Background: Thumb carpometacarpal joint (CMC) osteoarthritis is the most symptomatic hand arthritis but the long-term healthcare burden for managing this condition is unknown. We sought to compare total healthcare cost and utilisation for operative and nonoperative treatments of thumb CMC arthritis. Methods: We conducted a retrospective longitudinal analysis using a large nationwide insurance claims database. A total of 18,705 patients underwent CMC arthroplasty (trapeziectomy with or without ligament reconstruction tendon interposition) or steroid injections between 1 October 2015 and 31 December 2018. Primary outcomes, healthcare utilisation and costs were measured from 1 year pre-intervention to 3 years post-intervention. Generalised linear mixed effect models adjusted for potentially confounding factors such as the Elixhauser comorbidity score with propensity score matching were applied to evaluate the association between the primary outcomes and treatment type. Results: A total of 13,646 patients underwent treatment through steroid injections, and 5,059 patients underwent CMC arthroplasty. At 1 year preoperatively, the surgery group required $635 more healthcare costs (95% CI [594.28, 675.27]; p < 0.001) and consumed 42% more healthcare utilisation (95% CI [1.38, 1.46]; p < 0.0001) than the steroid injection group. At 3 years postoperatively, the surgery group required $846 less healthcare costs (95% CI [-883.07, -808.51], p < 0.0001) and had 51% less utilisation (95% CI [0.49, 0.53]; p < 0.0001) annually. Cumulatively over 3 years, the surgical group on average was $4,204 costlier than its counterpart secondary to surgical costs. Conclusions: CMC arthritis treatment incurs high healthcare cost and utilisation independent of other medical comorbidities. At 3 years postoperatively, the annual healthcare cost and utilisation for surgical patients were less than those for patients who underwent conservative management, but this difference was insufficient to offset the initial surgical cost. Level of Evidence: Level III (Therapeutic).
Electroencephalography (EEG) microstates are used to study cognitive processes and brain disease-related changes. However, dysfunctional patterns of microstate dynamics in Alzheimer's disease (AD) remain uncertain. To investigate microstate changes in AD using EEG and assess their association with cognitive function and pathological changes in cerebrospinal fluid (CSF). We enrolled 56 patients with AD and 38 age- and sex-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Patients with AD also underwent CSF examinations to assess biomarkers related to the disease. Stepwise regression was used to analyze the relationship between changes in microstate patterns and CSF biomarkers. Receiver operating characteristics analysis was used to assess the potential of these microstate patterns as diagnostic predictors for AD. Compared with HC, patients with AD exhibited longer durations of microstates C and D, along with a decreased occurrence of microstate B. These microstate pattern changes were associated with Stroop Color Word Test and Activities of Daily Living scale scores (all P < 0.05). Mean duration, occurrences of microstate B, and mean occurrence were correlated with CSF Aß 1-42 levels, while duration of microstate C was correlated with CSF Aß 1-40 levels in AD (all P < 0.05). EEG microstates are used to predict AD classification with moderate accuracy. Changes in EEG microstate patterns in patients with AD correlate with cognition and disease severity, relate to Aß deposition, and may be useful predictors for disease classification.
Systemic inflammatory stimulus is a risk factor for the incidence of ischemic stroke and contributes to poorer clinical outcomes. Solute carrier 15A3 (SLC15A3) is a peptide/histidine transporter that is implicated in regulating inflammatory responses. However, whether SLC15A3 affects the progression of ischemic stroke associated with systemic inflammation is unclear. The transient middle cerebral artery occlusion (tMCAO) mice with LPS administration (LPS/tMCAO) were prepared as an in vivo model, and LPS-induced BV2 cells under oxygen-glucose deprivation (OGD) exposure were utilized as an in vitro model. We found that SLC15A3 was highly expressed in the ischemic penumbra of LPS/tMCAO mice, and its inhibition reduced infarct area, attenuated neurological deficit, recovered motor function, and mitigated apoptotic neurons. Knockdown of SLC15A3 suppressed the proinflammatory M1-type markers and promoted the levels of M2-associated genes. The in vitro results confirmed that SLC15A3 overexpression promoted microglia polarizing towards M1 subtypes, while SLC15A3 inhibition exerted an opposite effect. In addition, we demonstrated that the p65 signaling pathway and HIF1α were activated by LPS/OGD. Luciferase reporter assay showed that inhibiting p65 using its specific inhibitor BAY 11-7082 or silencing HIF1α using siRNAs reduced the transcriptional activity of SLC15A3 in LPS/OGD-induced BV2 cells. Results in NIH 3T3 cells also confirmed that p65 and HIF1α directly bound to the SLC15A3 promoter to activate SLC15A3 transcription. In conclusion, this work shows that SLC15A3, transcriptionally activated by p65 and HIF1α, contributes to poor outcomes in ischemic stroke associated with systemic inflammation by promoting microglial cells polarizing towards M1 types.
Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, with the potential to metastasize. Metastases to bone and soft tissue are more frequent in advanced cases, where targeted therapy is the standard treatment. However, around 10-15% of patients develop disease progression despite treatment. Studies have shown the efficacy of ablation in managing bone and soft tissue metastases (1, 2), but there are no reports of ablation for treating GIST bone or soft tissue metastases. Case presentation: In 2022, a 58-year-old man complaining of left back pain was admitted to Sichuan Cancer Hospital. He had undergone radical resection of the primary gastric GIST and vertebral metastases in 2014 and 2018, respectively. In 2019, rib metastases still occurred despite the use of targeted therapy. During the course of radiotherapy, targeted therapy, and immunotherapy, he experienced persistent chest wall pain. In addition, new lesions occurred in the lungs and chest wall in 2022. After a thorough assessment, microwave ablation (MWA) was recommended in response to his demand for immediate pain relief. The large rib metastasis constricted the spleen, so we completed the ablation in two sessions to reduce the risk of complications. He had 17 months of follow-up until September 2023, during which time his discomfort was considerably reduced. Conclusion: For GIST patients with soft tissue and bone metastases, MWA may offer substantial immediate pain alleviation. When other treatment procedures fail to achieve adequate efficacy, it provides an option.
Multiple types of variations have been postulated to confer risk of schizophrenia and bipolar disorder, but majority of present GWAS solely focused on SNPs or small indels, and the impacts of structural variations (SVs) remain less understood. Nevertheless, accumulating evidence suggest that SVs may explain the association signals in certain GWAS hits. Here, we conducted pairwise linkage disequilibrium (LD) analyses of SNPs and SVs in populations from 1000 Genomes Project. Among the 299 psychiatric GWAS loci, 1213 SVs showed an LD of r2 > 0.1 with GWAS risk SNPs, and 66 of them were in moderate to strong LD (r2 > 0.6) with at least one GWAS risk SNP. Nine SVs were subject to further explorative analyses, including eQTL analysis in DLPFC, luciferase reporter gene assays, CRISPR/Cas9-mediated genome deletion and RT-qPCR. These assays highlighted several functional SVs showing regulatory effects on transcriptional activities, and some risk genes (e.g., BORCS7, GNL3) affected by the SVs were also annotated. Finally, mice overexpressing Borcs7 in the mPFC exhibited schizophrenia-like behaviors, such as abnormal prepulse inhibition and social dysfunction. These data suggest that SNPs association signals at GWAS loci might be driven by SVs, highlighting the necessities of considering such variants in future.
