Search Results (242)

The development of new organic nitrates is still relevant due to the clinical limitations of their use. Tetrahydrofurfuryl nitrate (NTHF) is a new organic nitrate obtained through a synthetic route of sugarcane. The aim of this research was to investigate the cardiovascular effects promoted by NTHF in rats. Isolated vascular smooth muscle cells (VSMC) were incubated with a specific probe and were analyzed in a flow cytometer to measure the NO concentration after NTHF treatment. Rat superior mesenteric rings were isolated and used for isometric tension recordings and the evaluation of the vasorelaxant activity induced by NTHF. For the in vivo study, polyethylene catheters were implanted into the abdominal aorta and inferior vena cava of the rats (weighing 250–300 g). NTHF increased NO levels in rat VSMCs. In anesthetized rats, NTHF induced hypotension and bradycardia after intravenous administration. These effects were attenuated after the administration of a sGC inhibitor, methylene blue. In the phenylephrine pre-contracted superior mesenteric artery of rats, NTHF (1 pM–10 μM) induced concentration-dependent vasodilatation in both the intact and removed endothelium. Furthermore, in the presence of NO° scavenging (C-PTIO and HDX) or ODQ, a sGC inhibitor, the vasorelaxation induced by NTHF was decreased. NTHF tolerance was evaluated in mesenteric artery rings previously exposed with isolated concentrations of the new organic nitrate. The vasorelaxant effect was not modified by exposure to nitrate. These results demonstrated that NTHF induced hypotension and bradycardia in vivo and a vasorelaxant effect with the participation of the NO-sGC-PKG pathway and triggering calcium-activated K⁺ channels without vascular tolerance induction. Full article

Background: To date, the only potential curative treatment for multiple myeloma (MM) remains allogeneic (allo) hematopoietic cell transplant (HCT), although, most patients will eventually relapse. In relapsed patients, donor lymphocyte infusions (DLIs) have been reported to control disease, but the optimal strategy prior to and doses of DLIs remain unclear. With this study (NCT03413800), we aimed to investigate the efficacy and toxicity of lenalidomide and dexamethasome (Len/Dex) followed by escalating pre-determined doses of DLIs in MM patients who relapsed after allo HCT. Methods: Patients aged 18–65 years with relapsed MM following upfront tandem autologous (auto)/allo HCT were eligible. Treatment consisted of six cycles of Len/Dex followed by three standardized doses of DLIs: 5 × 10⁶ CD3+/kg, 1 × 10⁷/kg and 5 × 10⁷/kg every 6 weeks. Bone marrow minimal measurable disease (MRD) using flow cytometry (10⁻⁵) was performed at enrolment, then every 3 months for 2 years or until disease progression, in a subset of patients. The primary endpoint was efficacy as measured by progression-free survival (PFS) at 2 years following Len/Dex/DLIs. Secondary objectives were safety including GVHD, response including MRD status and overall survival (OS). Results: A total of 22 patients participated in this study, including 62% with high-risk cytogenetics. With a median follow-up of 5.3 years (range: 4.1–6.1), PFS and OS were 26.5% (95% CI: 10.4–45.9%) and 69.2% (95% CI: 43.3–85.1%), respectively. Overall, the best responses achieved post-Len/Dex + DLIs were complete remission in 9.1%, very good partial response in 50%, and progressive disease in 40.9%. Among the nine patients tested for MRD, only two achieved a negative status after receiving DLIs. Six patients died, all due to disease progression. No acute GVHD was observed after DLIs. We report a very low incidence of moderate/severe chronic GVHD of 18.2% with no need for systemic immunosuppressants one year after diagnosis. No unexpected adverse events were observed. Interestingly, a positive correlation between response to Len/Dex re-induction and response to DLIs was found (p = 0.0032). Conclusions: Our findings suggest that Len/Dex/DLIs in second line treatment after upfront tandem auto/allo HCT in relapsed MM patients remains feasible and safe. With a potential correlation between induction chemotherapy and DLI responses, more potent induction regimens together with higher doses of DLIs should be considered in the future. Full article

