Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults.

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.

Induction of therapeutic immunity and cancer eradication through biofunctionalized liposome-like nanovesicles derived from irradiated-cancer cells.

Immunotherapy has revolutionized the treatment of cancer. However, its efficacy remains to be optimized. There are at least two major challenges in effectively eradicating cancer cells by immunotherapy. Firstly, cancer cells evade immune cell killing by down-regulating cell surface immune sensors. Secondly, immune cell dysfunction impairs their ability to execute anti-cancer functions. Radiotherapy, one of the cornerstones of cancer treatment, has the potential to enhance the immunogenicity of cancer cells and trigger an anti-tumor immune response. Inspired by this, we fabricate biofunctionalized liposome-like nanovesicles (BLNs) by exposing irradiated-cancer cells to ethanol, of which ethanol serves as a surfactant, inducing cancer cells pyroptosis-like cell death and facilitating nanovesicles shedding from cancer cell membrane. These BLNs are meticulously designed to disrupt both of the aforementioned mechanisms. On one hand, BLNs up-regulate the expression of calreticulin, an "eat me" signal on the surface of cancer cells, thus promoting macrophage phagocytosis of cancer cells. Additionally, BLNs are able to reprogram M2-like macrophages into an anti-cancer M1-like phenotype. Using a mouse model of malignant pleural effusion (MPE), an advanced-stage and immunotherapy-resistant cancer model, we demonstrate that BLNs significantly increase T cell infiltration and exhibit an ablative effect against MPE. When combined with PD-1 inhibitor (α-PD-1), we achieve a remarkable 63.6% cure rate (7 out of 11) among mice with MPE, while also inducing immunological memory effects. This work therefore introduces a unique strategy for overcoming immunotherapy resistance.

Genetic associations of protein-coding variants in venous thromboembolism.

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

A Quantum Spatial Graph Convolutional Neural Network Model on Quantum Circuits.

This article proposes a quantum spatial graph convolutional neural network (QSGCN) model that is implementable on quantum circuits, providing a novel avenue to processing non-Euclidean type data based on the state-of-the-art parameterized quantum circuit (PQC) computing platforms. Four basic blocks are constructed to formulate the whole QSGCN model, including the quantum encoding, the quantum graph convolutional layer, the quantum graph pooling layer, and the network optimization. In particular, the trainability of the QSGCN model is analyzed through discussions on the barren plateau phenomenon. Simulation results from various types of graph data are presented to demonstrate the learning, generalization, and robustness capabilities of the proposed quantum neural network (QNN) model.

Microglia and macrophage metabolism: a regulator of cerebral gliomas.

Reciprocal interactions between the tumor microenvironment (TME) and cancer cells play important roles in tumorigenesis and progression of glioma. Glioma-associated macrophages (GAMs), either of peripheral origin or representing brain-intrinsic microglia, are the majority population of infiltrating immune cells in glioma. GAMs, usually classified into M1 and M2 phenotypes, have remarkable plasticity and regulate tumor progression through different metabolic pathways. Recently, research efforts have increasingly focused on GAMs metabolism as potential targets for glioma therapy. This review aims to delineate the metabolic characteristics of GAMs within the TME and provide a summary of current therapeutic strategies targeting GAMs metabolism in glioma. The goal is to provide novel insights and therapeutic pathways for glioma by highlighting the significance of GAMs metabolism.

