Real-World Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System Database for Asciminib.

INTRODUCTION: Asciminib is primarily utilized for treating Philadelphia chromosome-positive chronic myeloid leukemia in its chronic phase among patients harboring the T315I mutation or those who have been previously treated with at least two tyrosine kinase inhibitors. The safety profile of asciminib across a broad patient population over an extended timeframe remains unverified. This study uses a real-world pharmacovigilance database to evaluate the adverse events (AEs) linked with asciminib, providing valuable insights for clinical drug safety. METHODS: Data from the FDA Adverse Event Reporting System (FAERS) database, spanning from October 2021 to December 2023, served as the basis for this analysis. The extent of disproportional events was assessed using sophisticated metrics such as the reporting odds ratio, proportional reporting ratio, information component, and empirical Bayesian geometric mean. RESULTS: Within the specified period, the FAERS database documented 3,913,574 AE reports, with asciminib being associated with 966 incidents. Reactions to asciminib spanned 27 system organ categories. Utilizing four distinct analytical algorithms, 663 significant preferred terms exhibiting disproportional frequencies were identified. Notably, this investigation uncovered 26 significant AEs linked to off-label asciminib use, encompassing conditions such as gynecomastia, nephrotic syndrome, orchitis, pyelonephritis, hepatotoxicity, and pancreatitis. The median onset time for asciminib-related AEs was 52.5 days, ranging from 17 to 122.75 days. CONCLUSION: The study sheds light on additional potential AEs associated with asciminib use, warranting further research to confirm these findings.

Potential diagnostic markers shared between non-alcoholic fatty liver disease and atherosclerosis determined by machine learning and bioinformatic analysis.

Background: Evidence indicates that chronic non-alcoholic fatty liver disease (NAFLD) can increase the risk of atherosclerosis (AS), but the underlying mechanism remains unclear. Objective: This study is intended for confirming key genes shared between NAFLD and AS, and their clinical diagnostic value to establish a foundation for searching novel therapeutic targets. Methods: We downloaded the Gene Expression Omnibus (GEO) datasets, GSE48452 and GSE89632 for NAFLD and GSE100927, GSE40231 and GSE28829 for AS. The progression of NAFLD co-expression gene modules were recognized via weighted gene co-expression network analysis (WGCNA). We screened for differentially expressed genes (DEGs) associated with AS and identified common genes associated with NAFLD and AS using Venn diagrams. We investigated the most significant core genes between NAFLD and AS using machine learning algorithms. We then constructed a diagnostic model by creating a nomogram and evaluating its performance using ROC curves. Furthermore, the CIBERSORT algorithm was utilized to explore the immune cell infiltration between the two diseases, and evaluate the relationship between diagnostic genes and immune cells. Results: The WGCNA findings associated 1,129 key genes with NAFLD, and the difference analysis results identified 625 DEGs in AS, and 47 genes that were common to both diseases. We screened the core RPS6KA1 and SERPINA3 genes associated with NAFLD and AS using three machine learning algorithms. A nomogram and ROC curves demonstrated that these genes had great clinical meaning. We found differential expression of RPS6KA1 in patients with steatosis and NASH, and of SERPINA3 only in those with NASH compared with normal individuals. Immune infiltration findings revealed that macrophage and mast cell infiltration play important roles in the development of NAFLD and AS. Notably, SERPINA3 correlated negatively, whereas RPS6KA1 correlated positively with macrophages and mast cells. Conclusion: We identified RPS6KA1 and SERPINA3 as potential diagnostic markers for NAFLD and AS. The most promising marker for a diagnosis of NAFLD and AS might be RPS6KA1, whereas SERPINA3 is the most closely related gene for NASH and AS. We believe that further exploration of these core genes will reveal the etiology and a pathological relationship between NAFLD and AS.

A fluorescent sensor based on single band bright red luminescent core-shell UCNPs for the high-sensitivity detection of glucose and glutathione.

