Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence.

PURPOSE: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. METHODS: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. RESULTS: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine ß hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient. CONCLUSION: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.

The roles of mutated SPINK1 gene in prostate cancer cells.

SPINK1-positive prostate cancer (PCa) has been identified as an aggressive PCa subtype. However, there is a lack of definite studies to elucidate the underlying mechanism of the loss of SPINK1 expression in most PCa cells except 22Rv1 cells, which are derived from a human prostatic carcinoma xenograft, CWR22R. The aim of this study was to investigate the mechanisms of SPINK1 protein positive/negative expression and its biological roles in PCa cell lines. SPINK1 mRNA was highly expressed in 22Rv1 cells compared with LNCaP, C4-2B, DU145, and PC-3 cells, and the protein was only detected in 22Rv1 cells. Among these cell lines, the wild-type SPINK1 coding sequence was only found in 22Rv1 cells, and two mutation sites, the c.194G>A missense mutation and the c.210T>C synonymous mutation, were found in other cell lines. Our further research showed that the mutations were associated with a reduction in SPINK1 mRNA and protein levels. Functional experiments indicated that SPINK1 promoted PC-3 cell proliferation, migration, and invasion, while knockdown of SPINK1 attenuated 22Rv1 cell proliferation, migration, and invasion. The wild-type SPINK1 gene can promote the malignant behaviors of cells more than the mutated ones. Cell cycle analysis by flow cytometry showed that SPINK1 decreased the percentage of cells in the G0/G1 phase and increased the percentage of S phase cells. We demonstrated that the c.194G>A and c.210T>C mutations in the SPINK1 gene decreased the mRNA and protein levels. The wild-type SPINK1 gene is related to aggressive biological behaviors of PCa cells and may be a potential therapeutic target for PCa.

Diagnosis and genetic analysis of a case with mandibuloacral dysplasia type B due to compound heterozygous mutations of the ZMPSTE24 gene.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, mainly caused by pathogenic variants of the LMNA and ZMPSTE24 genes. In this study, we reported the first case of a patient with type B cranial and mandibular dysplasia in China. The patient presented with distinctive facial features, feeding difficulties, significant physical retardation, and overall developmental delay with abnormal tooth and bone development. Trio-whole exome sequencing analysis showed that the patient carried compound heterozygous mutations of c.743C>T (p.Pro248Leu) (dbSNP: rs121908095) and the loss of exons 1-10 of the ZMPSTE24 gene. Sanger sequencing and real-time quantitative PCR (RT-qPCR) showed that these two mutations were inherited from the patient's phenotypically normal mother and father, respectively. By summarizing and analyzing the characteristics of this case and the pedigree of the family, we suggested that trio-whole-exome sequencing could be performed to assist in the diagnosis of diseases that are difficult to be diagnosed definitively based on clinical phenotypes. The publication of this case has improved clinicians' understanding of MAD disease and provide new clinical information for the subsequent genetic study of this disease.

Clinical characteristics and risk factors of nonalcoholic fatty liver disease in children with obesity.

BACKGROUND: With the increasing number of children with obesity worldwide, nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease among children. It is necessary to recognize the risk factors of NAFLD for prevention in childhood since NAFLD is asymptomatic in the early stage. OBJECTIVES: The objective of this study was to investigate possible risk factors of NAFLD in children with obesity, providing evidence for monitoring and prevention strategies at an early stage for obese children with NAFLD. METHODS: Data were collected from 428 children and adolescents aged 6-16 years recruited from the Children's Hospital at Nanjing Medical University from September 2015 to April 2018 and analyzed. Based on a combination of ultrasound results and alanine transaminase levels, subjects were divided into three groups: simple obesity (SOB), simple steatosis (SS), and nonalcoholic fatty hepatitis (NASH). Blood biochemical examination included glucose, insulin, uric acid, lipid profile and liver enzymes. RESULTS: Among 428 children with obesity, 235 (54.9%) had SS and 45 (10.5%) had NASH. Body mass index, body mass index standard deviation score (BMI-SDS), waist circumference, body fat, liver enzymes, uric acid and HOMA-IR level were significantly higher in the NASH group than in the SS and SOB groups (p < 0.001). 53.3% of the SS group and 49.8% of the NASH group had metabolic syndrome, significantly more than in the SOB group (19.6%, p < 0.001). After adjustment for confounding factors, logistic regression models revealed that NASH was associated with BMI-SDS ≥ 3, gender, hyperuricemia and insulin resistance. CONCLUSIONS: The prevalence of NASH in children with obesity is closely related to high BMI-SDS, gender, insulin resistance and hyperuricemia. These findings provide evidence that monitoring risk factors of childhood obesity can assist in developing prevention strategies for liver disease at an early stage.

