Plasma Activity Research Articles

Evaluation of pre-operative high dose corticosteroids in elective colorectal surgery and effects on gut barrier function: A phase 2 clinical trial

BackgroundPerioperative inflammation is a predictor of surgical complications and cancer prognosis in surgical oncology. Multimodal protocols are ongoing in order to find ways to control inflammation. A preoperative flash high-dose of corticosteroids has been suggested as a way to control perioperative inflammation, but its safety in colorectal surgery needs to be established prior to a phase 3 trial. The physiologic effects of such a dose should also be explored. MethodsProspective bicentric phase 2 single-arm study with a biological ancillary study. Patients were administered 20 mg/kg of methyl-prednisone before colorectal surgery. Primary outcome was major post-operative complications defined as a grade >II according to the Dindo-Clavien classification. Ancillary outcome was plasma endotoxin concentration and activity. ResultsSixty-seven patients were included. Twelve (17.9 % [90 %CI:10.9 %-29.6 %]) patients developed major post-operative complications. No homeostatic disturbances troubles were observed. Severe postoperative hyperglycemia concerned 3 (4 %) patients which were all non-diabetic. The concentrations of endotoxin (mass) and its activity lowered between the pre-operative time point and the day after surgery. ConclusionPre-operative single flash of high dose methylprednisolone (20 mg/kg) before elective colorectal surgery seemed safe. Our results suggest that corticosteroids could promote gut barrier integrity, reducing endotoxemia in patients with colorectal surgery. Further studies (in particular a large randomized controlled trial) are needed to confirm our findings and explore a potential benefit of corticosteroid in this population. ClinicalTrials.gov03437746

THE GLA D313Y MUTATION IN FABRY DISEASE: DIAGNOSTIC DILEMMAS AND THERAPEUTIC CONSIDERATIONS

Abstract Fabry disease is a genetic disorder caused by mutations in the GLA gene, which encodes alpha–galactosidase A, leading to enzyme dysfunction and subsequent accumulation of glycosphingolipids. In the classical form, it occurs in childhood or early adolescence with renal, cardiac, and neurological involvement, resulting in a poor prognosis. The GLA D313Y is a missense mutation resulting in a significant reduction of enzyme activity in plasma, while leukocyte enzyme activity remains within normal limits, leading to a "pseudo–deficiency" of enzyme activity with uncertain pathogenicity. In literature, it has been observed that individuals with this mutation may present predominantly with central neurologic manifestations, characterized by multifocal white matter lesions. Historically they do not receive indications for initiating enzyme replacement or molecular chaperone therapies. We present the case of a man affected by arterial hypertension and history of chronic lower limb pain who experienced a lacunar stroke at the age of 35. The GLA D313Y mutation was identified and enzyme activity assay in plasma was within normal limits, precluding the initiation of enzyme replacement therapy. Over the following years, he suffered two additional ischemic strokes, a progressive decline in renal function to stage 3, and acute coronary syndrome. Transthoracic echocardiography revealed hypertrophic non–obstructive cardiomyopathy (SIVd 20 mm) with normal biventricular ejection fraction. Cardiac magnetic resonance showed late gadolinium enhancement of inferior junctional and inferior wall in middle segment (Fig.1). Considering the patient‘s clinical conditions involving multi–organ impairment, an enzymatic activity test was performed on leukocytes, revealing a reduced activity. This prompted the decision to initiate enzyme replacement therapy. This case report supports the hypothesis that the D313Y mutation may be associated with a later presentation and not only neurological involvement. In our experience, it’s mandatory to proceed with the determination of leukocyte enzyme activity in presence of normal enzyme activity in plasma. As an alternative, the detection of glycosphingolipids’ accumulation could be useful, but myocardial and renal biopsy poses a high bleeding risk, especially in anticoagulated or antiaggregated patients. The authors propose considering the initiation of therapy in patients with the D313Y mutation who exhibit significant organ involvement.

The Role of Fibrinolytic Activity of Blood Plasma in the Development of Obstetric Complications in Overweight Pregnant Women with Metabolic Dysfunction-Associated Steatohepatitis: A Prospective Cohort Study

The Role of Fibrinolytic Activity of Blood Plasma in the Development of Obstetric Complications in Overweight Pregnant Women with Metabolic Dysfunction-Associated Steatohepatitis: A Prospective Cohort Study

A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300mg every 2weeks (Q2W) to every 4weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.