Since the late 1950s, radiopharmaceuticals have been used for diagnosis and treatment in clinical nuclear medicine in China. Over the decades, China has successfully established a relatively sophisticated system for radiopharmaceutical production and management, supported by state-of-the-art facilities. With the rapid growth of the national economy, the radiopharmaceutical market in China is expanding at a remarkable pace. This burgeoning market has led to an escalating demand for clinical-stage radiopharmaceuticals, either produced domestically or imported. Despite this positive trajectory, the development and application of radiopharmaceuticals in China have been hindered by several challenges that persist, such as inadequate research, insufficient investment, limited availability of radionuclides, shortage of trained personnel in related fields, and imperfections in policies and regulations. In an exciting development, the regulation reforms implemented since 2015 have positively affected China's drug regulatory system. The introduction of the "Mid- and Long-Term Development Plan (2021-2035) for Medical Isotopes" created concurrently an opportune environment for the advancement of innovative radiopharmaceuticals. In this review, we aim to provide an overview of the approval process for novel radiopharmaceuticals by the National Medical Products Administration and the status of radiopharmaceuticals in research and development in China. Preclinical development and clinical translation of radiopharmaceuticals are undergoing rapid evolution in China. As practitioners in the field in China, we provide several practical suggestions to stimulate open discussions and thoughtful consideration.
Drug Approval , Radiopharmaceuticals , Radiopharmaceuticals/therapeutic use , China , Humans
INTRODUCTION: The COVID-19 pandemic has changed healthcare service delivery. We examined the overall impact of COVID-19 on people living with HIV in British Columbia (BC), Canada, with a special focus on the potential impact of COVID-19 on antiretroviral treatment interruptions (TIs). METHODS: Purposive sampling was used to enrol people living with HIV aged ≥19 years across BC into the STOP HIV/AIDS Program Evaluation study between January 2016 and September 2018. Participants completed surveys at baseline enrolment and 18 and 36 months later. Additional COVID-19 questions were added to the survey in October 2020. TIs were defined as >60 days late for antiretroviral therapy (ART) refill using data from the BC HIV Drug Treatment Program. Generalized linear mixed models were used to examine trends in TIs over time and associations with reported health service access. RESULTS: Of 581 participants, 6.1%-7.7% experienced a TI during each 6-month period between March 2019 and August 2021. The frequency of TIs did not statistically increase during the COVID-19 epidemic. Among the 188 participants who completed the COVID-19 questionnaire, 32.8% reported difficulty accessing healthcare during COVID-19, 9.7% reported avoiding continuing a healthcare service due to COVID-19-related concerns, and 74.6% reported using virtual healthcare services since March 2020. In multivariable analysis, the odds of a TI in any 6-month period were not significantly different from March to August 2019. None of the reported challenges to healthcare services were associated with TIs. CONCLUSIONS: Although some participants reported challenges to accessing services or avoidance of services due to COVID-19, TIs were not more likely during COVID-19 than before.
The metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-ß deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.
Alzheimer Disease , Ammonia , Metabolomics , Phenotype , Humans , Alzheimer Disease/metabolism , Alzheimer Disease/genetics , Ammonia/metabolism , Aged , Female , Male , Middle Aged , Brain/metabolism , Brain/diagnostic imaging , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/genetics , Amyloid beta-Peptides/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Bile Acids and Salts/metabolism , Aged, 80 and over , Cohort Studies
Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia-reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.
Apoptosis , Copper , Mice, Inbred C57BL , Myocardial Reperfusion Injury , Myocytes, Cardiac , Sleep Deprivation , Animals , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Male , Copper/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Mice , Sleep Deprivation/physiopathology , Sleep Deprivation/metabolism , Sleep Deprivation/complications , Copper-Transporting ATPases/metabolism , Copper-Transporting ATPases/genetics , Norepinephrine/metabolism , Norepinephrine/pharmacology , Myocardium/metabolism , Myocardium/pathology , Sympathetic Nervous System/metabolism , Disease Models, Animal
BACKGROUND: Given the increasing attention to glycemic variability (GV) and its potential implications for cardiovascular outcomes. This study aimed to explore the impact of acute GV on short-term outcomes in Chinese patients with ST-segment elevation myocardial infarction (STEMI). METHODS: This study enrolled 7510 consecutive patients diagnosed with acute STEMI from 274 centers in China. GV was assessed using the coefficient of variation of blood glucose levels. Patients were categorized into three groups according to GV tertiles (GV1, GV2, and GV3). The primary outcome was 30-day all-cause death, and the secondary outcome was major adverse cardiovascular events (MACEs). Cox regression analyses were conducted to determine the independent correlation between GV and the outcomes. RESULTS: A total of 7136 patients with STEMI were included. During 30-days follow-up, there was a significant increase in the incidence of all-cause death and MACEs with higher GV tertiles. The 30-days mortality rates were 7.4% for GV1, 8.7% for GV2 and 9.4% for GV3 (p = 0.004), while the MACEs incidence rates was 11.3%, 13.8% and 15.8% for the GV1, GV2 and GV3 groups respectively (p < 0.001). High GV levels during hospitalization were significantly associated with an increased risk of 30-day all-cause mortality and MACEs. When analyzed as a continuous variable, GV was independently associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.679, 95% confidence Interval [CI] 1.005-2.804) and MACEs (HR 2.064, 95% CI 1.386-3.074). Additionally, when analyzed as categorical variables, the GV3 group was found to predict an increased risk of MACEs, irrespective of the presence of diabetes mellitus (DM). CONCLUSION: Our study findings indicate that a high GV during hospitalization was significantly associated with an increased risk of 30-day all-cause mortality and MACE in Chinese patients with STEMI. Moreover, acute GV emerged as an independent predictor of increased MACEs risk, regardless of DM status.
