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Fibrous networks constructed from high aspect ratio protein building blocks are ubiquitous in nature. Despite this ubiquity, the functional advantage of such building blocks over globular proteins is not understood. To answer this question, we engineered hydrogel network building blocks with varying numbers of protein L domains to control the aspect ratio. The mechanical and structural properties of photochemically crosslinked protein L networks were then characterised using shear rheology and small angle neutron scattering. We show that aspect ratio is a crucial property that defines network architecture and mechanics, by shifting the formation from translationally diffusion dominated to rotationally diffusion dominated. Additionally, we demonstrate that a similar transition is observed in the model living system: fibrin blood clot networks. The functional advantages of this transition are increased mechanical strength and the rapid assembly of homogenous networks above a critical protein concentration, crucial for in vivo biological processes such as blood clotting. In addition, manipulating aspect ratio also provides a parameter in the design of future bio-mimetic and bio-inspired materials. Fibrous networks constructed from high aspect ratio protein building blocks are ubiquitous in nature, but the functional advantage of such building blocks over globular proteins is not understood. Here, using shear rheology and small-angle neutron scattering, the authors characterise the mechanical and structural properties of photochemically crosslinked protein L and fibrin networks and show that aspect ratio is a crucial property that defines network architecture and mechanics. [ABSTRACT FROM AUTHOR]

In recent years, several biomarkers have been found to be associated with deep vein thrombosis (DVT). D-dimer is a degradation product of a cross-linked fibrin blood clot and has a negative value in the diagnosis of DVT. Prothrombin fragment 1 + 2 (p F1 + 2) is a non-thrombotic polypeptide that is cleaved from Prothrombin during its conversion to thrombin. The study aims to evaluate the D-dimer and to evaluate Prothrombin fragment 1 + 2 in urine and plasma in clinically suspected DVT patients. This study comprised of 30 patients who are clinically suspected cases of deep vein thrombosis, carried out from July 2018 to May 2020 in the Department of General Surgery, IMS BHU, Varanasi. In our study, D-dimer and plasma F1 + 2 both showed comparable results in patients of venous thromboembolism (VTE). Proximal DVT tended to have higher levels of D-dimer and had significantly higher levels of F1 + 2 than patients with distal DVT. In our study, a positive correlation was found between D-dimer and plasma F1 + 2 (r = 0.588 and p-value 0.006) in DVT-positive patients. There is no correlation between plasma D-dimer and urine F1 + 2 (r = − 0.0.07 and p-value 0.769) In conclusion, Prothrombin F1 + 2 is an important marker raised in patients with DVT. [ABSTRACT FROM AUTHOR]

