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1.
Int J Biol Macromol ; : 133413, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38945723

ABSTRACT

Dysphagia has emerged as a serious health issue facing contemporary society. Consuming thickened liquids is an effective approach for improving the swallowing safety for dysphagia patients. The thickening effect of chia seed gum (CSG), a novel thickener, in different dispersing media (water, orange juice, and skim milk) was investigated. Moreover, the potential application of CSG for dysphagia management was evaluated by comparison with xanthan gum (XG) and guar gum (GG). The thickened liquids prepared with 0.4 %-1.2 % (w/v) CSG, XG, and GG could be classified into levels 1-4, 2-4, and 1-3, respectively, according to the International Dysphagia Diet Standardization Initiative (IDDSI) framework. All the thickened liquids displayed shear-thinning characteristics that facilitated safe swallowing. The viscosities (η50) of CSG dissolved in water (0.202-1.027 Pa·s) were significantly greater than those of CSG dissolved in orange juice (0.070-0.690 Pa·s) and skim milk (0.081-0.739 Pa·s), indicating that CSG had a greater thickening effect in water than in orange juice and skim milk. Compared with those prepared with GG, the thickened liquids prepared with CSG and XG exhibited greater viscoelasticity, better water-holding capacity, and more compact networks. The findings suggested that CSG can be used as a potential thickener for thickening liquid foods to manage dysphagia.

2.
Mol Pharm ; 21(7): 3425-3433, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38836286

ABSTRACT

Fibrinogen-like protein 1 (FGL1) is a potential novel immune checkpoint target for malignant tumor diagnosis and therapy. Accurate detection of FGL1 levels in tumors via noninvasive PET imaging might be beneficial for managing the disease. To achieve this, multiple FGL1-targeting peptides (FGLP) were designed, and a promising candidate, 68Ga-NOTA-FGLP2, was identified through a high-throughput screening approach using microPET imaging of 68Ga-labeled peptides. Subsequent in vitro cell experiments showed that uptake values of 68Ga-NOTA-FGLP2 in FGL1 positive Huh7 tumor cells were significantly higher than those in FGL1 negative U87 MG tumor cells. Further microPET imaging showed that the Huh7 xenografts were clearly visualized with a favorable contrast. ROI analysis showed that the uptake values of the tracer in Huh7 xenografts were 2.63 ± 0.07% ID/g at 30 min p.i.. After treatment with an excess of unlabeled FGLP2, the tumor uptake significantly decreased to 0.54 ± 0.05% ID/g at 30 min p.i.. Moreover, the uptake in U87 MG xenografts was 0.44 ± 0.06% ID/g at the same time point. The tracer was excreted mainly through the renal system. 18F-FDG PET imaging was also performed in mice bearing Huh7 and U87 MG xenografts, respectively. However, there was no significant difference in the uptake between the tumors with different FGL1 expressions. Preclinical data indicated that 68Ga-NOTA-FGLP2 might be a suitable radiotracer for in vivo noninvasive visualization of tumors with abundant expression of FGL1. Further investigation of 68Ga-NOTA-FGLP2 for tumor diagnosis and therapy is undergoing.


Subject(s)
Gallium Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Animals , Humans , Mice , Positron-Emission Tomography/methods , Cell Line, Tumor , Radiopharmaceuticals/pharmacokinetics , Mice, Nude , Tissue Distribution , Peptides/chemistry , Mice, Inbred BALB C , Female , Heterocyclic Compounds, 1-Ring/chemistry
3.
J Am Heart Assoc ; 13(13): e032781, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38934873

