Signal detection of adverse reactions for bendamustine based on FDA adverse event reporting system.

BACKGROUND: This study aimed to analyze the adverse events to bendamustine using data obtained from the Food and Drug Administration open public data project (openFDA) and to provide a reference for its use in clinical practice. RESEARCH DESIGN AND METHODS: Adverse events (AEs) due to bendamustine usage reported from 1 January 2008 to 31 March 2023 were collected from the FDA Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian plausible propagation neural network (BCPNN), and multinomial gamma-Poisson distribution shrinking (MGPS) algorithms were used to identify signs of adverse reactions caused by bendamustine. RESULTS: A total of 4214 AE reports where bendamustine was considered as the first suspected drug were obtained from FAERS. The analysis revealed 214 AE risk signals, among which 141 met the criteria but they were not listed as possible side effects on the drug information sheet provided in the package. CONCLUSION: Our findings identified numerous common AEs with previously reported clinical observations. We also identified some signs of potential new AEs, indicating the need of careful clinical monitoring of patients treated with bendamustine and further risk identification research about this drug.

α-Cyanostilbene-based Molecule with the Synergistical Mechanisms of AIE, ESIPT and TICT: A New Schiff Base Probe for Selective Detection of Fe3+ and Reversible Response to HCl/NH3 Vapor.

We designed and synthesized a new Schiff base probe, which incorporated the salicylaldehyde-analogue α-cyanostilbene and benzophenone hydrazone by the imine linkage. Its chemical structure was verified by FT-IR, MALDI-TOF-MS, HR-MS and 1H/13C NMR technologies. It could exhibit a red fluorescence based on the synergistical effects of aggregation-induce emission (AIE), excited-state intramolecular proton transfer (ESIPT) and twisted intramolecular charge-transfer (TICT) in the aggregation or solid states. Interestingly, the TLC-based test strip loaded with the target compound showed the reversible fluorescence response to amine/acid vapor and on-site visual fluorescence quenching response to Fe3+. In THF/water mixtures (fw = 90%, 10 µM, pH = 7.4), the detection limit (DL) and the binding constant (Ka) of the developed probe towards Fe3+ were evaluated as 5.50 × 10- 8 M and 1.69 × 105, respectively. The developed probe was successfully applied for the detection of Fe3+ with practical, reliable, and satisfying results.

Printed Divisional Optical Biochip for Multiplex Visualizable Exosome Analysis at Point-of-Care.

Rapid detection of various exosomes is of great significance in early diagnosis and postoperative monitoring of cancers. Here, a divisional optical biochip is reported for multiplex exosome analysis via combining the self-assembly of nanochains and precise surface patterning. Arising from resonance-induced near-field enhancement, the nanochains show distinct color changes after capturing target exosomes for direct visual detection. Then, a series of divisional nanochain-based biochips conjugated with several specific antibodies are fabricated through designed hydrophilic and hydrophobic patterns. Because of the significant wettability difference, one sample droplet is precisely self-splitting into several microdroplets enabling simultaneous identification of multiple target exosomes in 30 min with a sensitivity of 6 × 107 particles mL-1 , which is about two orders lower than enzyme-linked immunosorbent assay. Apart from the trace amount detection, excellent semiquantitative capability is demonstrated to distinguish clinical exosomes from glioblastoma patients and healthy people. This method is simple, versatile, and highly efficient that can be extended as a diagnostic tool for many diseases, promoting the development of liquid biopsy.

CircMAP3K5 promotes cardiomyocyte apoptosis in diabetic cardiomyopathy by regulating miR-22-3p/DAPK2 Axis.