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Neovascular age-related macular degeneration (nAMD) is characterized by abnormal blood vessel growth from the choroid, leading to complications and eventual blindness. Despite anti-VEGF therapy, subretinal fibrosis remains a major concern, as VEGF/VEGF receptor-2 (VEGFR2) signaling can contribute to both angiogenesis and fibrosis. For the identification of the aqueous humor proteome, we performed liquid chromatography with tandem mass spectrometry analysis. To investigate the potential therapeutic effects of targeting the VEGF signaling pathway using apatinib, a highly selective VEGFR2 tyrosine kinase inhibitor, this study employed in vitro (THP-1 conditioned media-treated ARPE-19 cells) and in vivo (laser-induced choroidal neovascularization mouse) models of nAMD. This study revealed elevated VEGFR2 protein levels in the aqueous humor of nAMD patients, suggesting a potential target to mitigate neovascularization and fibrosis in nAMD. Apatinib effectively reduced VEGFA and αSMA levels in both in vitro and in vivo models. Moreover, apatinib showed improvement in laser-induced subretinal hyper-reflective lesions. The action mechanism was linked to the inhibition of VEGFR2 activation, leading to the suppression of both angiogenesis and fibrosis through the downregulation of STAT3 phosphorylation. Therefore, the VEGFR2 signaling pathway appears to play a central role in the development of nAMD by regulating both angiogenesis and fibrosis. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the role of oxylipins and lipid mediators in Pulmonary Embolism (PE), a serious cardiovascular condition associated with high morbidity and mortality rates. Methods: A total of 6,365 hospitalized patients with thrombosis and 200 healthy individuals were recruited as the control group from 2015 to 2023. Thrombus type, coagulation, and lipid-related parameters were statistically analysed. Additionally, lipidomic characteristics of serum samples from the PE and control groups were examined via LC-MS/MS for the first time. Results: Among the 6,365 hospitalized patients with thrombosis, 72.1% (4,587/6,365) had venous thromboembolism (VTE). Within the VTE group, the incidence of PE was 12.1% (555/4,587). In comparison to the healthy control (HC) group, the PE group exhibited significant elevations in coagulation-related parameters, such as factor VIII (F VIII) and von Willebrand factor (vWF) activities, while antithrombin III (AT III) and factor XII (F XII) activities were notably reduced. Lipid-related parameters, including serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (apoA), were significant reductions in PE patients (P < 0.0001), with areas under the curve (AUCs) exceeding 0.9. LC-MS/MS analysis of serum samples revealed 118 oxidized lipid metabolites. Compared to the HC group, the PE group exhibited 10 upregulated oxidized lipid metabolites, with the most significant difference observed in 20-hydroxyPGF2α derived from arachidonic acid (ARA). The study identified upregulated oxidized lipid metabolites primarily linked to the ARA metabolism signalling pathway. Conclusion: This research indicates a notable correlation between lipid metabolism and the occurrence and development of PE. Specifically, upregulation of the arachidonic acid metabolism signalling pathway may be an important pathogenic factor for PE, and 20-hydroxyPGF2α derived from ARA has potential as a biomarker for PE disease. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration is a progressive, blinding macular disease that has become a burden both in healthcare systems and the global economy. The vascular endothelial growth factor (VEGF) is the main agent involved in the pathogenic process of the disease. The main goal of the age-related macular degeneration treatment is to maintain and improve visual acuity by injecting intravitreal anti-VEGF agents in either a reactive or proactive manner. Subretinal and intraretinal fluids are the main biomarkers that should be considered when managing the frequency of the therapy. This review discusses both functional and morphological treatment criteria according to current recommendations as opposed to real-life situations encountered during day-to-day clinical practice and highlights situations in which the benefits of continuing therapy are arguable in terms of improving patients' quality of life. Optimizing the treatment regimen represents an important aim of current clinical ophthalmological practice, as age-related macular degeneration patients usually have a long follow-up period. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, there was increased interest in the issue of thrombotic complications of acute respiratory infections. Clinical reports and pathological studies have revealed that thrombus formation in COVID-19 may involve the venous and arterial vasculature. As thrombotic complications of infectious respiratory diseases are increasingly considered in the context of COVID-19, the fact that thrombosis in lung diseases of viral and bacterial etiology was described long before the pandemic is overlooked. Pre-pandemic studies show that bacterial and viral respiratory infections are associated with an increased risk of thrombotic complications such as myocardial infarction, ischemic stroke, pulmonary embolism, and other critical illnesses caused by arterial and venous thrombosis. This narrative review article aims to summarize the current evidence regarding thrombotic complications and their pathogenesis in acute lower respiratory tract infections. [ABSTRACT FROM AUTHOR]

The contact pathway of blood clotting has received intense interest in recent years as studies have linked it to thrombosis, inflammation, and innate immunity. Because the contact pathway plays little to no role in normal hemostasis, it has emerged as a potential target for safer thromboprotection, relative to currently approved antithrombotic drugs which all target the final common pathway of blood clotting. Research since the mid-2000s has identified polyphosphate, DNA, and RNA as important triggers of the contact pathway with roles in thrombosis, although these molecules also modulate blood clotting and inflammation via mechanisms other than the contact pathway of the clotting cascade. The most significant source of extracellular DNA in many disease settings is in the form of neutrophil extracellular traps (NETs), which have been shown to contribute to incidence and severity of thrombosis. This review summarizes known roles of extracellular polyphosphate and nucleic acids in thrombosis, with an emphasis on novel agents under current development that target the prothrombotic activities of polyphosphate and NETs. [ABSTRACT FROM AUTHOR]