Biomarkers , Blood Glucose , ST Elevation Myocardial Infarction , Humans , Male , Female , Middle Aged , ST Elevation Myocardial Infarction/mortality , ST Elevation Myocardial Infarction/blood , ST Elevation Myocardial Infarction/diagnosis , ST Elevation Myocardial Infarction/therapy , Blood Glucose/metabolism , Aged , China/epidemiology , Time Factors , Risk Factors , Risk Assessment , Biomarkers/blood , Cause of Death , Incidence , Retrospective Studies , Treatment Outcome
The main component of O-glycoproteins, mucin, is known to play important roles in physiological conditions and oncogenic processes, particularly correlated with poor prognosis in different carcinomas. Diffuse-type gastric cancer (DGC) has long been associated with genomic stability and unfavorable clinical outcomes. To investigate further, we obtained clinical information and the RNA-seq data of the TCGA-STAD cohort. Through the use of unsupervised clustering methods and GSEA, we identified two distinct clusters, characterized by higher and lower expression of MUC2 and MUC20, denoted as cluster 1 and cluster 2, respectively. Subsequently, employing CIBERSORT, it was determined that cluster 2 exhibited a higher tumor mutation burden (TMB) and a greater abundance of CD8+ T cells and activated CD4+ memory T cells, in addition to immune checkpoints (ICPs). On the other hand, cluster 1 showed a lower TIDE score estimation, indicating a higher probability of tumor immune escape. Furthermore, overexpression of MUC15 and MUC20 was confirmed through qPCR and Western blotting, and their specific roles in mediating the epithelial-mesenchymal transition (EMT) process of GC cells (SNU484 and Hs746t) were validated via CCK-8 assay and wound healing assay in vitro. These findings highlight the potential prognostic value of MUC20 and offer insights into the prospects of immunotherapy for DGC by targeting MUC20.
The compound 2-{[(trifluoromethyl)sulfonyl]oxy}propane-1,3-diyl bis(4-methylbenzenesulfonate) (TPB) is a crucial intermediate in the synthesis of 18F-radiolabeled cromolyn derivatives. In this work, we combine 1H NMR spectroscopy, X-ray crystallography, ab initio molecular dynamics, and NMR calculations to examine the structure, interactions, and solvation dynamics of the TPB molecule. In CDCl3, the CH2 groups within its glyceryl-derived linker exhibit a single set of proton signals in the 1H NMR measurements. However, when TPB is dissolved in DMSO-d6, distinct splitting patterns emerge despite its seemingly symmetric chemical structure. Crystallographic analysis further unveils the absence of overall symmetry in its three-dimensional arrangement. To elucidate these unique NMR features, we carry out ab initio molecular dynamics simulations and characterize the solvation structures and dynamics of TPB in CHCl3 and DMSO solutions. In contrast to the predominantly nonpolar nature of the CHCl3 solvents, DMSO directly participates in C-H···O hydrogen-bonding interactions with the solute molecule, leading to the splitting of its -CH2 chemical shifts into two distinct distributions. The comprehensive understanding of the structure and solvation interactions of TPB provides essential insights into its application in the radiofluorination reactions of cromolyn derivatives and holds promise for the future development of radiolabeled dimeric drugs.