ABSTRACT

BACKGROUND: This study assesses the diagnostic utility of strain parameters from cardiovascular magnetic resonance feature tracking across all cardiac chambers in patients with acute myocarditis, stratified by ejection fraction. METHODS AND RESULTS: Our cohort included 65 patients with acute myocarditis and 25 healthy controls; all underwent cardiac magnetic resonance imaging. Patients were divided into 2 groups based on left ventricular ejection fraction (EF)with a 55% cutoff: acute myocarditis with preserved EF, EF ≥55%, n=48; and acute myocarditis with reduced EF, EF <55%, n=17. The control group matched for age and sex. Cardiovascular magnetic resonance feature tracking evaluated strain parameters across all cardiac chambers. Both acute myocarditis with preserved EF and acute myocarditis with reduced EF groups showed significant decreases in left atrial peak early negative strain rate compared with controls. The acute myocarditis with reduced EF group had significantly reduced left ventricular circumferential strain relative to acute myocarditis with preserved EF and controls. Receiver operating characteristic curve analysis confirmed the diagnostic accuracy in distinguishing patients with acute myocarditis with preserved EF from controls, with left atrial peak early negative strain rate achieving 92.9% specificity, left ventricular circumferential strain demonstrating an area under the curve of 0.832, and similarly effective results for left ventricular longitudinal strain and right ventricular longitudinal strain. Additionally, left atrial peak early negative strain rate and left ventricular circumferential strain showed significant correlations with troponin I levels, indicating myocardial injury. CONCLUSIONS: Cardiovascular magnetic resonance feature-tracking-derived strain parameters, particularly left atrial peak early negative strain rate and left ventricular circumferential strain, effectively diagnose acute myocarditis across different EFs, enhancing diagnostic accuracy and facilitating early detection, notably in patients with preserved EF.


Subject(s)
Magnetic Resonance Imaging, Cine , Myocarditis , Stroke Volume , Ventricular Function, Left , Humans , Myocarditis/physiopathology , Myocarditis/diagnostic imaging , Myocarditis/diagnosis , Male , Female , Stroke Volume/physiology , Adult , Acute Disease , Ventricular Function, Left/physiology , Magnetic Resonance Imaging, Cine/methods , Middle Aged , Predictive Value of Tests , Case-Control Studies , Retrospective Studies
4.
Int J Biol Macromol ; 273(Pt 2): 133162, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38878925

ABSTRACT

Calcium ß-hydroxy-ß-methylbutyrate (CaHMB), a functional calcium salt, is used to maintain and improve muscle health. Here, a new hydrogel material prepared from alginate (ALG) with three M/G ratios (1:1, 2:1, and 1:2) and CaHMB (0-2 mg/mL) was investigated. CaHMB regulates the formation and properties of ALG hydrogels through chelation and hydrogen bonding. When the M/G ratio was 2:1, the anionic groups of CaHMB containing carboxyl and hydroxyl groups formed hydrogen bonds with the polysaccharide chains, hindering the capture of Ca2+ by the G-residue fragments of ALG, which in turn retarded the gelation process. The noncalcium cross-linked polysaccharide chain structure of ALG and the anionic group of CaHMB also affected the water distribution in the hydrogel, especially when M residue content ≥G residue content. Lower M/G ratios and higher CaHMB concentrations could increase the number of "egg box" crosslinking junctions of calcium alginate, and the microstructure was denser in the gel pores, resulting in a stronger gel strength and more free water bound in the gel matrix. This study provides a theoretical and methodological basis for the design of novel hydrogels by studying the crosslinking features of ALG/CaHMB.


Subject(s)
Alginates , Calcium , Hydrogels , Alginates/chemistry , Hydrogels/chemistry , Calcium/chemistry , Valerates/chemistry , Ions/chemistry , Hydrogen Bonding , Water/chemistry
5.
Food Chem X ; 22: 101466, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38808164

ABSTRACT

This study focused on binary hydrogels constructed from lotus rhizome starch (LRS) and three types of carrageenan (κ-C, ι-C, and λ-C). The enthalpy of LRS gelatinization was reduced by 32.1%-88.4% with the incorporation of carrageenan. Compared with ι-C and λ-C, the conformations of κ-C more facilitated the development of the binary hydrogel network structure. The ability of the LRS/carrageenan binary hydrogel to immobilize water was mainly related to the effect of different types of carrageenan on starch molecular ordering. LRS-based hydrogels were recognized as level 4 in the International Dysphagia Diet Standardization Initiative (IDDSI) framework. Nevertheless, the incorporation of carrageenan significantly reduced the ability of the LRS hydrogel to resist stress under large deformations, which might be favorable to oral processing and swallowing. This research provides preliminary evidence for relevant industries to use carrageenan to adjust LRS hydrogel properties and improve the quality of starch-based foods for dysphagia management.