Exploring acupuncture as a treatment for insomnia in perimenopausal women with stable angina pectoris: A protocol for a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Insomnia has emerged as a major public health issue jeopardizing human wellbeing. Furthermore, insomnia and angina arise concomitantly and exert reciprocal effects. Multiple studies suggest that perimenopausal females are more prone to experiencing both angina and insomnia, consequently substantially compromising their quality of life.Credible evidence suggests that acupuncture exerts a beneficial impact in alleviating insomnia. Nevertheless, the exhaustive investigation into the potential of acupuncture for mitigating insomnia co-occurring with stable angina in perimenopausal females remains a realm yet to be traversed in the realm of randomized controlled trials. Hence, the primary intent of this research protocol was to evaluate the effectiveness and safety profile of acupuncture when administered to perimenopausal subjects grappling with concomitant conditions of stable angina and insomnia. METHODS: This study entails a single-center, randomized, double-blind, placebo-controlled clinical trial. A total of 110 patients exhibiting insomnia concomitant with stable angina in the perimenopausal period will be enlisted and randomized to either acupuncture or sham acupuncture. Participants in both arms will undergo 30-minute sessions thrice weekly over a 12-week intervention period, with a 12-week maximum follow-up. The primary outcome measure is the Pittsburgh Sleep Quality Index(PSQI). Secondary outcomes encompass the Health-Related Quality of Life Questionnaire (SF-36), Dosage of sleeping pills, SAP-associated evaluations, including C-reactive protein (CRP), lipoprotein-associated phospholipase A2 (Lp-PLA2), cardiac fatty acid-binding protein levels (C-FABP), and the Seattle Angina Questionnaire (SAQ). Additionally, the study includes assessments using the Hamilton Depression Inventory (HAMD) and the Generalized Anxiety Disorder Scale (GAD-7). Primary and secondary outcomes will be evaluated at baseline, 4 weeks, 8 weeks, 12 weeks (upon completion of the intervention), and at an additional 12-week follow-up. Any adverse events will be rigorously classified and characterized with respect to time of onset and abatement, therapeutic interventions implemented, impact on the primary morbidity, and regression. DISCUSSION: The current study is poised to furnish pivotal clinical data on the utility of acupuncture for stable angina with concomitant insomnia in perimenopausal women, with the findings to be propagated through academic conferences and peer-reviewed publications. CLINICAL TRIAL REGISTRATION: Thai Clinical Trials Registry: TCTR20221121001. Registered 19 November 2022.

Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes.

Herpes simplex virus 1 (HSV-1) latent infection entails repression of viral lytic genes in neurons. By functional screening using luciferase-expressing HSV-1, we identify ten neuron-specific microRNAs potentially repressing HSV-1 neuronal replication. Transfection of miR-9, the most active candidate from the screen, decreases HSV-1 replication and gene expression in Neuro-2a cells. Ectopic expression of miR-9 from lentivirus or recombinant HSV-1 suppresses HSV-1 replication in male primary mouse neurons in culture and mouse trigeminal ganglia in vivo, and reactivation from latency in the primary neurons. Target prediction and validation identify transcription factors Oct-1, a known co-activator of HSV transcription, and all three Onecut family members as miR-9 targets. Knockdown of ONECUT2 decreases HSV-1 yields in Neuro-2a cells. Overexpression of each ONECUT protein increases HSV-1 replication in Neuro-2a cells, human induced pluripotent stem cell-derived neurons, and primary mouse neurons, and accelerates reactivation from latency in the mouse neurons. Mutagenesis, ChIP-seq, RNA-seq, ChIP-qPCR and ATAC-seq results suggest that ONECUT2 can nonspecifically bind to viral genes via its CUT domain, globally stimulate viral gene transcription, reduce viral heterochromatin and enhance the accessibility of viral chromatin. Thus, neuronal miR-9 promotes viral epigenetic silencing and latency by targeting multiple host transcription factors important for lytic gene activation.

Hyperbaric oxygen therapy for poststroke insomnia: a systematic review and meta-analysis protocol.