The exceptional biocompatibility and adaptability of hydrogels have garnered significant interest in the biomedical field for the fabrication of biomedical devices. However, conventional synthetic hydrogels still exhibit relatively weak and fragile properties. Drawing inspiration from the photosynthesis process, we developed a facile approach to achieve a harmonious combination of superior mechanical properties and efficient preparation of silk fibroin hydrogel through photo-cross-linking technology, accomplished within 60 s. The utilization of riboflavin and H2O2 enabled a sustainable cyclic photo-cross-linking reaction, facilitating the transformation from tyrosine to dityrosine and ultimately contributing to the formation of highly cross-linked hydrogels. These photo-cross-linking hydrogels exhibited excellent elasticity and restorability even after undergoing 1000 cycles of compression. Importantly, our findings presented that hydrogel-encapsulated adipose stem cells possess the ability to stimulate cell proliferation along with stem cell stemness. This was evidenced by the continuous high expression levels of OCT4 and SOX2 over 21 days. Additionally, the utilization of photo-cross-linking hydrogels can be extended to various material molding platforms, including microneedles, microcarriers, and bone screws. Consequently, this study offered a significant approach to fabricating biomedical hydrogels capable of facilitating real-time cell delivery, thereby introducing an innovative avenue for designing silk devices with exceptional machinability and adaptability in biomedical applications.
Several studies have suggested an association between exposure to various metals and the onset of type 2 diabetes (T2D). However, the results vary across different studies. We aimed to investigate the associations between serum metal concentrations and the risk of developing T2D among 8734 participants using a prospective cohort study design. We utilized inductively coupled plasmamass spectrometry (ICP-MS) to assess the serum concentrations of 27 metals. Cox regression was applied to calculate the hazard ratios (HRs) for the associations between serum metal concentrations on the risk of developing T2D. Additionally, 196 incident T2D cases and 208 healthy control participants were randomly selected for serum metabolite measurement using an untargeted metabolomics approach to evaluate the mediating role of serum metabolite in the relationship between serum metal concentrations and the risk of developing T2D with a nested casecontrol study design. In the cohort study, after Bonferroni correction, the serum concentrations of zinc (Zn), mercury (Hg), and thallium (Tl) were positively associated with the risk of developing T2D, whereas the serum concentrations of manganese (Mn), molybdenum (Mo), barium (Ba), lutetium (Lu), and lead (Pb) were negatively associated with the risk of developing T2D. After adding these eight metals, the predictive ability increased significantly compared with that of the traditional clinical model (AUC: 0.791 vs. 0.772, P=8.85×10-5). In the nested casecontrol study, a machine learning analysis revealed that the serum concentrations of 14 out of 1579 detected metabolites were associated with the risk of developing T2D. According to generalized linear regression models, 7 of these metabolites were significantly associated with the serum concentrations of the identified metals. The mediation analysis showed that two metabolites (2-methyl-1,2-dihydrophthalazin-1-one and mestranol) mediated 46.81% and 58.70%, respectively, of the association between the serum Pb concentration and the risk of developing T2D. Our study suggested that serum Mn, Zn, Mo, Ba, Lu, Hg, Tl, and Pb were associated with T2D risk. Two metabolites mediated the associations between the serum Pb concentration and the risk of developing T2D.
