RUNX1 targeting AKT3 promotes alveolar hypercoagulation and fibrinolytic inhibition in LPS induced ARDS.

BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are mainly responsible for massive alveolar fibrin deposition, which are closely related with refractory hypoxemia in acute respiratory distress syndrome (ARDS). Our previous study testified runt-related transcription factor (RUNX1) participated in the regulation of this pathophysiology in this syndrome, but the mechanism is unknown. We speculate that screening the downstream genes associated with RUNX1 will presumably help uncover the mechanism of RUNX1. METHODS: Genes associated with RUNX1 were screened by CHIP-seq, among which the target gene was verified by Dual Luciferase experiment. Then the efficacy of the target gene on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS was explored in vivo as well as in vitro. Finally, whether the regulatory effects of RUNX1 on alveolar hypercoagulation and fibrinolytic in ARDS would be related with the screened target gene was also sufficiently explored. RESULTS: Among these screened genes, AKT3 was verified to be the direct target gene of RUNX1. Results showed that AKT3 was highly expressed either in lung tissues of LPS-induced rat ARDS or in LPS-treated alveolar epithelia cell type II (AECII). Tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) were increasingly expressed both in lung tissues of ARDS and in LPS-induced AECII, which were all significantly attenuated by down-regulation of AKT3. Inhibition of AKT3 gene obviously ameliorated the LPS-induced lung injury as well as the collagen I expression in ARDS. RUNX1 overexpression not only promoted the expressions of TF, PAI-1, but also boosted AKT3 expression in vitro. More importantly, the efficacy of RUNX1 on TF, PAI-1 were all effectively reversed by down-regulation of AKT3 gene. CONCLUSION: AKT3 is an important target gene of RUNX1, through which RUNX1 exerted its regulatory role on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS. RUNX1/ATK3 signaling axis is expected to be a new target for the exploration of ARDS genesis and treatment.

Role of LL-37 in thrombotic complications in patients with COVID-19.

Blood clot formation induced by dysfunctional coagulation is a frequent complication of coronavirus disease 2019 (COVID-19) and a high-risk factor for severe illness and death. Neutrophil extracellular traps (NETs) are implicated in COVID-19-induced immunothrombosis. Furthermore, human cathelicidin, a NET component, can perturb the interaction between the SARS-CoV-2 spike protein and its ACE2 receptor, which mediates viral entry into cells. At present, however, the levels of cathelicidin antimicrobial peptides after SARS-CoV-2 infection and their role in COVID-19 thrombosis formation remain unclear. In the current study, we analyzed coagulation function and found a decrease in thrombin time but an increase in fibrinogen level, prothrombin time, and activated partial thromboplastin time in COVID-19 patients. In addition, the cathelicidin antimicrobial peptide LL-37 was upregulated by the spike protein and significantly elevated in the plasma of patients. Furthermore, LL-37 levels were negatively correlated with thrombin time but positively correlated with fibrinogen level. In addition to platelet activation, cathelicidin peptides enhanced the activity of coagulation factors, such as factor Xa (FXa) and thrombin, which may induce hypercoagulation in diseases with high cathelicidin peptide levels. Injection of cathelicidin peptides promoted the formation of thrombosis, whereas deletion of cathelicidin inhibited thrombosis in vivo. These results suggest that cathelicidin antimicrobial peptide LL-37 is elevated during SARS-CoV-2 infection, which may induce hypercoagulation in COVID-19 patients by activating coagulation factors.

VEGFR and DPP-IV as Markers of Severe COVID-19 and Predictors of ICU Admission.

The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18-93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19.

Thrombosis Models: An Overview of Common In Vivo and In Vitro Models of Thrombosis.

Occlusions in the blood vessels caused by blood clots, referred to as thrombosis, and the subsequent outcomes are leading causes of morbidity and mortality worldwide. In vitro and in vivo models of thrombosis have advanced our understanding of the complex pathways involved in its development and allowed the evaluation of different therapeutic approaches for its management. This review summarizes different commonly used approaches to induce thrombosis in vivo and in vitro, without detailing the protocols for each technique or the mechanism of thrombus development. For ease of flow, a schematic illustration of the models mentioned in the review is shown below. Considering the number of available approaches, we emphasize the importance of standardizing thrombosis models in research per study aim and application, as different pathophysiological mechanisms are involved in each model, and they exert varying responses to the same carried tests. For the time being, the selection of the appropriate model depends on several factors, including the available settings and research facilities, the aim of the research and its application, and the researchers' experience and ability to perform surgical interventions if needed.