6.
Cancer Lett ; 591: 216867, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38593919

ABSTRACT

Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.


Subject(s)
Autophagy , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Autophagy/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Epithelial-Mesenchymal Transition/drug effects , Nanoparticles , Apoptosis/drug effects , Animals , Ferroptosis/drug effects , Cell Death/drug effects
7.
Biosensors (Basel) ; 14(4)2024 Mar 31.
Article in English | MEDLINE | ID: mdl-38667164

ABSTRACT

Raman flow cytometry (RFC) uniquely integrates the "label-free" capability of Raman spectroscopy with the "high-throughput" attribute of traditional flow cytometry (FCM), offering exceptional performance in cell characterization and sorting. Unlike conventional FCM, RFC stands out for its elimination of the dependency on fluorescent labels, thereby reducing interference with the natural state of cells. Furthermore, it significantly enhances the detection information, providing a more comprehensive chemical fingerprint of cells. This review thoroughly discusses the fundamental principles and technological advantages of RFC and elaborates on its various applications in the biomedical field, from identifying and characterizing cancer cells for in vivo cancer detection and surveillance to sorting stem cells, paving the way for cell therapy, and identifying metabolic products of microbial cells, enabling the differentiation of microbial subgroups. Moreover, we delve into the current challenges and future directions regarding the improvement in sensitivity and throughput. This holds significant implications for the field of cell analysis, especially for the advancement of metabolomics.


Subject(s)
Flow Cytometry , Spectrum Analysis, Raman , Humans , Neoplasms , Animals
8.
J Cancer Res Ther ; 20(2): 658-664, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38687937

ABSTRACT

BACKGROUND: Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic therapy has shown promise as a treatment approach for LM. Thus, this study aimed to evaluate the features and responses to IT combined therapy and identify determinants affecting patients with leptomeningeal metastasis resulting from lung adenocarcinoma (LM-LA). METHODS: A retrospective analysis of medical records from our hospital database was performed, covering from April 2018 to August 2022, for 37 patients diagnosed with LM-LA and treated with IT combined therapy. Patients who received IT combined therapy for LM-LA were evaluated for demographic characteristics, treatment efficacy, survival, and variables that impacted them. RESULTS: The median overall survival (mOS) of 37 patients was 16.0 months, and the survival rates at 6 and 12 months were 75.7% and 35.1%, respectively. Among the 21 patients with LM-LA who received IT combined with tyrosine kinase inhibitors (TKIs), the mOS was 17.0 months, which was significantly longer than that of patients treated with IT combined with chemotherapy (7.0 months, P = 0.010) and the best supportive care (6.0 months, P = 0.001). However, no significant survival benefit was observed in patients treated with IT combined with TKIs when compared with those treated with IT combined with PD-1 (5.0 months, P = 0.249). Multivariate analysis indicated that the combination of TKIs was an independent favorable prognostic factor for patients with LM-LA. CONCLUSION: Combination treatment is regarded as an additional option for patients with LM-LA. Compared with other combination therapies in our study, IT combined with TKI therapy provided a better survival outcome for patients with LM-LA.