A hallmark of angiogenesis is the sprouting of endothelial cells. To replicate this event in vitro, biomaterial approaches can play an essential role in promoting cell migration. To study the capacity of a scaffold of fibrin (fibrinogen:thrombin mix) to support the movement of the endothelial cells, the migration area of spheroids formed with the HULEC cell line was measured. The cells were first allowed to form a spheroid using the hanging drop technique before being encapsulated in the fibrin gel. The cells' migration area was then measured after two days of embedding in the fibrin gel. Various conditions affecting fibrin gel polymerization, such as different concentrations of fibrinogen and thrombin, were evaluated alongside rheology, porosity, and fiber thickness analysis to understand how these factors influenced cell behavior within the composite biomaterial. Data point toward thrombin's role in governing fibrin gel polymerization; higher concentrations result in less rigid gels (loss tangent between 0.07 and 0.034) and increased cell migration (maximum concentration tested: 5 U/mL). The herein presented method allows for a more precise determination of the crosslinking conditions of fibrin gel that can be used to stimulate angiogenic sprouting. [ABSTRACT FROM AUTHOR]

Background and Objectives: Parkinson's disease (PD) is a neurodegenerative disorder involving depletion of dopaminergic neurons. Pathogenetic mechanisms leading to striatonigral degeneration are debatable. Chronic inflammation is proposed as one of the mechanisms. In any disease with underlying inflammation, immune system mediators called cytokines are released, leading to a procoagulant state. Our aim was to study the coagulation parameters in patients with PD and find their correlation with disease duration and antiparkinsonian drugs. Methods: This cross-sectional study was conducted between January 2021 and December 2021 in a tertiary care center. Sixty-eight patients with PD were subcategorized based on disease duration (<5 and ≥5 years), number of antiparkinsonian drugs (one drug and ≥2 drugs), and levodopa equivalent daily dose (LEDD; <350 and ≥350 mg). Hemoglobin (Hb), prothrombin time (PT), fibrinogen, bleeding time, and platelet aggregation study with adenosine diphosphate and collagen were assessed. Results: In our cohort of 68 patients, 53 were men and 15 were women. Mean disease duration was 5.97 ± 4.37 years. Hb was negatively associated with LEDD (P = 0.012) and duration of the disease (P = 0.02). Similarly, PT was negatively associated with disease duration (P = 0.041) and number of antiparkinsonian drugs (P = 0.03). LEDD showed a positive association with collagen-induced platelet aggregation (P = 0.03). Conclusions: In our study, patients using multiple antiparkinsonian drugs and higher LEDD were observed to have a prothrombotic state. Further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Infective endocarditis represents a rare, acquired condition in animals, but also in humans, that typically involves one of the heart valves and mainly affecting the mitral and aortic valves in dogs. This report describes the clinical signs, the diagnostic approach and the postmortem investigations of a case confirmed with infective endocarditis at the level of the aortic valve but also the presence of a main consequence of the disease, represented by the development of paravalvular abscesses and subsequent fistulous tracts between heart chambers. Infective endocarditis is a severe but rarely diagnosed disease, characterized by the presence of bacterial infection at the level of the cardiac valves. Although the incidence of the disease is very low, the consequences are severe and the prognosis is very poor, outlining a high mortality rate among cases. The present report highlights the case of a 7-year-old dog presented with abrupt changes in the respiratory pattern, obtunded and in lateral recumbency. The physical examination of the patient revealed fever and a IV/VI systolic heart murmur, with the point of maximal intensity on the left hemithorax. Echocardiography identified hyperechoic and cavitary changes beneath the aortic valves and a retrograde turbulent jet originating in the left ventricle outflow tract communicating with the left atrium through a rupture in the aortomitral intervalvular wall. Because of very unstable hemodynamic changes, the dog suddenly died despite the initiation of intensive care supportive treatment, and the postmortem evaluation of the heart confirms the suspicion of infective aortic endocarditis with the development of a paravalvular abscess and an aorto-left atrial fistula. [ABSTRACT FROM AUTHOR]