Investigation of two different human d-dimer assays in the horse.

BACKGROUND: D-dimer has value as a marker of thrombosis in critically ill horses and can provide additional information about prognosis. However, there are currently no equine species-specific d-dimer assays available, nor has there been any formal investigation of the applicability of human d-dimer assays in horses, so it is unknown, which assay performs best in this species. The aim of this study was therefore to evaluate and compare two human d-dimer assays for their applicability in horses. The study included four groups of horses: clinically healthy horses, horses with gastrointestinal (GI) disease and mild systemic inflammation based on low serum amyloid A (SAA) (low SAA group), horses with GI disease and strong systemic inflammation based on high SAA (high SAA group) and, horses with thrombotic GI disease caused by Strongylus vulgaris (also called non-strangulating intestinal infarction (NSII)) (NSII group). The assays evaluated were the STAGO STA-Liatest D-di + (Stago) and NycoCard™ D-dimer (NycoCard). Intra- and inter-coefficients of variation (CV) were assessed on two d-dimer concentrations, and linearity under dilution was evaluated. A group comparison was performed for both assays across the four groups of horses. A Spaghetti plot, Spearman Correlation, Passing Bablok regression and Bland-Altman plot were used to compare methods in terms of agreement. RESULTS: Ten horses were included in the clinically healthy group, eight in the low SAA group, eight in the high SAA group, and seven in the NSII group. For the Stago assay, intra- and inter-CVs were below the accepted level except for one inter-CV. The NycoCard assay did not meet the accepted level for any of the CVs. The linearity under dilution was acceptable for both the Stago and NycoCard. In the group comparison, both methods detected a significantly higher d-dimer concentration in the high SAA and NSII groups compared to the clinically healthy group. Method agreement showed slightly higher d-dimer concentrations with NycoCard compared to Stago. The overall agreement was stronger for the lower d-dimer concentrations. CONCLUSION: Both the Stago and the NycoCard were found to be applicable for use in horses but were not directly comparable.

Modelling the procoagulatory effect of Anastrozole relative to ERα and ERß expression in breast cancer cells.

BACKGROUND: Anastrozole is commonly used for the treatment of oestrogen receptor (ER)-positive breast cancer but can increase thromboembolic risk. It is unclear if ER presentation is associated with platelet-mediated hypercoagulation. We investigated the relationship between hypercoagulation and ERα and ERß expression in breast cancer cell lines under Anastrozole treatment. METHODS: In Model 1, MCF-7 or T47D cancer cells were treated with Anastrozole, then exposed to whole blood and platelet-rich plasma, modelling platelet engagement in the tumour bed. In Model 2, blood components were treated with Anastrozole, then exposed to cancer cells, modelling circulatory effects in the vasculature. Hypercoagulation was assessed as a combined function of thrombin activity, platelet CD62P and CD63 expression, and corresponding platelet ultrastructure. Tumour ERα and ERß were immunolocalised and following quantification assessed for correlation with hypercoagulatory parameters. RESULTS: Anastrozole enhanced hypercoagulation in both Models and cell lines. T47D cells induced more distinct features of hypercoagulation and responded by heightening ERß expression and sustaining expression of ERα, indicative of a more aggressive phenotype. Post-exposure to cell lines, CD62P and CD63 expression correlated, but this was not maintained following Anastrozole treatment. Substantive correlations could not be found explaining the changes in ER expression and hypercoagulatory parameters, indicating unknown causative factors. CONCLUSION: These results provide basic science evidence showing that the hypercoagulatory effects induced by Anastrozole treatment may be related to the tumour subphenotype. Clinical studies are required to determine whether tracking of hypercoagulatory parameters may hold value in describing subphenotypic alterations or metastatic potential during tumour progression.

Large tricuspid valve thrombus complicating COVID-19 pneumonia.