Subject(s)
Adenocarcinoma of Lung , Antineoplastic Combined Chemotherapy Protocols , Injections, Spinal , Lung Neoplasms , Humans , Male , Female , Middle Aged , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/secondary , Adenocarcinoma of Lung/mortality , Retrospective Studies , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Prognosis , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adult , Survival Rate , Meningeal Neoplasms/secondary , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/mortality , Treatment Outcome , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Meningeal Carcinomatosis/secondary , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/mortality , Combined Modality Therapy , Aged, 80 and over
9.
Nat Commun ; 15(1): 3649, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684671

ABSTRACT

Two-dimensional nanofluidics based on naturally abundant clay are good candidates for harvesting osmotic energy between the sea and river from the perspective of commercialization and environmental sustainability. However, clay-based nanofluidics outputting long-term considerable osmotic power remains extremely challenging to achieve due to the lack of surface charge and mechanical strength. Here, a two-dimensional all-natural nanofluidic (2D-NNF) is developed as a robust and highly efficient osmotic energy generator based on an interlocking configuration of stacked montmorillonite nanosheets (from natural clay) and their intercalated cellulose nanofibers (from natural wood). The generated nano-confined interlamellar channels with abundant surface and space negative charges facilitate selective and fast hopping transport of cations in the 2D-NNF. This contributes to an osmotic power output of ~8.61 W m-2 by mixing artificial seawater and river water, higher than other reported state-of-the-art 2D nanofluidics. According to detailed life cycle assessments (LCA), the 2D-NNF demonstrates great advantages in resource consumption (1/14), greenhouse gas emissions (1/9), and production costs (1/13) compared with the mainstream 2D nanofluidics, promising good sustainability for large-scale and highly-efficient osmotic power generation.

10.
Sci Total Environ ; 927: 172311, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38599416

ABSTRACT

Flotation technology is widely utilized to remove emulsified oil droplets from Produced water. Organic acid adsorption on the oil droplet surface affects bubble attachment, reducing oil removal efficiency. This investigation exploited the principle of similar dissolution to synthesize condensate bubbles (CB). The surface properties of oil droplets and CB and air bubbles (AB) were appraised using FTIR, zeta potential, interfacial tension, and contact angle measurements. The research also investigated the effects of acetic acids (AA) on the adhesion of oil droplets to AB and CB along with the underlying mechanism via the Extended Derjaguin-Landau-Verwey-Overbeek (EDLVO) interaction theory and the Stefan-Reynolds model of liquid film thinning, integrated with adhesion times. Flotation efficiency and kinetic dissimilarities between AB and CB were also examined. The results indicated that CB exhibits superior lipophilic hydrophobicity compared to AB, reduced induction and spreading times upon oil droplet attachment, and maximized oil removal efficiency. Furthermore, CB could mitigate the impact of AA on adhesion. The interaction barriers between CB and oil droplets were minimal, and the thinning rate of the hydration film was quicker than in AB. The conventional first-order model proved effective in fitting the AB flotation, whereas a delay constant was applied to the model of the CB flotation rate.

11.
Small ; : e2311344, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38661278

ABSTRACT

The effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg2+ can promote bone repair with immunoregulatory effect, but the underlying mechanism on adaptive immunity is still unclear. Here, by using chitosan and hyaluronic acid-coated Mg2+ (CSHA-Mg) in bone-deficient mice, it is shown that Mg2+ can inhibit the activation of CD4+ T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg2+ initiates the activation of the MAPK signaling pathway through TRPM7 channels on DCs. This process subsequently induces the downstream HIF-1α expression, a transcription factor that amplifies TGF-ß production and inhibits the effective T cell function. In vivo, knock-out of HIF-1α in DCs or using a HIF-1α inhibitor PX-478 reverses inhibition of bone inflammation and repair promotion upon Mg2+-treatment. Moreover, roxadustat, which stabilizes HIF-1α protein expression, can significantly promote immunosuppression and bone repair in synergism with CSHA-Mg. Thus, the findings identify a key mechanism for DCs and its HIF-1α-TGF-ß axis in the induction of immunosuppressive bone microenvironment, providing potential targets for bone regeneration.