INTRODUCTION: Insomnia stands as a frequent consequence of a cerebrovascular event, afflicting a substantial fraction of those who endure the aftermath of stroke. The ramifications of insomnia following a stroke can further exacerbate cognitive and behavioural anomalies while hindering the process of neurological convalescence. While several randomised controlled trials (RCTs) have scrutinised the effects of hyperbaric oxygen therapy (HBOT) on poststroke insomnia, the advantages and drawbacks persist in a state of ambiguity. We advocate for a systematic review and meta-analysis of randomised clinical trials to comprehensively evaluate the effectiveness and safety of HBOT in the context of poststroke insomnia. METHODS AND ANALYSIS: A systematic search will be conducted from nine major databases (PubMed, Web of Science, EMBASE, VIP Information Database, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, China Biomedical Literature Database and Wanfang Database, Physiotherapy Evidence Database (PEDro)) for HBOT for poststroke insomnia of RCTs. The search procedures will adhere to a rigorous approach, commencing from the inception date of each database and continuing until 1 November 2023, with inquiries conducted exclusively in English and Chinese. The primary outcome will focus on the alteration in the quality of sleep while secondary outcomes will encompass the evaluation of adverse events and the rate of reoccurrence. The process of selecting studies, extracting data and evaluating the quality of research will be carried out independently by two reviewers. The quality of the included literature will be assessed using the tools of the Cochrane Collaboration. Meta-analysis will be performed by using RevMan V.5.4 and STATA V.16.0.b software. Finally, the quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation method. ETHICS AND DISSEMINATION: As all data are derived from published investigations via databases without direct patient contact, ethical approval is obviated in this study. The scientific studies will be published in professional academic publications. PROSPERO REGISTRATION NUMBER: CRD42023468442.

Incidence and prognosis of cardiac conduction system diseases in hypertension: the STEP trial.

Patients with cardiac conduction system diseases (CSD) may have increased incidence and mortality of cardiovascular events. Here we report a post hoc analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) randomized clinical trial (ClinicalTrials.gov number, NCT03015311) concerning the effect of intensive blood pressure (BP) control on the incidence of new-onset CSD and the prognostic implications of preexisting or new-onset CSD. The incidence of new-onset CSD was similar in the intensive (n = 205, 6.42%) and standard (n = 188, 5.94%) treatment arms. Participants with preexisting CSD had a higher risk for acute decompensated heart failure. Increased age, male sex and increased body mass index were independently associated with increased risk for new-onset CSD. Our results suggest that intensive BP control may not reduce the incidence of new-onset CSD compared with standard BP control.

Prognostic Value of Leukocyte-Based Risk Model for Acute Kidney Injury Prediction in Critically Ill Acute Exacerbation of Chronic Obstructive Pulmonary Disease Patients.

Purpose: Acute kidney injury (AKI) is a common complication of acute exacerbation of chronic obstructive pulmonary disease (AECOPD), and inflammation is the potential link between AKI and AECOPD. However, little is known about the incidence and risk stratification of AKI in critically ill AECOPD patients. In this study, we aimed to establish risk model based on white blood cell (WBC)-related indicators to predict AKI in critically ill AECOPD patients. Material and Methods: For the training cohort, data were taken from the Medical Information Mart for eICU Collaborative Research Database (eICU-CRD) database, and for the validation cohort, data were taken from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The study employed logistic regression analysis to identify the major predictors of WBC-related biomarkers on AKI prediction. Subsequently, a risk model was developed by multivariate logistic regression, utilizing the identified significant indicators. Results: Finally, 3551 patients were enrolled in training cohort, 926 patients were enrolled in validation cohort. AKI occurred in 1206 (33.4%) patients in training cohort and 521 (56.3%) patients in validation cohort. According to the multivariate logistic regression analysis, four WBC-related indicators were finally included in the novel risk model, and the risk model had a relatively good accuracy for AKI in the training set (C-index, 0.764, 95% CI 0.749-0.780) as well as in the validation set (C-index, 0.738, 95% CI: 0.706-0.770). Even after accounting for other models, the critically ill AECOPD patients in the high-risk group (risk score > 3.44) still showed an increased risk of AKI (odds ratio: 4.74, 95% CI: 4.07-5.54) compared to those in low-risk group (risk score ≤ 3.44). Moreover, the risk model showed outstanding calibration capability as well as therapeutic usefulness in both groups for AKI and ICU mortality and in-hospital mortality of critical ill AECOPD patients. Conclusion: The novel risk model showed good AKI prediction performance. This risk model has certain reference value for the risk stratification of AECOPD complicated with AKI in clinically.

Application and progress of nanozymes in antitumor therapy.