The effect of neutral alpha glucosidase on semen parameters.

To investigate the relationship between the activity of neutral α-glucosidase in seminal plasma and semen quality. To explore the effect of secretory capability of the epididymis on male fertility. A retrospective analysis of 542 men treated in the Center for Reproductive Medicine and Infertility from February to December 2022, the semen parameters and neutral α-glucosidase were tested and compared among different groups. These 542 men included normozoospermia, oligospermia, asthenospermia and teratozoospermia. There was statistical difference in neutral alpha glucosidase (NAG) level among different groups with different sperm concentration, motility and morphology (P＜0.001). The NAG activity in seminal plasma was positively correlated with ejaculate volume and sperm concentration, meanwhile a very weak positive correlation was found between NAG level and sperm motility, sperm morphology, respectively. Our results indicated that the secretion of NAG affected the volume, concentration, motility and morphology of sperm to a certain extent. Given that NAG is a specific and marker enzyme in epididymis, where is the site of sperm maturation, we can conclude that there is a close relationship between NAG and sperm quality. Therefore, seminal plasma NAG has a definite clinical value in helping diagnosis of male infertility.

Control of spontaneous charging of sliding water drops by plasma-surface treatment

Slide electrification is the spontaneous separation of electric charges at the rear of water drops sliding over solid surfaces. This study delves into how surfaces treated with a low-pressure plasma impact water slide electrification. Ar, O2, and N2 plasma treatment reduced the drop charge and contact angles on glass, quartz, and SU-8 coated with 1H,1H,2H,2H-perfluoroctyltrichlorosilane (PFOTS), and polystyrene. Conversely, 64% higher drop charge was achieved using electrode-facing treatment in plasma chamber. Based on the zeta potential, Kelvin potential, and XPS measurements, the plasma effects were attributed to alterations of the topmost layer's chemistry, such as oxidation and etching, and superficially charge deposition. The surface top layer charges were less negative after electrode-facing and more negative after bulk plasma treatment. As a result, the zeta potential was less negative after electrode-facing and more negative after bulk plasma treatment. Although the fluorinated layer was applied after plasma activation, we observed a discernible impact of plasma-glass treatment on drop charging. Plasma surface modification offers a means to adjust drop charges: electrode-facing treatment of the fluorinated layer leads to an enhanced drop charge, while plasma treatment on the substrate prior to fluorination diminishes drop charges, all without affecting contact angles or surface roughness.

Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Detection of direct oral anticoagulants with the diluted Russel's viper venom time.

The activity of direct oral anticoagulants (DOAC) is important in acute clinical situations. Recent studies have suggested a strong influence of DOAC on the diluted Russel's Viper Venom Time (dRVVT). Therefore, it may be a suitable screening parameter for antithrombotic plasma activity of different DOAC. This prospective study aims to evaluate the sensitivity and specificity of dRVVT to detect residual DOAC activity at recommended plasma level thresholds. A total of 80 patients were recruited, with 20 each treated with one of the four approved DOAC (apixaban, edoxaban, rivaroxaban or dabigatran), respectively. Blood plasma was collected before (baseline), at plasma peak time, and 6 and 12 h after DOAC. DRVVT was measured using the screen (LA1) and confirm (LA2) assay for lupus anticoagulant and compared with DOAC plasma levels. A reference range was calculated based on the dRVVT values of 61 healthy blood donors. All DOAC significantly prolonged the dRVVT especially at higher DOAC plasma levels. The LA1 time ≥41 s had a sensitivity ≥98% to detect edoxaban, dabigatran and rivaroxaban plasma levels ≥30 ng/mL but it was only 87% for apixaban. Sensitivity was ≥98% for all DOAC with the LA2 assay ≥36 s. The negative predictive value of a DOAC plasma level <30 ng/mL and dRVVT LA2 <36 s was 99%. The dRVVT confirm assay (LA2) reliably detects residual DOAC plasma levels ≥30 ng/mL and could be useful to rapidly rule out relevant DOAC activity in emergency situations and to guide treatment decisions.