12.
Analyst ; 149(11): 3169-3177, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38639189

ABSTRACT

Small extracellular vesicles (sEVs), a form of extracellular vesicles, are lipid bilayered structures released by all cells. Large-scale studies on sEVs from clinical samples are necessary, but a major obstacle is the lack of rapid, reproducible, efficient, and low-cost methods to enrich sEVs. Acoustic microfluidics have the advantage of being label-free and biocompatible, which have been reported to successfully enrich sEVs. In this paper, we present a highly efficient acoustic microfluidic trap that can offer low and large volume compatible ways of enriching sEVs from biological fluids by flexible structure design. It uses the idea of pre-loading larger seed particles in the acoustic trap to enable sub-micron particle capturing. The microfluidic chip is actuated using a piezoelectric plate transducer attached to a silicon-glass bonding plate with circular cavities. Each cavity works as a resonant unit, excited at the frequency of both the half wave resonance in the main plane and inverted quarter wave resonance in the depth direction, which has the ability to strongly trap seed particles at the center, thereby improving the subsequent nanoparticle capture efficiency. Mean trapping efficiencies of 35.62% and 64.27% were obtained using 60 nm and 100 nm nanobeads, respectively. By the use of this technology, we have successfully enriched sEVs from cell culture conditioned media and blood plasma at a flow rate of 10 µL min-1. The isolated sEV subpopulations are characterized by NTA and TEM, and their protein cargo is determined by WB. This acoustic trapping chip provides a rapid and robust method to enrich sEVs from biofluids with high reproducibility and sufficient quantities. Therefore, it can serve as a new tool for biological and clinical research such as cancer diagnosis and drug delivery.


Subject(s)
Acoustics , Extracellular Vesicles , Extracellular Vesicles/chemistry , Humans , Microfluidic Analytical Techniques/instrumentation , Microfluidic Analytical Techniques/methods , Nanoparticles/chemistry , Lab-On-A-Chip Devices , Culture Media, Conditioned/chemistry
13.
Environ Res ; 251(Pt 2): 118692, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38493856

ABSTRACT

Overloading of nutrients such as nitrogen causes eutrophication of freshwater bodies. The spread of antibiotic resistance genes (ARGs) poses a threat to ecosystems. However, studies on the enrichment and spread of ARGs from increased nitrogen loading in algal-bacterial symbiotic systems are limited. In this study, the transfer of extracellular kanamycin resistance (KR) genes from large (RP4) small (pEASY-T1) plasmids into the intracellular and extracellular DNA (iDNA, eDNA) of the inter-algal environment of Chlorella pyrenoidosa was investigated, along with the community structure of free-living (FL) and particle-attached (PA) bacteria under different nitrogen source concentrations (0-2.5 g/L KNO3). The results showed that KR gene abundance in the eDNA adsorbed on solid particles (D-eDNA) increased initially and then decreased with increasing nitrogen concentration, while the opposite was true for the rest of the free eDNA (E-eDNA). Medium nitrogen concentrations promoted the transfer of extracellular KR genes into the iDNA attached to algal microorganisms (A-iDNA), eDNA attached to algae (B-eDNA), and the iDNA of free microorganisms (C-iDNA); high nitrogen contributed to the transfer of KR genes into C-iDNA. The highest percentage of KR genes was found in B-eDNA with RP4 plasmid treatment (66.2%) and in C-iDNA with pEASY-T1 plasmid treatment (86.88%). In addition, dissolved oxygen (DO) significantly affected the bacterial PA and FL community compositions. Nephelometric turbidity units (NTU) reflected the abundance of ARGs in algae. Proteobacteria, Cyanobacteria, Bacteroidota, and Actinobacteriota were the main potential hosts of ARGs. These findings provide new insights into the distribution and dispersal of ARGs in the phytoplankton inter-algal environment.