OBJECTIVES: To investigate the effect of Peitu Yimu(strengthening spleen and soothing liver) acupuncture on intestinal mucosal barrier function and corticotropin-releasing factor (CRF)/CRF receptor 1 (CRFR1) pathway in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), so as to explore its underlying mechanism in alleviating IBS-D. METHODS: Forty female SD rats were randomly divided into blank, model, electroacupuncture (EA), and agonist groups, with 10 rats in each group. Except for the blank group, rats in the other groups were given folium sennae infusion by gavage combined with chronic unpredictable mild stress to establish IBS-D model. Rats in the EA group received acupuncture at "Tianshu"(ST25) and EA at "Zusanli"(ST36) and "Taichong"(LR3) (2 Hz/15 Hz) on one side for 20 min, with the side chosen alternately every other day, for 14 days after modeling. Rats in the agonist group received acupuncture 30 min after intravenous injection of CRFR1 agonist urocortin, with the same manipulation method and time as the EA group. Before and after intervention, visceral pain threshold and stool Bristol scores were measured. Elevated plus maze test and open field test were used to detect anxiety and depression like behavior of rats. ELISA was used to detect the contents of CRF and CRFR1 in rats serum. Immunohistochemistry was used to detect the positive expressions of CRF, CRFR1, zonula occludens protein 1(ZO-1), occlusal protein(Occludin), and closure protein 1 (Claudin-1) in colon tissue. RESULTS: Compared with the blank group, the visceral pain threshold, open arm time percentage (OT%), total distance of movement in the open field test, and positive expression of ZO-1, Occludin, and Claudin-1 in colon were decreased (P<0.01, P<0.05), while Bristol stool scores, serum CRF and CRFR1 contents, and positive expressions of CRF and CRFR1 in colon were increased (P<0.01) in the model group. After intervention and compared with the model group, the visceral pain threshold, OT%, total distance of movement in the open field test, and positive expressions of ZO-1, Occludin, and Claudin-1 in colon were increased (P<0.05, P<0.01), while Bristol stool scores, serum CRF and CRFR1 contents, and positive expressions of CRF and CRFR1 in colon were decreased (P<0.01) in the EA groupï¼the Bristol stool scores, serum CRF content, and CRF positive expression in colon were significantly decreased in the agonist group (P<0.01). CONCLUSIONS: Peitu Yimu acupuncture can significantly improve visceral hypersensitivity and anxiety-depression state in IBS-D rats. Its mechanism may be related to the inhibition of CRF/CRFR1 pathway and restoration of intestinal tight junction protein expressions.
Acupuncture Therapy , Diarrhea , Intestinal Mucosa , Irritable Bowel Syndrome , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone , Animals , Irritable Bowel Syndrome/therapy , Irritable Bowel Syndrome/metabolism , Irritable Bowel Syndrome/genetics , Rats , Female , Humans , Intestinal Mucosa/metabolism , Diarrhea/therapy , Diarrhea/metabolism , Diarrhea/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Corticotropin-Releasing Hormone/genetics , Acupuncture Points , Disease Models, Animal , Zonula Occludens-1 Protein/metabolism , Zonula Occludens-1 Protein/genetics , Claudin-1/metabolism , Claudin-1/genetics
Alzheimer's disease (AD) stands as the prevalent progressive neurodegenerative disease, precipitating cognitive impairment and even memory loss. Amyloid biomarkers have been extensively used in the diagnosis of AD. However, amyloid proteins offer limited information about the disease process and accurate diagnosis depends on the presence of a substantial accumulation of amyloid deposition which significantly impedes the early screening of AD. In this study, we have combined plasma proteomics with an ensemble learning model (CatBoost) to develop a cost-effective and non-invasive diagnostic method for AD. A longitudinal panel has been identified that can serve as reliable biomarkers across the entire progression of AD. Simultaneously, we have developed a neural network algorithm that utilizes plasma proteins to detect stages of Alzheimer's disease. Based on the developed longitudinal panel, the CatBoost model achieved an area under the operating curve of at least 0.90 in distinguishing mild cognitive impairment from cognitively normal. The neural network model was utilized for the detection of three stages of AD, and the results demonstrated that the neural network model exhibited an accuracy as high as 0.83, surpassing that of the traditional machine learning model.