Studies aiming to understand the effects of storage on whole blood (WB) clotting often rely on characterizing coagulation under static conditions. Minimal work has explored the effects of physiologic shear on clot formation and thrombolysis utilizing fractionated and reconstituted whole blood (rWB) products. WB was fractionated into platelet‐free plasma, packed red blood cells, and platelets storing each component under its ideal conditions—including platelet cryopreservation. Recombination at their native ratios was accomplished over 91 days of storage and clotting/thrombolysis was analyzed utilizing thromboelastography and Chandler loop. rWB preserved clot strength through 91 days with minimal deviation from baseline, in contrast to WB stored at 4°C which experienced a significant decline by storage Day‐42. Clot formation under shear for both rWB and WB led to increased clot mass through storage. No significant deviation from baseline was appreciated until Day 70 of storage in rWB. Increasing degrees of thrombolysis were seen in both groups, with rWB significantly deviating from baseline at Day 70. No significant changes in overall clot architecture occurred throughout storage and recombination. This fractionation and recombination protocol serves as a method to further develop reproducible in vitro clot analogs for preclinical thrombolytic therapy screening. [ABSTRACT FROM AUTHOR]

Enolase is a 47 kDa enzyme that functions within the glycolysis and gluconeogenesis pathways involved in the reversible conversion of D-2-phosphoglycerate (2PGA) to phosphoenolpyruvate (PEP). However, in the context of host-pathogen interactions, enolase from different species of parasites, fungi and bacteria have been shown to contribute to adhesion processes by binding to proteins of the host extracellular matrix (ECM), such as fibronectin (FN) or laminin (LM). In addition, enolase is a plasminogen (PLG)-binding protein and induces its activation to plasmin, the main protease of the host fibrinolytic system. These secondary 'moonlighting' functions of enolase are suggested to facilitate pathogen migration through host tissues. This study aims to uncover the moonlighting role of enolase from the parasite Fasciola hepatica, shedding light on its relevance to host-parasite interactions in fasciolosis, a global zoonotic disease of increasing concern. A purified recombinant form of F. hepatica enolase (rFhENO), functioning as an active homodimeric glycolytic enzyme of ~94 kDa, was successfully obtained, fulfilling its canonical role. Immunoblotting studies on adult worm extracts showed that the enzyme is present in the tegument and the excretory/secretory products of the parasite, which supports its key role at the host-parasite interface. Confocal immunolocalisation studies of the protein in newly excysted juveniles and adult worms also localised its expression within the parasite tegument. Finally, we showed by ELISA that rFhENO can act as a parasitic adhesin by binding host LM, but not FN. rFhENO also binds PLG and enhances its conversion to plasmin in the presence of the tissue-type and urokinase-type PLG activators (t-PA and u-PA). This moonlighting adhesion-like function of the glycolytic protein enolase could contribute to the mechanisms by which F. hepatica efficiently invades and migrates within its host and encourages further research efforts that are designed to impediment this function by vaccination or drug design. Author summary: Fasciola hepatica is a parasitic worm causing fasciolosis, primarily affecting herbivorous mammals and posing a significant veterinary problem. Furthermore, it is a zoonosis, meaning it can be transmitted to humans. F. hepatica enters the definitive host through ingestion of contaminated aquatic plants, migrating through the intestine to settle in the liver bile ducts, where it matures into the adult stage. To migrate, it utilizes various invasion strategies, including the use of multifunctional proteins, known as 'moonlighting'. In this study, we produced and molecularly characterized the parasitic enzyme enolase as a moonlighting protein to understand F. hepatica invasion mechanisms. We produced recombinant enolase with glycolytic activity, its canonical function in parasite energy production. Additionally, we localised this enzyme in the parasite's tegument, in direct contact with the host, and studied its ability to elicit an immune response early in ovine infection. Finally, we demonstrated the ability of enolase to interact with the extracellular matrix and the host's fibrinolysis, a proteolytic system responsible for dissolving blood clots. These secondary functions of F. hepatica enolase, described here for the first time, along with its localisation, suggest this protein as an interesting antigen for fasciolosis control. [ABSTRACT FROM AUTHOR]

