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.

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.

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.

The Pacopexy procedure for left ventricular aneurysm: a 10-year clinical experience.

PURPOSE: To evaluate our 10-year clinical experience of performing the Pacopexy procedure for left ventricular aneurysm (LVA). METHODS: Between January, 1998 and November, 2015, a cohort of 92 patients with LVA underwent surgery to reshape the left ventricle. Fifty-seven patients underwent the Dor procedure and 35 underwent the Pacopexy procedure to emphasize the conical shape, whereby patch placement followed an oblique trajectory between the left ventricular apex and the septum below the aortic valve. RESULTS: The early-mortality rate was 4.34% (4/92; n = 2 in each group). The 10-year survival rate was 70.4 ± 7.9% in the Pacopexy group vs 41.7 ± 7.2% in the Dor group (p < 0.05), and the rate of freedom from hospital re-admission for heart failure (HF) or cardiac death was 60.0 ± 8.6% vs 28.8 ± 6.8%, respectively (p < 0.05). The Dor procedure and left ventricular end systolic volume index (LVESVI) ≥ 60 ml/m2 were strongly and significantly associated with long-term mortality and hospital re-admission for HF. CONCLUSIONS: The Pacopexy procedure is a reproducible surgical option for the treatment of LVA. The improved configuration achieved by the Pacopexy procedure has resulted in good long-term survival and a high degree of freedom from re-admission for HF in patients with advanced LVA.

Identify the critical protein-coding genes and long noncoding RNAs in cardiac myxoma.

Cardiac myxoma (CM) is the most common benign cardiac tumor which is mostly sporadic. Increasing evidence show that protein-coding genes (PCGs) and long noncoding RNAs (lncRNAs) play important roles in the pathology processes of multiple cancers. However, the functional roles and regulatory mechanisms of RNAs interaction in CM are still unclear. In this study, we investigated three pairs of surgically excised CM by high throughput sequencing and screened a set of PCGs and lncRNAs which were differentially expressed and could serve as expression markers in CM. By constructing protein-protein interactions (PPI) and lncRNA-mRNA coexpressing network, we screened out a CM-related hub lncRNA-mRNA modules, which were enriched in different pathways such as MAPK and TGF-beta whose imbalance were validated by q-PCR. In addition, we identified a specific dysregulated competing endogenous RNA (ceRNA) network in CM by integrating lncRNA-miRNA-mRNA interactions. These results will help us to understand the interaction mechanisms of RNAs in CM and provide novel PCGs and lncRNAs as potential therapeutic targets for CM.

The transcripts of CRF and CRF receptors under fasting stress in Dabry's sturgeon (Acipenser dabryanus Dumeril).

Dabry's sturgeon (Acipenser dabryanus Dumeril, 1868) belongs to Sturgeon and is distributed throughout the mainstream of the upper Yangtze River. While there is little research onphysiological mechanism of Dabry's sturgeon, such as feeding regulation by the CRF system. At present, CRF is thought to regulate feeding via CRF receptors (CRF-Rs) in several mammals, but relatively few studies of CRF and feeding exist in teleosts. Herein, the transcripts of CRF and CRF-Rs under fasting stress in Dabry's sturgeon (Acipenser dabryanus Dumeril) have been explored. A full length Dabry's sturgeon CRF cDNA of 953 bp was identified, which contained a 447 bp open reading frame (ORF). A partial CRF-R1 cDNA of 1053 bp and CRF-R2 cDNA of 906 bp corresponding to the coding sequences (CDS) was obtained. In addition, analysis of the tissue distribution of CRF and CRF-Rs mRNAs revealed they were widely distributed in the central and peripheral nervous systems. Furthermore, periprandial (preprandial and postprandial), fasting, and re-feeding experiments revealed CRF mRNA was significantly increased 1 h and 3 h after feeding and CRF and CRF-Rs transcripts were significantly decreased after 10 days fasting, and significantly increased on re-feeding on day 10. These results suggest that CRF and CRF-Rs might regulate feeding by acting as satiety factors.

Tailoring Laser-Generated Plasmas for Efficient Nuclear Excitation by Electron Capture.

The optimal parameters for nuclear excitation by electron capture in plasma environments generated by the interaction of ultrastrong optical lasers with solid matter are investigated theoretically. As a case study we consider a 4.85 keV nuclear transition starting from the long-lived ^{93m}Mo isomer that can lead to the release of the stored 2.4 MeV excitation energy. We find that due to the complex plasma dynamics, the nuclear excitation rate and the actual number of excited nuclei do not reach their maximum at the same laser parameters. The nuclear excitation achievable with a high-power optical laser is up to twelve and up to six orders of magnitude larger than the values predicted for direct resonant and secondary plasma-mediated excitation at the x-ray free electron laser, respectively. Our results show that the experimental observation of the nuclear excitation of ^{93m}Mo and the subsequent release of stored energy should be possible at laser facilities available today.

Sequential treatment combining cladribine-based re-induction, myeloablative allogeneic HSCT, and prophylactic donor lymphocyte infusion: a promising treatment for refractory acute myeloid leukemia.

We describe the first multicenter prospective study to assess the efficacy, safety, and immune reconstitution of a novel sequential transplant approach in 24 patients with primary induction failure/relapsed acute myeloid leukemia (AML). The sequential regimen consisted of cladribine 5 mg/m2/day and cytarabine 2 g/m2/day for 5 days and mitoxantrone 7 mg/m2/day for 3 days, followed by myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) using intravenous busulfan (3.2 mg/kg/day) for 4 days and cyclophosphamide (60 mg/kg/day) for 2 days. Patients in CR without acute graft-versus-host disease at day + 90 received prophylactic donor lymphocyte infusion (pDLI). At the time of transplantation, a marrow blast infiltration > 20% or any level of circulating blasts was found in 62.5% of patients. The cumulative incidence of relapse at 2 years was 29.8%. Overall survival (OS) was 74.5% at 1 year and 56.5% at 2 years. Leukemia-free survival (LFS) at 1 and 2 years was 62.5 and 50.5%, respectively. Multivariate analysis demonstrated that haploidentical related donor, pDLI, and experiencing chronic graft-versus-host disease (cGVHD) were protective from relapse. Total T cells and T cell subsets in peripheral blood recovered at 3 months post-HSCT. The expressions of immune checkpoints (cytotoxic T lymphocyte antigen 4 and programmed death 1) were extremely low in T cells over the first 1 year post-transplantation.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.