Low-cost O2 plasma activation assisted direct bonding of β-Ga2O3 and Si substrates in air

This study presents a novel technique for directly bonding β-Ga2O3 and Si substrates using O2 plasma activation at room temperature. The activation process resulted in excellent surface hydrophilicity and roughness. Annealing in an N2 atmosphere revealed a bonding strength of 6.23 MPa, with partial fracture of the Si substrate. The bonding interface was observed by TEM and EDS. A distorted amorphous intermediate layer with a thickness of 100 nm and amorphous bubbles were observed in the bonding interface. In addition, the Ga, O, and Si elements were diffused and enriched, forming approximately 30 nm nodules at the bonding interface. This method offers a promising approach for integrating wide bandgap semiconductor materials in devices, bypassing the need for vacuum treatment.

Molecular therapy and nucleic acid adeno-associated virus-based gene therapy delivering combinations of two growth-associated genes to MPS IVA mice

Mucopolysaccharidosis type IVA (MPS IVA) is caused by a deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme responsible for the degradation of specific glycosaminoglycans (GAGs). The progressive accumulation of GAGs leads to various skeletal abnormalities (short stature, hypoplasia, tracheal obstruction) and several symptoms in other organs. To date, no treatment is effective for patients with bone abnormalities. To improve bone pathology, we propose a novel combination treatment with the AAV vectors expressing GALNS enzyme and a C-type natriuretic peptide (CNP; NPPC gene) as a growth-promoting agent for MPS IVA. In this study, an MPS IVA mouse model was treated with an AAV vector expressing GALNS combined with another AAV vector expressing NPPC gene, followed for 12 weeks. After the combination therapy, bone growth in mice was induced with increased enzyme activity in tissues (bone, liver, heart, lung) and plasma. Moreover, there were significant changes in bone morphology in CNP-treated mice with increased CNP activity in plasma. Delivering combinations of CNP and GALNS gene therapies enhanced bone growth in MPS IVA mice more than in GALNS gene therapy alone. Enzyme expression therapy alone fails to reach the bone growth region; our results indicate that combining it with CNP offers a potential alternative.

Coordinated d-p hybridized hcp@fcc NiRu alloy doped by interstitial atoms for boosting urea-assisted simulated seawater electrolysis at industrial current densities

The production of hydrogen through seawater electrolysis has recently garnered increasing concern. However, hydrogen evolution reaction (HER) by alkaline seawater electrocatalysis is severely impeded by the slow H2O adsorption and H* binding kinetics at industrial current densities. Herein, a face-centered cubic/hexagonal close packed (fcc/hcp) NiRu alloy heterojunction was fabricated on Ni foam (N doped NiRu-inf/NF) by a low-temperature nitrogen plasma activation. Simultaneously, nitrogen atoms are introduced into the alloy to facilitate d-p hybridization. When N doped NiRu-inf/NF is integrated into a dual-electrode cell for urea-assisted seawater electrolysis, it achieves 100 mA cm−2 with an ultra-low voltage of 1.36 V and excellent stability. Density functional theory (DFT) verifies that the robust d-p hybridization among Ni, Ru and N exhibits more energy level matching for H2O molecule adsorption at the Ru sites, while simultaneously reducing the interaction between H* and Ni sites in N-doped NiRu-inf.

Si/InP direct wafer bonding: A first-principles study

The direct bonding mechanism of Si/InP is systematically investigated using first-principles calculations. Charge density analysis reveals that Si can be bonded with either In or P and is polar covalent. The single Si-P bond is stronger than the Si-In bond and has a shorter bond length, the Si-P bond length is 2.356 Å compared to 2.590 Å for the Si-In ones, as it involves the sharing of electron pairs and a large transfer and redistribution of electrons. Notably, molecular dynamics simulations show that the interfacial strength of Si bonded to In is greater at room temperature. This is because, after sufficient relaxation, although the average strength of the Si-P bonds is still greater than that of Si-In, the number of Si-In bonds is approximately four times that of the Si-P bonds. The radial distribution function of the atoms in the interfacial layer further confirms that the terminal interface is stronger than the P-terminal interface. Appropriate annealing treatment can effectively increase the number and strength of bonds at the interface. Finally, the bonding mechanism of the oxygen plasma activation is studied using reaction kinetics. These findings contribute to the precise control and optimization of bonding processes, ultimately improving the reliability of optoelectronic integration.

The first selective VAP-1 inhibitor in China, TT-01025-CL: safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses.

