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Abstract Background The high transmissibility of the Omicron variants of severe acute respiratory syndrome coronavirus 2 continues to impose a significant burden on public health systems worldwide. Continuous mutations in the virus challenge the efficacy of vaccines and prior immunity from other variants, posing a severe threat to human health. Therefore, there is an urgent need to predict mutations of the Omicron variants and identify key factors influencing their spread. This study investigated critical amino acid mutations of the Omicron variants using epidemiological data and the mechanisms underlying their transmission. The aim was to understand the key factors driving the spread of the Omicron variants and provide insights for effective control and prevention strategies. Methods A total of 488,646 Omicron cases recorded between December 2021 and February 2023 were analyzed using a sliding time window and the Epi Score model, which has high accuracy for the identification of mutation sites. MutPred2, PolyPhen2 and VarSite tools were used to predict future mutations and identify factors driving the prevalence of the Omicron variants. Results Epi Scores showed fluctuating patterns at mutation sites, highlighting N969K, Y505H, N764K, T478K, and S371F mutations on the spike protein as significant for future prevention efforts. The spread of the Omicron variants was linked to changes in the viral entry pathway and improved angiotensin‐converting enzyme 2 (ACE2) binding and immune evasion tactics. Conclusions The findings of this study reveal trends in the evolution of the Omicron variants, including altered cell entry, increased affinity for ACE2, and evasion of the immune system. These factors are critical for understanding the global spread of the Omicron variants and developing effective control strategies.

Abstract Machine learning (ML) has achieved substantial success in performing healthcare tasks in which the configuration of every part of the ML pipeline relies heavily on technical knowledge. To help professionals with borderline expertise to better use ML techniques, Automated ML (AutoML) has emerged as a prospective solution. However, most models generated by AutoML are black boxes that are challenging to comprehend and deploy in healthcare settings. We conducted a systematic review to examine AutoML with interpretation systems for healthcare. We searched four databases (MEDLINE, EMBASE, Web of Science, and Scopus) complemented with seven prestigious ML conferences (AAAI, ACL, ICLR, ICML, IJCAI, KDD, and NeurIPS) that reported AutoML with interpretation for healthcare before September 1, 2023. We included 118 articles related to AutoML with interpretation in healthcare. First, we illustrated AutoML techniques used in the included publications, including automated data preparation, automated feature engineering, and automated model development, accompanied by a real‐world case study to demonstrate the advantages of AutoML over classic ML. Then, we summarized interpretation methods: feature interaction and importance, data dimensionality reduction, intrinsically interpretable models, and knowledge distillation and rule extraction. Finally, we detailed how AutoML with interpretation has been used for six major data types: image, free text, tabular data, signal, genomic sequences, and multi‐modality. To some extent, AutoML with interpretation provides effortless development and improves users' trust in ML in healthcare settings. In future studies, researchers should explore automated data preparation, seamless integration of automation and interpretation, compatibility with multi‐modality, and utilization of foundation models.

Abstract Background Patient navigators, whose value has become increasingly apparent, still face significant challenges, including a lack of support, funding, and recognition. These challenges have been exacerbated in the wake of COVID‐19 pandemic. Methods This study explored the potential use of artificial intelligence (AI) in patient navigation. Data were collected through structured surveys and individual interviews with patient navigators from a variety of institutions and professional backgrounds. The data were analyzed to understand the current state of patient navigation, identify existing gaps, and suggest best practices for the future. Results The findings showed that patient navigators (a) have diverse backgrounds and responsibilities, (b) lack technology support for their work, (c) are at risk for burnout, with the extent varying based on the level of technical support received, and (d) report significant overlap between current barriers and those that could potentially be addressed with AI‐driven technologies. Conclusion A novel intervention, that is enabled by AI and other technologies and tailored to individual needs, has the potential to reduce burnout, increase capacity, and help ensure the sustainability of patient navigation and other areas of healthcare. By addressing the specific needs of individual patients, this type of intervention could help improve the overall effectiveness of patient navigation and support the long‐term sustainability of the role.

Abstract Background Major salivary duct carcinomas (MSDCs) often involve the regional lymph nodes (LNs). However, the clinical value of LN parameters in patients with MSDCs is unclear. We aimed to investigate the optimal cut‐off points for number of positive LNs (PLNN) and ratio of positive LNs (PLNRs) and their prognostic value in patients with MSDC. Study Design Retrospective cohort. Methods We retrospectively reviewed relevant data extracted from the Surveillance, Epidemiology, and End Results database on patients with MSDC who had undergone surgery between 2004 and 2016. The optimal PLNN and positive lymph node ratio (PLNR) cut‐off points were identified using the X‐tile program. Kaplan–Meier and Cox regression analyses were performed to determine prognostic factors. Results Overall, 290 patients were enrolled, 57.6% of whom had LN metastases. Advanced T stage in the submandibular gland and unpaired lesions were associated with LN involvement. Positive LNs, late T stage, and submandibular gland location were associated with poor overall survival (OS). The 5‐year OS rates of patients with negative and positive LNs were 74.3% and 36.5%, respectively. PLNN > 16 and PLNR > 0.48 were the best cut‐off points. The 5‐year OS of patients with PLNN ≤ 16 and PLNN > 16 was 42.8% and 15.4%, respectively. The 5‐year OS rates were 46.8% for patients with PLNR ≤ 0.48 and 26.3% for patients with PLNR > 0.48. PLNR was a strong prognostic factor for patients with MSDC with LN metastases. Conclusions PLNR reflects both the effects of LN dissection and PLNN. Furthermore, its prognostic value in patients with MSDC exceeds that of PLNN. Patients with high PLNRs should be followed closely after surgery.