BACKGROUND: Hemostatic disturbances with coronavirus disease 2019 (COVID-19) can predispose to tricuspid and right heart thrombi in very rare instances. AIM: We describe a 29-year-old female patient without a previous cause of thrombosis who developed large tricuspid valve thrombus (TVT) and moderate-to-severe tricuspid regurgitation (TR) during the course of COVID-19 infection. MATERIALS AND METHODS: Persistant fever and tachycardia with thrombocytopenia and high d-dimer increased the index of suspicion. The diagnosis was made by bedside transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR). Surgery was performed for thrombectomy and tricuspid valve replacement with a tissue valve. DISCUSSION AND CONCLUSION: Detection of TVT in COVID-19 patients on the basis of high index of suspicion, bedside TTE and noninvasive CMR helps early surgical treatment and subsequent reduction of mortality and hospital stay.

Strategies for Therapeutic Amelioration of Aberrant Plasma Zn2+ Handling in Thrombotic Disease: Targeting Fatty Acid/Serum Albumin-Mediated Effects.

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn2+ in blood plasma. Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70-85% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.

Major Depressive Disorder in a Patient with Systemic Lupus Erythematous, Pulmonary Hypertension, and Hypercoagulation: A Case Report.

Major depressive disorder is characterized by the presence of single or repeated major depressive episodes, which are considered periods of 2 weeks of depressive moods featuring impaired neurovegetative functioning, psychomotor activity, and cognition, as well as suicidal thoughts. Major depressive disorder is commonly associated with other medical conditions, especially chronic and systemic medical illnesses. Cardiovascular diseases are among the most related, especially pulmonary hypertension, a cardiovascular disorder that results in increased pulmonary circulation pressure--with an average resting pulmonary artery pressure of at least 25 mmHg--and which the WHO has associated with several other conditions, including connective tissue diseases such as scleroderma and systemic lupus erythematosus (SLE). The patient in this case is a 39-year-old woman diagnosed with major depressive disorder and SLE-associated pulmonary artery hypertension, which has been associated with hypercoagulable states, as observed in this instance. The complicated associations between these problems require collaboration between disciplines to establish optimal treatment integrity, with palliative care necessary to improve this patient's quality of life.

Perspectives on vaccine induced thrombotic thrombocytopenia.

As the novel SARS-CoV-2 continues to infect numerous individuals worldwide, one of the leading approaches in dealing with the global health crisis is vaccination against the COVID-19. Due to recent reports, vaccination with ChAdOx1 nCov-19 (developed by Oxford and AstraZeneca) may result in a vaccine-induced catastrophic thrombotic thrombocytopenia disorder. Thus, as of March 16 of 2021, vaccination programs in 18 countries had been suspended until further examination, including Sweden, Germany and France. This disorder presents as extensive thrombosis in atypical sites, primarily in the cerebral venous, alongside thrombocytopenia and the production of autoantibody against platelet-factor 4 (PF4). PF4 autoantibody has the ability to binds the human FcRγIIA receptor of platelets and contribute to their aggregation. This rare adverse effect extremely resembles the clinical presentation of the classical immune-mediated HIT disorder, which occurs following exposure to heparin. Surprisingly, none of these patients had been pre-exposed to heparin before disease onset, leading to the hypothesis that a viral antigen from the vaccine had triggered the response. Importantly, COVID-19 had been associated with numerous autoimmune manifestations, including the production of pathogenic autoantibodies, new onset of autoimmune diseases and disorders. As the ChAdOx1 nCov-19 vaccination leads to the synthesis of specific SARS-CoV-2-proteins, they may trigger a production of PF4 autoantibody though molecular mimicry phenomena, while vaccination compounds lead to a rigorous bystander activation of immune cells. If existing, removing such homological sequences from the vaccine may eliminate this phenomenon. In contrast, it needs to be emphasized that the ChAdOx1 nCoV-19 vaccine was found to be safe and efficacious against symptomatic COVID-19 in randomized controlled trials, which included 23,848 participants from the UK, Brazil and South Africa.

Sickle cell disease and COVID-19: Susceptibility and severity.

We surveyed published papers and an international sickle cell disease (SCD) registry to detect susceptibility and clinical course of coronavirus disease 2019 (COVID-19) in SCD patients. COVID-19 presentation was mild in children and moderate in many SCD adults. Regarding increased comorbidities with age, it seems severe COVID-19 to be more common in older SCD patients. Although the overall outcome of COVID-19 was favorable in SCD children, a high rate of pediatric intensive care unit admission should be considered in managing these patients. To explain COVID-19 outcome in SCD patients, the possible benefits of hydroxyurea therapy could be considered. The obtained results should be interpreted, considering low cases from sub-Saharan people, younger age of SCD patients compared to general population, a bias toward registry of the more severe form of disease, the effect of pre-existing comorbidities with multisystem organ damage, and the role of health socio-economic determinants.