Introduction: TT-01025-CL is an oral, irreversible small molecule that potently inhibits vascular adhesion protein-1 (VAP-1) for the treatment of inflammation associated with non-alcoholic steatohepatitis (NASH). The objectives of this study were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of TT-01025-CL, a VAP-1 inhibitor, in healthy Chinese volunteers. Methods: Double-blind, placebo-controlled, dose-escalation studies were conducted in subjects randomized to receive oral once-daily TT-01025-CL (ranges: 10-300mg [single dose]; 20-100mg for 7days [multiple doses]) or placebo under fasting conditions. Safety and tolerability were monitored throughout the study. Pharmacokinetic (PK) parameters were determined using non-compartment analysis. The activity of semicarbazide-sensitive amine oxidase (SSAO)-specific amine oxidase and the accumulation of methylamine in plasma were evaluated as pharmacodynamic (PD) biomarkers. Results: A total of 36 (single-dose group) and 24 (multiple-dose group) subjects were enrolled in the study. No serious adverse events (AEs) were reported, and no subject discontinued due to an AE. All treatment-emergent adverse events (TEAEs) were mild and moderate in intensity. No dose-dependent increase in the intensity or frequency of events was observed. TT-01025-CL was rapidly absorbed after administration. In the single-ascending dose (SAD) study, median Tmax ranged from 0.5 to 2h and mean t1/2z ranged from 2.09 to 4.39h. PK was linear in the range of 100-300mg. The mean Emax of methylamine ranged from 19.167 to 124.970ng/mL, with mean TEmax ranging from 13.5 to 28.0h. The complete inhibition (>90%) of SSAO activity was observed at 0.25-0.5h post-dose and was maintained 48-168h post-dose. In the multiple-ascending dose (MAD) study, a steady state was reached by day 5 in the 40mg and 100mg dose groups. Negligible accumulation was observed after repeated dosing. PK was linear in the range of 20-100mg. Plasma methylamine appeared to plateau at doses of 20mg and above, with mean Emax ranging from 124.142 to 156.070ng/mL and mean TEmax ranging from 14.2 to 22.0h on day 7. SSAO activity in plasma was persistently inhibited throughout the treatment period. No evident change in methylamine and SSAO activity was observed in the placebo groups. Conclusion: TT-01025-CL was safe and well-tolerated at a single dose of up to 300mg and multiple doses of up to 100mg once daily for 7 consecutive days. Absorption and elimination occurred rapidly in healthy volunteers. Linearity in plasma exposure was observed. TT-01025-CL inhibited SSAO activity rapidly and persistently in humans. The profile of TT-01025-CL demonstrates its suitability for further clinical development.

Integrated pharmacokinetic-pharmacodynamic modeling and metabolomic research on polyphenol-rich fraction of Thymus quinquecostatus Celak. Alleviating cerebral ischemia-reperfusion injury

Ethnopharmacological relevanceThymus quinquecostatus Celak., a member of thymus genus in Lamiaceae family, has been used as a folk medicine for relieving exterior syndrome and alleviating pain in China. The polyphenol-rich fraction (PRF) derived from Thymus quinquecostatus Celak. had been validated that it can protect cerebral ischemia-reperfusion injury (CIRI) by activating Keap1/Nrf2/HO-1 signaling pathway.Aim of this study: To explore effective components and their pharmacokinetic and pharmacodynamic characteristics as well as possible mechanisms of PRF in treating CIRI. Materials and methodsNormal treated group (NTG) and tMCAO model treated group (MTG) rats were administrated PRF intragastrically. The prototype components and metabolites of PRF in plasma and brain were analyzed by the UPLC-Q-Exactive Orbitrap MSn method. Subsequently, the pharmacokinetics properties of indicative components were performed based on HPLC-QQQ-MS/MS. SOD and LDH activities were determined to study the pharmacodynamic (PD) properties of PRF. The PK-PD relationship of PRF was constructed. In addition, the effect of PRF on endogenous metabolites in plasma and brain was investigated using metabolomic method. ResultsSalvianic acid A, caffeic acid, rosmarinic acid, scutellarin, and apigenin-7-O-glucuronide were selected as indicative components based on metabolic analysis. The non-compartmental parameters were calculated for indicative components in plasma and brain of NTG and MTG rats. Furthermore, single-component and multi-component PK-PD modeling involved Emax, Imax PD models for effect indexes were fitted as well as ANN models were established, which indicated that these components can work together to regulate SOD and LDH activities in plasma and SOD activity in brain tissue to improve CIRI. Additionally, PRF may ameliorate CIRI by regulating the disorder of endogenous metabolites in lipid metabolism, amino acid metabolism, and purine metabolism pathways in vivo, among which lipid metabolism and purine metabolism are closely related to oxidative stress. ConclusionThe PK-PD properties of effect substances and mechanisms of PRF anti-CIRI were further elaborated. The findings provide a convincing foundation for the application of T. quinquecostatus Celak. in the maintenance of human health disorders.