Abstract Background Histopathological patterns of periampullary cancers (PAC) provide valuable information for clinicians in the selection of effective postoperative therapies and serve as a prognostic marker for patients. Therefore, this study was conducted to determine the surgical management and histopathological patterns of PAC necessary to achieve excellent surgical outcomes. Methods This prospective study was conducted from October 2021 to September 2023 at Ibn Sina Specialized Hospital, Khartoum, Sudan. Eighty patients diagnosed with resectable PAC were enrolled. Results PAC was more prevalent in male patients (52.5%), with a male: female ratio of 1.1:1.0. The peak incidence occurred between 46 and 60 years, representing 38.75% of patients. The most significant reported comorbidity was cigarette smoking (36.25% of patients). Scleral icterus was found in 47.5% of patients. Pancreatic head cancer was found in 55% of patients. Histopathological analysis revealed adenocarcinoma in 82.5% of patients. R0 resection (tumor‐free margins) was the most common resection category (87.5% of patients). Lymphovascular invasion was detected in 37.5% of patients. Malignant lymph node involvement (1–3 nodes) was found 47.5% of patients. Perineural invasion was found in 55%. Finally, the most common histopathological differentiation of PAC was well‐differentiated (Grade I) in 67.5% of patients. The mortality rate was 0%. Conclusions Updated knowledge regarding the management modalities of PAC is a prerequisite for accurate histopathological assessment and good surgical outcomes. Furthermore, histopathological analysis helps clinicians to select effective postoperative therapies for greater improvement in survival outcomes.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is one of the most common urological diseases and the most common subtype of renal cell carcinoma. Nuclear mitochondria‐related genes (MTRGs) play an essential role in cancer, but their effect on ccRCC has not been clarified. This work aimed to investigate the role of nuclear MTRGs in ccRCC. Methods We collected nuclear MTRGs from the MITOMAP database and obtained the ccRCC profile from the TCGA database. Gene expression validation came from the GEO database. The ccRCC subtypes were determined by unsupervised clustering analysis based on the nuclear MTRGs. Immune scores were computed using the EPIC algorithm. The drug sensitivity scores were calculated using GDSC resources. A nomogram explored the diagnostic value of the nuclear MTRGs. Results In total, 11 nuclear MTRGs were identified as both related to prognosis and differentially expressed in ccRCC, showing a significant positive correlation with CD274 expression. We determined two subtypes of ccRCC based on these genes and found remarkable differences in survival status, immune infiltration, mutation landscape, and drug sensitivity between the two subtypes. The high‐MTRG group had a better prognosis and a lower tumor stage than the low‐MTRG group. Immune checkpoint blockade therapy was more effective for the high‐MTRG group. A nomogram based on the nuclear MTRGs concluded that patients with a higher score had poorer survival. SUCLA2 (succinate‐CoA ligase ADP‐forming subunit beta) was identified as the hub gene linked to ccRCC. High SUCLA2 expression showed a correlation with better survival and a negative correlation with the tumor mutation burden in ccRCC. Pan‐cancer analysis revealed wide‐ranging roles for SUCLA2 across human tumors. Conclusions Nuclear MTRGs play vital roles in determining the molecular features, immune infiltration, and drug sensitivity of ccRCC. High levels of nuclear MTRGs may indicate a better prognosis for patients with ccRCC. SUCLA2 is a representative nuclear MTRG and may serve as a protective biomarker in ccRCC. Our study provides therapeutic guidance and potential biomarkers for ccRCC patients, and contributes to the advancement of precision medicine.

Abstract Background This study evaluated the performance of generative artificial intelligence (AI) models on the Orthopaedic In‐Training Examination (OITE), an annual exam administered to U.S. orthopaedic residency programs. Methods ChatGPT 3.5 and Bing AI GPT 4.0 were evaluated on standardised sets of multiple‐choice questions drawn from the American Academy of Orthopaedic Surgeons OITE online question bank spanning 5 years (2018–2022). A total of 1165 questions were posed to each AI system. The performance of both systems was standardised using the latest versions of ChatGPT 3.5 and Bing AI GPT 4.0. Historical data of resident scores taken from the annual OITE technical reports was used as a comparison. Results Across the five datasets, ChatGPT 3.5 scored an average of 55.0% on the OITE questions. Bing AI GPT 4.0 scored higher with an average of 80.0%. In comparison, the average performance of orthopaedic residents in national accredited programs was 62.1%. Bing AI GPT 4.0 outperformed ChatGPT 3.5 and Accreditation Council for Graduate Medical Education examinees, and analysis of variance analysis demonstrated p

Abstract Mycobacterium tuberculosis, which mainly affects the lungs but can also invade other systems, presents a diagnostic challenge when co‐existing with autoimmune disease. We report a case of 31‐year‐old Asian woman with anti‐synthetase syndrome who developed abdominal and subcutaneous lumps during treatment, along with elevated tumor markers, raising suspicion of malignancy. Pathological examination revealed M. tuberculosis infection, changing the diagnosis to multifocal extrapulmonary tuberculosis. This case highlights the need for prompt and detailed evaluations, and the importance of broad differential diagnosis.

Abstract Background Agitated saline contrast echocardiography, essential for patent foramen ovale detection, typically uses a 10 mL saline protocol, which may lead to operator fatigue and compromise diagnostic accuracy. This study aimed to identify an optimal saline volume that balances diagnostic efficacy and minimizes operator fatigue. Methods Fifty‐three patients with suspected patent foramen ovale underwent echocardiography using three saline protocols: 10 mL (9 mL saline + 1 mL air), 7 mL (6.4 mL saline + 0.6 mL air), and 5 mL (4.6 mL saline + 0.4 mL air). The protocols were evaluated for their impact on microbubble signal intensity in the right atrium, right‐to‐left shunt grading, and operator fatigue, as assessed by the Borg CR10 scale. Results The signal intensities were comparable between the 10 mL and 7 mL protocols, while the 5 mL protocol showed significantly lower signal intensities at all time points (p

Abstract Bionic lubricant materials are a class of materials inspired by natural organisms and offer excellent lubrication properties and biocompatibility. In the field of sports medicine, their application opens up new possibilities for the prevention and treatment of sports‐related diseases. The authors will introduce the existing theoretical models of friction in the locomotor system, the characteristics and advantages of biomimetic lubrication materials and discuss in depth their applications in the field of sports medicine. The development of bionic lubrication materials opens up unprecedented opportunities for sports medicine to provide more effective and long‐lasting treatment options for patients.

Abstract Background Schizophrenia (SCZ) is a severe mental disorder of multifactorial origin in which the role of amino acids is relatively unknown. Based on the hypothesis that there is an imbalance in amino acid levels in individuals with SCZ compared with healthy controls (HCs), the aim of this study was to identify the 20 proteinogenic amino acids involved in protein synthesis. Methods This study included 43 sex‐ and age‐matched individuals: 20 HCs and 23 with SCZ diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria. Using proton nuclear magnetic resonance, we identified the serum levels of the 20 amino acids proteinogenic. We perform multivariate statistical exploratory analyzes to identify compounds, quantify, and identify the main biomarkers of SCZ. Results We identified the serum levels of 19 of the 20 amino acids. Cysteine, the main precursor of glutathione, was not detected. Multivariate exploratory analysis identified lysine, Tryptophan (TRP), and glutamate as possible biomarkers of SCZ. Both lysine and TRP levels were lower and glutamate levels were higher in individuals with SCZ than in HCs. The observed reduction in plasma TRP levels in SCZ was attributed to the activation of the kynurenine pathway and has implications for serotonin synthesis. A strong positive correlation was observed between lysine and TRP, and a weak negative correlation between lysine and glutamate. This result is consistent with the lysine catalysis process because lysine degradation generates glutamate and favors an increase in dopamine. Conclusions The results are consistent with the lysine catalysis process because lysine degradation generates glutamate and favors an increase in dopamine. We were unable to identify any studies suggesting a relationship between lysine catabolism and SCZ pathophysiology, but we recognize this association as innovative.