Background: FMS-like tyrosine kinase 3 (FLT3) mutations or internal tandem duplication occur in 30% of acute myeloid leukemia (AML) cases. In these cases, FLT3 inhibitors (FLT3i) are approved for induction treatment and relapse. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the recommended post-induction therapy for suitable patients. However, the role of FLT3i therapy after alloHSCT remains unclear. Therefore, we investigated the three currently available FLT3i, gilteritinib, midostaurin, and quizartinib, in terms of their immunosuppressive effect on dendritic cells (DCs). DCs are professional antigen-presenting cells inducing T-cell responses to infectious stimuli. Highly activated DCs can also cause complications after alloHSCT, such as triggering Graft versus Host disease, a serious and potentially life-threatening complication after alloHSCT. Methods: To study the immunomodulatory effects on DCs, we differentiated murine and human DCs in the presence of FLT3i and performed immunophenotyping by flow cytometry and cytokine measurements and investigated gene and protein expression. Results: We detected a dose-dependent immunosuppressive effect of midostaurin, which decreased the expression of costimulatory markers like CD86, and found a reduced secretion of pro-inflammatory cytokines such as IL-12, TNFα, and IL-6. Mechanistically, we show that midostaurin inhibits TLR and TNF signaling and NFκB, PI3K, and MAPK pathways. The immunosuppressive effect of gilteritinib was less pronounced, while quizartinib did not show truncation of relevant signaling pathways. Conclusions: Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs. Full article

Background/Objectives: Luteolin (LUT) is a natural flavonoid with known anti-inflammatory, antioxidant, and anti-cancer properties. Cervical cancer, particularly prevalent in certain regions, remains a significant health challenge due to its high recurrence and poor response to treatment. This study aimed to investigate the anti-tumor effects of LUT on human cervical epidermoid carcinoma cells (Ca Ski), focusing on cell growth inhibition, apoptosis induction, and regulation of mitochondrial membrane potential. Methods: Ca Ski cells were treated with varying concentrations of LUT (0, 25, 50, 100 µM) for different time periods (24, 48, 72 hours). Cell viability was measured using the MTT assay, apoptosis was assessed by flow cytometry with annexin V-FITC/PI staining, and changes in mitochondrial membrane potential were evaluated using JC-1 staining. Caspase-3 activation was examined by flow cytometry, and expression of apoptosis-related proteins (caspase-3, -8, -9, AIF) was analyzed via Western blotting. Results: LUT significantly inhibited the growth of Ca Ski cells in a dose- and time-dependent manner, with the most pronounced effects observed at 100 µM over 72 hours. Flow cytometry confirmed that LUT induced apoptosis without causing necrosis. Mitochondrial membrane potential was reduced after LUT treatment, coinciding with increased caspase-3 activation. Western blot analysis revealed the upregulation of pro-apoptotic proteins caspase-3, -8, -9, and AIF, indicating that LUT induces apoptosis through the intrinsic mitochondrial pathway. Conclusions: Luteolin effectively inhibits cervical cancer cell proliferation and induces apoptosis by disrupting mitochondrial membrane potential and activating caspases. These findings suggest that LUT holds potential as a therapeutic agent for cervical cancer, with further studies needed to explore its in vivo efficacy and broader clinical applications. Full article

Endothelial dysfunction (ED) is closely associated with most cardiovascular diseases. Experimental models are needed to analyze the potential impact of ED on cardioprotection in constant pressure Langendorff systems (CPLS). One cardioprotective strategy against ischemia/reperfusion injury (I/RI) is conditioning with the lipid emulsion Intralipid (IL). Whether ED modulates the cardioprotective effect of IL remains unknown. The aim of the study was to transfer a protocol using a constant flow Langendorff system for the induction of ED into a CPLS, without the loss of smooth muscle cell functionality, and to analyze the cardioprotective effect of IL against I/RI under ED. In isolated hearts of male Wistar rats, ED was induced by 10 min perfusion of a Krebs–Henseleit buffer containing 60 mM KCl (K+), and the vasodilatory response to the vasodilators histamine (endothelial-dependent) and sodium–nitroprusside (SNP, endothelial-independent) was measured. A CPLS was employed to determine cardioprotection of pre- or postconditioning with 1% IL against I/RI. The constant flow perfusion of K+ reduced endothelial response to histamine but not to SNP, indicating reduced vasodilatory functionality of endothelial cells but not smooth muscle cells. Preconditioning with IL reduced infarct size and improved cardiac function while postconditioning with IL had no effect. The induction of ED neither influenced infarct size nor affected the cardioprotective effect by preconditioning with IL. This protocol allows for studies of cardioprotective strategies under ED in CLPS. The protection by preconditioning with IL seems to be mediated independently of a functional endothelium. Full article