Subject(s)
Bacteria , Drug Resistance, Microbial , Eutrophication , Gene Transfer, Horizontal , Microalgae , Symbiosis , Microalgae/genetics , Microalgae/drug effects , Bacteria/genetics , Bacteria/drug effects , Drug Resistance, Microbial/genetics , Chlorella/genetics , Chlorella/drug effects , Nitrogen
14.
Front Immunol ; 15: 1362543, 2024.
Article in English | MEDLINE | ID: mdl-38504986

ABSTRACT

Introduction: Glioblastoma (GBM) presents significant challenges due to its malignancy and limited treatment options. Precision treatment requires subtyping patients based on prognosis. Disulfidptosis, a novel cell death mechanism, is linked to aberrant glucose metabolism and disulfide stress, particularly in tumors expressing high levels of SLC7A11. The exploration of disulfidptosis may provide a new perspective for precise diagnosis and treatment of glioblastoma. Methods: Transcriptome sequencing was conducted on samples from GBM patients treated at Tiantan Hospital (January 2022 - December 2023). Data from CGGA and TCGA databases were collected. Consensus clustering based on disulfidptosis features categorized GBM patients into two subtypes (DRGclusters). Tumor immune microenvironment, response to immunotherapy, and drug sensitivity were analyzed. An 8-gene disulfidptosis-based subtype predictor was developed using LASSO machine learning algorithm and validated on CGGA dataset. Results: Patients in DRGcluster A exhibited improved overall survival (OS) compared to DRGcluster B. DRGcluster subtypes showed differences in tumor immune microenvironment and response to immunotherapy. The predictor effectively stratified patients into high and low-risk groups. Significant differences in IC50 values for chemotherapy and targeted therapy were observed between risk groups. Discussion: Disulfidptosis-based classification offers promise as a prognostic predictor for GBM. It provides insights into tumor immune microenvironment and response to therapy. The predictor aids in patient stratification and personalized treatment selection, potentially improving outcomes for GBM patients.


Subject(s)
Glioblastoma , Humans , Glioblastoma/genetics , Glioblastoma/therapy , Multiomics , Immunotherapy , Algorithms , Cell Death , Tumor Microenvironment
15.
Brief Bioinform ; 25(2)2024 Jan 22.
Article in English | MEDLINE | ID: mdl-38436558

ABSTRACT

Recently, there has been a growing interest in variable selection for causal inference within the context of high-dimensional data. However, when the outcome exhibits a skewed distribution, ensuring the accuracy of variable selection and causal effect estimation might be challenging. Here, we introduce the generalized median adaptive lasso (GMAL) for covariate selection to achieve an accurate estimation of causal effect even when the outcome follows skewed distributions. A distinctive feature of our proposed method is that we utilize a linear median regression model for constructing penalty weights, thereby maintaining the accuracy of variable selection and causal effect estimation even when the outcome presents extremely skewed distributions. Simulation results showed that our proposed method performs comparably to existing methods in variable selection when the outcome follows a symmetric distribution. Besides, the proposed method exhibited obvious superiority over the existing methods when the outcome follows a skewed distribution. Meanwhile, our proposed method consistently outperformed the existing methods in causal estimation, as indicated by smaller root-mean-square error. We also utilized the GMAL method on a deoxyribonucleic acid methylation dataset from the Alzheimer's disease (AD) neuroimaging initiative database to investigate the association between cerebrospinal fluid tau protein levels and the severity of AD.


Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/genetics , Computer Simulation , Databases, Factual , Linear Models , Protein Processing, Post-Translational
16.
Sci Transl Med ; 16(739): eadd8936, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38507467

ABSTRACT

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.