Abstract Background Tissue eosinophilia is a diagnostically challenging entity. An accurate diagnosis can benefit the patient with appropriate treatment. Histopathology is the gold standard. Manual counting results in errors and is time consuming. Artificial intelligence (AI) acts like a human brain in terms of memory and reproducibility. Methods The aim of this study was to determine the eosinophil count in gastrointestinal biopsies using AI and compare it with the manual method. A total of 400 digital images of hematoxylin and eosin‐stained slides of gastrointestinal biopsies were included in the study. Annotations were performed on images containing eosinophils. The neural network prepared using the Python language was a modified U‐Net architecture containing five down blocks and five up blocks. The results obtained using the AI model were compared with manual counts. Pearson's correlation coefficient and Cohen's kappa coefficient of agreement were used for statistical analysis. Results Pearson's correlation coefficient demonstrated a strong positive correlation between AI and manual eosinophil (0.8), which suggests a very strong correlation. The Cohen's kappa coefficient of agreement was 0.85, which corresponds to excellent agreement. Conclusions The manual eosinophil count and AI predictions demonstrated a very strong positive correlation. It is necessary to count eosinophils using an AI model because it saves time, and eliminates interobserver variability and human error.

Abstract Background Some studies suggest that the metabolic alterations linked to obesity in humans may increase the likelihood of developing dementia. However, there are currently no existing meta‐analyses exploring the possible occurrence of dementia in patients with metabolically healthy obesity (MHO). In the present study, we aimed to investigate a potential correlation between individuals with MHO and the likelihood of developing dementia. Method Our research focused on searching three databases to locate pertinent studies starting from January 10, 2023. We used sensitivity analysis, the Egger's test, and a visual funnel plot to separately assess the reliability of the research results and publication bias. We conducted this study according to a pre‐established protocol in the PROSPERO registry (CRD42023449459). Results We incorporated three potential cohort investigations. Individuals with good metabolic health and obesity showed a decreased likelihood of developing dementia compared with those who were metabolically healthy but not obese (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.68–0.92). In contrast, individuals who were metabolically unhealthy and nonobese had an increased likelihood of developing dementia (HR = 1.33; 95% CI 1.25–1.42), whereas the population with metabolically unhealthy obesity did not exhibit a notable association with dementia onset (HR = 1.06; 95% CI 0.83–1.37). Conclusion According to our meta‐analysis, patients with MHO had a reduced likelihood of developing general dementia and Alzheimer disease. Maintaining a well‐functioning metabolism can provide advantages in reducing the occurrence of dementia.

Abstract Background Peritoneal dialysis (PD) and conventional in‐center hemodialysis (HD) are treatment options for patients with end‐stage kidney disease (ESKD). However, their impact on all‐cause mortality is unclear. Methods We conducted a multicenter, open‐label, randomized, non‐inferiority trial to determine the effect of dialysis modality on mortality in patients with ESKD. Eligible patients were recruited from 30 sites across China and assigned to receive either PD or HD in a ratio of 1:1. The primary outcome was all‐cause mortality. Non‐inferiority was defined as the upper bound of the one‐sided 95% confidence interval (CI) for the hazard ratio (HR) being ≤1.25. Results A total of 414 patients with incident ESKD were randomly assigned to PD (n = 213) or HD (n = 201). During a median follow‐up of 1.7 years, 37 patients in the PD group and 31 in the HD group died, giving respective event rates per patient‐year of 0.061 and 0.071. The HR for mortality on PD in comparison with HD was 0.76 (95% CI 0.47–1.24) after adjustment for age, sex, and diabetes status, achieving the limit for non‐inferiority. There were more adverse events (p = 0.003), serious adverse events (p = 0.009), and adverse events leading to hospitalization (p = 0.003) in the PD group than in the HD group; however, there was no significant between‐group difference in adverse events leading to death or discontinuation of treatment. Conclusions PD was non‐inferior to conventional in‐center HD in terms of survival in patients with ESKD. Our findings underscore the need for shared decision‐making between physicians and patients regarding the selection of dialysis modality. Trial registration Registered at ClinicalTrials.gov (NCT01413074).

Abstract Background This study aimed to investigate the effectiveness of the Mostafa Maged maneuver compared with bimanual uterine compression for the management of postpartum hemorrhage during vaginal delivery. Methods This was a prospective study involving 200 patients divided into two groups with 100 patients in each group. Group I received (Mostafa Maged maneuver), and Group II received (routine bimanual uterine compression). The Mostafa Maged maneuver requires placing the right hand in the posterior fornix and positioning the left hand on the uterine fundus and posterior uterine wall via the abdomen exteriorly. The subsequent step involves holding the entire uterus against the symphysis pubis. We determined the duration of each maneuver until practitioner fatigue and evaluated whether oxytocin was administered after compression for each maneuver. Results No patients required blood transfusions in Group I (Mostafa Maged maneuver), unlike in Group II, in which 17/100 patients received blood transfusions after bimanual compression. There was a statistically significant difference (p

Abstract Adult patients with patent ductus arteriosus (PDA) have a higher procedural risk during transcatheter PDA closures than infants and children. Limited information is available on transcatheter occlusion in patients with PDA and concomitant comorbidities such as leukemia. We report a case of a 32‐year‐old man with chronic myeloid leukemia who developed sudden hemoptysis during PDA catheter closure. Immediate treatment involved embolization of a bleeding bronchial artery with polyvinyl alcohol particles. The patient successfully underwent PDA closure and hematopoietic cell transplantation 3 months later. This case emphasizes the importance of evaluating fragile vasculature in patients with comorbid chronic diseases.

Abstract Background The incidence of lung cancer combined with pulmonary tuberculosis has been increasing, but there is relatively limited published literature on the topic of lung cancer combined with tuberculosis (LC‐PTB) from a bibliometric perspective. Therefore, in this study, we aimed to quantitatively analyze the LC‐PTB‐related literature to better understand the current status of this field and identify future research trends. Methods We searched for articles related to LC‐PTB using the Web of Science Core Collection (SCI‐E) and conducted a visual analysis of publication quantity, countries, institutions, authors, journals, references, and keywords using bibliometric software (CiteSpace, VOSviewer, and Scimago Graphica). Results As of January 8, 2024, a total of 460 publications related to LC‐PTB were included for analysis from 3705 retrieved records. The number of publications has been increasing almost yearly, with most from China (n = 123), followed by the United States (n = 77). Taipei Medical University contributed the most publications (n = 11). Jing‐Yang Huang and Yung‐Po Liaw (eight documents each) ranked first among the included authors. The Journal of Thoracic Oncology was the most productive academic journal on LC‐PTB. The aggregation of key nodes in the co‐citation network and the chronological sequence indicated that LC‐PTB research has shifted from initial hotspots such as lung diseases, bronchitis, and exposure to recent areas, including immunotherapy, immune checkpoint inhibitors, and nivolumab. Conclusion In this study, we visualized the current status of LC‐PTB research as well as future trends using bibliometric methods, providing new insights into the differential diagnosis of LC‐PTB and its related promoting mechanisms.

