Search

β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction. In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction. The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results. BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm. [ABSTRACT FROM AUTHOR]

Background: Epigenetic age accelerations (EAAs) are a promising new avenue of research, yet their investigation in subacute thyroiditis (SAT) remains scarce. Our study endeavors to fill this void by exploring the potential causal association between EAAs and SAT., Methods: Our study utilized publicly available genome-wide association study (GWAS) data of European ancestry to conduct a bidirectional Mendelian randomization (MR) study. Five MR methods were employed to measure causal association between EAAs and SAT multiple analyses were utilized to perform quality control., Results: Our study evaluated causal association between SAT and four EAAs, included GrimAge acceleration (GrimAA), Hannum age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), intrinsic epigenetic age acceleration (IEAA). Results showed that there is a significant causal association between PhenoAA and SAT (OR 1.109, 95% CI 1.000-1.228, p = 0.049, by IVW method). On the contrary, SAT was associated with IEAA (OR 0.933, 95% CI 0.884-0.984, p = 0.011, by IVW method; OR 0.938, 95% CI 0.881-0.998, p = 0.043, by weighted median method). Leave-one-out sensitivity analysis, heterogeneity test, pleiotropy test, and MR-PRESSO analysis provide good quality control., Conclusion: The bidirectional MR analysis concluded that an increase in PhenoAA was correlated with a higher risk of SAT, indicating a potential causal relationship between PhenoAA and risk of SAT. Conversely, SAT was found to be closely associated with IEAA, suggesting that SAT may accelerate the aging process. Slowing down biological aging has emerged as a new research direction in curbing SAT., (© 2024. The Author(s).)

Background: Breast cancer (BC) is the most common cancer in women, and its progression is closely related to the phenomenon of anoikis. Anoikis, the specific programmed death resulting from a lack of contact between cells and the extracellular matrix, has recently been recognized as playing a critical role in tumor initiation, maintenance, and treatment. The ability of cancer cells to resist anoikis leads to cancer progression and metastatic colonization. However, the impact of anoikis on the prognosis of BC patients remains unclear., Method: This study utilized data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to collect transcriptome and clinical data of BC patients. Anoikis-related genes (ARGs) were classified into subtypes A and B through consensus clustering. Subsequently, survival prognosis analysis, immune cell infiltration analysis, and functional enrichment analysis were performed for both subtypes. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, a set of 10 ARGs related to prognosis was identified. Immune cell infiltration and tumor microenvironment analyses were conducted on these 10 ARGs to develop a prognostic model. Furthermore, single-cell data analysis and real-time polymerase chain reaction (RT-PCR) analysis were employed to study the expression of the 10 identified prognostic ARGs in BC cells., Results: One hundred thirty-five ARGs were identified as differentially expressed genes in the TCGA and GEO databases, with 42 of them associated with the survival prognosis of BC patients. Analyses involving Principal Component Analysis (PCA), t-Distributed Stochastic Neighbor Embedding (t-SNE), and Uniform Manifold Approximation and Projection (UMAP) revealed distinct expression patterns of ARGs between types A and B. Patients in type A exhibited worse survival prognosis and lower immune cell infiltration compared to type B. Subsequent analyses identified 10 key ARGs (YAP1, PIK3R1, BAK1, PHLDA2, EDA2R, LAMB3, CD24, SLC2A1, CDC25C, and SLC39A6) relevant to BC prognosis. Kaplan-Meier analysis indicated that high-risk patients based on these ARGs had a poorer BC prognosis. Additionally, Cox regression analysis established gender, age, T (tumor), N (nodes), and risk score as predictive factors in a nomogram model for BC. The model demonstrated diagnostic value for BC patients at 1, 3, and 5 years. Decision curve analysis (DCA) verified the risk score as a reliable predictor of BC patient survival rates. Moreover, RT-PCR results confirmed differential expressions of YAP1, PIK3R1, BAK1, PHLDA2, CD24, SLC2A1, and CDC25C in BC cells, with SLC39A6, EDA2R, and LAMB3 showing low expression levels., Conclusion: ARGs markers can be used as BC biomarkers for risk stratification and survival prediction in BC patients. Besides, ARGs can be used as stratification factors for individualized and precise treatment of BC patients., (© 2024. The Author(s).)

Background: Chronic pain and inflammation are common features of rheumatic conditions such as Psoriatic Arthritis (PsA) and Axial Spondyloarthritis (axSpA), often needing prolonged medication treatment for effective management. Maintaining drug retention is essential for both achieving disease control and improving patients' quality of life. This study investigates the influence of pain catastrophizing, a psychological response to pain, on the drug retention rates of PsA and axSpA patients., Methods: A two-year prospective multicenter observational study involved 135 PsA and 71 axSpA patients. Pain Catastrophizing Scale (PCS) was employed to assess pain catastrophizing. Univariable and multivariable regression analyses were utilized to identify factors associated with drug retention., Results: In the PsA group, patients early discontinuing therapy showed higher baseline disease activity as well as higher incidence of comorbid fibromyalgia. Notably, pain catastrophizing, specifically the domains of Helplessness, Magnification, and Rumination, were significantly elevated in PsA patients who interrupted the treatment. Multivariable analysis confirmed pain catastrophizing as an independent predictor of drug suspension within two years. In axSpA, drug discontinuation was associated with female gender, shorter disease duration, higher baseline disease activity as well as elevated levels of pain catastrophizing. Univariable analysis supported the role of pain catastrophizing, including its domains, as predictors of treatment interruption. However, limited events in axSpA patients precluded a multivariate analysis., Conclusion: This prospective study emphasizes the impact of pain catastrophizing on drug retention in patients with PsA and axSpA., (© 2024. The Author(s).)

Background: Echocardiography-based ultrasomics analysis aids Kawasaki disease (KD) diagnosis but its role in predicting coronary artery lesions (CALs) progression remains unknown. We aimed to develop and validate a predictive model combining echocardiogram-based ultrasomics with clinical parameters for CALs progression in KD., Methods: Total 371 KD patients with CALs at baseline were enrolled from a retrospective cohort (cohort 1, n = 316) and a prospective cohort (cohort 2, n = 55). CALs progression was defined by increased Z scores in any coronary artery branch at the 1-month follow-up. Patients in cohort 1 were split randomly into training and validation set 1 at the ratio of 6:4, while cohort 2 comprised validation set 2. Clinical parameters and ultrasomics features at baseline were analyzed and selected for models construction. Model performance was evaluated by area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) and decision curve analysis (DCA) in the training and two validation sets., Results: At the 1-month follow-ups, 65 patients presented with CALs progression. Three clinical parameters and six ultrasomics features were selected to construct the model. The clinical-ultrasomics model exhibited a good predictive capability in the training, validation set 1 and set 2, achieving AUROCs of 0.83 (95% CI, 0.75-0.90), 0.84 (95% CI, 0.74-0.94), and 0.73 (95% CI, 0.40-0.86), respectively. Moreover, the AUPRC values and DCA of three model demonstrated that the clinical-ultrasomics model consistently outperformed both the clinical model and the ultrasomics model across all three sets, including the training set and the two validation sets., Conclusions: Our study demonstrated the effective predictive capacity of a prediction model combining echocardiogram-based ultrasomics features and clinical parameters in predicting CALs progression in KD., (© 2024. The Author(s).)

Some forms of Sjögren's syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter ® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging., (© 2024. The Author(s).)