Developing superporous hemostatic sponges with simultaneously enhanced permeability and mechanical properties remains challenging but highly desirable to achieve rapid hemostasis for non-compressible hemorrhage. Typical approaches to improve the permeability of hemostatic sponges by increasing porosity sacrifice mechanical properties and yield limited pore interconnectivity, thereby undermining the hemostatic efficacy and subsequent tissue regeneration. Herein, we propose a temperature-assisted secondary network compaction strategy following the phase separation-induced primary compaction to fabricate the superporous chitosan sponge with highly-interconnected porous structure, enhanced blood absorption rate and capacity, and fatigue resistance. The superporous chitosan sponge exhibits rapid shape recovery after absorbing blood and maintains sufficient pressure on wounds to build a robust physical barrier to greatly improve hemostatic efficiency. Furthermore, the superporous chitosan sponge outperforms commercial gauze, gelatin sponges, and chitosan powder by enhancing hemostatic efficiency, cell infiltration, vascular regeneration, and in-situ tissue regeneration in non-compressible organ injury models, respectively. We believe the proposed secondary network compaction strategy provides a simple yet effective method to fabricate superporous hemostatic sponges for diverse clinical applications. Developing porous hemostatic sponges remains challenging. Here, authors proposed a temperature-assisted secondary network compaction strategy following the phase separation induced primary compaction to fabricate the superporous chitosan sponges. [ABSTRACT FROM AUTHOR]

Cell migration is fundamental to both development and adult physiology, including gastrulation, brain development, angiogenesis, wound healing, bone remodeling, tissue homeostasis, and the immune response. Additionally, misguided cellular migration is implicated in disease pathologies such as cancer metastasis and fibrosis. The microenvironment influences cell migration modes such as mesenchymal, amoeboid, lobopodial, and collective, and these are governed through local signaling by affecting the gene expression and epigenetic alteration of migration-related genes. Plasticity in switching between migration modes is essential for key cellular processes across various contexts. Understanding the mechanisms of cell migration modes and its plasticity is essential for unraveling the complexities of this process and revealing its implications in physiological and pathological contexts. This review focuses on different modes of cell migration, including their aberrant migration in disease pathologies and how they can be therapeutically targeted in disease conditions such as cancer. [ABSTRACT FROM AUTHOR]

Background: Pseudothrombocytopenia (PTCP) can be caused by anticoagulants or pre-analytical issues. The authors present a case of PTCP attributed to pre-analytical issues in a 68-year-old male patient. Methods: The platelet count results were obtained using both the impedance and fluorescence channels of Sysmex XN-10. The blood film was scanned using both Cellavision DM96 and a microscope. Results: The flag for PLT-Clumps and the scattergram from the PLT-F channel indicated the presence of platelet aggregation. Fibrin could be observed at the feathered end of the blood film. A diagnosis of PTCP resulting from pre-analytical issues was made. Conclusions: The presence of fibrin in a blood film is a critical indicator for diagnosing PTCP due to pre-analytical issues. [ABSTRACT FROM AUTHOR]