[17 beta-hydroxysteroid dehydrogenase 3 deficiency due to novel compound heterozygous variants of HSD17B3 gene in a sib pair].

OBJECTIVE: To explore the genetic basis for a sib pair featuring 17beta-hydroxysteroid dehydrogenase type 3 deficiency. METHODS: Genomic DNA was extracted from the proband, her sister, and their parents, and was subjected to sequencing analysis with a gene panel for sexual development. Suspected variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Both the proband and her sister were found to harbor novel compound heterozygous missense variants of the HSD17B3 gene, namely c.839T>C (p.Leu280Pro) and c.239G>T (p.Arg80Leu), which were derived respectively from their mother and father. The variants were unreported previously and predicted to be deleterious by PolyPhen2, MutationTaster and other online software. Based on the American College of Medical Genetics and Genomics standards and guidelines, both c.839T>C(p.Leu280Pro) and c.239G>T (p.Arg80Leu) were predicted to be likely pathogenic (PM2+PP1+PP2+PP3+PP4, PM2+PM5+PP1+PP2+PP3+PP4). CONCLUSION: The compound heterogeneous variants of the HSD17B3 gene probably underlay the disease in this sib pair. 17beta-hydroxysteroid dehydrogenase type 3 deficiency may lack specific clinical features and laboratory index, genetic testing can facilitate a definitive diagnosis.

Artemisinin and dihydroartemisinin promote ß-cell apoptosis induced by palmitate via enhancing ER stress.

Artemisinin (ART) and dihydroartemisinin (DHA) are first-line antimalarial drugs and have been reported to have anti-obesity effects. Hyperlipidemia is associated with ß-cell damage in obese subjects, which could contribute to the pathogenesis of type 2 diabetes. In addition to their anti-obesity effects, ART and DHA also have protective roles in some diseases. Thus, we investigated the effects of ART and DHA in palmitate-induced ß-cell apoptosis and the underlying mechanism. In this study, the rat pancreatic ß-cell line INS-1 and mouse pancreatic ß-cell line MIN6 were cultured with palmitate (PA) (0.1 mM) to induce cell apoptosis in the presence or absence of ART or DHA. Cell apoptosis was investigated by using flow cytometry, and the expression of ER stress markers, including CHOP, GRP78 and PDI, was detected by Western blotting and/or qRT-PCR. The results showed that ART and DHA significantly increased the apoptosis of ß-cells induced by PA and exacerbated the ER stress caused by PA. An inhibitor of ER stress, 4-phenylbutyric acid (4-PBA), significantly ameliorated cell apoptosis caused by ART and DHA in PA-treated ß-cells, consistent with the inhibition of ER stress. Together, the findings from the current study suggested that ART and DHA may promote lipid disorder-associated ß-cell injury via enhancing ER stress when they were used to treat obesity.

Evidence for disruption of diurnal salivary cortisol rhythm in childhood obesity: relationships with anthropometry, puberty and physical activity.