Abstract Salamanders possess remarkable regenerative capacities for organ regeneration among tetrapod vertebrates. Previous research has primarily focused on studying the regeneration of canonical tissues or organs such as limbs, tail, brain, spinal cord, heart, and lens. The advancements made in these areas have broader implications for understanding regeneration and developing therapeutic approaches for these organs, not only in salamanders but also in other vertebrates. In recent years, there has been an increasing interest in studying the regeneration of non‐canonical organs in salamanders, such as the liver, lungs, kidneys, and pancreas. This diversification of research has opened up new avenues and provided potential solutions to challenging clinical problems. This review aims to summarize the progress made in the field of non‐canonical organ regeneration in salamanders and provides an outlook on future research directions.

Abstract Background The aims of this paper are to introduce Open spinal endoscopy (OSE), which is a new single hole split‐type spinal endoscopic technique that can achieve adequate decompression and lumbar discectomy with preservation of the facet joints and posterior ligamentous complex, and to determine whether it can be widely performed. Methods Data from 58 patients who were treated for lumbar disc herniation using the open spinal endoscopic technique at Anhui No. 2 Provincial People's Hospital between July, 2021 and February, 2022 were retrospectively analyzed. Pain in the lower back and legs was evaluated using the visual analog scale (VAS) score, neurologic status by the Japanese Orthopedic Association (JOA) score, and degree of disability by the Oswestry Disability Index (ODI). These evaluations were performed on the day before surgery and at the final postoperative follow‐up. Surgical outcomes were assessed using the modified MacNab criteria. The method described by Dohzono and Matsumura was used to evaluate facet joint preservation. Results After surgery, the VAS score decreased from 8.4 ± 3.1 to 0.8 ± 0.8 (p

Abstract Baveno VII criteria (B7C) and Baveno VI criteria (B6C) have been widely used to estimate the risk of hepatic decompensation. However, the impact of age on these criteria warrants further investigation. The international, multicenter cohort study included 1138 patients with compensated cirrhosis (median follow‐up of 40.6 months), aiming to evaluate the value of age in predicting hepatic decompensation. We identified age as an independent predictor of hepatic decompensation, with 60 years determined as the optimal cut‐off value. The occurrence of decompensation was 18.7% and 6.7% in the older (age ≥60 years) and younger (age 0.05). In conclusion, our study demonstrated that integrating age into the Baveno criteria could enhance the assessment of hepatic decompensation. Age should be considered before discharging patients with compensated cirrhosis from the surveillance of hepatic decompensation.

Abstract Lipoprotein(a) [Lp(a)] is an emerging predictor for atherosclerotic cardiovascular disease (ASCVD) but the association from a perspective on current risk stratification was unknown. A cohort of 9944 Chinese patients with ASCVD was recruited and refined into very‐high‐risk (VHR) and non‐VHR subgroups according to current guideline. Lp(a) plasma levels were divided by its concentration (

Abstract Acute anterior uveitis (AAU) is a common extra‐articular manifestation of ankylosing spondylitis (AS), particularly in patients positive for the human leucocyte antigen (HLA)‐B27 genetic marker. To explore the underlying mechanisms of HLA‐B27+ AS‐associated AAU, we employed single‐cell RNA sequencing to profile the transcriptomes of peripheral blood mononuclear cells in three HLA‐B27+ AS‐associated AAU patients and three healthy controls (HCs). We identified 11 distinct immune cell clusters, with a particular focus on monocytes, revealing six subsets, including three previously unidentified subsets, namely, GTPase immune‐associated proteins, Th17‐related, and lncRNA monocytes, with unique gene expression patterns. Significant differences in monocyte composition, activation states, and gene expression were observed between patients and HCs, particularly within HLA monocyte subpopulations. Notably, enhanced expression of X‐inactive specific transcript and myeloid cell nuclear differentiation antigen genes was validated across monocyte subclusters in patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis highlighted significant enrichment in antigen processing and presentation pathways, shedding light on the disease's molecular mechanisms. These findings provide novel insights into the molecular mechanisms of HLA‐B27+ AS‐associated AAU and may contribute to the development of targeted diagnostic and therapeutic strategies. Further clinical validation is essential.

Abstract Identification of therapeutic targets can directly elucidate the mechanism and effect of drug therapy, which is a central step in drug development. The disconnect between protein targets and phenotypes under complex mechanisms hampers comprehensive target understanding. Metabolomics, as a systems biology tool that captures phenotypic changes induced by exogenous compounds, has emerged as a valuable approach for target identification. A comprehensive overview was provided in this review to illustrate the principles and advantages of metabolomics, delving into the application of metabolomics in target identification. This review outlines various metabolomics‐based methods, such as dose–response metabolomics, stable isotope‐resolved metabolomics, and multiomics, which identify key enzymes and metabolic pathways affected by exogenous substances through dose‐dependent metabolite–drug interactions. Emerging techniques, including single‐cell metabolomics, artificial intelligence, and mass spectrometry imaging, are also explored for their potential to enhance target discovery. The review emphasizes metabolomics' critical role in advancing our understanding of disease mechanisms and accelerating targeted drug development, while acknowledging current challenges in the field.

Abstract Tumor immunotherapy has significantly transformed the field of oncology over the past decade. An optimal tumor immunotherapy would ideally elicit robust innate and adaptive immune responses within tumor immune microenvironment (TIME). Unfortunately, immune system experiences functional decline with chronological age, a process termed “immunosenescence,” which contributes to impaired immune responses against pathogens, suboptimal vaccination outcomes, and heightened vulnerability to various diseases, including cancer. In this context, we will elucidate hallmarks and molecular mechanisms underlying immunosenescence, detailing alterations in immunosenescence at molecular, cellular, organ, and disease levels. The role of immunosenescence in tumorigenesis and senescence‐related extracellular matrix (ECM) has also been addressed. Recognizing that immunosenescence is a dynamic process influenced by various factors, we will evaluate treatment strategies targeting hallmarks and molecular mechanisms, as well as methods for immune cell, organ restoration, and present emerging approaches in immunosenescence for tumor immunotherapy. The overarching goal of immunosenescence research is to prevent tumor development, recurrence, and metastasis, ultimately improving patient prognosis. Our review aims to reveal latest advancements and prospective directions in the field of immunosenescence research, offering a theoretical basis for development of practical anti‐immunosenescence and anti‐tumor strategies.