Traditionally, traffic characteristics such as speed, volume, and travel time are obtained from a range of sensors and systems such as inductive loop detectors (ILDs), automatic number plate recognition cameras (ANPR), and GPS-equipped floating cars. However, many issues associated with these data have been identified in the existing literature. Although roadside surveillance cameras cover most road segments, especially on freeways, existing techniques to extract traffic data (e.g., speed measurements of individual vehicles) from video are not accurate enough to be employed in a proactive traffic management system. Therefore, this paper aims to develop a technique for estimating traffic data from video captured by surveillance cameras. This paper then develops a deep learning-based video processing algorithm for detecting, tracking, and predicting highly disaggregated vehicle-based data, such as trajectories and speed, and transforms such data into aggregated traffic characteristics such as speed variance, average speed, and flow. By taking traffic observations from a high-quality LiDAR sensor as ‘ground truth’, the results indicate that the developed technique estimates lane-based traffic volume with an accuracy of 97%. With the application of the deep learning model, the computer vision technique can estimate individual vehicle-based speed calculations with an accuracy of 90–95% for different angles when the objects are within 50 m of the camera. The developed algorithm was then utilised to obtain dynamic traffic characteristics from a freeway in southern China and employed in a statistical model to predict monthly crashes. Full article

Acquiring real-time status information of the distribution system forms the foundation for optimizing the management of power system operations. However, missing measurements, bad data, and inaccurate system models present a formidable challenge for distribution system state estimation (DSSE) in practical applications. This paper proposes a physics-informed graphical learning state estimation approach, to address these limitations by integrating power flow equations and GraphSAGE. The generalization ability of GraphSAGE for unknown nodes is used to perform inductive learning of measurement information. For unseen measurement points in the training set, the simulation proves that the proposed approach can still satisfactorily predict the state quantity. The training process is guided by power flow equations to ensure it has physical significance. Additionally, the possibility of applying the proposed approach to an actual distribution area is explored. Equivalent preprocessing of the three-phase voltage measurement data of the actual distribution area is conducted to improve the estimation accuracy of the transformer measurement points and simplify the computation required for state estimation. Full article

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia. There is currently no effective treatment for VCID. Resveratrol (RSV) is considered an antioxidant; however, our group has observed pleiotropic effects in stroke paradigms, suggesting more effects may contribute to mechanistic changes beyond antioxidative properties. The main goal of this study was to investigate if administering RSV twice a week could alleviate cognitive declines following the induction of a VCID model. Additionally, our aim was to further describe whether this treatment regimen could decrease cell death in brain areas vulnerable to changes in cerebral blood flow, such as the hippocampus and medial septum. We hypothesized RSV treatments in a mouse model of gradual cerebral hypoperfusion protect against cognitive impairment. We utilized gradual bilateral common carotid artery stenosis (GBCCAS) via the surgical implantation of ameroid constrictor devices. RSV treatment was administered on the day of implantation and twice a week thereafter. Cerebral perfusion was measured by laser speckle contrast imaging, and cognitive functions, including the recognition memory, the spatial working memory, and associative learning, were assessed by novel object recognition (NOR), Y-maze testing, and contextual fear conditioning (CFC), respectively. RSV treatment did not alleviate cerebral perfusion deficits but mitigated cognitive deficits in CFC and NOR after GBCCAS. Despite these deficits, no hippocampal pathology was observed; however, cholinergic cell loss in the medial septum was significantly increased after GBCCAS. This cholinergic cell loss was mitigated by RSV. This study describes a novel mechanism by which chronic RSV treatments protect against a VCID-induced cognitive decline through the preservation of cholinergic cell viability to improve memory performance. Full article