Wound infection and excessive blood loss are the two major challenges associated with trauma injuries that account for 10% of annual deaths in the United States. Nitric oxide (NO) is a gasotransmitter cell signaling molecule that plays a crucial role in the natural wound healing process due to its antibacterial, anti-inflammatory, cell proliferation, and tissue remodeling abilities. Tranexamic acid (TXA), a prothrombotic agent, has been used topically and systemically to control blood loss in reported cases of epistaxis and combat-related trauma injuries. Its properties could be incorporated in wound dressings to induce immediate clot formation, which is a key factor in controlling excessive blood loss. This study introduces a novel, instant clot-forming NO-releasing dressing, and fabricated using a strategic bi-layer configuration. The layer adjacent to the wound was designed with TXA suspended on a resinous bed of propolis, which is a natural bioadhesive possessing antibacterial and anti-inflammatory properties. The base layer, located furthest away from the wound, has an NO donor, S-nitroso-N-acetylpenicillamine (SNAP), embedded in a polymeric bed of Carbosil®, a copolymer of polycarbonate urethane and silicone. Propolis was integrated with a uniform layer of TXA in variable concentrations: 2.5, 5.0, and 7.5 vol % of propolis. This design of the TXA-SNAP-propolis (T-SP) wound dressing allows TXA to form a more stable clot by preventing the lysis of fibrin. The lactate dehydrogenase-based platelet adhesion assay showed an increase in fibrin activation with 7.5% T-SP as compared with control within the first 15 min of its application. A scanning electron microscope (SEM) confirmed the presence of a dense fibrin network stabilizing the clot for fabricated dressing. The antibacterial activity of NO and propolis resulted in a 98.9 ± 1% and 99.4 ± 1% reduction in the colony-forming unit of Staphylococcus aureus and multidrug-resistant Acinetobacter baumannii, respectively, which puts forward the fabricated dressing as an emergency first aid for traumatic injuries, preventing excessive blood loss and soil-borne infections., (© 2024 Wiley Periodicals LLC.)

The maintenance of phosphate homeostasis serves as a foundation for energy metabolism and signal transduction processes in all living organisms. Inositol pyrophosphates (PP-InsPs), composed of an inositol ring decorated with monophosphate and diphosphate moieties, and inorganic polyphosphate (polyP), chains of orthophosphate residues linked by phosphoanhydride bonds, are energy-rich biomolecules that play critical roles in phosphate homeostasis. There is a complex interplay between these two phosphaterich molecules, and they share an interdependent relationship with cellular adenosine triphosphate (ATP) and inorganic phosphate (Pi). In eukaryotes, the enzymes involved in PP-InsP synthesis show some degree of conservation across species, whereas distinct enzymology exists for polyP synthesis among different organisms. In fact, the mechanism of polyP synthesis in metazoans, including mammals, is still unclear. Early studies on PPInsP and polyP synthesis were conducted in the slime mould Dictyostelium discoideum, but it is in the budding yeast Saccharomyces cerevisiae that a clear understanding of the interplay between polyP, PP-InsPs, and Pi homeostasis has now been established. Recent research has shed more light on the influence of PP-InsPs on polyP in mammals, and the regulation of both these molecules by cellular ATP and Pi levels. In this review we will discuss the cross-talk between PP-InsPs, polyP, ATP, and Pi in the context of budding yeast, slime mould, and mammals. We will also highlight the similarities and differences in the relationship between these phosphate-rich biomolecules among this group of organisms. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis). Clots are, of course, a well-known consequence of atrial fibrillation. We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF. We consider known 'risk factors' for AF, and in particular, exogenous stimuli such as infection and air pollution by particulates, both of which are known to cause AF. The external accompaniments of both bacterial (lipopolysaccharide and lipoteichoic acids) and viral (SARS-CoV-2 spike protein) infections are known to stimulate fibrinaloid microclots when added in vitro, and fibrinaloid microclots, as with other amyloid proteins, can be cytotoxic, both by inducing hypoxia/reperfusion and by other means. Strokes and thromboembolisms are also common consequences of AF. Consequently, taking a systems approach, we review the considerable evidence in detail, which leads us to suggest that it is likely that microclots may well have an aetiological role in the development of AF. This has significant mechanistic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer and has a poor prognosis. Patients with PDAC are at high risk of developing thromboembolic events, which is a leading cause of morbidity and mortality following cancer progression. Plasma-derived coagulation is the most studied process in cancer-associated thrombosis. Other blood components, such as platelets, red blood cells, and white blood cells, have been gaining less attention. This narrative review addresses the literature on the role of cellular components in the development of venous thromboembolism (VTE) in patients with PDAC. Blood cells seem to play an important role in the development of VTE. Altered blood cell counts, i.e., leukocytosis, thrombocytosis, and anemia, have been found to associate with VTE risk. Tumor-related activation of leukocytes leads to the release of tissue factor-expressing microvesicles and the formation of neutrophil extracellular traps, initiating coagulation and forming a scaffold for thrombi. Tissue factor-expressing microvesicles are also thought to be released by PDAC cells. PDAC cells have been shown to stimulate platelet activation and aggregation, proposedly via the secretion of podoplanin and mucins. Hypofibrinolysis, partially explained by increased plasminogen activator inhibitor-1 activity, is observed in PDAC. In short, PDAC-associated hypercoagulability is a complex and multifactorial process. A better understanding of cellular contributions to hypercoagulability might lead to the improvement of diagnostic tests to identify PDAC patients at highest risk of VTE. [ABSTRACT FROM AUTHOR]