Subject(s)
Antibodies , Arthritis, Experimental , Immunoconjugates , Steroids , Humans , Animals , Mice , Pharmaceutical Preparations , Receptors, Glucocorticoid/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Disease Models, Animal , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use
17.
J Med Virol ; 96(2): e29447, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38305064

ABSTRACT

With the emergence of the Omicron variant, the number of pediatric Coronavirus Disease 2019 (COVID-19) cases requiring hospitalization and developing severe or critical illness has significantly increased. Machine learning and multivariate logistic regression analysis were used to predict risk factors and develop prognostic models for severe COVID-19 in hospitalized children with the Omicron variant in this study. Of the 544 hospitalized children including 243 and 301 in the mild and severe groups, respectively. Fever (92.3%) was the most common symptom, followed by cough (79.4%), convulsions (36.8%), and vomiting (23.2%). The multivariate logistic regression analysis showed that age (1-3 years old, odds ratio (OR): 3.193, 95% confidence interval (CI): 1.778-5.733], comorbidity (OR: 1.993, 95% CI:1.154-3.443), cough (OR: 0.409, 95% CI:0.236-0.709), and baseline neutrophil-to-lymphocyte ratio (OR: 1.108, 95% CI: 1.023-1.200), lactate dehydrogenase (OR: 1.993, 95% CI: 1.154-3.443), blood urea nitrogen (OR: 1.002, 95% CI: 1.000-1.003) and total bilirubin (OR: 1.178, 95% CI: 1.005-3.381) were independent risk factors for severe COVID-19. The area under the curve (AUC) of the prediction models constructed by multivariate logistic regression analysis and machine learning (RandomForest + TomekLinks) were 0.7770 and 0.8590, respectively. The top 10 most important variables of random forest variables were selected to build a prediction model, with an AUC of 0.8210. Compared with multivariate logistic regression, machine learning models could more accurately predict severe COVID-19 in children with Omicron variant infection.


Subject(s)
COVID-19 , Child, Hospitalized , Humans , Child , Infant , Child, Preschool , COVID-19/diagnosis , Logistic Models , SARS-CoV-2 , Cough , Machine Learning , Retrospective Studies
18.
Food Chem ; 445: 138732, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38367558

ABSTRACT

In this study, a straightforward approach is presented for the first time to anchor Ir nanoparticles on the surface of uniform polyaniline (PANi) nanotubes (NTs), which can be used as an efficient peroxidase (POD)-like catalyst. The morphology and chemical structure of the PANi-Ir nanocomposite are characterized by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray diffractometer (XRD), Raman and X-ray photoelectron spectroscopy (XPS) measurements. Owing to the strong interaction between Ir nanoparticles and PANi, a remarkable catalytic enhancement is achieved compared to the bare Ir black catalyst and individual PANi NTs, dominating withan electron transfer mechanism. Furthermore, an efficient colorimetric sensor for ascorbic acid (AA) is developed with a low detection limit of 1.0 µM (S/N = 3), and a total antioxidant capacity (TAC) sensing platform is also constructed for the rigorous detection and analysis of fruits and vegetables.


Subject(s)
Aniline Compounds , Nanoparticles , Nanotubes , Antioxidants , Vegetables , Iridium , Peroxidase , Fruit , Nanotubes/chemistry , Nanoparticles/chemistry , Peroxidases
19.
Article in English | MEDLINE | ID: mdl-38332514