Background: Accurate assessment of therapy response to chemotherapy could possibly offer a bladder-sparing approach in selected patients with localized muscle-invasive bladder cancer (MIBC). The aim of this study was to evaluate whether [¹⁵O]H₂O PET/MRI can be used for assessment of complete local pathological response to preoperative chemotherapy in patients with MIBC. Methods: This prospective pilot study included 13 patients with MIBC treated with neoadjuvant or induction chemotherapy and subsequent radical cystectomy. Patients underwent a [¹⁵O]H₂O PET/MRI scan before chemotherapy and another scan after chemotherapy before radical cystectomy. Volumes of interest were delineated on T2-weighted MRI and transferred to parametric images for dynamic analysis. Tumor blood flow (TBF) was estimated by [¹⁵O]H₂O PET. Changes in TBF were compared with histopathology. The Wilcoxon matched-pairs signed-ranks test was used for comparing pre- and post-chemotherapy measurements. Results: Mean TBF decreased by 49%. Mean TBF in complete responders (ypT0N0/ypTis) was not significantly different from non-complete responders (≥ypT1) (p = 0.52). Conclusions: Despite a measurable decrease in TBF after chemotherapy treatment, we were not able to estimate a TBF threshold for identifying complete responders to chemotherapy for MIBC patients. Further studies are needed to elucidate the potential of [¹⁵O]H₂O PET/MRI in assessing therapy response in MIBC. Full article

The paper deals with the dynamics of a resistance spot welding system. At the core of this system is a transformer, which is powered on the primary side by a pulse-width modulated inverter and has a full-wave output rectifier on the secondary side that provides a direct welding current. The entire system is nonlinear, due to magnetic hysteresis and electronics. The electronics prevent the current from flowing in all parts of the welding transformer at separate time intervals during the voltage supply period; therefore, not all the parameters affect the dynamic of currents and voltages all the time so the system is also time-variant. To design a high-performance welding system and to predict the maximum possible welding current at a specific load, it is necessary to know the welding and primary currents. The leakage inductances of the system can reduce the maximum welding current significantly at higher frequencies and the same load. There are several methods to determine these currents, each with its drawbacks. Measurements are time-consuming, using professional software is expensive and requires time to learn and free open-source software has many limitations and does not guarantee the correctness of the results. The article presents a new, fourth option—a theoretical derivation of analytical expressions that facilitate straightforward and rapid calculation of the welding and primary currents of the resistance spot welding system with symmetrical secondary branches. The derivation of the mathematical expressions is based on the equivalent circuits that describe the system in different operating states. The results of the numerical simulations confirmed the derived expressions completely. Full article

Senecavirus A (SVA) is a picornavirus that is endemic in swine, causing a vesicular disease clinically indistinguishable from other vesicular diseases, like foot-and-mouth disease. The widespread viral circulation, constant evolution, and economic losses caused to the swine industry emphasize the need for measures to control the agent. In this study, we evaluated the immunogenicity of a whole-virus-inactivated vaccine using a representative contemporary Brazilian SVA strain in Balb/ByJ mice. The animals were vaccinated with two doses by an intramuscular route. The humoral response induced by the vaccination was evaluated by an in-house ELISA assay for IgG detection. The cellular response was assessed by flow cytometry after in vitro SVA stimulation in splenocyte cultures from vaccinated and non-vaccinated groups. Protection against SVA was assessed in the experimental groups following an oral challenge with the homologous virus. The vaccination induced high levels of IgG antibodies and the proliferation of CD45R/B220⁺sIgM⁺, CD3e⁺CD69⁺, and CD3e⁺CD4⁺CD44⁺CD62L⁻ cells. These results indicate the immunogenicity and safety of the vaccine formulation in a murine model and the induction of humoral and cellular response against SVA. Full article