As the reliable biomarkers to evaluate the diabetes and neurological disease, sensitive and accurate detection of glucose and glutathione (GSH) in biological samples is necessary for early precaution and diagnosis of related-diseases. The single red upconversion nanoparticles (UCNPs) especially with core-shell structure can penetrate deeper biological tissues and cause less energy loss and thus have higher sensitivity and accuracy. Additionally, an enzyme-controlled cascade signal amplification (ECSAm) strategy will further enhance sensitivity. Herein, using single red UCNPs with core-shell structure as the luminescent material, a fluorescent sensor based on ECSAm was developed for the highly sensitive and accurate detection of glucose and GSH. Under the optimal conditions, the limits of detection for glucose and GSH by fluorescent method were 0.03 µM and 0.075 µM, separately. This assay was used to analyze the content of glucose and GSH in serum samples, and the obtained data was close to that of commercial blood glucose and GSH detection kit. The developed sensor platform based on single red UCNPs with core-shell structure and ECSAm can be a promising method for the accurate and sensitive detection of glucose and GSH in biological samples.

Unlabelled LRET biosensor based on double-stranded DNA for the detection of anthraquinone anticancer drugs.

Based on upconversion nanoparticles (UCNPs) as energy donor and herring sperm DNA (hsDNA) as molecular recognition element, an unlabelled upconversion luminescence (UCL) affinity biosensor was constructed for the detection of anthraquinone (AQ) anticancer drugs in biological fluids. AQ anticancer drugs can insert into the double helix structure of hsDNA on the surface of UCNPs, thereby shortening the distance from UCNPs. Therefore, the luminescence resonance energy transfer (LRET) phenomenon is effectively triggered between UCNPs and AQ anticancer drugs. Hence, AQ anticancer drugs can be quantitatively detected according to the UCL quenching rate. The biosensor showed good sensitivity and stability for the detection of daunorubicin (DNR) and doxorubicin (ADM). For the detection of DNR, the linear range is 1-100 µg·mL-1 with a limit of detection (LOD) of 0.60 µg·mL-1, and for ADM, the linear range is 0.5-100 µg·mL-1 with a LOD of 0.38 µg·mL-1. The proposed biosensor provides a convenient method for monitoring AQ anticancer drugs in clinical biological fluids in the future.

The novel GLP-1/GIP dual agonist DA3-CH improves rat type 2 diabetes through activating AMPK/ACC signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) accounts for more than 95% of all diabetes. DA3-CH is a novel dual receptor agonist of glucagon like peptide-1 (GLP-1) and glucose dependent insulin stimulating polypeptide (GIP). The regulatory role of DA3-CH in T2DM has not been reported. METHODS: T2DM rat model was established successfully with high sugar and fat feed and streptomycin (STZ) induction. The mRNA and protein expression were measured with RT-PCR and western blotting. The apoptosis level in the pancreatic tissue was evaluated with Tunel staining. Blood glucose, fat, and oxidative stress indicators were measured. RESULTS: DA3-CH greatly improved T2DM symptoms by reducing blood glucose, blood fat, pancreatic tissue injury, apoptosis, and oxidative stress condition. The inactivation of Adenylate activated protein kinase (AMPK)/acetyl CoA carboxylase (ACC) signaling pathway in T2DM rats was promoted by DA3-CH. The influence of DA3-CH was significantly reversed by Com-C, the inhibitor of AMPK/ACC signaling pathway. CONCLUSIONS: DA3-CH might improve T2DM through targeting AMPK/ACC signaling pathway. This study might provide a novel therapeutic strategy for the prevention and treatment of T2DM through targeting DA3-CH and AMPK/ACC signaling pathway.

Inhibitory effects of total triterpenoids isolated from the Hedyotis diffusa willd on H1975 cells.