BACKGROUND: Diabetic cardiomyopathy (DCM) is one of the serious complications of the accumulated cardiovascular system in the long course of diabetes. To date, there is no effective treatment available for DCM. Circular RNA (circRNA) is a novel r2egulatory RNA that participates in a variety of cardiac pathological processes. However, the regulatory role of circular RNA MAP3K5 (circMAP3K5) in DCM is largely unclear. METHODS AND RESULTS: Microarray analysis of DCM rats' heart circular RNAs was performed and the highly species-conserved circRNA mitogen-activated protein kinase kinase kinase 5 (circMAP3K5) was identified, which participates in DCM processes. High glucose-provoked cardiotoxicity leads to the up-regulation of circMAP3K5, which mechanistically contributes to cardiomyocyte cell death. Also, in high glucose-induced H9c2 cardiomyocytes, the level of apoptosis was significantly increased, as well as the expression of circMAP3K5. In contrast, the depletion of circMAP3K5 could reduce high glucose-induced apoptosis in cardiomyocytes. In terms of mechanism, circMAP3K5 acts as a miR-22-3p sponge and miR-22-3p directly target death-associated protein kinase 2 (DAPK2) in H9c2 cardiomyocytes, where in circMAP3K5 upregulates DAPK2 expression by targeting miR-22-3p. Moreover, we also found that miR-22-3p inhibitor and pcDNA DAPK2 could antagonize the protective effects brought by the depletion of circMAP3K5. CONCLUSION: CircMAP3K5 is a highly conserved noncoding RNA that is upregulated during DCM process. We concluded that circMAP3K5 promotes high glucose-induced cardiomyocyte apoptosis by regulating the miR-22-3p/DAPK2 axis. The results of this study highlight a novel and translationally important circMAP3K5-based therapeutic approach for DCM.

Molecular Biomarkers and Recent Liquid Biopsy Testing Progress: A Review of the Application of Biosensors for the Diagnosis of Gliomas.

Gliomas are the most common primary central nervous system tumors, with a high mortality rate. Early and accurate diagnosis of gliomas is critical for successful treatment. Biosensors are significant in the detection of molecular biomarkers because they are simple to use, portable, and capable of real-time analysis. This review discusses several important molecular biomarkers as well as various biosensors designed for glioma diagnosis, such as electrochemical biosensors and optical biosensors. We present our perspectives on the existing challenges and hope that this review can promote the improvement of biosensors.

Generation of whole tumor cell vaccine for on-demand manipulation of immune responses against cancer under near-infrared laser irradiation.

The therapeutic efficacy of whole tumor cell vaccines (TCVs) is modest, which has delayed their translation into personalized immunotherapies in the clinic. Here, we develop a TCV platform based on photothermal nanoparticle-loaded tumor cells, which can be rationally applied to diverse tumor types to achieve on-demand boost of anti-tumor immune responses for inhibiting tumor growth. During the fabrication process, mild photothermal heating by near-infrared (NIR) laser irradiation induces the nanoparticle-bearing tumor cells to express heat shock proteins as endogenous adjuvants. After a single vaccination at the back of tumor-bearing mice, non-invasive NIR laser irradiation further induces mild hyperthermia at vaccination site, which promotes the recruitment, activation, and antigen presentation by dendritic cells. Using an indicator we term fluctuation of tumor growth rate, we determine appropriate irradiation regimens (including optimized irradiation intervals and times). This TCV platform enables on-demand NIR manipulation of immune responses, and we demonstrate potent therapeutic efficacy against six murine models that mimick a range of clinical scenarios, including a model based on humanized mice and patient-derived tumor xenografts.

SGLT2 inhibitor dapagliflozin alleviates intramyocardial hemorrhage and adverse ventricular remodeling via suppressing hepcidin in myocardial ischemia-reperfusion injury.