Abstract The filamentous temperature‐sensitive (Fts) protein FtsEX plays a pivotal role in Escherichia coli (E. coli) cell division by facilitating the activation of peptidoglycan hydrolysis through the adaptor EnvC. FtsEX belongs to the type VII ATP‐binding cassette (ABC) transporter superfamily, which harnesses ATP energy to induce mechanical force, triggering a cascade of conformational changes that activate the pathway. However, the precise mechanism by which FtsEX initiates mechanotransmission remains elusive. Due to the inherent instability of this type of ABC transporter protein in vitro, the conformation of FtsEX has solely been determined in the stabilized ATP‐bound state. To elucidate the dynamics of FtsEX, we characterized FtsEX and EnvC of various functional structures through cryo‐electron microscopy (cryo‐EM) and homology modeling. We validated the structures by molecular dynamics simulations. By site‐directed mutagenesis and phenotype screening, we also identified the functional residues involved in allosteric communication between FtsE and FtsX as well as FtsX and EnvC. Additionally, we discovered a potential role of phospholipids in stabilizing the complex conformation during mechanotransmission. This comprehensive exploration significantly enhances our understanding of the intricate mechanisms governing bacterial cell division and unveils potential molecular targets for developing innovative antimicrobial drugs to combat antibiotic resistance.

Abstract Small molecule drugs are increasingly emerging as innovative and effective treatments for various diseases, with mRNA therapeutics being a notable representative. The success of COVID‐19 vaccines has underscored the transformative potential of mRNA in RNA therapeutics. Within the RNA family, there is another unique type known as circRNA. This single‐stranded closed‐loop RNA molecule offers notable advantages over mRNA, including enhanced stability and prolonged protein expression, which may significantly impact therapeutic strategies. Furthermore, circRNA plays a pivotal role in the pathogenesis of various diseases, such as cancers, autoimmune disorders, and cardiovascular diseases, making it a promising clinical intervention target. Despite these benefits, the application of circRNA in clinical settings remains underexplored. This review provides a comprehensive overview of the current state of synthetic circRNA therapeutics, focusing on its synthesis, optimization, delivery, and diverse applications. It also addresses the challenges impeding the advancement of circRNA therapeutics from bench to bedside. By summarizing these aspects, the review aims to equip researchers with insights into the ongoing developments and future directions in circRNA therapeutics. Highlighting both the progress and the existing gaps in circRNA research, this review offers valuable perspectives for advancing the field and guiding future investigations.

Abstract Metal oxide sensor‐based electronic nose (E‐Nose) technology provides an easy to use method for breath analysis by detection of volatile organic compound (VOC)‐induced changes of electrical conductivity. Resulting signal patterns are then analyzed by machine learning (ML) algorithms. This study aimed to establish breath analysis by E‐Nose technology as a diagnostic tool for severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) pneumonia within a multi‐analyst experiment. Breath samples of 126 subjects with (n = 63) or without SARS‐CoV‐2 pneumonia (n = 63) were collected using the ReCIVA® Breath Sampler, enriched and stored on Tenax sorption tubes, and analyzed using an E‐Nose unit with 10 sensors. ML approaches were applied by three independent data analyst teams and included a wide range of classifiers, hyperparameters, training modes, and subsets of training data. Within the multi‐analyst experiment, all teams successfully classified individuals as infected or uninfected with an averaged area under the curve (AUC) larger than 90% and misclassification error lower than 19%, and identified the same sensor as most relevant to classification success. This new method using VOC enrichment and E‐Nose analysis combined with ML can yield results similar to polymerase chain reaction (PCR) detection and superior to point‐of‐care (POC) antigen testing. Reducing the sensor set to the most relevant sensor may prove interesting for developing targeted POC testing.

Abstract Advanced metastasis of hepatocellular carcinoma (HCC) significantly contributes to high death rates among patients. The efficiency of targeted therapies and chemotherapeutic agents shows individual variability. Therefore, there is no effective treatment for advanced HCC. Zinc finger proteins (ZFPs) are known to be crucial in various tumors, especially on HCC. In our study, we verified that ZFP41 could suppress the progression and metastasis of HCC through in vitro and in vivo experiments. During the past years, N6‐methyladenine (m6A) regulation has also been increasingly reported in HCC. To investigate whether ZFP41 could be regulated via m6A methylation, our results showed that YTHDF3 bound to the mRNA of ZFP41 and degrade it. Subsequently, to further elucidate the function of ZFP41, we identified Snail, a well‐known oncogenic molecule, through RNA‐seq. As a canonical component in the epithelial‐to‐mesenchymal transition (EMT) pathway, Snail plays a pivotal role and is a critical marker for tumor invasion and metastasis. Our results showed ZFP41 could inhibit Snail and the EMT pathway through its transcriptional repression. In conclusion, our study revealed that ZFP41 is a potential prognostic element for patients with HCC, and targeting ZFP41 might be used for translational clinical applications as a promising therapeutic target.

Abstract Cancer neuroscience is an emerging field that investigates the intricate relationship between the nervous system and cancer, gaining increasing recognition for its importance. The central nervous system governs the development of the nervous system and directly affects brain tumors, and the peripheral nervous system (PNS) shapes the tumor microenvironment (TME) of peripheral tumors. Both systems are crucial in cancer initiation and progression, with recent studies revealing a more intricate role of the PNS within the TME. Tumors not only invade nerves but also persuade them through remodeling to further promote malignancy, creating a bidirectional interaction between nerves and cancers. Notably, immune cells also contribute to this communication, forming a triangular relationship that influences protumor inflammation and the effectiveness of immunotherapy. This review delves into the intricate mechanisms connecting the PNS and tumors, focusing on how various immune cell types influence nerve‒tumor interactions, emphasizing the clinical relevance of nerve‒tumor and nerve‒immune dynamics. By deepening our understanding of the interplay between nerves, cancer, and immune cells, this review has the potential to reshape tumor biology insights, inspire innovative therapies, and improve clinical outcomes for cancer patients.

Abstract Diabetic nephropathy (DN) is a frequent and costly complication of diabetes with limited understandings of mechanisms and therapies. Emerging evidence points to the important roles of interleukin‐33 (IL‐33) in acute kidney injury, yet its contribution to DN is still unclear. We here found a ubiquitous increase of IL‐33 and its receptor (ST2) in murine models and patients with DN. Surprisingly, both IL‐33 and ST2 knockdown aggravated renal lesions in DN, while overexpression of IL‐33 also exacerbated the condition. Further population‐based analyses revealed a positive correlation of IL‐33 expression with renal dysfunction in DN patients. Individuals with high IL‐33 expression‐related polygenic risk score had a higher DN risk. These findings confirmed the harmful effects of IL‐33 on DN. Conversely, endogenous and exogenous partial reduction of IL‐33 signaling conferred renoprotective effects in vivo and in vitro. Mechanistically, IL‐33 induced senescence by regulating cell cycle factors in HK‐2 cells, and accordingly senescence led to renal cell damage through the secretion of senescence‐related secretory phenotype (SASP) including IL‐33 and prostaglandins. Together, elevated IL‐33 accelerates cellular senescence to drive DN possibly by SASP production, while a partial blockage improves renal injury and senescence. Our findings pinpoint a possible and new avenue for DN interventions.