Background: Paraspinal muscle degeneration occurs with age; however, it is unknown whether strength and endurance change with muscle cross-sectional area (CSA) and fatty infiltration (FI) parameters in Chinese healthy individuals., Methods: A total of 94 asymptomatic Chinese volunteers were enrolled in this study. The participants were divided into three groups: young (20-39 years old, n = 27), middle-aged (40-59 years old, n = 49), and elderly (≥ 60 years old, n = 18). CSA and FI of the psoas (PS), quadratus lumborum (QL), multifidus (MF), and erector spinae (ES) were measured using magnetic resonance imaging. The Bionix Sim3 Pro was used to evaluate the maximum isometric torque and the Ito test to evaluate endurance., Results: The CSA of the PS and ES in the elderly group was smaller than those in the other groups, while the CSA of QL in the young group was larger than that in the other groups. There were differences in the MF and ES FI among the three groups. The maximum isometric torque and endurance test time decreased with increasing age; however, these differences were not statistically significant. Maximum isometric torque positively correlated with the average paraspinal muscle CSA and negatively correlated with the torque and FI of the MF and ES muscles. The endurance test was found to be positively correlated with the FCSA of the MF and to be negatively correlated with the FI of the MF and ES. PS and QL can predict the maximum isometric torque, and MF and PS can predict the endurance time., Conclusion: MF and ES showed earlier degeneration than PS and QL. MF is the first paraspinal muscle to undergo functional area atrophy, and it plays an important role in the endurance test. The maximum moment of equal length in all directions of the lumbar spine is not completely symmetrical, but it is correlated with the imaging parameters of the paraspinal muscles. QL and PS were more activated in the lumbar activity., Trial Registration: The study was registered in Chinese Clinical Trial Registry and the registration number is ChiCTR2000039073 on 15/10/2020 ( https://www.chictr.org.cn/showproj.html?proj=62785 ). Ethical Approval was obtained from the Peking University Third Hospital Medical Science Research Ethics Committee (IRB00006761-M2020305)., (© 2024. The Author(s).)

Objectives: Thrombocytosis is a clinical condition generally associated with poor prognosis in patients with cancer. Thrombocytosis may be present after lung cancer resection, but the clinical significance of thrombocytosis remains unclear. Herein, we evaluated whether postoperative thrombocytosis was a negative prognostic factor in patients undergoing thoracoscopic lobectomy for lung cancer., Methods: It was a retrospective monocentric study including consecutive patients undergoing thoracoscopic lobectomy for lung cancer from January 2020 to January 2023. The outcome of patients with postoperative thrombocytosis (defined as platelet count ≥ 450 × 10^9/L at 24 h after the surgery and confirmed at postoperative day 7) was compared with a control group. Postoperative morbidity, mortality, and survival were compared between the two groups to define whether thrombocytosis negatively affected outcomes., Results: Our study population included 183 patients; of these, 22 (12%) presented postoperative thrombocytosis: 9 (5%) mild thrombocytosis (451-700 × 10^9/L), 10 (5%) moderate thrombocytosis (701-900 × 10^9/L), and 3 (2%) severe thrombocytosis (901-1000 × 10^9/L). No significant differences were found regarding postoperative morbidity (p = 0.92), mortality (p = 0.53), overall survival (p = 0.45), and disease-free survival (p = 0.60) between the two study groups. Thrombocytosis was associated with higher rate of atelectasis (36% vs. 6%, p < 0.001) and residual pleural effusion (31% vs. 8%, p = 0.0008). Thrombocytosis group was administered low-dose acetylsalicylic acid for 10 days and no thrombotic events were observed. In all cases the platelet count returned to be within normal value at postoperative day 30., Conclusions: Postoperative thrombocytosis seems to be a transient condition due to an inflammatory state and it does not affect the surgical outcome and survival after thoracoscopic lobectomy., (© 2024. The Author(s).)

Background: X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits., Methods: We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls., Results: We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up., Conclusions: This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies., (© 2024. The Author(s).)

Background: Enterovirus A71 (EV-A71), as a neurotropic virus, mainly affects infants and young children under the age of 5. EV-A71 infection causes hand-foot-mouth disease and herpetic angina, and even life-threatening neurological complications. However, the molecular mechanism by which EV-A71 induces nervous system damage remains elusive. The viral protease 3C plays an important role during EV-A71 infection and is also a key intersection of virus-host interactions. Previously, we used yeast two-hybrid to screen out the host protein Double-stranded RNA-binding protein Staufen homolog 2 (Stau2), an important member involved in neuronal mRNA transport, potentially interacts with 3C., Methods: We used coimmunoprecipitation (Co-IP) and immunofluorescence assay (IFA) to confirm that EV-A71 3C interacts with Stau2. By constructing the mutant of Stau2, we found the specific site where the 3C protease cleaves Stau2. Detection of VP1 protein using Western blotting characterized EV-A71 viral replication, and overexpression or knockdown of Stau2 exhibited effects on EV-A71 replication. The effect of different cleavage products on EV-A71 replication was demonstrated by constructing Stau2 truncates., Results: In this study, we found that EV-A71 3C interacts with Stau2. Stau2 is cleaved by 3C at the Q507-G508 site. Overexpression of Stau2 promotes EV-A71 VP1 protein expression, whereas depletion of Stau2 by small interfering RNA inhibits EV-A71 replication. Stau2 is essential for EV-A71 replication, and the product of Stau2 cleavage by 3C, 508-570 aa, has activity that promotes EV-A71 replication. In addition, we found that mouse Stau2 is also cleaved by EV-A71 3C at the same site., Conclusions: Our research provides an example for EV-A71-host interaction, enriching key targets of host factors that contribute to viral replication., (© 2024. The Author(s).)

Background: The expansion of sequencing technologies as a result of the response to the COVID-19 pandemic enabled pathogen (meta)genomics to be deployed as a routine component of surveillance in many countries. Scaling genomic surveillance, however, comes with associated costs in both equipment and sequencing reagents, which should be optimized. Here, we evaluate the cost efficiency and performance of different read lengths in identifying pathogens in metagenomic samples. We carefully evaluated performance metrics, costs, and time requirements relative to choices of 75, 150 and 300 base pairs (bp) read lengths in pathogen identification., Results: Our findings revealed that moving from 75 bp to 150 bp read length approximately doubles both the cost and sequencing time. Opting for 300 bp reads leads to approximately two- and three-fold increases, respectively, in cost and sequencing time compared to 75 bp reads. For viral pathogen detection, the sensitivity median ranged from 99% with 75 bp reads to 100% with 150-300 bp reads. However, bacterial pathogens detection was less effective with shorter reads: 87% with 75 bp, 95% with 150 bp, and 97% with 300 bp reads. These findings were consistent across different levels of taxa abundance. The precision of pathogen detection using shorter reads was comparable to that of longer reads across most viral and bacterial taxa., Conclusions: During disease outbreak situations, when swift responses are required for pathogen identification, we suggest prioritizing 75 bp read lengths, especially if detection of viral pathogens is aimed. This practical approach allows better use of resources, enabling the sequencing of more samples using streamlined workflows, while maintaining a reliable response capability., (© 2024. The Author(s).)

Background: Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine., Methods: We conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database., Results: Six single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10 - 7 ): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10 - 9 ). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure., Conclusion: The identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology., Trial Registration: Not applicable., (© 2024. The Author(s).)