It is estimated that non-small-cell lung cancer (NSCLC) is responsible for 80% of human deaths related to lung cancer worldwide. Currently, it has been discovered that two transcription factors. Nuclear factor-κB (NF-κB) and Signal transducer and activator of transcription 3 (STAT3) were the main factors affecting inflammation and cancer, and their activation promoted lung cancer cell proliferation. Hedyotis diffusa Willd. (H. diffusa) is an herbal Chinese medicine, which has always been used for the treatment of malignant tumors in clinical. Previous research found that H. diffusa could inhibit the proliferation of H1975 cells, but the specific mechanisms remain elusive. We investigated the effects of total triterpenes extracted from H. diffusa (TTH) on the migration, proliferation and apoptosis of H1975 cells. Cell-cycle and immunofluorescence analysis showed that TTH could block H1975 cells at G0/G1 phase and induce apoptosis of experimental cells. The protein levels of Bcl-2 were decreased, while the levels of pro-apoptotic Bax were increased. In addition, TTH could also inhibit the migration of H1975 cells through downregulated MMP-2 and MMP-9 and upregulated TIMP-2. Further research found that the level of phospho-STAT3 was significantly decreased after administration of TTH. And protein expression level of NF-κB in nucleus was decreased after TTH treatment, while NF-κB in cytoplasm increased. These results suggested that TTH could inhibit the proliferation and migration of H1975 cells, and also could induce cell apoptosis. These effects were closely connected to the activation of NF-κB and the phosphorylation of STAT3.

A colorimetric sensor for acid phosphatase activity detection based on acridone derivative as visible-light-stimulated oxidase mimic.

Currently, organic artificial enzymes as biocatalysts have been extensively used to construct various colorimetric sensors. However, exploiting a potential organic artificial enzyme with high catalytic efficiency still remains a challenge. To address this issue, herein, we synthesize an acridone derivative 10-benzyl-2-amino-acridone (BAA). The synthesized BAA exhibits an intrinsic visible-light-stimulated oxidase-like activity, which is capable of oxidizing various chromogenic substrates without destructive hydrogen peroxide (H2O2) under visible light stimulation, resulting in colored products. The reaction system can be regulated by switching light on and off, which is milder and more reliable means than others H2O2-dependent. The photocatalytic mechanism of BAA is investigated in detail. However, l-ascorbic acid (AA), an antioxidant generating from the acid phosphatase (ACP)-mediated hydrolysis of 2-phospho-l-ascorbic acid (AAP), is able to inhibit the catalytic activity of BAA. Based on the above properties, a facile, photo-switchable and low-cost colorimetric sensing strategy is developed for ACP detection. The linear range is 0.05-2.5 U/L (r = 0.9994), and the limit of detection (LOD) is 0.0415 U/L. Moreover, the proposed sensing system can be applied for monitoring ACP activity in practical samples, demonstrating promising applications in clinical analysis and biosensor platform.

A signal amplification electrochemical aptasensor for the detection of breast cancer cell via free-running DNA walker.

Herein, a signal magnification electrochemical aptasensor for the detection of breast cancer cell via free-running DNA walker is constructed. Theoretically, just one DNA walker, released by target cell-responsive reaction, can automatically cleave all D-RNA (a chimeric DNA/RNA oligonucleotide with a cleavage point rArU) anchored on electrode into shorter produces, giving rise to considerably detectable signal finally. Under the optimal conditions, the electrochemical signal decreased linearly with the concentration of MCF-7 cell. The linear range is from 0 to 500 cells mL(-1) with a detection limit of 47 cellsmL(-1). In a word, this approach may have advantages over traditional reported DNA machines for bioassay, particularly in terms of ease of operation, cost efficiency, free of labeling and of complex track design, which may hold great potential for wide application.

An immobilization-free electrochemical impedance biosensor based on duplex-specific nuclease assisted target recycling for amplified detection of microRNA.

An immobilization-free electrochemical impedance biosensor for microRNA detection was developed in this work, which was based on both the duplex-specific nuclease assisted target recycling (DSNATR) and capture probes (Cps) enriched from the solution to electrode surface via magnetic beads (MBs). In the absence of miR-21, Cps cannot be hydrolyzed due to the low activity of duplex-specific nuclease (DSN) against ssDNA. Therefore, the intact Cps could be attached to the surface of magnetic glass carbon electrode (MGCE), resulting in a compact negatively charged layer as well as a large charge-transfer resistance. While in the presence of miR-21, it hybridized with Cp to form a DNA-RNA heteroduplex. Due to the considerable cleavage preference for DNA in DNA-RNA hybrids, DSN hydrolyzed the target-binding part of the Cp while liberating the intact miR-21 to hybridize with a new Cp and initiate the second cycle of hydrolysis. In this way, a single miR-21 was able to trigger the permanent hydrolysis of multiple Cps. Finally, all Cps were digested. Thus, the negatively charged layer could not be formed, resulting in a small charge-transfer resistance. By employing the above strategy, the proposed biosensor achieved ultrahigh sensitivity toward miR-21 with a detection limit of 60aM. Meanwhile, the method showed little cross-hybridization among the closely related miRNA family members even at the single-base-mismatched level. Successful attempts were made in applying the approach to detect miR-21 in human serum samples of breast cancer patients.