Abstract Circulating tumor DNA (ctDNA) methylation, an innovative liquid biopsy biomarker, has emerged as a promising tool in early cancer diagnosis, monitoring, and prognosis prediction. As a noninvasive approach, liquid biopsy overcomes the limitations of traditional tissue biopsy. Among various biomarkers, ctDNA methylation has garnered significant attention due to its high specificity and early detection capability across diverse cancer types. Despite its immense potential, the clinical application of ctDNA methylation faces substantial challenges pertaining to sensitivity, specificity, and standardization. In this review, we begin by introducing the basic biology and common detection techniques of ctDNA methylation. We then explore recent advancements and the challenges faced in the clinical application of ctDNA methylation in liquid biopsies. This includes progress in early screening and diagnosis, identification of clinical molecular subtypes, monitoring of recurrence and minimal residual disease (MRD), prediction of treatment response and prognosis, assessment of tumor burden, and determination of tissue origin. Finally, we discuss the future perspectives and challenges of ctDNA methylation detection in clinical applications. This comprehensive overview underscores the vital role of ctDNA methylation in enhancing cancer diagnostic accuracy, personalizing treatments, and effectively monitoring disease progression, providing valuable insights for future research and clinical practice.

Abstract DNA damage response (DDR) pathway is the coordinated cellular network dealing with the identification, signaling, and repair of DNA damage. It tightly regulates cell cycle progression and promotes DNA repair to minimize DNA damage to daughter cells. Key proteins involved in DDR are frequently mutated/inactivated in human cancers and promote genomic instability, a recognized hallmark of cancer. Besides being an intrinsic property of tumors, DDR also represents a unique therapeutic opportunity. Indeed, inhibition of DDR is expected to delay repair, causing persistent unrepaired breaks, to interfere with cell cycle progression, and to sensitize cancer cells to several DNA‐damaging agents, such as radiotherapy and chemotherapy. In addition, DDR defects in cancer cells have been shown to render these cells more dependent on the remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over the past two decades has led to the synthesis and testing of hundreds of small inhibitors against key DDR proteins, some of which have shown antitumor activity in human cancers. In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state‐of‐art of ataxia‐telangiectasia mutated, ataxia‐telangiectasia‐and‐Rad3‐related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.

Abstract Neoadjuvant immunochemotherapy (NAIC) achieves superior clinical benefits over neoadjuvant chemotherapy (NAC) in multiple types of human cancers, including gastric adenocarcinoma (GAC). However, it is poorly understood how the malignant epithelial cells and tumor immune microenvironment (TIME) might respond distinctly to NAIC and NAC that underlies therapeutic efficacy. Here treatment‐naive and paired tumor tissues from multiple centers were subjected to pathological, immunological, and transcriptomic analysis. NAIC demonstrated significantly increased rate of pathological complete response compared to NAC (pCR: 25% vs. 4%, p

Abstract Metabolism serves not only as the organism's energy source but also yields metabolites crucial for maintaining tissue homeostasis and overall health. Intestinal stem cells (ISCs) maintain intestinal homeostasis through continuous self‐renewal and differentiation divisions. The intricate relationship between metabolic pathways and intestinal homeostasis underscores their crucial interplay. Metabolic pathways have been shown to directly regulate ISC self‐renewal and influence ISC fate decisions under homeostatic conditions, but the cellular and molecular mechanisms remain incompletely understood. Understanding the intricate involvement of various pathways in maintaining intestinal homeostasis holds promise for devising innovative strategies to address intestinal diseases. Here, we provide a comprehensive review of recent advances in the regulation of intestinal homeostasis. We describe the regulation of intestinal homeostasis from multiple perspectives, including the regulation of intestinal epithelial cells, the regulation of the tissue microenvironment, and the key role of nutrient metabolism. We highlight the regulation of intestinal homeostasis and ISC by nutrient metabolism. This review provides a multifaceted perspective on how intestinal homeostasis is regulated and provides ideas for intestinal diseases and repair of intestinal damage.

Abstract The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.

Abstract Colorectal cancer (CRC) remains challenging to diagnose, necessitating the identification of a noninvasive biomarker that can differentiate it from other conditions such as inflammatory bowel diseases (IBD) and diverticular disease (DD). Raman spectroscopy (RS) stands out as a promising technique for monitoring blood biochemical profiles, with the potential to identify distinct signatures identifying CRC subjects. We performed RS analysis on dried plasma from 120 subjects: 32 CRC patients, 37 IBD patients, 20 DD patients, and 31 healthy controls. We also conducted longitudinal studies of CRC patient's postsurgery to monitor the spectral changes over time. We identified six spectral features that showed significant differences between CRC and non‐CRC patients, corresponding to tryptophan, tyrosine, phenylalanine, lipids, carotenoids, and disulfide bridges. These features enabled the classification of CRC patients with an accuracy of 87.5%. Moreover, longitudinal analysis revealed that the spectral differences normalized over 6 months after surgery, indicating their association with the presence of the disease. Our study demonstrates the potential of RS to identify specific biomolecular signatures related to CRC. These results suggest that RS could be a novel screening and monitoring tool, providing valuable insights for the development of noninvasive and accurate diagnostic methods for CRC.

Abstract Repair and preservation of the injured meniscus has become paramount in clinical practice. However, the complexities of various clinic stitching techniques for meniscus repair pose challenges for grassroots doctors. Hence, there is a compelling interest in innovative therapeutic strategies such as bioadhesives. An ideal bioadhesive must cure quickly in aqueous and blood environments, bind strongly, endure arthroscopic washing pressures, and degrade appropriately for tissue regeneration. Here, we present a tetra‐poly (ethylene glycol) (PEG)‐based hydrogel bioadhesive, boasting high biocompatibility, ultrafast gelation, facile injectable operation, and favorable mechanical strength. In view of the synergistic effects of chemical anchor and physical chain entanglement to tightly bind the meniscus, a seamless interface was formed between the surrounding meniscal tissues and hydrogels, enabling the longitudinal tear of the meniscus fused in situ to withstand large tensile force with the adhesive strength of 541.5 ± 31.4 kPa and arthroscopic washout resistance of 29.4 kPa. Superior to existing commercial adhesives, ours allows sutureless application and arthroscopic assistance, without requiring specialized clinical skills. This research is expected to significantly impact our understanding of meniscal healing and ultimately promote a simpler process for achieving functional and structural recovery in torn menisci.