The Sterculia genus is comprised of approximately 300 species, which have been widely used as traditional medicines to treat inflammation, snake bites, gastrointestinal diseases, skin diseases, microbial infections and many other diseases. To gain a comprehensive understanding of the therapeutic potential of Sterculia plants, an extensive literature search was conducted in CNKI, Bing, Wanfang Database, Springer Database, Elsevier Database, Google Scholar, Baidu Scholar, PubMed, and other similar websites from January 1971 to March 2024. The research indicated that Sterculia species predominantly contain flavonoids, terpenoids, phenylpropanoids, fatty acids, alkaloids and other chemical components. A wide range of pharmacologic activities such as anti-inflammatory, antioxidant, antibacterial and other biological activities have been reported. Nevertheless, there isn't much scholarly research on the therapeutic material basis of the genus Sterculia. This review reports the ethnobotany, phytochemicals, and biological activities of the plants in the Sterculia genus as herbal remedies.
BACKGROUND: Predictive biomarkers and models of immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC). However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision tree model. METHODS: We consolidated data from 3,288 ICI-treated patients with NSCLC across real-world multicenter, public cohorts and the Choice-01 trial (ClinicalTrials.gov: NCT03856411). Over 50 features were examined for predicting durable clinical benefits (DCBs) from ICIs. Noteworthy biomarkers were identified to establish a decision tree model. Additionally, we explored the tumor microenvironment and peripheral CD8+ programmed death-1 (PD-1)+ T cell receptor (TCR) profiles. FINDINGS: Multivariate logistic regression analysis identified tumor histology, PD-ligand 1 (PD-L1) expression, tumor mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations were associated with DCB. The decision tree (DT10) model, using the ten clinicopathological and genomic markers, showed superior performance in predicting DCB in the training set (area under the curve [AUC] = 0.82) and consistently outperformed other models in test sets. DT10-predicted-DCB patients manifested longer survival, an enriched inflamed tumor immune phenotype (67%), and higher peripheral TCR diversity, whereas the DT10-predicted-NDB (non-durable benefit) group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. CONCLUSIONS: The model effectively predicted DCB after front-/subsequent-line ICI treatment, with or without chemotherapy, for squamous and non-squamous lung cancer, offering clinicians valuable insights into efficacy prediction using cost-effective variables. FUNDING: This study was supported by the National Key R&D Program of China.
The neurotoxicity of Semen Strychni has been reported recently in several clinical cases. Therefore, this study was conducted to investigate the role of HMGB1 in a model of neurotoxicity induced by Semen Strychni and to assess the potential alleviating effects of glycyrrhizic acid (GA), which is associated with the regulation of HMGB1 release. Forty-eight SD rats were intraperitoneally injected with Semen Strychni extract (175 mg/kg), followed by oral administration of GA (50 mg/kg) for four days. After treatment of SS and GA, neuronal degeneration, apoptosis, and necrosis were observed via histopathological examination. Inflammatory cytokines (TNF-α and IL-1ß), neurotransmitter associated enzymes (MAO and AChE), serum HMGB1, nuclear and cytoplasmic HMGB1/ph-HMGB1, and the interaction between PP2A, PKC, and HMGB1 were evaluated. The influence of the MAPK pathway was also examined. As a result, this neurotoxicity was characterized by neuronal degeneration and apoptosis, the induction of pro-inflammatory cytokines, and a reduction in neurotransmitter-metabolizing enzymes. In contrast, GA treatment significantly ameliorated the abovementioned effects and alleviated nerve injury. Furthermore, Semen Strychni promoted HMGB1 phosphorylation and its translocation between the nucleus and cytoplasm, thereby activating the NF-κB and MAPK pathways, initiating various inflammatory responses. Our experiments demonstrated that GA could partially reverse these effects. In summary, GA acid alleviated Semen Strychni-induced neurotoxicity, possibly by inhibiting HMGB1 phosphorylation and preventing its release from the cell.
Glycyrrhizic Acid , HMGB1 Protein , Rats, Sprague-Dawley , Animals , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , HMGB1 Protein/metabolism , HMGB1 Protein/antagonists & inhibitors , Rats , Male , Phosphorylation/drug effects , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/metabolism