Label-free microRNA detection based on terbium and duplex-specific nuclease assisted target recycling.

In this paper, we describe a novel label-free fluorescence method for microRNA-21 (miR-21) detection based on terbium (Tb(3+)) and duplex-specific nuclease (DSN) assisted target recycling. Capture probes (Cps), containing a target-binding part and a signal-output part, are immobilized on magnetic beads (MBs). In the presence of the target miR-21, it hybridizes with the target-binding part of a Cp to form a DNA-RNA heteroduplex. Due to the considerable cleavage preference for DNA in DNA-RNA hybrids, DSN hydrolyzes the target-binding part of the Cp while liberating the intact target miR-21 to hybridize with a new Cp and initiate the second cycle of hydrolysis. Eventually, through magnetic separation, only the signal-output part of the Cp could remain in solution and function as a signalling flare to increase the fluorescence intensity of Tb(3+) dramatically. By employing the above strategy, this approach can gain an amplified fluorescent signal and detect as low as 8 fM miR-21 under the optimized conditions. Moreover, due to the high selectivity of DSN, the method shows little cross-hybridization among the closely related miRNA family members even at the single-base-mismatched level. Successful attempts were made in applying the approach to detect miR-21 in human cell lysate samples of breast cancer patients.

A signal-on fluorescent aptasensor based on single-stranded DNA-sensitized luminescence of terbium (III) for label-free detection of breast cancer cells.

Breast cancer is the most common type of malignant tumor in women. Recently, it has been shown that detection of breast cancer tumor cells outside the primitive tumor is an effective early diagnosis with great prognostic and clinical utility. For this purpose, we developed a signal-on fluorescence aptasensor for label-free, facile and sensitive detection of MCF-7 breast cancer cells. Due to target-aptamer specific recognition and single-stranded DNA-sensitized luminescence of terbium (III), the proposed aptasensor exhibits excellent sensitivity with detection limit as low as 70 cells mL(-1). Compared with common organic dyes and the emerging nano-technological probes, the combination of terbium (III) and single-stranded DNA signal probe (Tb(3+)-SP) serves as a more powerful bio-probe because of its stable optical property, good biocompatibility and free from complex synthesis. The feasibility investigations have illustrated the potential applicability of this aptasensor for selective and sensitive detection of MCF-7 breast cancer cells. Moreover, this proposed aptasensor can be also extended for the determination of other tumor cancers or bio-molecules by altering corresponding aptamers. Taken together, this easy-to-perform aptasensor may represent a promising way for early screening and detection of tumor cancers or other bio-molecules in clinical diagnosis.

Enzyme-free and label-free fluorescence sensor for the detection of liver cancer related short gene.

Non-invasive early diagnosis of liver cancer is the most effective way to improve the survival rate. In this paper, we developed a label-free and enzyme-free fluorescent biosensor based on target recycling and Thioflavin T (ThT) induced G-quadruplex formation for MXR7 (liver cancer related short gene) detection in human serum. The proposed sensor can detect the target DNA in the concentration range of 0-350fM with the detection limit as low as 10fM. Due to the outstanding structural selectivity of ThT for G-quadruplex, this sensor possesses better discrimination ability and higher sensitivity. Furthermore, this enzyme-free and label-free fluorescence sensor has demonstrated to be capable of detecting target DNA in human serum samples because of its high selectivity and sensitivity. The mechanism employed in this study represents a promising path toward directing liver cancer detection in human serum. In addition, this strategy may be extended to detect other cancer related genes by choosing a rational DNA probe according to different sequences of targets.

Ultraselective electrochemiluminescence biosensor based on locked nucleic acid modified toehold-mediated strand displacement reaction and junction-probe.