BACKGROUND: The aim of this study was to examine the characteristics of diurnal cortisol rhythm in childhood obesity and its relationships with anthropometry, pubertal stage and physical activity. METHODS: Thirty-five children with obesity (median age: 11.80[interquartile range 10.30, 13.30] and median BMI z-score: 3.21[interquartile range 2.69, 3.71]) and 22 children with normal weight (median age: 10.85[interquartile range 8.98, 12.13] and median BMI z-score: - 0.27[interquartile range - 0.88, 0.35]) were recruited. Saliva samples were collected at 08:00, 16:00 and 23:00 h. Cortisol concentrations at 3 time points, corresponding areas under the curve (AUCs) and diurnal cortisol slope (DCS) were compared between the two groups. Anthropometric measures and pubertal stage were evaluated, and behavioural information was obtained via questionnaires. RESULTS: Children with obesity displayed significantly lower cortisol08:00 (median [interquartile range]: 5.79[3.42,7.73] vs. 8.44[5.56,9.59] nmol/L, P = 0.030) and higher cortisol23:00 (median [interquartile range]: 1.10[0.48,1.46] vs. 0.40[0.21,0.61] nmol/L, P < 0.001) with a flatter DCS (median [interquartile range]: - 0.29[- 0.49, 0.14] vs. -0.52[- 0.63, 0.34] nmol/L/h, P = 0.006) than their normal weight counterparts. The AUC increased with pubertal development (AUC08:00-16:00:P = 0.008; AUC08:00-23:00: P = 0.005). Furthermore, cortisol08:00 was inversely associated with BMI z-score (ß = - 0.247, P = 0.036) and waist-to-height ratio (WHtR) (ß = - 0.295, P = 0.027). Cortisol23:00 was positively associated with BMI z-score (ß = 0.490, P<0.001), WHtR (ß = 0.485, P<0.001) and fat mass percentage (FM%) (ß = 0.464, P<0.001). Absolute values of DCS were inversely associated with BMI z-score (ß = - 0.350, P = 0.009), WHtR (ß = - 0.384, P = 0.004) and FM% (ß = - 0.322, P = 0.019). In multivariate analyses adjusted for pubertal stage and BMI z-score, Cortisol08:00, AUC08:00-16:00 and absolute values of DCS were inversely associated with the relative time spent in moderate to vigorous intensity physical activity (P < 0.05). AUC16:00-23:00 was positively associated with relative non-screen sedentary time and negatively associated with sleep (P < 0.05). CONCLUSIONS: The disorder of diurnal salivary cortisol rhythm is associated with childhood obesity, which is also influenced by puberty development and physical activity. Thus, stabilizing circadian cortisol rhythms may be an important approach for childhood obesity.

Diagnostic value of pituitary volume in girls with precocious puberty.

BACKGROUND: To date, the gonadotropin-releasing hormone (GnRH) stimulation test is still the gold standard for precocious puberty (PP) diagnosis. However, it has many disadvantages, including low sensitivity, high cost, and invasive operation. This study aims to evaluate whether magnetic resonance imaging (MRI)-derived variables, including pituitary volume (PV), could be used as diagnostic factors for PP in girls, providing a non-invasive diagnostic approach for PP. METHODS: A total of 288 young female patients who presented to the Clinic of Pediatric Endocrinology for evaluation of PP from January 2015 to December 2017 were enrolled. The sample included 90 girls diagnosed with premature thelarche (PT), 133 girls determined as idiopathic central precocious puberty (ICPP), 35 early pubertal girls, and 30 normal girls. All patients received pituitary MRI examinations. RESULTS: The largest PV and pituitary height were shown in the ICPP and pubertal groups, followed by the PT group. The receiver operating characteristic (ROC) curve analysis showed that PV is a predictive marker for ICPP, with a sensitivity of 54.10% and a specificity of 72.20% at the cutoff value of 196.01 mm3. By univariate analysis, PV was positively associated with peak luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), age, bone age, and body mass index (BMI) (all P < 0.05). However, bone age and peak LH were the only significant predictors of PV as demonstrated by the stepwise multivariate regression analysis (Model: PV = 9.431 * bone age + 1.230 * peak LH + 92.625 [P = 0.000, R2 = 0.159]). CONCLUSIONS: The PV in the ICPP group was significantly higher than in PT and control groups, but there was no reliable cutoff value to distinguish ICPP from PT. Pituitary MRI should be combined with clinical and laboratory tests to improve the diagnostic value of PV for PP.

Antimicrobial activity and mechanism of the human milk-sourced peptide Casein201.