ABSTRACT

STUDY DESIGN: Retrospective observational study. OBJECTIVE: To describe the epidemiology of Schmorl's nodes (SN) of primarily developmental cause (SNd) and SN of primarily acquired cause (SNa) separately in the thoracic spine in subjects aged 35-90 years old. SUMMARY OF BACKGROUND DATA: The epidemiology of SN and its relationship with age and gender remain controversial. Based on a pathophysiological hypothesis and the different morphological characteristics, two subtypes of SN may exist and should be considered separately. PATIENTS AND METHODS: Chest CT scans of subjects who came to our institution for health check aged 35-90 years old were retrospectively reviewed. Presence or absence of SN was recorded for each thoracic vertebra. The SNs were further classified into SNd and SNa. The prevalence, location and relationship with age, gender and bone mineral density (BMD) were evaluated separately for the two subtypes. RESULTS: Of the 848 subjects (407 female, mean age, 53±12.2 y) included, 15.7% had SNs. Of the 303 SNs, 49.2% were SNd and 48.5% were SNa. Aging increased the prevalence of SNa while it was not related to the prevalence of SNd. Males had significantly more SNd than females (11.3% vs 4.7%, P<0.001), while the prevalence of SNa was not different between the two genders (10.2% vs 9.1%, P=0.666). A similar distribution of SNd and SNa among thoracic vertebral levels was appreciated, with T9 most frequently involved. Subjects with SNa had lower lumbar BMD than controls (P=0.006), while no significant difference in BMD was found between subjects with SNd and controls (P=0.166). CONCLUSIONS: The clinical characteristics of SN differ based on the developmental and acquired subtype, including the relationship with age, gender and BMD. The subtypes may be considered as distinct clinical entities as a result.

20.
JAMA Netw Open ; 7(1): e2350814, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38190182

ABSTRACT

Importance: Sibling death is a highly traumatic event, but empirical evidence on the association of sibling death in childhood and early adulthood with subsequent risk of incident cardiovascular disease (CVD) remains limited. Objective: To evaluate the association between sibling death in the early decades of life and subsequent risk of incident early-onset CVD. Design, Setting, and Participants: This population-based cohort study included 2 098 659 individuals born in Denmark from 1978 to 2018. Follow-up started at age 1 year or the date of the first sibling's birth, whichever occurred later, and it ended at the first diagnosis of CVD, the date of death, emigration, or December 31, 2018, whichever came first. Data analyses were conducted from November 1, 2021, through January 10, 2022. Exposures: The death of a sibling. Main Outcomes and Measures: The outcome was early-onset CVD. Cox models were used to estimate hazard ratios (HRs) with 95% CIs. Results: This study included 2 098 659 individuals (1 076 669 [51.30%] male; median [IQR] age at death of sibling, 11.48 [4.68-21.32] years). During the median (IQR) follow-up of 17.52 (8.85-26.05) years, 1286 and 76 862 individuals in the bereaved and nonbereaved groups, respectively, were diagnosed with CVD. Sibling death in childhood and early adulthood was associated with a 17% increased risk of overall CVD (HR, 1.17; 95% CI, 1.10-1.23; cumulative incidence in bereaved individuals, 1.96% [1.61%-2.34%]; cumulative incidence in nonbereaved individuals at age 41 years, 1.35% [1.34%-1.37%]; cumulative incidence difference: 0.61% [95% CI, 0.24%-0.98%]). Increased risks were also observed for most type-specific CVDs, in particular for myocardial infarction (HR, 1.66; 95% CI, 1.12-2.46), ischemic heart disease (HR, 1.52; 95% CI, 1.22-1.90), and heart failure (HR, 1.50; 95% CI, 1.00-2.26). The association was observed whether the sibling died due to CVD (HR, 2.54; 95% CI, 2.04-3.17) or non-CVD (HR, 1.13; 95% CI, 1.06-1.19) causes. The increased risk of CVD was more pronounced for individuals who lost a twin or younger sibling (HR, 1.25; 95% CI, 1.15-1.36) than an elder sibling (HR, 1.11; 95% CI, 1.03-1.20). Conclusions and Relevance: In this cohort study of the Danish population, sibling death in childhood and early adulthood was associated with increased risks of overall and most type-specific early-onset CVDs, with the strength of associations varying by cause of death and age difference between sibling pairs. The findings highlight the need for extra attention and support to the bereaved siblings to reduce CVD risk later in life.


Subject(s)
Cardiovascular Diseases , Cardiovascular System , Heart Failure , Male , Humans , Female , Adult , Aged , Infant , Child, Preschool , Child , Adolescent , Young Adult , Siblings , Cardiovascular Diseases/epidemiology , Cohort Studies
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