The effect of combined atmospheric plasma/UV treatments on improving the durability of organophosphorus flame retardants applied to polyester fabrics

Following application of three commercially available, flame retardants (FR) to polyester and exposure to an atmospheric plasma in the presence or absence of simultaneous UV 308 nm excimer laser radiation, the retentions to a 30 min 40 °C water-soak for the mono- and dimeric cyclophosphonate (PE-CONC and PCO 900 respectively) and a 30 min methanol-soak treatment for the resorcinol bis(diphenyl phosphate) (RDP) agents were generally enhanced with respect to unexposed controls. These results suggested that the formation of PET-FR bonding had occurred as a consequence of plasma/UV exposure. The effect of plasma/UV process sequence (pre-exposure and/or post exposure with respect to FR impregnation) as well as plasma gas type, showed that maximum post-soaking FR retentions occurred when both pre- and post-exposure conditions operated.Plasma/UV exposed fabrics both before and after soaking treatments were examined for morphological changes by SEM and surface phosphorus retention by EDX, FTIR-ATR, XPS as well as TGA/DTG/DTA, each of which showed evidence on the surface of changes in surface topography, increased phosphorus levels and modified thermal behaviour. When subjected to vertical fabric strip flammability testing, these changes were insufficient to generate significant changes in the burning rate apart from in post-methanol soaked, RDP-containing fabrics where almost all plasma/UV process sequences reduced specimen burning rates.During all experiments, the presence or absence of the UV laser radiation appeared to have no obvious effect on post-soaking FR retentions, suggesting that its presence is not required since plasma activation alone appears to be the key to improving PET-FR bonding.

Impact of feeding Artemia franciscana enriched with various oil resources on growth, blood biochemical and behavioral indices, and survival of Oreochromis niloticus

Abstract The main objective of the present trial was to examine the efficacy of feeding tilapia fry fish on Artemia franciscana diets supplemented with various oil emulsion resources in terms of performance, behavior indices, survival rate, blood biochemical parameters, and immunological response. Four hundred Nile tilapia fry (weighing 0.15±0.05 g and measuring 2.17±0.08 cm) were randomly allocated into four equal groups (each with five repetitions) and acclimatized for fifteen days. The first group served as the control and received unenriched Artemia franciscana (G0), while the remaining three groups were fed Artemia franciscana diets enriched with different oil resources (0.5 mL oil per Liter for 6 hours): soybean oil (G1), sesame oil (G2), and rice bran oil (G3). Behavioral observations were recorded during the 45-day experimental period. At the end of the feeding trial, the chemical composition and fatty acid content of both Artemia and fingerlings were analyzed. Furthermore, the growth performance, survival, and immune response of the fingerlings were evaluated. The results indicated noticeable improvements in behavioral measurements (feeding, foraging and schooling), performance (final length, final weight, net weight gain, feed conversion ratio and specific growth rate), survival, and immune response among fry fish supplemented with enriched Artemia, particularly those enriched with soybean oil. Additionally, the chemical composition and fatty acid content of both Artemia and fish fry were significantly enhanced when oil emulsions are applied, with soybean oil demonstrating the most prominent improvements. Whereas, supplementing fry fish Artemia diets with oil resulted in lower liver enzyme activity and higher protein component levels in plasma in comparison to the control group. In brief, feeding Nile tilapia fry fish Artemia diets enriched with a soybean oil emulsion (0.5 mL/L) is recommended for promoting high performance, immunological activity, and survival throughout the early stage till fingerlings phase.

Effects of Erythropoietin-Promoted Fracture Healing on Bone Turnover Markers in Cats.