Tumors remain one of the major threats to public health and there is an urgent need to design new pharmaceutical agents for their diagnosis and treatment. In recent years, due to the rapid development of nanotechnology, biotechnology, catalytic science, and theoretical computing, subtlety has gradually made great progress in research related to tumor diagnosis and treatment. Compared to conventional drugs, enzymes can improve drug distribution and enhance drug enrichment at the tumor site, thereby reducing drug side effects and enhancing drug efficacy. Nanozymes can also be used as tumor tracking imaging agents to reshape the tumor microenvironment, providing a versatile platform for the diagnosis and treatment of malignancies. In this paper, we review the current status of research on enzymes in oncology and analyze novel oncology therapeutic approaches and related mechanisms. To date, a large number of nanomaterials, such as noble metal nanomaterials, nonmetallic nanomaterials, and carbon-based nanomaterials, have been shown to be able to function like natural enzymes, particularly with significant advantages in tumor therapy. In light of this, the authors in this review have systematically summarized and evaluated the construction, enzymatic activity, and their characteristics of nanozymes with respect to current modalities of tumor treatment. In addition, the application and research progress of different types of nicknames and their features in recent years are summarized in detail. We conclude with a summary and outlook on the study of nanozymes in tumor diagnosis and treatment. It is hoped that this review will inspire researchers in the fields of nanotechnology, chemistry, biology, materials science and theoretical computing, and contribute to the development of nano-enzymology.

Theoretical Investigation of a Coumarin Fluorescent Probe for Distinguishing the Detection of Small-Molecule Biothiols.

Monitoring the level of biothiols in organisms would be beneficial for health inspections. Recently, 3-(2'-nitro vinyl)-4-phenylselenyl coumarin as a fluorescent probe for distinguishing the detection of the small-molecule biothiols cysteine/homocysteine (Cys/Hcy) and glutathione (GSH) was developed. By introducing 4-phenyselenium as the active site, the probe CouSeNO2/CouSNO2 was capable of detecting Cys/Hcy and GSH in dual fluorescence channels. Theoretical insights into the fluorescence sensing mechanism of the probe were provided in this work. The details of the electron excitation process in the probe and sensing products under optical excitation and the fluorescent character were analyzed using the quantum mechanical method. All these theoretical results would provide insight and pave the way for the molecular design of fluorescent probes for the detection of biothiols.

Evaluation of the efficacy and safety of endoscopic band ligation in the treatment of bleeding from mild to moderate gastric varices type 1.

BACKGROUND: According to practice guidelines, endoscopic band ligation (EBL) and endoscopic tissue adhesive injection (TAI) are recommended for treating bleeding from esophagogastric varices. However, EBL and TAI are known to cause serious complications, such as hemorrhage from dislodged ligature rings caused by EBL and hemorrhage from operation-related ulcers resulting from TAI. However, the optimal therapy for mild to moderate type 1 gastric variceal hemorrhage (GOV1) has not been determined. Therefore, the aim of this study was to discover an individualized treatment for mild to moderate GOV1. AIM: To compare the efficacy, safety and costs of EBL and TAI for the treatment of mild and moderate GOV1. METHODS: A clinical analysis of the data retrieved from patients with mild or moderate GOV1 gastric varices who were treated under endoscopy was also conducted. Patients were allocated to an EBL group or an endoscopic TAI group. The differences in the incidence of varicose relief, operative time, operation success rate, mortality rate within 6 wk, rebleeding rate, 6-wk operation-related ulcer healing rate, complication rate and average operation cost were compared between the two groups of patients. RESULTS: The total effective rate of the two treatments was similar, but the efficacy of EBL (66.7%) was markedly better than that of TAI (39.2%) (P < 0.05). The operation success rate in both groups was 100%, and the 6-wk mortality rate in both groups was 0%. The average operative time (26 min) in the EBL group was significantly shorter than that in the TAI group (46 min) (P < 0.01). The rate of delayed postoperative rebleeding in the EBL group was significantly lower than that in the TAI group (11.8% vs 45.1%) (P < 0.01). At 6 wk after the operation, the healing rate of operation-related ulcers in the EBL group was 80.4%, which was significantly greater than that in the TAI group (35.3%) (P < 0.01). The incidence of postoperative complications in the two groups was similar. The average cost and other related economic factors were greater for the EBL than for the TAI (P < 0.01). CONCLUSION: For mild to moderate GOV1, patients with EBL had a greater one-time varix eradication rate, a greater 6-wk operation-related ulcer healing rate, a lower delayed rebleeding rate and a lower cost than patients with TAI.