Background: To evaluate the outcomes of intravitreal faricimab (IVF) for refractory neovascular age-related macular degeneration (nAMD) and investigate the impact of baseline optical coherence tomography, biomarkers for total IVF injections are needed. Methods: A retrospective analysis of 33 eyes of patients who completed one year (52 W) of treatment with IVF. The eyes received four IVF injections (6 mg/0.05 mL) as the upload phase. Thereafter, the treatment interval was extended to 8 or 12 weeks if disease activity was not recorded. The outcome measures included best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and retinal fluid distribution. Results: A total of 33 eyes were included. CMT decreased significantly at 52 W (p < 0.01). BCVA and SFCT did not change significantly at 52 W (p > 0.05). The number of eyes with subretinal fluid decreased significantly at 52 W (p < 0.01). Complete fluid resolution was achieved in 20 eyes (60%). The total number of injections was significantly negatively correlated with the presence of hyperreflective dots at baseline (HRDs, p < 0.01) and SFCT at baseline (p < 0.01). Conclusions: IVF led to a significant reduction in CMT with stabilization of BCVA. The total number of injections was lower in eyes with HRDs and increased SFCT at baseline. This might provide clues regarding response to IVF for future studies. [ABSTRACT FROM AUTHOR]

Background: The predictive value of thrombus perviousness in acute ischemic stroke (AIS), as measured by computed tomography (CT), has been intensively studied with conflicting results. In this study, we investigate the predictive potential of the novel concept of dynamic perviousness using three-dimensional (3D) volumetric evaluation of occlusive thrombi. Methods: The full thrombus volume in 65 patients with a hyperdense artery sign on non-contrast CT (NCCT), who underwent mechanical thrombectomy (MT), was segmented. Perviousness maps were computed voxel-wise for the entire thrombus volume as thrombus attenuation increase (TAI) between NCCT and CT angiography (CTA) as well as between CTA and late venous phase CT (CTV). Perviousness was analyzed for its association with NIHSS at admission, Thrombolysis In Cerebral Infarction (TICI) score, and number of MT passes. Results: The mean late-uptake TAI of thrombi with NIHSS scores greater than 21 at admission was approximately 100% higher than for lower scored NIHSS (p between 0.05 and 0.005). Concerning revascularization results, thrombi requiring less than four MT passes had ca. 80% higher group mean late-uptake TAI than clots requiring four or more passes (p = 0.03), and thrombi with TICI score III had ca. 95% higher group mean late-uptake TAI than thrombi with TICI II (p = 0.03). Standard perviousness showed no significant correlation with MT results. Conclusion: Standard thrombus perviousness of 3D clot volume is not associated with revascularization results in AIS. In contrast, dynamic perviousness assessed with a voxel-wise characterization of 3D thrombi volume may be a better predictor of MT outcomes than standard perviousness. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19. [ABSTRACT FROM AUTHOR]