Background: The prognosis, recurrence rates, and secondary prevention strategies varied significantly among different subtypes of acute ischemic stroke (AIS). Machine learning (ML) techniques can uncover intricate, non-linear relationships within medical data, enabling the identification of factors associated with etiological classification. However, there is currently a lack of research utilizing ML algorithms for predicting AIS etiology., Objective: We aimed to use interpretable ML algorithms to develop AIS etiology prediction models, identify critical factors in etiology classification, and enhance existing clinical categorization., Methods: This study involved patients with the Third China National Stroke Registry (CNSR-III). Nine models, which included Natural Gradient Boosting (NGBoost), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Random Forest (RF), Light Gradient Boosting Machine (LGBM), Gradient Boosting Decision Tree (GBDT), Adaptive Boosting (AdaBoost), Support Vector Machine (SVM), and logistic regression (LR), were employed to predict large artery atherosclerosis (LAA), small vessel occlusion (SVO), and cardioembolism (CE) using an 80:20 randomly split training and test set. We designed an SFS-XGB with 10-fold cross-validation for feature selection. The primary evaluation metrics for the models included the area under the receiver operating characteristic curve (AUC) for discrimination and the Brier score (or calibration plots) for calibration., Results: A total of 5,213 patients were included, comprising 2,471 (47.4%) with LAA, 2,153 (41.3%) with SVO, and 589 (11.3%) with CE. In both LAA and SVO models, the AUC values of the ML models were significantly higher than that of the LR model (P < 0.001). The optimal model for predicting SVO (AUC [RF model] = 0.932) outperformed the optimal LAA model (AUC [NGB model] = 0.917) and the optimal CE model (AUC [LGBM model] = 0.846). Each model displayed relatively satisfactory calibration. Further analysis showed that the optimal CE model could identify potential CE patients in the undetermined etiology (SUE) group, accounting for 1,900 out of 4,156 (45.7%)., Conclusions: The ML algorithm effectively classified patients with LAA, SVO, and CE, demonstrating superior classification performance compared to the LR model. The optimal ML model can identify potential CE patients among SUE patients. These newly identified predictive factors may complement the existing etiological classification system, enabling clinicians to promptly categorize stroke patients' etiology and initiate optimal strategies for secondary prevention., (© 2024. The Author(s).)

Background: There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF., Methods: PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14., Results: Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P < 0.00001; I 2  = 70%), pregnancy rate (RR = 3.88; 95% CI: 1.94 ~ 7.79; P = 0.0001; I 2  = 0%), count of births (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P < 0.00001; I 2  = 69%) and counts of different types of follicles. In addition, it elevates the level of AMH (SMD = 4.15; 95% CI: 2.75 ~ 5.54; P < 0.00001; I 2  = 88%) and E2 (SMD = 2.88; 95% CI: 2.02 ~ 3.73; P < 0.00001; I 2  = 80%) expression, while reducing FSH expression (SMD = -5.05; 95% CI: -6.60 ~ -3.50; P < 0.00001; I 2  = 90%). Subgroup analysis indicates that the source of EVs, animal species, modeling method, administration route, and test timepoint affected efficacy. Trial sequential analysis showed that there was sufficient evidence to confirm the effects of stem cell-derived EVs on birth counts, ovarian weights, and follicle counts. However, the impact of stem cell-derived EVs on pregnancy rates needs to be further demonstrated through more animal experimental evidence., Conclusions: Stem cell-derived EVs demonstrate safety and efficacy in treating POF animal models, with potential improvements in fertility outcomes., Trial Registration: PROSPERO registration number: CRD42024509699., (© 2024. The Author(s).)

Glucokinase (GCK), a key enzyme in glucose metabolism, plays a central role in glucose sensing and insulin secretion in pancreatic β-cells, as well as glycogen synthesis in the liver. Mutations in the GCK gene have been associated with various monogenic diabetes (MD) disorders, including permanent neonatal diabetes mellitus (PNDM) and maturity-onset diabetes of the young (MODY), highlighting its importance in maintaining glucose homeostasis. Additionally, GCK gain-of-function mutations lead to a rare congenital form of hyperinsulinism known as hyperinsulinemic hypoglycemia (HH), characterized by increased enzymatic activity and increased glucose sensitivity in pancreatic β-cells. This review offers a comprehensive exploration of the critical role played by the GCK gene in diabetes development, shedding light on its expression patterns, regulatory mechanisms, and diverse forms of associated monogenic disorders. Structural and mechanistic insights into GCK's involvement in glucose metabolism are discussed, emphasizing its significance in insulin secretion and glycogen synthesis. Animal models have provided valuable insights into the physiological consequences of GCK mutations, although challenges remain in accurately recapitulating human disease phenotypes. In addition, the potential of human pluripotent stem cell (hPSC) technology in overcoming current model limitations is discussed, offering a promising avenue for studying GCK-related diseases at the molecular level. Ultimately, a deeper understanding of GCK's multifaceted role in glucose metabolism and its dysregulation in disease states holds implications for developing targeted therapeutic interventions for diabetes and related disorders., (© 2024. The Author(s).)

Background: Pathogenic variants of MYH7, which encodes the beta-myosin heavy chain protein, are major causes of dilated and hypertrophic cardiomyopathy., Methods: In this study, we used whole-genome sequencing data to identify MYH7 variants in 397 patients with various cardiomyopathy subtypes who were participating in the National Project of Bio Big Data pilot study in Korea. We also performed in silico analyses to predict the pathogenicity of the novel variants, comparing them to known pathogenic missense variants., Results: We identified 27 MYH7 variants in 41 unrelated patients with cardiomyopathy, consisting of 20 previously known pathogenic/likely pathogenic variants, 2 variants of uncertain significance, and 5 novel variants. Notably, the pathogenic variants predominantly clustered within the myosin motor domain of MYH7. We confirmed that the novel identified variants could be pathogenic, as indicated by high prediction scores in the in silico analyses, including SIFT, Mutation Assessor, PROVEAN, PolyPhen-2, CADD, REVEL, MetaLR, MetaRNN, and MetaSVM. Furthermore, we assessed their damaging effects on protein dynamics and stability using DynaMut2 and Missense3D tools., Conclusions: Overall, our study identified the distribution of MYH7 variants among patients with cardiomyopathy in Korea, offering new insights for improved diagnosis by enriching the data on the pathogenicity of novel variants using in silico tools and evaluating the function and structural stability of the MYH7 protein., (© 2024. The Author(s).)

Background: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis., Case Presentation: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition., Conclusions: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS., (© 2024. The Author(s).)

Gene expression is an intricate biological process that bridges gap between the genotype and the phenotype. Canonical and hereditable epigenetic mechanisms, such as histone and DNA modifications, regulate the release of genetic information encoded in DNA without altering the underlying sequence. Many other non-canonical players, such as chromatin regulators and noncoding RNAs, are also involved in regulating gene expression. Recently, RNA modifications (epitranscriptomics) have been shown to hold enormous potential in shaping cellular transcriptomes. However, their co-transcriptional nature and uncertain heritability mean that they fall outside the current definition of epigenetics, sparking an ongoing debate in the field. Here we will discuss the relationship between canonical and non-canonical epigenetic mechanisms that govern gene expression and offer our perspective on whether (or not) epitranscriptomic modifications can be classified as epigenetic mechanisms., (© 2024. The Author(s).)