Whipple's disease of the respiratory system: A case report.

Whipple's disease (WD) is a multiple-system chronic disease caused by Tropheryma whipplei (T. whipplei) infection. The present study describes 3 cases of WD with clinical manifestations of cough, chest pain, headache, dyspnea, sputum, joint pain, abdominal pain, diarrhea and weight loss. Chest computed tomography (CT) showed signs of plaques, nodules and pleural thickening; and bronchoscopic alveolar lavage fluid metagenomic-sequencing indicated that it was T. whipplei. One patient was treated with meropenem as the starting regimen and two patients were treated with ceftriaxone as the starting regimen. Furthermore, two patients were provided with a maintenance regimen of cotrimoxazole and one was given a maintenance regimen of minocycline, which was combined with meropenem and ceftriaxone in order to improve their cough, chest pain, headache and dyspnea symptoms. To the best of our knowledge, there are few reports on WD of the respiratory system caused by T. whipplei, and differential diagnosis is the key to clinical diagnosis. When WD of the respiratory system is difficult to diagnose, metagenomic second-generation sequencing (mNGS) may be a better choice, which can achieve early diagnosis and early treatment. However, its clinical value is still limited; therefore, more research needs to be conducted in the future.

Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma.

Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.

Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment.

Background: The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. Methods: The in vivo senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the in vitro model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation in vitro. RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. Results: We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8+ T cell-mediated antitumor immunity. Conclusions: TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.

Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors.

The ubiquitous methyltransferases employing SAM as the methyl donor have emerged as potential targets in many disease treatments, especially in anticancer. Therefore, developing SAM-competitive inhibitors of methyltransferases is of great interest to the drug research. To explore this direction, herein, we rationally designed a series of nucleoside derivatives as potent PRMT5 inhibitors with novel scaffold. The representative compounds A2 and A8 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other PRMTs and PKMTs. Further cellular experiments revealed that compounds A2 and A8 potently reduced the level of sDMA and inhibited the proliferation of Z-138 and MOLM-13 cell lines by inducing apoptosis. Moreover, compounds A8 which had favorable pharmacokinetic properties exhibited potent antitumor efficacy without the loss of body weight in a subcutaneous MOLM-13 xenograft model. In summary, our efforts provided a series of novel nucleoside analogs as potent PRMT5 inhibitors and may also offer a new strategy to develop SAM analogs as other methyltransferases' inhibitors.

FBW7/GSK3ß mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer.