Intramyocardial hemorrhage (IMH), a reperfusion therapy-associated complication, is the extravasation of red blood cells caused by severe microvascular injury. IMH is an independent predictor of adverse ventricular remodeling (AVR) after acute myocardial infarction (AMI). Hepcidin, a major regulator of iron uptake and systemic distribution, is a key factor affecting AVR. However, the role of cardiac hepcidin in the development of IMH has not been completely elucidated. This study aimed to explore if sodium-dependent glucose co-transporter 2 inhibitor (SGLT2i) exerts therapeutic effects on IMH and AVR by suppressing hepcidin and to elucidate the underlying mechanisms. SGLT2i alleviated IMH and AVR in the ischemia-reperfusion injury (IRI) mouse model. Additionally, SGLT2i downregulated the cardiac levels of hepcidin in IRI mice, suppressed M1-type macrophage polarization, and promoted M2-type macrophage polarization. The effects of hepcidin knockdown on macrophage polarization were similar to those of SGLT2i in RAW264.7 cells. SGLT2i treatment or hepcidin knockdown inhibited the expression of MMP9, an inducer of IMH and AVR, in RAW264.7 cells. Regulation of macrophage polarization and reduction of MMP9 expression by SGLT2i and hepcidin knockdown is achieved through activation of pSTAT3. In conclusion, this study demonstrated that SGLT2i alleviated IMH and AVR by regulating macrophage polarization. The potential mechanism through which SGLT2i exerted its therapeutic effect seems to involve the downregulation of MMP9 via the hepcidin-STAT3 pathway.

The novel HLA-DRB1*14:07:03 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DRB1*14:07:03 differs from HLA-DRB1*14:07:01 by one nucleotide in exon 2.

All-printed point-of-care immunosensing biochip for one drop blood diagnostics.

Designing and preparing a fast and easy-to-use immunosensing biochip are of great significance for clinical diagnosis and biomedical research. In particular, sensitive, specific, and early detection of biomarkers in trace samples promotes the application of point-of-care testing (POCT). Here, we demonstrate an all-printed immunosensing biochip with the characteristics of hydrodynamic enrichment and photonic crystal-enhanced fluorescence. Direct quantitative detection of cardiac biomarkers via one drop of blood is achieved in 10 min. After simulating the hydrodynamic behavior of one droplet serum on the printed assay, creatine kinase-MB (CK-MB) has been recognized and located on the photonic crystal arrays. Benefiting from the fluorescence enhancement effect, quantitative detection of CK-MB has been demonstrated from 0.01 ng ml-1 to 100 ng ml-1, which is superior to the conventional enzyme-linked immunosorbent assay (ELISA). This strategy provides a general and easy-to-use approach for fast quantitative detection of biomarkers, which would be improved further for portable clinical diagnostics and home medical monitoring.

Host-guest interactions of indocyanine green with ß-cyclodextrin permit real-time characterization of the rat lymphatic system.

Objective: Fluorescence contrast technology using indocyanine green (ICG) could be useful for the rapid, dynamic, and objective assessment of blood vessels and the surrounding tissues when combined with near-infrared (NIR) imaging. Although ICG is a clinically available NIR fluorescence imaging probe, it can easily aggregate and is, thus, unstable. In the present study, we examined the efficacy of a host-guest ICG-ß-cyclodextrin (CD) complex, which is used in pharmaceutics to improve the water solubility, stability, and bioavailability of hydrophobic molecules, for NIR imaging after hind footpad administration in a rat model. Methods: To verify the performance of the ICG-ß-CD complex with the host-guest self-assembly method in vivo, we performed simultaneous small animal (IVIS Spectrum system; PerkinElmer, Waltham, MA) and clinical (DIGI-MIH-001 near-infrared fluorescence imaging system; Beijing Digital Precision Medical Technology Co, Ltd, Beijing, China) imaging and evaluated the fluorescent properties of the ICG-ß-CD complex in the hind footpad model of Sprague-Dawley male rats. Results: We successfully prepared the ICG-ß-CD complex. Compared with ICG, in vivo experiments showed that this complex had reduced absorbance at 710 nm and increased absorbance at 780 nm, indicating that it could prevent the dimeric aggregation of ICG, and a significantly higher fluorescence intensity at 730 nm excitation. After injection of 1.25 mg/mL of ICG or ICG-ß-CD complex solutions into the rat hind footpad, fluorescent NIR lymphatic images were observed with both imaging systems. During the 12-hour observation period, the signal background ratio of ICG-ß-CD showed a greater acute increase and a higher signal background ratio compared with ICG. The signal background ratio of ICG-ß-CD was 125 to 100 from 260 to 540 minutes. These in vivo data suggest that ICG-ß-CD has greater diffusion from the injection site and faster transport to the lymphatic system compared with ICG. Conclusions: ICG-ß-CD showed faster lymphatic transport than ICG, allowing for more rapid lymphatic NIR imaging. Thus, the ICG-ß-CD complex might be a promising fluorescent agent for clinical lymphatic NIR imaging.