Background: Our research endeavored to develop a robust predictive signature grounded in super-enhancer-related genes (SERGs), with the dual objectives of forecasting survival outcomes and evaluating the tumor immune microenvironment (TiME) in hepatocellular carcinoma (HCC)., Methods: HCC RNA-sequencing data were retrieved from The Cancer Genome Atlas (TCGA), and 365 patients were randomly assigned to training or testing sets in 1:1 ratio. SERGs of HCC were downloaded from Super-Enhancer Database (SEdb). On the basis of training set, a SERGs signature was identified, and its prognostic value was confirmed by internal and external validation (GSE14520) sets. We subsequently examined the model for potential functional enrichment and the degree of tumor immune infiltration. Additionally, we carried out in vitro experiments to delve into the biological functions of CBX2 gene., Results: An SE-related prognostic model including CBX2, TPX2, EFNA3, DNASE1L3 and SOCS2 was established and validated. According to this risk model, patients in the high-risk group had a significantly worse prognosis, and their immune cell infiltration was significantly different from that of low-risk group. Moreover, the high-risk group exhibited a significant enrichment of tumor-associated pathological pathways. The SERGs signature can generally be utilized to screen HCC patients who are likely to respond to immunotherapy, as there is a positive correlation between the risk score and the Tumor Immune Dysfunction and Exclusion (TIDE) score. Furthermore, the downregulation of the CBX2 gene expression was found to inhibit HCC cell viability, migration, and cell cycle progression, while simultaneously promoting apoptosis., Conclusions: We developed a novel HCC prognostic model utilizing SERGs, indicating that patients with high-risk score not only face a poorer prognosis but also may exhibit a diminished therapeutic response to immune checkpoint inhibitors (ICIs). This model is designed to tailor personalized treatment strategies to the individual needs of each patient, thereby improving the overall clinical outcomes for HCC patients. Furthermore, CBX2 is a promising candidate for therapeutic intervention in HCC., (© 2024. The Author(s).)

Background: Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics., Methods: We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance., Results: In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer., Conclusion: Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer., (© 2024. The Author(s).)

Background: Benign prostatic hyperplasia (BPH) is a prevalent condition in aging males, leading to bladder outlet obstruction (BOO) and associated urinary symptoms. With increasing life expectancy, the incidence of BPH and its co-morbidities, like inguinal hernia, has risen. This study explores the efficacy of combining transurethral resection of the prostate (TURP) and inguinal hernioplasty in a single surgical session to address both conditions, potentially reducing the need for multiple hospitalizations and surgical interventions., Methods: This retrospective study at Chi Mei Medical Center included patients from 2014 to 2023 who underwent concurrent TURP and inguinal hernioplasty. A total of 85 patients met the criteria defined for this study. Preoperative, intraoperative, and postoperative characteristics were meticulously documented. Outcomes evaluated included the duration of the surgery, incidence of intraoperative and postoperative complications, duration of Foley catheterization, length of hospital stay, and treatment efficacy. Additionally, we conducted a comparative assessment of the surgical outcomes between two distinct techniques for inguinal hernia repair: open hernioplasty and laparoscopic hernioplasty (LH)., Results: In 85 patients who met the criteria, the mean age was 71.1 ± 7.8 years. The study reported no significant intraoperative complications, and postoperative care was focused on monitoring for blood loss, infection, and managing pain. The average postoperative hospital stay was 2.9 ± 1.0 days and the mean duration of catheterization was 51.6 ± 16.7 h, with a minimal complication rate observed during the one-year follow-up. A significant reduction in both operative duration and catheterization interval was observed in patients undergoing LH as opposed to those receiving open hernioplasty., Conclusion: Concurrent TURP and inguinal hernioplasty effectively manage BOO due to BPH and inguinal hernias with minimal complications, suggesting a viable approach to reducing hospital stays and surgical interventions. Laparoscopic techniques, in particular, offer benefits in operative efficiency and recovery time, making combined surgery a feasible option for selected patients., (© 2024. The Author(s).)

Background: Remnant cholesterol (RC) exert a significant influence on atherosclerotic cardiovascular disease development. However, the prognostic implications of RC in menopausal women received percutaneous coronary intervention (PCI) who experiencing acute coronary syndrome (ACS) remain uncertain., Methods: RC was derived by subtracting the sum of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol from the total cholesterol. Kaplan-Meier survival and Cox regression analysis were employed for assessing the correlation between continuous RC levels and composite and individual adverse events in Q1-Q4 quartiles. Receiver operator characteristic (ROC) curves, derived from Cox regression, were employed for analyzing the relationship between RC and both composite and individual adverse events., Results: 1505 consecutive menopausal women who underwent PCI and diagnosed with ACS were included. Kaplan-Meier survival analysis demonstrated a progressive reduction in composite adverse event survival rates across the four groups, observed in both the general population and among diabetic individuals, as RC values increased (Log-rank P < 0.001). The analysis of multivariate Cox regression indicated RC remained independently associated with both composite and individual adverse events. ROC analysis showed that RC enhanced the area under the curve both in total and diabetic populations for composite adverse events., Conclusion: Among menopausal women diagnosed with ACS who underwent PCI, heightened levels of RC were found to be independently correlated with an increased occurrence of adverse events., (© 2024. The Author(s).)

Background: Early detection and treatment are effective methods for the management of oral squamous cell carcinoma (OSCC), which can be facilitated by the detection of tumor-specific OSCC biomarkers. The epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) are important therapeutic targets for OSCC. Multispectral fluorescence molecular imaging (FMI) can facilitate the detection of tumor multitarget expression with high sensitivity and safety. Hence, we developed Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes, in combination with multispectral FMI, to sensitively and noninvasively identify EGFR and PD-L1 expression for the detection and comprehensive treatment of OSCC., Methods: The expression of EGFR and PD-L1 was analyzed using bioinformatics data sources and specimens. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes were developed and tested on preclinical OSCC cell line and orthotopic OSCC mouse model, fresh OSCC patients' biopsied samples, and further clinical mouthwash trials were conducted in OSCC patients., Results: EGFR and PD-L1 were specifically expressed in human OSCC cell lines and tumor xenografts. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes can specifically target to the tumor sites in an in situ human OSCC mouse model with good safety. The detection sensitivity and specificity of Nimotuzumab-ICG in patients were 96.4% and 100%, and 95.2% and 88.9% for Atezolizumab-Cy5.5., Conclusions: EGFR and PD-L1 are highly expressed in OSCC, the combination of which is important for a precise prognosis of OSCC. EGFR and PD-L1 expression can be sensitively detected using the newly synthesized multispectral fluorescence imaging probes Nimotuzumab-ICG and Atezolizumab-Cy5.5, which can facilitate the sensitive and specific detection of OSCC and improve treatment outcomes., Trial Registration: Chinese Clinical Trial Registry, ChiCTR2100045738. Registered 23 April 2021, https://www.chictr.org.cn/bin/project/edit?pid=125220., (© 2024. The Author(s).)

Objective: To assess whether diffusion and perfusion MRI derived parameters could non-invasively predict PD-L1 and Ki-67 status in primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL)., Methods: We retrospectively analyzed DWI, DSC-PWI, and morphological MRI (mMRI) in 88 patients with PCNS-DLBCL. The mMRI features were compared using chi-square tests or Fisher exact test. Minimum ADC (ADC min ), mean ADC(ADC mean ), relative minimum ADC (rADC min ), relative mean ADC (rADC mean ), and relative maximum CBV (rCBV max ) values were compared in PCNS-DLBCL with different molecular status by using the Mann-Whitney U test. The diagnostic performances were evaluated by receiver operating characteristic curves., Results: PCNS-DLBCL with high PD-L1 expression demonstrated a significantly higher ADC min value than those with low PD-L1. The ADC mean and rADC mean values were significantly lower in PCNS-DLBCL with high Ki-67 status compared with those in low Ki-67 status. Other ADC, CBV parameters, and mMRI features did not show any association with these molecular statuses The diagnostic efficacy of ADC values in assessing PD-L1 and Ki-67 status was relatively low, with area under the curves (AUCs) values less than 0.7., Conclusions: DWI-derived ADC values can provide some relevant information about PD-L1 and Ki-67 status in PCNS-DLBCL, but may not be sufficient to predict their expression due to the rather low diagnostic performance., (© 2024. The Author(s).)