In orthopaedics, erythropoietin (EPO) is applied in the preoperative management of anaemic patients, but also as a stimulating factor to assist bone regeneration due to its angiogenic and osteoinductive potential. Since orthopaedists mainly rely on their clinical experience to assess bone healing, additional and more objective methods such as studying the dynamics of bone markers are needed. Therefore, the aim of this study was to investigate the plasma activity of bone-specific alkaline phosphatase (BALP), the N-terminal propeptide of type I collagen (PINP), the C-terminal telopeptide of type I collagen (CTX), and deoxypyridinoline (DPD) during the first 2 months of healing of comminuted fractures in cats, either non-stimulated or locally stimulated with recombinant human erythropoietin (rhEPO). The study included twelve cats of mixed breeds, aged 7.2 ± 4 months, weighing 2.11 ± 1.1 kg, with comminuted diaphyseal fractures of the femur. Surgical treatment with plate osteosynthesis was performed in all animals. The cats were randomly divided into two groups-a control (n = 6) and an EPO group (n = 6). The locally applied EPO leads to the increased activity of bone formation markers (BALP and PINP) during the second week after the osteosynthesis, preceding the peaks in the control group by two weeks. The studied bone resorption markers (DPD, CTX) varied insignificantly during the studied period. In conclusion, erythropoietin could serve as a promoter of bone healing in comminuted fractures in cats.

Characterization of Biomarkers of Thrombo-Inflammation in Patients with First-Diagnosed Atrial Fibrillation.

Patients with first-diagnosed atrial fibrillation (FDAF) exhibit major adverse cardiovascular events (MACEs) during follow-up. Preclinical models have demonstrated that thrombo-inflammation mediates adverse cardiac remodeling and atherothrombotic events. We have hypothesized that thrombin activity (FIIa) links coagulation with inflammation and cardiac fibrosis/dysfunction. Surrogate markers of the thrombo-inflammatory response in plasma have not been characterized in FDAF. In this prospective longitudinal study, patients presenting with FDAF (n = 80), and 20 matched controls, were included. FIIa generation and activity in plasma were increased in the patients with early AF compared to the patients with chronic cardiovascular disease without AF (controls; p < 0.0001). This increase was accompanied by elevated biomarkers (ELISA) of platelet and endothelial activation in plasma. Pro-inflammatory peripheral immune cells (TNF-α+ or IL-6+) that expressed FIIa-activated protease-activated receptor 1 (PAR1) (flow cytometry) circulated more frequently in patients with FDAF compared to the controls (p < 0.0001). FIIa activity correlated with cardiac fibrosis (collagen turnover) and cardiac dysfunction (NT-pro ANP/NT-pro BNP) surrogate markers. FIIa activity in plasma was higher in patients with FDAF who experienced MACE. Signaling via FIIa might be a presumed link between the coagulation system (tissue factor-FXa/FIIa-PAR1 axis), inflammation, and pro-fibrotic pathways (thrombo-inflammation) in FDAF.

PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

Improvement in Biocompatibility and Biointegration of Human Acellular Dermal Matrix through Vacuum Plasma Surface Treatment.

Efforts are ongoing to enhance the functionality of human acellular dermal matrices (hADMs), which are extensively utilized in reconstructive surgeries. Among these efforts, plasma treatments, particularly vacuum plasma treatments, have recently emerged in the medical field. This study aims to investigate the efficacy of a vacuum plasma treatment in enhancing the biocompatibility and biointegration of hADMs. Utilizing a plasma activator (ACTILINK reborn, Plasmapp Co., Ltd., Daejeon, Republic of Korea), hADMs were treated and evaluated through in vitro and in vivo analyses. Hydrophilicity changes were gauged by the blood absorption times, while SEM imaging was used to analyze physical surface deformation. Protein adsorption was measured with fluorescently labeled bovine serum albumin and fibronectin. For the in vivo study, mice were implanted with plasma-treated and untreated hADMs, and the post-implantation effects were analyzed through histological and immunofluorescence microscopy. The plasma-treated hADMs demonstrated a significantly enhanced hydrophilicity compared to the untreated samples. SEM imaging confirmed the maintenance of the microroughness after the treatment. The treated hADMs showed a significant reduction in fibronectin adsorption, a critical factor for cellular adhesion. In vivo, the plasma-treated hADMs exhibited reduced capsule formation and enhanced fibroblast infiltration, indicating improved biocompatibility and integration. These findings highlight the potential of a plasma treatment to enhance the performance of hADMs in clinical settings, offering a promising avenue for improving reconstructive surgery outcomes.