Dynamical Control of Nuclear Isomer Depletion via Electron Vortex Beams.

Some nuclear isomers are known to store a large amount of energy over long periods of time, with a very high energy-to-mass ratio. Here, we describe a protocol to achieve the external control of the isomeric nuclear decay by using electron vortex beams whose wave function has been especially designed and reshaped on demand. Recombination of these electrons into the isomer's atomic shell can lead to the controlled release of the stored nuclear energy. On the example of ^{93m}Mo, we show theoretically that the use of tailored electron vortex beams increases the depletion by 4 orders of magnitude compared to the spontaneous nuclear decay of the isomer. Furthermore, specific orbitals can sustain an enhancement of the recombination cross section for vortex electron beams by as much as 6 orders of magnitude, providing a handle for manipulating the capture mechanism. These findings open new prospects for controlling the interplay between atomic and nuclear degrees of freedom, with potential energy-related and high-energy radiation source applications.

Human umbilical cord-derived stem cell sheets improve left ventricular function in rat models of ischemic heart failure.

INTRODUCTION: Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are among the most promising cell therapy sources used to treat ischemic heart disease. Cell sheet engineering has been used to transplant stem cells and improve their therapeutic effectiveness. We aimed to evaluate the effectiveness of UC-MSC sheets in the treatment of chronic ischemic heart failure. METHODS AND RESULTS: Flow cytometric analysis showed that UC-MSCs were positive for CD73, CD90, and CD105. UC-MSC sheets were produced from UC-MSCs using temperature-responsive culture dishes. Afterward, these sheets were transplanted onto the epicardial surface at the infarct heart in rat models of chronic ischemic heart failure. At four weeks after the transplantation, echocardiography analysis revealed that the cardiac function of the UC-MSC sheets group was significantly better than that of the suspension and myocardial infarction (MI) only groups. Furthermore, histological examinations revealed that the left ventricular remodeling was attenuated compared with the suspension and MI-only groups. In the UC-MSC slice group, the neovascular den and cell size in the infarct margin region were was significantly improved than in the suspension and MI-only groups. Also, the UC-MSC sheets inhibited the PI3K/AKT/mTOR signaling pathway in chronic ischemic heart failure. CONCLUSIONS: UC-MSC sheets can maintain cardiac function and attenuate ventricular remodeling in chronic ischemic heart failure, indicating that this strategy would be a promising therapeutic option in the clinical scenario.

Ibrutinib as monotherapy versus combination therapy in Chinese patients with relapsed/refractory mantle cell lymphoma: A multicenter study.

BACKGROUND: Ibrutinib has revolutionized the treatment of mantle cell lymphoma (MCL). Both ibrutinib monotherapy and ibrutinib-based combination therapy are important salvage options for patients with relapsed/refractory (R/R) MCL. The real-world efficacy and safety profile of the two strategies in Chinese patients with R/R MCL remain unclarified. METHODS: In the present study, data of 121 R/R MCL patients who received either ibrutinib monotherapy (N = 68) or ibrutinib combination therapy (N = 53) in 13 medical centers in China were retrospectively reviewed. RESULTS: With a median follow-up of 20.5 months, the overall response rate was 60.3% versus 84.9% (p = 0.003), complete remission rate was 16.2% versus 43.4% (p < 0.001), and median progression-free survival (PFS) was 18.5 months (95% confidence interval [CI], 12.1-21.8) vs. 30.8 months (95% CI, 23.5-NR) (hazard ratio, 0.53 [95% CI, 0.30-0.93]; p = 0.025), with ibrutinib monotherapy and ibrutinib-based combination therapy, respectively. Subgroup analysis showed that patients with male gender, no refractory disease, Ki67 <30%, previous line of therapy = 1, non-blastoid subtype, and the number of extranodal sites involved <2 might benefits more from the combination therapy. Treatment-emergent adverse events were similar, except for a higher incidence of all grade neutropenia in the ibrutinib combination group (12.7% vs. 32.0%, p = 0.017). CONCLUSIONS: Ibrutinib combination therapy demonstrated potentially superior efficacy and comparable tolerability to ibrutinib monotherapy. Ibrutinib-based combination therapy could be one of the prominent treatment options for R/R MCL patients.