Background: Bone loss of residual alveolar ridges is a great challenge in the field of dental implantology. Deproteinized bovine bone mineral (DBBM) is commonly used for bone regeneration, however, it is loose and difficult to handle in clinical practice. Hyaluronic acid (HA) shows viscoelasticity, permeability and excellent biocompatibility. The aim of this study is to evaluate whether high-molecular-weight (MW) HA combined with DBBM could promote new bone formation in rat calvarial critical size defects (CSDs)., Materials and Methods: Rat calvarial CSDs (5 mm in diameter) were created. Rats (n = 45) were randomly divided into 3 groups: HA-DBBM compound grafting group, DBBM particles only grafting group and no graft group. Defect healing was assessed by hematoxylin-eosin staining and histomorphometry 2, 4 and 8 weeks postop, followed by Micro-CT scanning 8 weeks postop. Statistical analyses were performed by ANOVA followed by Tukey's post hoc test with P < 0.05 indicating statistical significance., Results: All rats survived after surgery. Histomorphometric evaluation revealed that at 2, 4 and 8 weeks postop, the percentage of newly formed bone was significantly greater in HA-DBBM compound grafting group than in the other two groups. Consistently, Micro-CT assessment revealed significantly more trabecular bone (BV/TV and Tb.N) in HA-DBBM compound group than in the other two groups, respectively (P < 0.05). Moreover, the trabecular bone was significantly more continuous (Tb.Pf) in HA-DBBM compound group than in the other two groups, respectively (P < 0.05)., Conclusion: HA not only significantly promoted new bone formation in rats calvarial CSDs but also improved the handling ability of DBBM., (© 2024. The Author(s).)

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants., (© 2024. The Author(s).)

Background: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models., Results: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue., Conclusions: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues., (© 2024. The Author(s).)

Background: In recent decades, early rehabilitation after Achilles tendon rupture (ATR) repair has been proposed. The aim of this prospective cohort study was to compare different immobilisation durations in order to determine the optimal duration after open surgery for ATR repair., Methods: This study included 1088 patients (mean age, 34.9 ± 5.9 years) who underwent open surgery for acute ATR repair. The patients were categorised into four groups (A, B, C, and D) according to postoperative immobilisation durations of 0, 2, 4, and 6 weeks, respectively. All patients received the same suture technique and a similar rehabilitation protocol after brace removal,; they were clinically examined at 2, 4, 6, 8, 10, 12, 14, and 16 weeks postoperatively, with a final follow-up at a mean of 19.0 months. The primary outcome was the recovery time for the one-leg heel-rise height (OHRH). Secondary outcomes included the time required to return to light exercise (LE) and the recovery times for the range of motion (ROM). Data regarding the surgical duration, complications, the visual analogue scale (VAS) score for pain, the Achilles tendon Total Rupture Score (ATRS), and the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale score were also collected., Results: The recovery times for OHRH, LE, and ROM were significantly shorter in groups A and B than in groups C and D (P < 0.001). The VAS scores decreased over time, reaching 0 in all groups by 10 weeks. The mean scores in groups A and B were higher than those in the other groups at 2 and 4 weeks (P < 0.001), whereas the opposite was true at 8 weeks (P < 0.001). ATRS and the AOFAS Ankle-Hindfoot scale score increased across all groups over time, showing significant between-group differences from weeks 6 to 16 (P < 0.001) and weeks 6 to 12 (P < 0.001). The mean scores were better in groups A and B than in groups C and D. Thirty-eight complications (3.5%) were observed, including 20 re-ruptures and 18 superficial infections. All complications were resolved at the last follow-up, with no significant between-group differences., Conclusions: Immobilisation for 2 weeks after open surgery for ATR repair may be the optimal strategy for early rehabilitation with relatively minimal pain and other complications., Trial Registration: ClinicalTrials.gov (NCT04663542)., (© 2024. The Author(s).)

Background: Selecting informative genes or eliminating uninformative ones before any downstream gene expression analysis is a standard task with great impact on the results. A carefully curated gene set significantly enhances the likelihood of identifying meaningful biomarkers., Method: In contrast to the conventional forward gene search methods that focus on selecting highly informative genes, we propose a backward search method, DenoiseIt, that aims to remove potential outlier genes yielding a robust gene set with reduced noise. The gene set constructed by DenoiseIt is expected to capture biologically significant genes while pruning irrelevant ones to the greatest extent possible. Therefore, it also enhances the quality of downstream comparative gene expression analysis. DenoiseIt utilizes non-negative matrix factorization in conjunction with isolation forests to identify outlier rank features and remove their associated genes., Results: DenoiseIt was applied to both bulk and single-cell RNA-seq data collected from TCGA and a COVID-19 cohort to show that it proficiently identified and removed genes exhibiting expression anomalies confined to specific samples rather than a known group. DenoiseIt also showed to reduce the level of technical noise while preserving a higher proportion of biologically relevant genes compared to existing methods. The DenoiseIt Software is publicly available on GitHub at https://github.com/cobi-git/DenoiseIt., (© 2024. The Author(s).)

Background: Endothelial cellular senescence is emerging as a key mechanism of age-related vascular dysfunction. Disruption of the endothelium glycocalyx and shedding of the syndecan (SDC) ectodomains have been associated with several age-related diseases. Although SDC4 is highly expressed in endothelial cells, its levels and shedding in senescent endothelial cells and vascular endothelial dysfunction associated with aging are still unknown., Methods: To assess whether SDC4 expression was affected by inflammatory conditions, we evaluated its levels in young human umbilical vein endothelial cells (HUVECs) treated with TNF-α at a concentration of 50 ng/mL for 24 h and in cells undergoing replicative senescence. Plasma levels of SDC4 were evaluated in two previously recruited cohorts of (i) subjects with type 2 diabetes (T2D, n = 110) followed for a median of 16.8 years and age- and gender-matched healthy subjects (n = 100), and (ii) middle-aged subjects with mild-to-moderate dyslipidemia. Binomial logistic regression was used to assess whether SDC4 levels could be prognostic for major adverse cardiovascular events (MACE)., Results: In the in vitro study, we showed that HUVECs, when exposed to TNF-α or undergoing replicative senescence, exhibited elevated expression levels of SDC4 and matrix metallopeptidase 9 (MMP-9), as well as increased shedding of SDC4 into the extracellular microenvironment, in comparison to actively proliferating young HUVECs. Analysis of human samples revealed that patients with T2D without complications exhibited higher SDC4 levels compared to healthy controls and those with T2D vascular complications. In particular, patients with a history of major adverse cardiovascular events (MACE) had lower SDC4 levels. The longitudinal evaluation revealed that higher SDC4 levels predict the onset of new MACE during a 16.8-year follow-up. In the second cohort, no significant association was observed between SDC4 and endothelial dysfunction, assessed by flow-mediated dilation (FMD) or nitric oxide metabolites. SDC4 levels correlated positively with C-reactive protein (CRP) in both cohorts and with PAI-1 in the cohort of patients with T2D., Conclusion: Overall, we conclude that the shedding of SDC4 from endothelial cells increases under acute (TNF-α treatment) and chronic (senescence) inflammatory conditions and that increased circulating SDC4 levels are associated with systemic inflammation in pathological aging., (© 2024. The Author(s).)