Abstract Fibrous networks constructed from high aspect ratio protein building blocks are ubiquitous in nature. Despite this ubiquity, the functional advantage of such building blocks over globular proteins is not understood. To answer this question, we engineered hydrogel network building blocks with varying numbers of protein L domains to control the aspect ratio. The mechanical and structural properties of photochemically crosslinked protein L networks were then characterised using shear rheology and small angle neutron scattering. We show that aspect ratio is a crucial property that defines network architecture and mechanics, by shifting the formation from translationally diffusion dominated to rotationally diffusion dominated. Additionally, we demonstrate that a similar transition is observed in the model living system: fibrin blood clot networks. The functional advantages of this transition are increased mechanical strength and the rapid assembly of homogenous networks above a critical protein concentration, crucial for in vivo biological processes such as blood clotting. In addition, manipulating aspect ratio also provides a parameter in the design of future bio-mimetic and bio-inspired materials.

Introduction: Early diagnosis and aggressive treatment of pulmonary embolism (PE) are crucial for preventing severe complications after total knee arthroplasty (TKA). This study aimed to examine the efficacy of measuring oxygen saturation (SpO2) using a pulse oximeter for early diagnosis of PE after total knee arthroplasty (TKA). Materials and methods: We consecutively examined 1645 patients who underwent TKA between January 2015 and November 2019. Postoperative SpO2 was measured with a pulse oximeter, which was stopped if SpO2 was maintained at ≥ 95% until postoperative day 2 (POD2). To diagnose PE, computed tomographic pulmonary angiography (CTPA) was performed for specific indications, including persistently low SpO2 < 95% (group 1), sudden decrease in SpO2 (group 2), and decrease in SpO2 after POD3 with presenting symptoms (group 3). Also, we divided the patients into unilateral, simultaneous and sequential TKA groups and compared the results with specific statistical techniques. Results: Of the 1645 patients who underwent TKA, there were 20 patients with PE (1.2%), and symptomatic PE was observed in only 4 patients (0.24%). CTPA was performed in 58 (3.5%) patients, of whom 20 were diagnosed with PE. In groups 1 (n = 34), 2 (n = 21), and 3 (n = 3), CTPA was performed 2.4, 2.6, and 8.3 days after TKA, respectively, and 12, 8, and 0 patients were diagnosed with PE, respectively. Of the 782, 416, and 447 unilateral, simultaneous, and sequential (done in same admission with interval 1 or 2 weeks) patients with TKA, 38, 18, and 2 received CTPA, and 13, 6, and 1 were diagnosed with PE, respectively. All patients diagnosed with PE have persistently low SpO2 < 95% (group 1), or sudden decrease in SpO2 (group 2) until POD2. Of the patients diagnosed with PE, SpO2 decreased without the presentation of symptoms in 16 patients (11 and 5 from groups 1 and 2, respectively) and with the presentation of symptoms, such as mild dyspnea and chest discomfort, in 4 patients (1 and 3 from groups 1 and 2, respectively). Conclusions: Measuring SpO2 using a pulse oximeter until POD2 was an effective method for early diagnosis of PE after TKA. No case of morbidity or mortality was observed after early diagnosis with early stage CTPA and management of PE. We recommend measuring SpO2 with a pulse oximeter for early diagnosing of PE in TKA. [ABSTRACT FROM AUTHOR]

The evaluation of informative significance of homeostasis disturbance by degree of severity was carried out, and then the development of prognostic algorithms and verification of their effectiveness. It should be noted that all patients had deep burns from 10% to 45% of the body surface. Exactly these victims made up the basic array with the help of which the tasks on estimation of information significance and development of prognostic algorithm were solved. Adequate preoperative measures allowed to improve both the indices of the circulatory system and the clotting system in patients with mild and medium degree of plasmoporia. [ABSTRACT FROM AUTHOR]