 (3, 4), 4 (4, 5) scores respectively, and were greater than overall scores (3 (2, 4) scores), so they could be recommended as the preferred drugs for moderate chronic tic disorders, the recommendation for initial mild Tourette syndrome (TS) treatment was the same as preferred drugs for moderate chronic tic disorders. Similarly, clonidine, aripiprazole, tiapride and haloperidol could be recommended as the preferred drugs for other kinds of tic disorders. As for the second monotherapy, the preferred drugs for moderate transient tic disorders, mild chronic tic disorders and severe TS were all aripiprazole, tiapride, haloperidol, sulpiride, clonidine and topiramate. While clonidine, aripiprazole, tiapride could be considered as preferred drugs for severe transient tic disorders, moderate to severe chronic tic disorders and mild to moderate tic disorders. In the investigation of monotherapy for newly diagnosed tic disorders in children with comorbidities, for moderate chronic tic disorders and TS comorbid with obsessive-compulsive disorder, aripiprazole (4 (3, 5) scores) and sertraline (4 (3, 4) scores) were preferred drugs,the median scores of which were all greater than overall scores (3 (3, 4) scores), they were also the preferred treatment for severe transient tic disorders and mild chronic tic disorders. For mild and moderate transient tic disorders, severe chronic tic disorders and TS comorbid with obsessive-compulsive disorder, aripiprazole, fluvoxamine, fluoxetine, haloperidol and sertraline were preferred drugs. When comorbid with attention deficit hyperactivity disorder (ADHD), severe transient tic disorders, moderate chronic tic disorders and TS, tomoxetine and clonidine were recommended as preferred drugs (both 4 (4, 5) scores), and tomoxetine and clonidine were also the preferred treatment for severe TS. For severe chronic tic disorders comorbid with ADHD, clonidine (5(4, 5) scores) was preferred drug, greater than overall scores (4 (3, 5) scores), while for mild and moderate transient tic disorders clonidine, tomoxetine, guanidine and methylphenidate were recommended as preferred drugs. For mild chronic tic disorders and TS comorbid with ADHD tomoxetine was preferred drug. When comorbid with sleep disorders, there were no preferred drugs for mild transient tic disorders; estazolam (3 (2, 3) scores) was the preferred drug for mild chronic tic disorders and TS comorbid with sleep disorders. For othe kind of tic disorders comorbid with sleep disorders, estazolam, melatonin and clonazepam were preferred drugs. When comorbid with anxiety and depressive disorders, for all kinds of tic disorders sertraline was recommended as preferred drugs, the median scores of sertraline were all (4 (3, 5) scores) in severe transient tic disorders, moderate to severe chronic tic disorders and moderate TS, and greater than overall scores (3 (3, 4) scores). While severe chronic tic disorders comorbid with anxiety and depressive disorders, fluvoxamine could also be chosen as preferred drugs.Conclusions:Drug therapy is not recommended for mild transient tic disorders, while tiapride, aripiprazole, clonidine, and haloperidol are mainly preferred drugs for the other kinds of tic disorders. Corresponding drugs should be selected when tic disorders are combined with obsessive-compulsive disorder, ADHD, sleep disorders, anxiety, depression, etc.