Tripartite motif-containing 24 (TRIM24), also known as transcriptional intermediary factor 1α (TIF1α), is the founding member of TIF1 family. Recent evidence indicates that aberrant expression of TRIM24, functions as an oncogene, is associated with poor prognosis across various cancer types. TRIM24 exhibits a multifaceted structure comprising an N-terminal TRIM region with a RING domain, B-box type 1 and type 2 domains, and a coiled-coil region, as well as a C-terminal plant-homeodomain (PHD)-bromodomain. The bromodomain serves as a 'reader' of epigenetic histone marks, regulating chromatin structure and gene expression by linking associated proteins to acetylated nucleosomal targets, thereby controlling transcription of genes. Notably, bromodomains have emerged as compelling targets for cancer therapeutic development. In addition, TRIM24 plays specialized roles as a signal transduction molecule, orchestrating various cellular signaling cascades in cancer cells. Herein, we review the recent advancements in understanding the functions of TRIM24, and demonstrate the research progress in utilizing TRIM24 as a target for cancer therapy., (© 2024. The Author(s).)

Background: The effect of plasma hepcidin concentrations on the long-term risk of developing adverse cardiovascular outcomes in people with type 2 diabetes mellitus (T2DM) is unclear., Methods: We followed for a median of 55.6 months 213 outpatients with established T2DM (45.5% women, mean age 69 ± 10 years; BMI 28.7 ± 4.7 kg/m 2 ; median diabetes duration 11 years). Baseline plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. The primary study outcome was a composite of all-cause mortality or incident nonfatal cardiovascular events (inclusive of myocardial infarction, permanent atrial fibrillation, ischemic stroke, or new hospitalization for heart failure)., Results: 42 patients developed the primary composite outcome over a median follow-up of 55.6 months. After stratifying patients by baseline hepcidin tertiles [1st tertile: median hepcidin 1.04 (IQR 0.50-1.95) nmol/L, 2nd tertile: 3.81 (IQR 3.01-4-42) nmol/L and 3rd tertile: 7.72 (IQR 6.37-10.4) nmol/L], the risk of developing the primary composite outcome in patients in the 3rd tertile was double that of patients in the 1st and 2nd tertile combined (unadjusted hazard ratio [HR] 2.32, 95%CI 1.27-4.26; p = 0.007). This risk was not attenuated after adjustment for age, sex, adiposity measures, smoking, hypertension, statin use, antiplatelet medication use, plasma hs-C-reactive protein and ferritin concentrations (adjusted HR 2.53, 95%CI 1.27-5.03; p = 0.008)., Conclusions: In outpatients with T2DM, higher baseline hepcidin concentrations were strongly associated with an increased long-term risk of overall mortality or nonfatal cardiovascular events, even after adjustment for established cardiovascular risk factors, plasma ferritin concentrations, medication use, and other potential confounders., (© 2024. The Author(s).)

Background: H 2 S imbalances in the intestinal tract trigger Crohn's disease (CD), a chronic inflammatory gastrointestinal disorder characterized by microbiota dysbiosis and barrier dysfunction. However, a comprehensive understanding of H 2 S generation in the gut, and the contributions of both microbiota and host to systemic H 2 S levels in CD, remain to be elucidated. This investigation aimed to enhance comprehension regarding the sulfidogenic potential of both the human host and the gut microbiota., Results: Our analysis of a treatment-naive CD cohorts' fecal metagenomic and biopsy metatranscriptomic data revealed reduced expression of host endogenous H 2 S generation genes alongside increased abundance of microbial exogenous H 2 S production genes in correlation with CD. While prior studies focused on microbial H 2 S production via dissimilatory sulfite reductases, our metagenomic analysis suggests the assimilatory sulfate reduction (ASR) pathway is a more significant contributor in the human gut, given its high prevalence and abundance. Subsequently, we validated our hypothesis experimentally by generating ASR-deficient E. coli mutants ∆cysJ and ∆cysM through the deletion of sulfite reductase and L-cysteine synthase genes. This alteration significantly affected bacterial sulfidogenic capacity, colon epithelial cell viability, and colonic mucin sulfation, ultimately leading to colitis in murine model. Further study revealed that gut microbiota degrade sulfopolysaccharides and assimilate sulfate to produce H 2 S via the ASR pathway, highlighting the role of sulfopolysaccharides in colitis and cautioning against their use as food additives., Conclusions: Our study significantly advances understanding of microbial sulfur metabolism in the human gut, elucidating the complex interplay between diet, gut microbiota, and host sulfur metabolism. We highlight the microbial ASR pathway as an overlooked endogenous H 2 S producer and a potential therapeutic target for managing CD. Video Abstract., (© 2024. The Author(s).)

Objectives: In this study, we aimed to validate the performance of the PAX1 and JAM3 methylation (PAX1 m /JAM3 m ) test as a triage tool for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3 +) in non-16/18 high-risk human papillomavirus-positive patients (non-16/18 hrHPV +)., Methods: The triage performance of liquid-based cytology (LBC) and the PAX1 m /JAM3 m test for detecting CIN3 + were compared., Results: In total, 1851 participants had cervical histological outcomes and were included in the analysis. The sensitivity/specificity of the LBC test results with atypical squamous cells of undetermined significance or worse (LBC ≥ ASCUS) and the PAX1 m /JAM3 m test were 90.1%/26.7% and 84.8%/88.5%, respectively. PAX1 m /JAM3 m ( +) had the highest diagnostic AUC (0.866, 95% confidence interval (CI) 0.837-0.896) in the whole cohort. All cancers (n = 20) were detected by PAX1 m /JAM3 m (+). Compared with LBC ≥ ASCUS, PAX1 m /JAM3 m (+) reduced the number of patients who needed referral for colposcopy by 57.21% (74.66% vs. 17.45%). The odds ratios for detecting CIN3 + by LBC ≥ ASCUS and PAX1 m /JAM3 m (+) were 3.3 (95% CI 2.0-5.9) and 42.6 (27.1-69.6), respectively (p < 0.001). The combination of LBC ≥ ASCUS or PAX1 m /JAM3 m (+) slightly increased the diagnostic sensitivity (98.0%, 95% CI: 95.8-100%) and referral rate (77.09%) but reduced the diagnostic specificity (24.8%, 22.7-26.8%)., Conclusions: In non-16/18 hrHPV(+) women, PAX1 m /JAM3 m was superior to cytology for detecting CIN3 + . Compared with LBC ≥ ASCUS, PAX1 m /JAM3 m (+) reduced the number of significant referrals to colposcopy without compromising diagnostic sensitivity., (© 2024. The Author(s).)

Background: Adherence to healthy lifestyle habits has become a mainstream approach for lessening the burden of cardiovascular disease (CVD) during initial prevention efforts. The purpose of this study was to investigate the prevalence of four healthy lifestyle habits, the associated factors, and their impact on all-cause and cardiovascular mortality among residents of Guangxi Zhuang Autonomous Region., Methods: From 2015 to 2019, individuals between the ages of 35 and 75 from Guangxi Zhuang Autonomous Region were recruited through the ChinaHeart Million Person Project. Our study examined four healthy lifestyle habits: not smoking, no or moderate amounts of alcohol, sufficient leisure time physical activity (LTPA) and a balanced diet., Results: Out of the 19,969 individuals involved, the majority, 77.3% did not smoke, while 96.7% had limited alcohol intake, 24.5% engaged in sufficient LTPA, 5.5% followed a balanced diet, and merely 1.7% adhered to all four healthy lifestyle habits. Participants who were women, older, nonfarmers, living in cities, with a high income or level of education, or had hypertension or diabetes were more likely to follow all four healthy lifestyle habits (p < 0.001). People who followed the three healthy lifestyle habits had reduced chances of death from all cause (HR 0.34[95% CI:0.15,0.76]) and cardiovascular-related death (HR 0.23 [95% CI: 0.07, 0.68]) (p < 0.01) over a median period of 3.5 years., Conclusions: In Guangxi Province, the level of adherence to healthy lifestyle habits is very minimal. Therefore, population-specific health promotion strategies are urgently needed., (© 2024. The Author(s).)