Hindered phenol antioxidants and benzophenone UV absorbers are common polymer additives and often used in combination applications to enhance the anti-aging performance of polymer materials. This study primarily aims to incorporate hindered phenol and benzophenone structures into a single molecule to develop a multifunctional polymer additive with good anti-aging performance. Thus, a novel potential polymer anti-aging agent, namely 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid 3-(4-benzoyl-3-hydroxyphenoxy)propyl ester (3C), was synthesized using 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 3-bromo-1-propanol, and 2,4-dihydroxybenzophenone as raw materials by two-step procedure. The structure of compound 3C was characterized by nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), Fourier-transform infrared (FT-IR) spectroscopy, and X-ray single crystal diffraction. Its thermal stability and UV resistance were assessed using thermogravimetric analysis (TGA) and UV absorption spectroscopy (UV). The compound 3C as an additive was incorporated into the preparation of polyolefin elastomer (POE) films. The anti-aging performance of POE films was evaluated by measuring parameters such as oxidation induction time, melt flow index, transmittance, and infrared spectra of the artificially aged POE films. The results indicate that the compound 3C exhibits a promising anti-aging performance in both thermo-oxidative aging and ultraviolet aging tests of POE films and is a potential polymer anti-aging agent. Full article

Contactless inductive flow tomography (CIFT) is a flow measurement technique allowing for visualization of the global flow in electrically conducting fluids. The method is based on the principle of induction by motion: very weak induced magnetic fields arise from the fluid motion under the influence of a primary excitation magnetic field and can be measured precisely outside of the fluid volume. The structure of the causative flow field can be reconstructed from the induced magnetic field values by solving the according linear inverse problem using appropriate regularization methods. The concurrent use of more than one excitation magnetic field is necessary to fully reconstruct three-dimensional liquid metal flows. In our laboratory demonstrator experiment, we impose two excitation magnetic fields perpendicular to each other to a mechanically driven flow of the liquid metal alloy GaInSn. In the first approach, the excitation fields are multiplexed. Here, the temporal resolution of the measurement needs to be kept as high as possible. Consecutive application by multiplexing enables determining the flow structure in the liquid with a temporal resolution down to 3 s with the existing equipment. In another approach, we concurrently apply two sinusoidal excitation fields with different frequencies. The signals are disentangled on the basis of the lock-in principle, enabling a successful reconstruction of the liquid metal flow. Full article

Over the last decade, electromagnetic induction (EMI) measurements have been increasingly used for investigating soil salinization caused by the use of brackish or saline water as an irrigation source. EMI measurements proved to be a powerful tool for providing spatial information on the investigated soil because of the correlation between the output geophysical parameter, i.e., the electrical conductivity, to soil moisture and salinity. In addition, their non-invasive nature and their capability to collect a high amount of data over broad areas and in a relatively short time makes these measurements attractive for monitoring flow and transport dynamics, which are otherwise undetectable with conventional measurements. In an experimental field, EMI measurements were collected during the growth season of tomatoes and irrigated with three different irrigation strategies. Time-lapse data were collected over three months in order to visualize changes in electrical conductivity associated with soil salinity. A rigorous time-lapse inversion procedure was set for modeling the soil salinization induced by brackish irrigation water. A clear soil response in terms of an increase in electrical conductivity (EC) in the upper soil layer confirmed the reliability of the geophysical tool to predict soil salinization trends. Full article

In recent decades, the dynamics of road vehicle traffic have significantly evolved, compelling traffic engineers to develop innovative traffic monitoring solutions, especially for dense road networks. Traditional methods for measuring traffic volume along road sections may no longer suffice for modern traffic control systems. This is particularly true for induction loops, a widely used method since the last century. In contrast, measuring techniques using microwaves or visible light offer better accuracy but are often hindered by the high cost of sensors. This paper presents new techniques for measuring traffic flow and other parameters that adapt to changing traffic dynamics using low-cost optical distance sensors. Our study demonstrates that the integration of multiple monitoring approaches enhances measurement accuracy, contingent on the dynamics and specific characteristics of the traffic. The results indicate that cheap optical distance sensors are particularly well suited for use in smart city road networks. Full article