INTRODUCTION: Casein201 is one of the human milk sourced peptides that differed significantly in preterm and full-term mothers. This study is designed to demonstrate the biological characteristics, antibacterial activity and mechanisms of Casein201 against common pathogens in neonatal infection. METHODOLOGY: The analysis of biological characteristics was done by bioinformatics. Disk diffusion method and flow cytometry were used to detect the antimicrobial activity of Casein201. Killing kinetics of Casein201 was measured using microplate reader. The antimicrobial mechanism of Casein201 was studied by electron microscopy and electrophoresis. RESULTS: Bioinformatics analysis indicates that Casein201 derived from ß-casein and showed significant sequence overlap. Antibacterial assays showed Casein201 inhibited the growth of S taphylococcus aureus and Y ersinia enterocolitica. Ultrastructural analyses revealed that the antibacterial activity of Casein201 is through cytoplasmic structures disintegration and bacterial cell envelope alterations but not combination with DNA. CONCLUSION: We conclude the antimicrobial activity and mechanism of Casein201. Our data demonstrate that Casein201 has potential therapeutic value for the prevention and treatment of pathogens in neonatal infection.

Insights from lncRNAs Profiling of MIN6 Beta Cells Undergoing Inflammation.

Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by chronic and progressive apoptotic destruction of pancreatic beta cells. During the initial phases of T1DM, cytokines and other inflammatory mediators released by immune cells progressively infiltrate islet cells, induce alterations in gene expression, provoke functional impairment, and ultimately lead to apoptosis. Long noncoding RNAs (lncRNAs) are a new important class of pervasive genes that have a variety of biological functions and play key roles in many diseases. However, whether they have a function in cytokine-induced beta cell apoptosis is still uncertain. In this study, lncRNA microarray technology was used to identify the differently expressed lncRNAs and mRNAs in MIN6 cells exposed to proinflammatory cytokines. Four hundred forty-four upregulated and 279 downregulated lncRNAs were detected with a set filter fold-change ≧2.0. To elucidate the potential functions of these lncRNAs, Gene Ontology (GO) and pathway analyses were used to evaluate the potential functions of differentially expressed lncRNAs. Additionally, a lncRNA-mRNA coexpression network was constructed to predict the interactions between the most strikingly regulated lncRNAs and mRNAs. This study may be utilized as a background or reference resource for future functional studies on lncRNAs related to the diagnosis and development of new therapies for T1DM.

[Integrins mediate the migration of HepG2 cells induced by low shear stress].

Low shear stress is a component of the tumor microenvironment in vivo and plays a key role in regulating cancer cell migration and invasion. The integrin, as a mechano-sensors mediating and integrating mechanical and chemical signals, induce the adhesion between cells and extracellular matrix (ECM). The purpose of this study is to investigate the effect of low shear stress (1.4 dyn/cm2)on the migration of HepG2 cells and the expression of integrin. Scratch wound migration assay was performed to examine the effect of low shear stress on the migration of HepG2 cells at 0 h, 1 h, 2 h and 4 h, respectively. F-actin staining was used to detect the expression of F-actin in HepG2 cells treated with low shear stress at 2 h and 4 h. Western blot analysis was carried out to determine the effect of low shear stress on the expression of integrin at different durations. The results showed that the migrated distance of HepG2 cells and the expression of F-actin increased significantly compared with the controls. The integrin alpha subunits showed a different time-dependent expression, suggesting that various subunits of integrin exhibit different effects in low shear stress regulating cancer cells migration.

Individual, family and social-related factors of eating behavior among Chinese children with overweight or obesity from the perspective of family system.