Abstract Pharmacological agents regarding the most optimal treatments of acute pancreatitis remain. One‐carbon metabolism nutrients as therapeutic agents in many diseases might be involved in acute pancreatitis. The roles are acquired exploration in acute pancreatitis. We utilized Mendelian randomization to assess the causal impact of folate, homocysteine, and vitamin B12 (VB12) on acute pancreatitis. Wild‐type and corresponding genetically modified mouse models were used to verify the genetic correlating findings. A negative association between genetically predicted serum VB12 levels and risks of acute pancreatitis was identified in human population. The transcobalamin receptor (TCblR)/CD320 gene ablation that decreased cellular VB12 uptake and ATP production in pancreatic tissues promoted necrosis, resulting in much severe pathological changes of induced acute pancreatitis in mice. VB12 pretreatment and posttreatment dramatically increased ATP levels in pancreatic tissues and reduced the necrosis, then the elevated levels of amylase in serum, the levels of CK‐19, the activity of trypsin, and T lymphocyte infiltration in pancreatic tissues, prevented the pancreatic gross loss and ameliorated histopathological changes of mouse pancreases with induced acute pancreatitis. The results reveal that VB12 is potential as a therapeutic agent to inhibit tissue injuries and adaptive inflammatory responses in the pancreas in patients with acute pancreatitis.

Abstract Esophageal cancer (EC) is identified as a predominant health threat worldwide, with its highest incidence and mortality rates reported in China. The complex molecular mechanisms underlying EC, coupled with the differential incidence of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) across various regions, highlight the necessity for in‐depth research targeting molecular pathogenesis and innovative treatment strategies. Despite recent progress in targeted therapy and immunotherapy, challenges such as drug resistance and the lack of effective biomarkers for patient selection persist, impeding the optimization of therapeutic outcomes. Our review delves into the molecular pathology of EC, emphasizing genetic and epigenetic alterations, aberrant signaling pathways, tumor microenvironment factors, and the mechanisms of metastasis and immune evasion. We further scrutinize the current landscape of targeted therapies, including the roles of EGFR, HER2, and VEGFR, alongside the transformative impact of ICIs. The discussion extends to evaluating combination therapies, spotlighting the synergy between targeted and immune‐mediated treatments, and introduces the burgeoning domain of antibody–drug conjugates, bispecific antibodies, and multitarget‐directed ligands. This review lies in its holistic synthesis of EC's molecular underpinnings and therapeutic interventions, fused with an outlook on future directions including overcoming resistance mechanisms, biomarker discovery, and the potential of novel drug formulations.

Abstract Cancer is a leading cause of morbidity and mortality worldwide, and an increase in incidence is estimated in the next future, due to population aging, which requires the development of highly tolerable and low‐toxicity cancer treatment strategies. The use of nanotechnology to tailor treatments according to the genetic and immunophenotypic characteristics of a patient's tumor, and to allow its targeted release, can meet this need, improving the efficacy of treatment and minimizing side effects. Nanomedicine‐based approach for the diagnosis and treatment of cancer is a rapidly evolving field. Several nanoformulations are currently in clinical trials, and some have been approved and marketed. However, their large‐scale production and use are still hindered by an in‐depth debate involving ethics, intellectual property, safety and health concerns, technical issues, and costs. Here, we survey the key approaches, with specific reference to organ‐on chip technology, and cutting‐edge tools, such as CRISPR/Cas9 genome editing, through which nanosystems can meet the needs for personalized diagnostics and therapy in cancer patients. An update is provided on the nanopharmaceuticals approved and marketed for cancer therapy and those currently undergoing clinical trials. Finally, we discuss the emerging avenues in the field and the challenges to be overcome for the transfer of nano‐based precision oncology into clinical daily life.

Abstract IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, resulting in end‐stage renal disease and increased mortality rates. Prognostic biomarkers reflecting molecular mechanisms for effective IgAN management are urgently needed. Analysis of kidney single‐cell transcriptomic sequencing data demonstrated that IgAN expressed high‐expression levels of inflammatory cytokines TNFSF10, TNFSF12, CCL2, CXCL1, and CXCL12 than healthy controls (HCs). We also measured the urine proteins in 120 IgAN (57 stable and 63 progressive) and 32 HCs using the proximity extension assay (PEA), and the multivariable and least absolute shrinkage and selection operator (LASSO) logistic regression analysis both revealed that CXCL12, MCP1 were the prognostic significant variables to predict IgAN progression severity. These two proteins exhibited negative correlation with the estimated glomerular filtration rate (eGFR) and patients with higher expression levels of these two proteins had a higher probability to have poorer renal outcome. We further developed a risk index model utilizing CXCL12, MCP1, and baseline clinical indicators, which achieved an impressive area under the curve (AUC) of 0.896 for prediction of IgAN progression severity. Our study highlights the significance of the inflammatory protein biomarkers for noninvasive prediction of IgAN severity and progression, offering valuable insights for clinical management.

Abstract Cognitive impairments, which can be caused by neurodegenerative and cerebrovascular disease, represent a growing global health crisis with far‐reaching implications for individuals, families, healthcare systems, and economies worldwide. Notably, neurodegenerative‐induced cognitive impairment often presents a different pattern and severity compared to cerebrovascular‐induced cognitive impairment. With the development of computational technology, machine learning techniques have developed rapidly, which offers a powerful tool in radiomic analysis, allowing a more comprehensive model that can handle high‐dimensional, multivariate data compared to the traditional approach. Such models allow the prediction of the disease development, as well as accurately classify disease from overlapping symptoms, therefore facilitating clinical decision making. This review will focus on the application of machine learning‐based radiomics on cognitive impairment caused by neurogenerative and cerebrovascular disease. Within the neurodegenerative category, this review primarily focuses on Alzheimer's disease, while also covering other conditions such as Parkinson's disease, Lewy body dementia, and Huntington's disease. In the cerebrovascular category, we concentrate on poststroke cognitive impairment, including ischemic and hemorrhagic stroke, with additional attention given to small vessel disease and moyamoya disease. We also review the specific challenges and limitations when applying machine learning radiomics, and provide our suggestion to overcome those limitations towards the end, and discuss what could be done for future clinical use.

Abstract The TRIM (tripartite motif) family, with TRIM28 as a key member, plays a vital role in regulating health and disease. TRIM28 contains various functional domains essential for transcriptional regulation, primarily through its interaction with KRAB‐ZNF proteins, which influence chromatin remodeling and gene expression. Despite extensive research, the precise mechanisms by which TRIM28 impacts health and disease remain elusive. This review delves into TRIM28’s multifaceted roles in maintaining health, contributing to a variety of diseases, and influencing cancer progression. In cancers, TRIM28 exhibits a dual nature, functioning as both a tumor promoter and suppressor depending on the cellular context and cancer type. The review also explores its critical involvement in processes such as DNA repair, cell cycle regulation, epithelial‐to‐mesenchymal transition, and the maintenance of stem cell properties. By uncovering TRIM28’s complex roles across different cancers and other diseases, this review underscores its potential as a therapeutic target. The significance of TRIM28 as a versatile regulator opens the door to innovative therapeutic strategies, particularly in cancer treatment and the management of other diseases. Ongoing research into TRIM28 may yield key insights into disease progression and novel treatment options.