A pilot study evaluating the Calibrated Automated Thrombogram assay and application of plasma-thromboelastography for detection of hemostatic aberrations in horses with gastrointestinal disease.

BACKGROUND: Critically ill horses, such as horses with gastrointestinal (GI) disease, often suffer from hemostatic aberrations. Global hemostatic tests examining the initiation of coagulation, clot strength and fibrinolysis, such as the Calibrated Automated Thrombogram (CAT) and plasma-thromboelastography (TEG) have not been evaluated in horses. This study aimed to evaluate CAT and apply plasma-TEG in horses. Test performance of CAT was evaluated on equine platelet poor plasma with intra- and inter-assay variability (CV) and a heparin dilution curve. To examine clinical performance of both tests, group comparisons were assessed comparing healthy horses, horses with mild and severe GI disease with both CAT and plasma-TEG. RESULTS: For CAT, intra- and inter-assay CVs were established for lag-time (1.7, 4.7%), endogenous thrombin potential (1.6, 4.6%), peak (2.6, 3.9%) and time to peak (ttPeak) (1.9, 3.4%). Increasing heparin concentrations led to the expected decrease in thrombin generation. In the group comparison analysis, CAT showed significant higher peak (p = 0.04) and ttPeak (p = 0.008) in the severe GI disease group compared to horses with mild GI disease and healthy horses, respectively. Plasma-TEG showed an increased angle (p = 0.032), maximum amplitude (p = 0.017) and shear elastic force (G) (p = 0.017) in the severe GI disease group compared to healthy horses. CONCLUSIONS: CAT performed well in horses. Both CAT and plasma-TEG identified hemostatic aberrations in horses with severe GI disease compared to healthy horses. Further studies including more horses, are needed to fully appreciate the use of CAT and plasma-TEG in this species.

Elevated CA125 is Related to Stroke Due to Cancer- Associated Hypercoagulation.

BACKGROUND: Cancer-associated hypercoagulation is one of the major pathophysiological mechanisms of stroke in cancer patients. Carcinomatous mucins are considered to play an important role in cancer-associated hypercoagulation. Therefore, carbohydrate antigen-125 (CA125), which is a typical mucin molecule and mucin-producing tumor marker, may be related to stroke due to cancer-associated hypercoagulation. AIMS: We aimed to clarify the association of CA125 with a hypercoagulable state in acute stroke patients with active cancer. METHODS: We studied 77 acute ischemic stroke patients with active cancer who had undergone CA125 measurement. The study patients were categorized into hypercoagulation or non-hypercoagulation groups. The hypercoagulation group was defined as stroke patients with a D-dimer value exceeding 3 µg/mL and multiple vascular territory infarcts. Elevation of tumor markers was defined as values more than twice the upper limit of the normal range. RESULTS: Forty-five (58%) and 32 (42%) patients were classified into hypercoagulation and non-hypercoagulation groups, respectively. The hypercoagulation group showed elevated CA125 and CEA levels, no history of hypertension, and pancreatic cancer more frequently, and higher CRP values, lower hemoglobin values, longer prothrombin time and lower platelet counts than the non-hypercoagulation group. In multivariable analysis, only elevation of CA125 was independently associated with the hypercoagulation group (adjusted odds ratio: 5.59 [95% confidence interval]: 1.33-26.41). CONCLUSIONS: CA125, a tumor marker for mucin-producing tumors, was related to stroke due to cancer- associated hypercoagulation. CA125 may be a potential biomarker for cancer-associated hypercoagulation.

Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation.

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

HEMOSTATIC POTENTIAL ASSESSMENT OF PATIENTS WITH LIVER CIRRHOSIS AND ATRIAL FIBRILLATION BY LOW-FREQUENCY PIEZOELECTRIC THROMBOELASTOGRAPHY.