Background: Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging., Methods: Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO 2 )-loaded nanoprobes (Cur@PC-HA/CeO 2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice., Results: Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO 2 , thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission., Conclusion: This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses., (© 2024. The Author(s).)

Gene therapy has made considerable strides in recent years. More than 4000 protein-coding genes have been implicated in more than 6000 genetic diseases; next-generation sequencing has dramatically revolutionized the diagnosis of genetic diseases. Most genetic diseases are considered very rare or ultrarare, defined here as having fewer than 1:100,000 cases, but only one of the 12 approved gene therapies (excluding RNA therapies) targets an ultrarare disease. This article explores three gene supplementation therapy approaches suitable for various rare genetic diseases: lentiviral vector-modified autologous CD34 + hematopoietic stem cell transplantation, systemic delivery of adeno-associated virus (AAV) vectors to the liver, and local AAV delivery to the cerebrospinal fluid and brain. Together with RNA therapies, we propose a potential business model for these gene therapies., (© 2024. The Author(s).)

Background: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial., Methods: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality., Results: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT., Conclusion: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant., (© 2024. The Author(s).)

The prevention and treatment of gastrointestinal mucosal injury caused by a plateau hypoxic environment is a clinical conundrum due to the unclear mechanism of this syndrome; however, oxidative stress and microbiota dysbiosis may be involved. The Robinia pseudoacacia L. flower, homologous to a functional food, exhibits various pharmacological effects, such as antioxidant, antibacterial, and hemostatic activities. An increasing number of studies have revealed that plant exosome-like nanoparticles (PELNs) can improve the intestinal microbiota and exert antioxidant effects. In this study, the oral administration of Robinia pseudoacacia L. flower exosome-like nanoparticles (RFELNs) significantly ameliorated hypoxia-induced gastric and small intestinal mucosal injury in mice by downregulating hypoxia-inducible factor-1α (HIF-1α) and HIF-2α expression and inhibiting hypoxia-mediated ferroptosis. In addition, oral RFELNs partially improved hypoxia-induced microbial and metabolic disorders of the stomach and small intestine. Notably, RFELNs displayed specific targeting to the gastrointestinal tract. In vitro experiments using gastric and small intestinal epithelial cell lines showed that cell death caused by elevated HIF-1α and HIF-2α under 1% O 2 mainly occurred via ferroptosis. RFELNs obviously inhibited HIF-1α and HIF-2α expression and downregulated the expression of NOX4 and ALOX5, which drive reactive oxygen species production and lipid peroxidation, respectively, suppressing ferroptosis under hypoxia. In conclusion, our findings underscore the potential of oral RFELNs as novel, naturally derived agents targeting the gastrointestinal tract, providing a promising therapeutic approach for hypoxia-induced gastric and small intestinal mucosal ferroptosis., (© 2024. The Author(s).)

Background: Congenital Myasthenic Syndromes (CMS) are rare genetic diseases, which share as a common denominator muscle fatigability due to failure of neuromuscular transmission. A distinctive clinical feature of presynaptic CMS variants caused by defects of the synthesis of acetylcholine is the association with life-threatening episodes of apnea. One of these variants is caused by mutations in the SLC5A7 gene, which encodes the sodium-dependent HC-3 high-affinity choline transporter 1 (CHT1). To our knowledge there are no published cases of this CMS type in Latin America., Case Presentation: We present two cases of CHT1-CMS. Both patients were males presenting with repeated episodes of apnea, hypotonia, weakness, ptosis, mild ophthalmoparesis, and bulbar deficit. The first case also presented one isolated seizure, while the second case showed global developmental delay. Both cases, exhibited incomplete improvement with treatment with pyridostigmine., Conclusions: This report emphasizes the broad incidence of CMS with episodic apnea caused by mutations in the SLC5A7 gene and the frequent association of this condition with serious manifestations of central nervous system involvement., (© 2024. The Author(s).)

Background: We evaluated the prevalence of "heart stress" (HS) based on NT-proBNP cut-points proposed by the 2023 Consensus of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in asymptomatic patients with T2DM and hypertension or high-normal blood pressure (BP) eligible for SGLT2 inhibitors (SGLT2i) and/or GLP-1 receptor agonists (GLP1-RA), drugs with proven benefits on reducing the incidence of HF, hospitalizations, cardiovascular events and mortality., Methods: A cross-sectional multicentric study was conducted on 192 consecutive outpatients, aged ≥ 55 years, with hypertension or high-normal BP, referred to three diabetology units. NT-proBNP was collected before starting new anti-diabetic therapy. Patients with known HF were excluded, and participants were classified based on the age-adjusted NT-proBNP cut-points., Results: Mean age: 70.3 ± 7.8 years (67.5% males). Patients with obesity (BMI ≥ 30 Kg/m 2 ): 63.8%. Median NT-proBNP: 96.0 (38.8-213.0) pg/mL. Prevalence of chronic kidney disease (CKD, eGFR < 60 mL/min/1.73m 2 ): 32.1%. Mean arterial BP: 138.5/77.0 ± 15.8/9.9 mmHg. The NT-proBNP values, according to the proposed age-adjusted cut-points, classified 28.6% of patients as "HS likely" (organize elective echocardiography and specialist evaluation), 43.2% as "HS not likely" (a grey area, repeat NT-proBNP at six months) and 28.2% as "very unlikely HS" (repeat NT-proBNP at one year). The presence of CKD and the number of anti-hypertensive drugs, but not glycemic parameters, were independently associated with HS., Conclusions: According to NT-proBNP, over a quarter of T2DM patients with hypertension/high-normal BP, among those eligible for SGLT2i and/or GLP1-RA, were already at risk of cardiac damage, even subclinical. Most would receive an indication to echocardiogram and be referred to a specialist, allowing the early implementation of effective strategies to prevent or delay the progression to advanced stages of cardiac disease and overt HF., (© 2024. The Author(s).)

Background: Calcification is common in advanced atheromatous plaque, but its clinical significance remains unclear. This study aimed to assess the prevalence of plaque calcification in the moderate-to-severe internal carotid artery stenosis and investigate its relationship with ipsilateral ischemia., Methods: The retrospective study included 178 patients detected with proximal internal carotid artery (pICA) stenosis of ≥ 50% on multidetector computed tomography at Zhejiang Hospital from January 2019 to March 2023. Association between plaque calcification characteristics (calcification thickness, position, type, circumferential extent, calcium volume and calcium score) and ipsilateral cerebrovascular events was analyzed., Results: The 178 patients (mean age 71.24 ± 10.02 years, 79.78% males) had 224 stenosed pICAs overall. Plaque calcification was noted in 200/224 (89.29%) arteries. Calcification rates were higher in older age-groups. Calcification volume (r = 0.219, p < 0.001) and calcification score (r = 0.230, p < 0.001) were correlated with age. Ipsilateral ischemic events were significantly more common in the noncalcification group than in the calcification group (χ 2  = 4.160, p = 0.041). The most common calcification type was positive rim sign calcification (87/200, 43.50%), followed by bulky calcification (66/200, 33.00%); both were significantly associated with ischemic events (χ 2  = 10.448, p = 0.001 and χ 2  = 4.552, p = 0.033, respectively). Calcification position, thickness, and circumferential extent, and calcification volume and score, were not associated with ischemic events. In multivariate analysis, positive rim signs (OR = 2.795, 95%CI 1.182-6.608, p = 0.019) was an independent predictor of ischemic events., Conclusions: Plaque calcification in proximal internal carotid artery is common, and prevalence increases with age. Calcification characteristics could be predictive of ipsilateral ischemic events. The positive rim sign within plaque is a high-risk factor for a future ischemic event., (© 2024. The Author(s).)