Locked nucleic acid (LNA) is applied in toehold-mediated strand displacement reaction (TMSDR) to develop a junction-probe electrochemiluminescence (ECL) biosensor for single-nucleotide polymorphism (SNP) detection in the BRCA1 gene related to breast cancer. More than 65-fold signal difference can be observed with perfectly matched target sequence to single-base mismatched sequence under the same conditions, indicating good selectivity of the ECL biosensor.

An ultrasensitive label-free electrochemical biosensor for microRNA-21 detection based on a 2'-O-methyl modified DNAzyme and duplex-specific nuclease assisted target recycling.

Based on a highly efficient 2'-O-methyl modified G-quadruplex-hemin DNAzyme and duplex-specific nuclease (DSN) assisted target recycling, a novel label-free electrochemical biosensor for microRNA-21 (miR-21) detection is developed here. By employing the strategy, this DNA biosensor can detect as low as 8 aM miR-21 and exhibits high discrimination ability even against a single-base mismatch.

A fluorescent aptasensor based on DNA-scaffolded silver-nanocluster for ochratoxin A detection.

The selective detection of ultratrace amounts of ochratoxin A (OTA) is extremely important for food safety since it is one of the most toxic and widespread mycotoxin. Here we develop a signal-on fluorescent biosensor for detection of OTA based on fluorescent DNA-scaffolded silver-nanocluster (AgNCs), structure-switching of anti-OTA aptamer (Ap) and magnetic beads (MBs), and demonstrate its feasibility in the application of detecting OTA in real samples of wheat. The method exhibits superior sensitivity with a detection limit as low as 2 pg/mL OTA with high specificity. To the best of our knowledge, this is the first attempt to detect OTA based on DNA-scaffolded AgNCs, which possesses relatively high fluorescence quantum yield and photostability with regard to traditional organic dyes and quantum dots. Moreover, combined with the merits of MBs and aptamer, the proposed sensor has many advantages such as fabrication easiness, operation convenience, low cost, and being fast and portable, which may represent a promising path toward routine OTA control.

Label-free fluorescent biosensor based on the target recycling and Thioflavin T-induced quadruplex formation for short DNA species of c-erbB-2 detection.

Non-invasive early diagnosis of breast cancer is the most effective way to improve the survival rate and increase more chances of breast-conserving. In this paper, we developed a label-free fluorescent biosensor based on nuclease assisted target recycling and Thioflavin T-induced quadruplex formation for short DNA species of c-erbB-2 detection in saliva. By employing the strategy, the sensor can detect as low as 20fM target DNA with high discrimination ability even against single-base mismatch sequence. To the best of our knowledge, the proposed sensor is the first attempt to apply Thioflavin T that possesses outstanding structural selectivity for G-quadruplex in DNA amplification techniques, which may represent a promising path toward direct breast cancer detection in saliva at the point of care.

Label-free electrochemical biosensor using home-made 10-methyl-3-nitro-acridone as indicator for picomolar detection of nuclear factor kappa B.

A new acridone derivative 10-methyl-3-nitro-acridone (MNA) with excellent electrochemical activity was synthesized in this paper. Using it as an electrochemical indicator, a signal-on and label-free electrochemical biosensor was developed for picomolar determination of nuclear factor kappa B (NF-κB) in serum. Initially, linear double-stranded DNA (dsDNA) probes, which contain a protein-binding site specific to NF-κB, were self-assembled on the surface of a glass carbon electrode (GCE). If the NF-κB was absent, the dsDNA probes were cut into ss-DNA fragments by the digestion of ExoIII, resulting in a low electrochemical signal of MNA due to the weak binding affinity of MNA to ss-DNA. On the contrary, in the presence of NF-κB, it could bind with the dsDNA probes at the specific site and hinder the digestion of ExoIII, resulting in a significant increase of electrochemical response due to the intercalation of MNA into the dsDNA probes. By employing the above strategy, this sensor could detect as low as 40 pM NF-κB with high specificity. To the best of our knowledge, the proposed sensor is the first attempt to use acridone derivative as an electrochemical indicator for NF-κB detection, which may represent a promising path toward clinical diagnosis and drug developments.