Purpose: The purpose of the present study is to examine the factors contributing to the development of eating behavior in overweight and obese children from the perspective of the family system. Methods: A cross-sectional survey was conducted by using convenience sampling method to select 388 participants in two primary schools in Jiangsu, China. Individual, family and social-related factors were collected. Individual factors included age, gender, ethnicity, single child, social anxiety, depression, physical activity, sleep duration, screen time. Family factors included family environment, family structure, family function, family income, parenting style, parental feeding behavior, home food environment and marital satisfaction. Social-related factors included place of residence, number of surrounding restaurants and social support. Univariate analysis, correlation analysis and multivariate analysis were used to identify factors of eating behavior among Chinese children with overweight and obese. Results: In this study, 388 participants took part with a 94.865% response rate. In the univariate analysis, the significant differences regarding Dutch Eating Behavior Questionnaire (DEBQ) scores were found between children aged 6-9 years and those aged >9 years. Correlation analysis indicated that parent's nutrition literacy (r = 0.118, P < 0.05), pressure to eat (r = 0.212, P < 0.01), perception of child weight (r = -0.112, P < 0.05) and family function (r = -0.563, P < 0.01) were associated with children's eating behavior. With regard to psychosocial factors, children's social anxiety (r = 0.299, P < 0.01) and depressive symptoms (r = 0.081, P < 0.05) were in positive correlation with eating behavior. The independent variables included in the initial model were age, father's employment status, social anxiety, maternal punishment and harshness, parents' nutrition literacy, pressure to eat, family function and perception of child weight. These variables in the final model accounted for 20.7% of the variance. Conclusion: We found that age, father's employment status, social anxiety, maternal punishment and harshness, parents' nutrition literacy, pressure to eat, family function and perception of child weight have great effect on children's eating behavior who are overweight or obese. As early childhood is a critical timeline for child development, children's social anxiety, parenting style, parent's nutrition literacy, parent's feeding behavior and family function should be intervened to promote eating behavior. Intervention programs aimed at promoting healthy eating behaviors among children, thereby mitigating the risk of pediatric obesity, should primarily target parents.

Microenvironment-responsive metal-phenolic network release platform with ROS scavenging, anti-pyroptosis, and ECM regeneration for intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) can be caused by aging, injury, and genetic factors. The pathological changes associated with IVDD include the excessive accumulation of reactive oxygen species (ROS), cellular pyroptosis, and extracellular matrix (ECM) degradation. There are currently no approved specific molecular therapies for IVDD. In this study, we developed a multifunctional and microenvironment-responsive metal-phenolic network release platform, termed TMP@Alg-PBA/PVA, which could treat (IL-1ß)-induced IVDD. The metal-phenolic network (TA-Mn-PVP, TMP) released from this platform targeted mitochondria to efficiently scavenge ROS and reduce ECM degradation. Pyroptosis was suppressed through the inhibition of the IL-17/ERK signaling pathway. These findings demonstrate the versatility of the platform. And in a rat model of IVDD, TMP@Alg-PBA/PVA exhibited excellent therapeutic effects by reducing the progression of the disease. TMP@Alg-PBA/PVA, therefore, presents clinical potential for the treatment of IVDD.

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together.

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

The link between obesity and insulin resistance among children: Effects of key metabolites.

BACKGROUND: Childhood obesity became a severe public health challenge, and insulin resistance (IR) was one of the common complications. Both obesity and IR were considered as the basis of metabolic disorders. However, it is unclear which common key metabolites are associated with childhood obesity and IR. METHODS: The children were divided into normal weight and overweight/obese groups. Fasting blood glucose and fasting insulin were measured, and homeostasis model assessment of insulin resistance was calculated. Liquid chromatography-tandem mass spectrometry was applied for metabonomic analysis. Multiple linear regression analysis and correlation analysis explored the relationships between obesity, IR, and metabolites. Random forests were used to rank the importance of differential metabolites, and relative operating characteristic curves were used for prediction. RESULTS: A total of 88 normal-weight children and 171 obese/overweight children participated in the study. There was a significant difference between the two groups in 30 metabolites. Childhood obesity was significantly associated with 10 amino acid metabolites and 20 fatty acid metabolites. There were 12 metabolites significantly correlated with IR. The ranking of metabolites in random forest showed that glutamine, tyrosine, and alanine were important in amino acids, and pyruvic-ox-2, ethylmalonic-2, and phenyllactic-2 were important in fatty acids. The area under the curve of body mass index standard deviation  score (BMI-SDS) combined with key amino acid metabolites and fatty acid metabolites for predicting IR was 80.0% and 76.6%, respectively. CONCLUSIONS: There are common key metabolites related to IR and obese children, and these key metabolites combined with BMI-SDS could effectively predict the risk of IR.

Transvaginal ultrasound parameters to evaluate cervical favorability and predict the outcome of induction of labor.