Development of machine learning models for mortality risk prediction after cardiac surgery.

Background: We developed machine learning models that combine preoperative and intraoperative risk factors to predict mortality after cardiac surgery. Methods: Machine learning involving random forest, neural network, support vector machine, and gradient boosting machine was developed and compared with the risk scores of EuroSCORE I and II, Society of Thoracic Surgeons (STS), as well as a logistic regression model. Clinical data were collected from patients undergoing adult cardiac surgery at the First Medical Centre of Chinese PLA General Hospital between December 2008 and December 2017. The primary outcome was post-operative mortality. Model performance was estimated using several metrics, including sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC). The visualization algorithm was implemented using Shapley's additive explanations. Results: A total of 5,443 patients were enrolled during the study period. The mean EuroSCORE II score was 3.7%, and the actual in-hospital mortality rate was 2.7%. For predicting operative mortality after cardiac surgery, the AUC scores were 0.87, 0.79, 0.81, and 0.82 for random forest, neural network, support vector machine, and gradient boosting machine, compared with 0.70, 0.73, 0.71, and 0.74 for EuroSCORE I and II, STS, and logistic regression model. Shapley's additive explanations analysis of random forest yielded the top-20 predictors and individual-level explanations for each prediction. Conclusions: Machine learning models based on available clinical data may be superior to clinical scoring tools in predicting postoperative mortality in patients following cardiac surgery. Explanatory models show the potential to provide personalized risk profiles for individuals by accounting for the contribution of influencing factors. Additional prospective multicenter studies are warranted to confirm the clinical benefit of these machine learning-driven models.

Injectable Cryogels Associate with Adipose-Derived Stem Cells for Cardiac Healing After Acute Myocardial Infarctions.

Treatment of adipose-derived stem cells (ADSCs) provides support for novel methods of conveying baseline cell protein endothelial cells to promote acute myocardial infarction in gelatin sericin (GS) lamin-coated antioxidant systems (GS@L). The ratio of fixity modules, pores, absorption, and inflammation in the range of ka (65 ka), 149 ±39.8 µm, 92.2%, 42 ± 1.38, and 29 ± 1.9 were observed in the synthesized frames for GS. Herein, ADSC-GS@L was prepared, and the relevant substance for the development of cardiac regenerative applications was stable and physically chemical. In vitro assessments of ADSC-GS@L injectable cryogels established the enhanced survival rates of the cell and improved pro- angiogenic factors as well as pro-inflammatory expression, confirming the favorable outcomes of fractional ejections, fibro-areas, and vessel densities with reduced infraction dimensions. The novel ADSC-injecting cryogel method could be useful for successful heart injury therapies during acute myocardial infarction. Additionally, the method could be useful for successful heart injury therapies during coronary heart disease.

Effect of diabetes mellitus on long-term outcomes of surgical revascularization in patients with ischemic heart failure: a propensity score-matching study.