Abstract Regulated cell death (RCD) is crucial for the elimination of abnormal cells. In recent years, strategies aimed at inducing RCD, particularly apoptosis, have become increasingly important in cancer therapy. However, the ability of tumor cells to evade apoptosis has led to treatment resistance and relapse, prompting extensive research into alternative death processes in cancer cells. A recent study identified a novel form of RCD known as disulfidptosis, which is linked to disulfide stress. Cancer cells import cystine from the extracellular environment via solute carrier family 7 member 11 (SLC7A11) and convert it to cysteine using nicotinamide adenine dinucleotide phosphate (NADPH). When NADPH is deficient or its utilization is impaired, cystine accumulates, leading to the formation of disulfide bonds in the actin cytoskeleton, triggering disulfidptosis. Disulfidptosis reveals a metabolic vulnerability in tumors, offering new insights into cancer therapy strategies. This review provides a detailed overview of the mechanisms underlying disulfidptosis, the current research progress, and limitations. It also highlights innovative strategies for inducing disulfidptosis and explores the potential of combining these approaches with traditional cancer therapies, particularly immunotherapy, to expedite clinical translation.

Abstract Mutations in isocitrate dehydrogenase (IDH) are important markers of glioma prognosis. However, few studies have examined the gene expression regulatory network (GRN) in IDH‐mutant and wild‐type gliomas. In this study, single‐cell RNA sequencing and spatial transcriptome sequencing were used to analyze the GRN of cell subsets in patients with IDH‐mutant and wild‐type gliomas. Through gene transcriptional regulation analysis, we identified the M4 module, whose transcription factor activity is highly expressed in IDH wild‐type gliomas compared to IDH‐mutants. Enrichment analysis revealed that these genes were predominantly expressed in microglia and macrophages, with significant enrichment in interferon‐related signaling pathways. Interferon regulatory factor 7 (IRF7), a transcription factor within this pathway, showed the highest percentage of enrichment and was primarily localized in the core region of wild‐type IDH tumors. A machine‐learning prognostic model identified novel subgroups within the wild‐type IDH population. Additionally, IRF7 was shown to promote the proliferation and migration of T98G and U251 cells in vitro, and its knockdown affected glioma cell proliferation in vivo. This study systematically established the regulatory mechanism of IDH transcriptional activity in gliomas at the single‐cell level and drew a corresponding cell map. The study presents a transcriptional regulatory activity map for IDH wild‐type gliomas, involving single‐cell RNA sequencing and spatial transcriptomics to identify gene regulatory networks, machine learning models for IDH subtyping, and experimental validation, highlighting the role of IRF7 in glioma progression.

Abstract Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by the early presence of amyloid‐β (Aβ) and hyperphosphorylated tau. Identifying the neuropathological changes preceding cognitive decline is crucial for early intervention. Axon initial segment (AIS) maintains the orderly structure of the axon and is responsible for initiating action potentials (APs). To investigate the role of AIS in early stages of AD pathogenesis, we focused on alterations in the AIS of neurons from APP/PS1 mouse models harboring familial AD mutations. AIS length and electrophysiological properties were assessed in neurons using immunostaining and patch‐clamp techniques. The expression and function of ankyrin G (AnkG) isoforms were evaluated by western blot and rescue experiments. We observed a significant shortening of AIS in APP/PS1 mice, which correlated with impaired action potential propagation. Furthermore, a decrease in the 480 kDa isoform of AnkG was observed. Rescue of this isoform restored AIS plasticity and improved long‐term potentiation in APP/PS1 neurons. Our study implicates AIS plasticity alterations and AnkG dysregulation as early events in AD. The restoration of AIS integrity by the 480 kDa AnkG isoform presents a potential therapeutic strategy for AD, underscoring the importance of targeting AIS stability in neurodegenerative diseases.

Abstract Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia‐inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age‐related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia‐targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia‐induced pathways to enhance healthy aging and reduce the burden of age‐related diseases.

Abstract N6‐methyladenosine (m6A) is the most abundant RNA modification in eukaryotic cells. Previous studies have shown that m6A plays a critical role under both normal physiological and pathological conditions. Hematopoiesis and differentiation are highly regulated processes, and recent studies on m6A mRNA methylation have revealed how this modification controls cell fate in both normal and malignant hematopoietic states. However, despite these insights, a comprehensive understanding of its complex roles between normal hematopoietic development and malignant hematopoietic diseases remains elusive. This review first provides an overview of the components and biological functions of m6A modification regulators. Additionally, it highlights the origin, differentiation process, biological characteristics, and regulatory mechanisms of hematopoietic stem cells, as well as the features, immune properties, and self‐renewal pathways of leukemia stem cells. Last, the article systematically reviews the latest research advancements on the roles and mechanisms of m6A regulatory factors in normal hematopoiesis and related malignant diseases. More importantly, this review explores how targeting m6A regulators and various signaling pathways could effectively intervene in the development of leukemia, providing new insights and potential therapeutic targets. Targeting m6A modification may hold promise for achieving more precise and effective leukemia treatments.

Abstract Cholangiocarcinoma (CCA) was identified as a malignant tumor with rising incidence and mortality rates, and the roles of long noncoding RNA (lncRNA) in CCA remained not entirely clear. In this study, LINC00511 had high expression in CCA, which was closely related to poor prognosis. Knockdown of LINC00511 significantly inhibited cell malignant biological behaviors. It also affected the stemness of CCA, evidenced by decreased SOX2 protein expression. Moreover, the study revealed the interaction of LINC00511, YTHDF2, and SOX2 in CCA. Specifically, LINC00511 facilitated the formation of a complex with YTHDF2 on SOX2 mRNA, which uniquely enhances the mRNA's stability through m6A methylation sites. This stabilization appears crucial for maintaining malignant behaviors in CCA cells. Additionally, LINC00511 modulated SOX2 expression via the PI3K/AKT signaling pathway. Meanwhile, SOX2 can also promote LINC00511 expression as an upstream transcription factor, thereby confirming a positive feedback loop formed by LINC00511, YTHDF2, and SOX2, which plays a significant role in the occurrence and development of CCA. Finally, the study successfully constructed two patient‐derived xenograft models, revealing the vital role of LINC00511 in CCA development. In summary, this research provides a comprehensive understanding of the role of LINC00511 in the pathogenesis of CCA.