OBJECTIVE: To compare the values of transvaginal ultrasound (TVU) and Bishop score (BS) for predicting outcomes of induction of labor (IOL). METHODS: The BS and TVU were assessed before IOL. TVU parameters included cervical length (CL) and E-Cervix comprising the cervical hard ratio (HR) and the mean strain level of internal os (IOS). Study end-points included the duration of the latent phase within 15 or 18 h and delivery within 24 h. RESULTS: In multivariable logistic regression models, at the first two end-points, the areas under the curve (AUCs) for CL with HR were 0.733 and 0.777, and the AUCs for CL with IOS were 0.754 and 0.787, respectively, The AUC for HR was 0.750 at the third end-point. With receiver operating characteristic (ROC) analysis, the best cut-off value for CL was ≤1.38 cm and that for IOS was ≥0.35. The AUCs of the TVU scoring system by the cut-off values for CL and IOS for the three end-points were 0.784, 0.833, and 0.855, respectively. The predicting values of both methods were better than those of the BS (AUC = 0.672, 0.694, and 0.687, respectively). CONCLUSION: Cervical length along with E-Cervix showed better predictive values for successful induction compared with the BS.

Role of cuproptosis in understanding diseases.

Cell death is involved in a wide range of physiological and pathological processes. Recently, the term "cuproptosis" was coined to describe a novel type of cell death. This type of cell death, characterized by copper accumulation and proteotoxic stress, is a copper-dependent manner of death. Despite the progress achieved toward a better understanding of cuproptosis, mechanisms and related signaling pathways in physiology and pathology across various diseases remain to be proved. This mini review summarizes current research on cuproptosis and diseases, providing insights into prospective clinical therapies via targeting cuproptosis.

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer.

Objectives: Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification. We aimed to assess the utility of immunohistochemistry (IHC) staining for MMR protein expression and polymerase chain reaction (PCR)-based MSI assays in EC and the correlation between MMR/MSI status and various clinicopathological parameters. Methods: We reviewed the clinical and pathological information of 333 patients with EC. MMR protein expression was assessed as retained or lost to determine MMR status by IHC staining, and MSI status was identified by PCR capillary electrophoresis (PCR-CE) testing with a National Cancer Institute (NCI) panel. The correlation of MMR/MSI status with clinicopathological features was determined by statistical analysis. Discrepant results were further analyzed using an alternative PCR-CE MSI (Promega panel) method, MLH1 promoter methylation assays, and next-generation sequencing (NGS). Results: Among the EC patients, the overall percentage of dMMR was 25.2%, and the overall percentage of MSI-H was 24%. Among the dMMR patients, 50 (59.5%) showed loss of MLH1 and PMS2 expression, 19 (22.6%) loss of MSH2 and MSH6 expression, and seven (8.3%) and eight (9.5%) loss of PMS2 and MSH6 expression, respectively. The dMMR subgroup was significantly younger than the pMMR subgroup, especially for <60-years-old patients (p = 0.038). In addition, we identified a strong correlation between MMR/MSI status and high-grade endometrioid or nonendometrioid components (p = 0.004 or p = 0.003). IHC staining and PCR-CE assay results showed a high level of overall concordance (98.8%, Cohen's κ = 0.98). Four patients were found to have dMRR/MSS in both examinations. We reanalyzed them with additional methods. One case showed MLH1 promotor methylation, and the other three cases harbored MSH6 germline pathogenic variations. One of the cases with MSH6 deficiency was reanalyzed as MSI-H by alternative PCR-CE assay or NGS testing. Conclusions: This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.

The lymphatic system: a therapeutic target for central nervous system disorders.

The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis, metabolite clearance, and immune surveillance. The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology. They emerge as major pathways for fluid exchange. The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity. The lymphatic system, through its role in the clearance of neurotoxic proteins, autoimmune cell infiltration, and the transmission of pro-inflammatory signals, participates in the pathogenesis of a variety of neurological disorders, including neurodegenerative and neuroinflammatory diseases and traumatic injury. Vascular endothelial growth factor C is the master regulator of lymphangiogenesis, a process that is critical for the maintenance of central nervous system homeostasis. In this review, we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.