Thrombotic cardiovascular diseases are a prevalent factor contributing to both physical impairment and mortality. Thrombolysis and ischemic mitigation have emerged as leading contemporary therapeutic approaches for addressing the consequences of ischemic injury and reperfusion damage. Herein, an innovative cellular-cloaked spermatozoon-driven microcellular submarine (SPCS), comprised of multimodal motifs, was designed to integrate nano-assembly thrombolytics with an immunomodulatory ability derived from innate magnetic hyperthermia. Rheotaxis-based navigation was utilized to home to and cross the clot barrier, and finally accumulate in ischemic vascular organs, where the thrombolytic motif was "switched-on" by the action of thrombus magnetic red blood cell-driven magnetic hyperthermia. In a murine model, the SPCS system combining innate magnetic hyperthermia demonstrated the capacity to augment delivery efficacy, produce nanotherapeutic outcomes, exhibit potent thrombolytic activity, and ameliorate ischemic tissue damage. These findings underscore the multifaceted potential of our designed approach, offering both thrombolytic and ischemia-mitigating effects. Given its extended therapeutic effects and thrombus-targeting capability, this biocompatible SPCS system holds promise as an innovative therapeutic agent for enhancing efficacy and preventing risks after managing thrombosis., (© 2024. The Author(s).)

Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC., (© 2024. The Author(s).)

Pseudo-Meigs syndrome is a rare syndrome characterized by hydrothorax and ascites associated with pelvic masses, and patients occasionally present with elevated serum cancer antigen-125 (CA125) levels. Hydropic leiomyoma (HLM) is an uncommon subtype of uterine leiomyoma characterized by hydropic degeneration and secondary cystic changes. Rapidly enlarging HLMs accompanied by hydrothorax, ascites, and elevated CA125 levels may be misdiagnosed as malignant tumors. Here, we report a case of HLM in a 45-year-old Chinese woman who presented with ascites and hydrothorax. Preoperative abdominopelvic CT revealed a giant solid mass in the fundus uteri measuring 20 × 15 × 12 cm. Her serum CA125 level was elevated to 247.7 U/ml, while her hydrothorax CA125 level was 304.60 U/ml. The patient was initially diagnosed with uterine malignancy and underwent total abdominal hysterectomy and adhesiolysis. Pathological examination confirmed the presence of a uterine hydropic leiomyoma with cystic changes. After tumor removal, the ascites and hydrothorax subsided quickly, with no evidence of recurrence. The patient's serum CA125 level decreased to 116.90 U/mL on Day 7 and 5.6 U/mL on Day 40 postsurgery. Follow-up data were obtained at 6 months, 1 year, and 2 years after surgery, and no recurrence of ascites or hydrothorax was observed. This case highlights the importance of accurate diagnosis and appropriate management of HLM to achieve successful outcomes., (© 2024. The Author(s).)

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a multifaceted neurodevelopmental psychiatric condition that typically emerges during childhood but often persists into adulthood, significantly impacting individuals' functioning, relationships, productivity, and overall quality of life. However, the current diagnostic process exhibits limitations that can significantly affect its overall effectiveness. Notably, its face-to-face and time-consuming nature, coupled with the reliance on subjective recall of historical information and clinician subjectivity, stand out as key challenges. To address these limitations, objective measures such as neuropsychological evaluations, imaging techniques and physiological monitoring of the Autonomic Nervous System functioning, have been explored., Methods: The main aim of this study was to investigate whether physiological data (i.e., Electrodermal Activity, Heart Rate Variability, and Skin Temperature) can serve as meaningful indicators of ADHD, evaluating its utility in distinguishing adult ADHD patients. This observational, case-control study included a total of 76 adult participants (32 ADHD patients and 44 healthy controls) who underwent a series of Stroop tests, while their physiological data was passively collected using a multi-sensor wearable device. Univariate feature analysis was employed to identify the tests that triggered significant signal responses, while the Informative k-Nearest Neighbors (KNN) algorithm was used to filter out less informative data points. Finally, a machine-learning decision pipeline incorporating various classification algorithms, including Logistic Regression, KNN, Random Forests, and Support Vector Machines (SVM), was utilized for ADHD patient detection., Results: Results indicate that the SVM-based model yielded the optimal performance, achieving 81.6% accuracy, maintaining a balance between the experimental and control groups, with sensitivity and specificity of 81.4% and 81.9%, respectively. Additionally, integration of data from all physiological signals yielded the best results, suggesting that each modality captures unique aspects of ADHD., Conclusions: This study underscores the potential of physiological signals as valuable diagnostic indicators of adult ADHD. For the first time, to the best of our knowledge, our findings demonstrate that multimodal physiological data collected via wearable devices can complement traditional diagnostic approaches. Further research is warranted to explore the clinical applications and long-term implications of utilizing physiological markers in ADHD diagnosis and management., (© 2024. The Author(s).)

Background: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile., Methods: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment., Results: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1., Conclusions: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings., (© 2024. The Author(s).)

Background: DNA hypermethylation and hotspot mutations were frequently observed in the upstream and core promoter of telomerase reverse transcriptase (TERT), respectively, and they were associated with increased TERT expression and adverse clinical outcomes in thyroid cancer. In TERT promoter mutant cancer cells, the hypomethylated TERT mutant allele was active and the hypermethylated TERT wild-type allele was silenced. However, whether and how the upstream promoter methylation regulates TERT expression in TERT mutation-negative cells were largely unknown., Methods: DNA demethylating agents 5-azacytidine and decitabine and a genomic locus-specific demethylation system based on dCas9-TET1 were used to assess the effects of TERT upstream promoter methylation on TERT expression, cell growth and apoptosis of thyroid cancer cells. Regulatory proteins binding to TERT promoter were identified by CRISPR affinity purification in situ of regulatory elements (CAPTURE) combined with mass spectrometry. The enrichments of selected regulatory proteins and histone modifications were evaluated by chromatin immunoprecipitation., Results: The level of DNA methylation at TERT upstream promoter and expression of TERT were significantly decreased after treatment with 5-azacytidine or decitabine in TERT promoter wild-type thyroid cancer cells. Genomic locus-specific demethylation of TERT upstream promoter induced TERT downregulation, along with cell apoptosis and growth inhibition. Consistently, demethylating agents sharply inhibited the growth of thyroid cancer cells harboring hypermethylated TERT but had little effect on cells with TERT hypomethylation. Moreover, we identified that the chromatin remodeling protein CHD4 binds to methylated TERT upstream promoter and promotes its transcription by suppressing the enrichment of H3K9me3 and H3K27me3 at TERT promoter., Conclusions: This study uncovered the mechanism of promoter methylation mediated TERT activation in TERT promoter mutation-negative thyroid cancer cells and indicated TERT upstream promoter methylation as a therapeutic target for thyroid cancer., (© 2024. The Author(s).)

Background: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes., Methods: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery., Results: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP., Conclusion: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives., (© 2024. The Author(s).)