OBJECTIVE: The aim: Our aim was to assess the hemostatic potential of patients with liver cirrhosis and atrial fibrillation by LPTEG global coagulation assay, to investigate changes in LPTEG parameters according to the stage of liver cirrhosis and compare results with liver cirrhosis group. PATIENTS AND METHODS: Materials and methods: We performed a prospective cross-sectional study including 70 patients with liver cirrhosis and atrial fibrillation, 36 patients with liver cirrhosis and 20 healthy individuals. LPTEG parameters were measured using ARP-01M "Mednord" in order to assess coagulation abnormalities. RESULTS: Results: t1 and Intensity of contact coagulation didn't differ (p>0,05), Constant of thrombin activity was increased (47.53±0.8vs.34.51±1.88, p<0.001), t3 was reduced (5,0±0.1vs.6.7±0.36 p<0.001), Intensity of coagulation drive was increased (52.8±1.8vs.38.55±1.54, p = 0.001), Intensity of clot polymerization was increased (19.66±0.28vs.16.29±0.28,p<0.001), time t5 was reduced (32.94±0.36 vs. 36.8±1.30, p<0.01), Maximum amplitude was increased (655.7±9.19 vs. 547±19.38, p<0.001), Intensity of total coagulation was increased (19.41±0.34vs.15,09±0.56, p<0.001), Intensity of clot retraction and lysis was increased (4.1±0.07vs.3±0.15, p<0.001) and Coefficient of total anticoagulant activity was increased (2.81±0.05 vs. 2.48 ± 0.06, p<0.001) compared to liver cirrhosis. CONCLUSION: Conclusions: In patients with liver cirrhosis and atrial fibrillation the hemostatic potential is significantly shifted towards hypercoagulation with a gradual worsening of coagulation disorders, starting from the compensated stage of liver cirrhosis.

SN50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome mice through inhibiting NF-κB p65 translocation.

BACKGROUND: It has been confirmed that NF-κB p65 signaling pathway is involved in the regulation of alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS). Whether SN50, a NF-κB cell permeable inhibitor, could attenuate alveolar hypercoagulation and fibrinolysis inhibition in ARDS remains to be elucidated. PURPOSE: We explored the efficacy and potential mechanism of SN50 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS in mice. MATERIALS AND METHODS: Mouse ARDS was made by 50 µl of lipopolysaccharide (LPS) (4 mg/ml) inhalation. Male BALB/c mice were intraperitoneally injected with different does of SN50 1 h before LPS inhalation. Lung tissues were collected for hematoxylin-eosin (HE) staining, wet/dry ratio. Pulmonary expressions of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), collagen III, as well as phosphorylated p65 (p-p65), p65 in nucleus (p'-p65), IκBα and IKKα/ß were measured. Bronchoalveolar lavage fluid (BALF) was gathered to test the concentrations of TF, PAI-1, activated protein C (APC) and thrombinantithrombin complex (TAT). DNA binding activity of NF-κB p65 was also determined. RESULTS: After LPS stimulation, pulmonary edema and exudation and alveolar collapse occured. LPS also stimulated higher expressions of TF and PAI-1 in lung tissues, and higher secretions of TF, PAI-1, TAT and low level of APC in BALF. Pulmonary collagen III expression was obviously enhanced after LPS inhalation. At same time, NF-κB signaling pathway was activated with LPS injury, shown by higher expressions of p-p65, p'-p65, p-IKKα/ß, p-Iκα in pulmonary tissue and higher level p65 DNA binding activity. SN50 dose-dependently inhibited TF, PAI-1 and collagen IIIexpressions, and decreased TF, PAI-1, TAT but increased APC in BALF. SN50 treatment attenuated pulmonary edema, exudation and reduced lung tissue damage as well. SN50 application significantly reduced p'-p65 expression and weakened p65 DNA binding activity, but expressions of p-p65, p-IKKα/ß, p-Iκα in cytoplasm of pulmonary tissue were not affected. CONCLUSIONS: SN 50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in ARDS via inhibition of NF-κB p65 translocation. Our data demonstrates that NF-κB p65 pathway is a viable new therapeutic target for ARDS treatment.

Is Porphyromonas gingivalis involved in Parkinson's disease?

Porphyromonas gingivalis, a major subgingival plaque bacterium in periodontitis, has recently attracted much attention as a possible microbial driver in Alzheimer's disease. In the present paper, another common neuroinflammatory disease, Parkinson's disease (PD), is discussed. A recent study found major virulence factors of P. gingivalis such as gingipain R1 (RgpA) and lipopolysaccharide in the blood circulation of a PD population. The current review reveals how features such as systemic inflammation, hypercoagulation, presence of amyloid fibrin(ogen) in plasma, and marked ultrastructural changes in platelets, probably induced by P. gingivalis, may affect the development of PD. Several other clinical studies have also demonstrated an association between periodontitis and PD. Even if the risk of periodontal diseases causing neurological disorders needs to be better substantiated, that should not keep us from trying to prevent them by performing careful daily dental hygiene.