BACKGROUND: Diabetes mellitus (DM) is an important risk factor in the long-term outcomes of surgical revascularization. However, few studies have focused on patients with ischemic heart failure (IHF) and DM, and the results are controversial. This study aimed to evaluate the effect of DM on the long-term outcomes of IHF patients undergoing coronary artery bypass grafting (CABG). METHODS: In this propensity-matched study, data of IHF patients who underwent CABG in our hospital from January 2007 to December 2017 were analyzed. With a mean 73-month follow-up time, the patients were divided into two groups according to whether they had DM. The primary endpoint was all-cause death, and the secondary endpoint was a composite of all-cause death, stroke, recurrent myocardial infarction, and revascularization. RESULTS: There was no significant difference in all-cause mortality between the two groups (5.8% vs. 4.1%, P = 0.216). The incidence of main adverse cardiovascular and cerebrovascular events (MACCE) in the secondary endpoint was significantly higher in the DM group than that in the non-DM group (10.4% vs. 8.1%, P = 0.023). CONCLUSIONS: DM can negatively affect the long-term outcomes of IHF patients undergoing CABG by significantly increasing the overall incidence of MACCE, though the long-term survival does not show a significant difference between the DM and non-DM patients.

An Immune Risk Score Predicts Survival of Patients with Acute Myeloid Leukemia Receiving Chemotherapy.

PURPOSE: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. EXPERIMENTAL DESIGN: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. RESULTS: Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. CONCLUSIONS: Our immune risk score complements current AML prediction models.

microRNA-30e up-regulation alleviates myocardial ischemia-reperfusion injury and promotes ventricular remodeling via SOX9 repression.

AIM: At present, studies have focused on microRNAs (miRNAs) in myocardial ischemia-reperfusion injury (MI/RI). But the specific role of miR-30e hasn't been fully explored. Thus, this study is to uncover the mechanism of miR-30e in MI/RI. METHODS: MI/RI models of rats and hypoxia/reoxygenation injury (H/R) models of H9C2 cardiomyocytes were established. Rats were injected with miR-30e and SRY-related high mobility group-box gene 9 (SOX9)-related oligonucleotides or vectors to explore their roles in MI/RI. H9C2 cardiomyocytes were transfected with restored miR-30e and depleted SOX9 to decipher their function in H/R injury. miR-30e and SOX9 expression in myocardial tissues and cardiomyocytes were detected. Online website prediction and luciferase activity assay were applied to validate the targeting relationship between miR-30e and SOX9. RESULTS: Decreased miR-30e and increased SOX9 were found in myocardial tissues of MI/RI rats and H/R-treated cardiomyocytes. miR-30e targeted SOX9. miR-30e up-regulation or SOX9 down-regulation reduced cardiac function damage and suppressed oxidative stress, inflammation, cardiomyocyte apoptosis and myocardial enzymes in myocardial tissues of MI/RI rats. Restoring miR-30e or silencing SOX9 energized cell viability and inhibited apoptosis of H/R-treated cardiomyocytes. Down-regulating SOX9 reversed the effects of miR-30e down-regulation on myocardial injury, ventricular remodeling, cardiomyocyte damage and apoptosis in MI/RI. CONCLUSION: It is concluded that miR-30e elevation alleviated cardiac function damage and promoted ventricular remodeling via SOX9 repression.

Disease severity of respiratory syncytial virus (RSV) infection correlate to a novel set of five amino acid substitutions in the RSV attachment glycoprotein (G) in China.

Human respiratory syncytial virus (RSV) is one of the major viruses of acute respiratory tract disease among infants and young children. We performed molecular epidemiology analysis of RSV among inpatient children in Guangzhou, China. Phylogenetic and Bayesian analysis showed that genotype ON1 was the only subgroup A virus in this study. Interestingly, the majority of Guangzhou ON1 strains formed a well-supported cluster, and these strains shared a novel set of five amino acid substitutions that never illustrated before. Furthermore, the degree of disease severity was assessed using a severity scoring system. The patients carrying the novel RSV A strain were associated with milder respiratory symptoms compared to other RSV A positives. In conclusion, a specific set of five amino acid substitutions was found in China and further analysis showed that disease severity was associated with these alterations. These findings will provide valuable information for the pathogenic mechanism and vaccine development of RSV.