BACKGROUND: The development of radioresistance seriously hinders the efficacy of radiotherapy in lung cancer. However, the underlying mechanisms by which radioresistance occurs are still incompletely understood. The N6-Methyladenosine (m6A) modification of RNA is involved in cancer progression, but its role in lung cancer radioresistance remains elusive. This study aimed to identify m6A regulators involved in lung cancer radiosensitivity and further explore the underlying mechanisms to identify therapeutic targets to overcome lung cancer radioresistance. METHODS: Bioinformatic mining was used to identify the m6A regulator IGF2BP2 involved in lung cancer radiosensitivity. Transcriptome sequencing was used to explore the downstream factors. Clonogenic survival assays, neutral comet assays, Rad51 foci formation assays, and Annexin V/propidium iodide assays were used to determine the significance of FBW7/IGF2BP2/SLC7A5 axis in lung cancer radioresistance. Chromatin immunoprecipitation (ChIP)-qPCR analyses, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP)-qPCR analyses, RNA pull-down analyses, co-immunoprecipitation analyses, and ubiquitination assays were used to determine the feedback loop between IGF2BP2 and SLC7A5 and the regulatory effect of FBW7/GSK3ß on IGF2BP2. Mice models and tissue microarrays were used to verify the effects in vivo. RESULTS: We identified IGF2BP2, an m6A "reader", that is overexpressed in lung cancer and facilitates radioresistance. We showed that inhibition of IGF2BP2 impairs radioresistance in lung cancer both in vitro and in vivo. Furthermore, we found that IGF2BP2 enhances the stability and translation of SLC7A5 mRNA through m6A modification, resulting in enhanced SLC7A5-mediated transport of methionine to produce S-adenosylmethionine. This feeds back upon the IGF2BP2 promoter region by further increasing the trimethyl modification at lysine 4 of histone H3 (H3K4me3) level to upregulate IGF2BP2 expression. We demonstrated that this positive feedback loop between IGF2BP2 and SLC7A5 promotes lung cancer radioresistance through the AKT/mTOR pathway. Moreover, we found that the ubiquitin ligase FBW7 functions with GSK3ß kinase to recognize and degrade IGF2BP2. CONCLUSIONS: Collectively, our study revealed that the m6A "reader" IGF2BP2 promotes lung cancer radioresistance by forming a positive feedback loop with SLC7A5, suggesting that IGF2BP2 may be a potential therapeutic target to control radioresistance in lung cancer.

Plasma metabolic profiles predict future dementia and dementia subtypes: a prospective analysis of 274,160 participants.

BACKGROUND: Blood-based biomarkers for dementia are gaining attention due to their non-invasive nature and feasibility in regular healthcare settings. Here, we explored the associations between 249 metabolites with all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) and assessed their predictive potential. METHODS: This study included 274,160 participants from the UK Biobank. Cox proportional hazard models were employed to investigate longitudinal associations between metabolites and dementia. The importance of these metabolites was quantified using machine learning algorithms, and a metabolic risk score (MetRS) was subsequently developed for each dementia type. We further investigated how MetRS stratified the risk of dementia onset and assessed its predictive performance, both alone and in combination with demographic and cognitive predictors. RESULTS: During a median follow-up of 14.01 years, 5274 participants developed dementia. Of the 249 metabolites examined, 143 were significantly associated with incident ACD, 130 with AD, and 140 with VaD. Among metabolites significantly associated with dementia, lipoprotein lipid concentrations, linoleic acid, sphingomyelin, glucose, and branched-chain amino acids ranked top in importance. Individuals within the top tertile of MetRS faced a significantly greater risk of developing dementia than those in the lowest tertile. When MetRS was combined with demographic and cognitive predictors, the model yielded the area under the receiver operating characteristic curve (AUC) values of 0.857 for ACD, 0.861 for AD, and 0.873 for VaD. CONCLUSIONS: We conducted the largest metabolome investigation of dementia to date, for the first time revealed the metabolite importance ranking, and highlighted the contribution of plasma metabolites for dementia prediction.

Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis.

Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment due to acquired drug resistance. Epigenetic regulation is known to contribute to cisplatin resistance; nevertheless, the underlying mechanisms remain poorly understood. Here, we showed that lysine-specific demethylase 5B (KDM5B) was overexpressed and correlates with tumor progression and cisplatin resistance in patients with NPC. We also showed that specific inhibition of KDM5B impaired the progression of NPC and reverses cisplatin resistance, both in vitro and in vivo. Moreover, we found that KDM5B inhibited the expression of ZBTB16 by directly reducing H3K4me3 at the ZBTB16 promoter, which subsequently increased the expression of Topoisomerase II- α (TOP2A) to confer cisplatin resistance in NPC. In addition, we showed that the deubiquitinase USP7 was critical for deubiquitinating and stabilizing KDM5B. More importantly, the deletion of USP7 increased sensitivity to cisplatin by disrupting the stability of KDM5B in NPC cells. Therefore, our findings demonstrated that USP7 stabilized KDM5B and promoted cisplatin resistance through the ZBTB16/TOP2A axis, suggesting that targeting KDM5B may be a promising cisplatin-sensitization strategy in the treatment of NPC.