Prognostic significance of preoperative plasma fibrinogen levels in primary gastrointestinal stromal tumours: a retrospective cohort study.

BACKGROUND: Improved prediction of prognosis for gastrointestinal stromal tumours (GISTs) has become increasingly important since the introduction of targeted therapy. Here, we aimed to evaluate the prognostic significance of preoperative plasma fibrinogen (Fib) levels in patients with primary GISTs and to analyse their correlations with clinicopathological characteristics. METHODS: A total of 201 previously untreated patients with primary GISTs who had undergone radical surgery at our institution between October 2004 and July 2018 were enrolled. The optimal cut-off value for Fib levels was calculated using time-dependent receiver-operating characteristic curve analysis. RFS, the primary endpoint, was calculated by the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox regression models were calculated. RESULTS: High preoperative plasma Fib levels were detected as an independent adverse prognostic factor (p = 0.008, hazard ratio 3.136, 95% CI 1.356‒7.256). Furthermore, high preoperative plasma Fib levels also indicated a poor prognosis within the modified National Institutes of Health (mNIH) high-risk subgroup (p = 0.041). In addition, preoperative plasma Fib levels showed a positive correlation with several prognostic factors and even a linear relationship with tumour size (Spearman correlation coefficient [r] = 0.411, p < 0.001). CONCLUSIONS: Our results suggest that high preoperative plasma Fib levels may indicate a poor prognosis in patients with primary GISTs. As a cost-effective biomarker, preoperative assessment of plasma Fib levels may help to further risk stratify patients with mNIH high-risk GISTs and instruct the application of targeted therapy.

Hypercoagulation and complement: Connected players in tumor development and metastases.

Hypercoagulation is a common feature of several tumors to the extent that individuals with coagulation defects often present with occult visceral cancers. Recent evidence has shown that hypercoagulation is not just a mere secondary effect due to the presence of the tumor, rather it actively contributes to tumor development and dissemination. Among the numerous mechanisms that can contribute to cancer-associated hypercoagulation, the ones involving immune-mediated processes are gaining increasing attention. In particular, complement cascade and hypercoagulation are one inducing the other in a vicious circle that involves neutrophil extracellular traps (NETs) formation. Together, in this feedback loop, they can promote the protumorigenic phenotype of immune cells and the protection of tumor cells from immune attack, ultimately favouring tumor development, progression and metastases formation. In this review, we summarize the role of these processes in cancer development and highlight new possible intervention strategies based on anticoagulants that can arrest this vicious circle.

Hyperbaric oxygen treatment results in a group of Turkish central retinal artery occlusion patients with a combined presence of thrombophilic mutations.

Background: Central retinal artery occlusion (CRAO) is a rare ocular-ischemic syndrome causing irreversible blindness. Its pathophysiology has not been clarified, and no targeted therapies are available yet. Hyperbaric oxygen (HBO2) therapy is already an approved therapy for CRAO and has been shown to improve the visual acuity of CRAO patients safely. However, further clinical data are required to classify HBO2 therapy as a type-I general agreement for CRAO. Materials and Methods: Eleven patients with non-arteritic CRAO were enrolled. Patient demographics, medical history, detailed eye examinations, HBO2 therapy results, pre-/post HBO2 therapy visual acuity measurements and genotypes for common thrombophilic mutations (Factor V G1691A Leiden, Factor II G20210A, MTHFR A1298C, MTHFR C677T, and PAI-1-675 4G/5G) were obtained. Result: Six patients (54%) responded to HBO2 therapy compared to five non-responders (46%). Patients admitted before 12 hours responded well to HBO2 therapy. No systemic diseases nor advanced age were statistically correlated to CRAO. A combination of mutations rather than single mutations for each patient could be seen as responsible for CRAO. No Factor V G1691A Leiden mutations and only one FII G20210A mutation were observed. Eight patients (72%) had MTHFR 677T allele, five patients (45%) had MTHFR 1298C allele, and 10 patients (91%) had the PAI-1-675 4G allele. Conclusion: Not a single mutation but a combination of mutations and other unknown factors probably lead to CRAO, and if intervention is timely, HBO2 therapy offers improvement in visual acuity safely.