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In neonates admitted to the neonatal intensive care unit (NICU), arterial and venous thromboembolism is a major cause of morbidity and death which could be attributed to multiple risk factors exposure. This study aimed to evaluate the clinical characteristics, laboratory and radiological assessments, predisposing risk factors, and outcomes of thrombosis in neonates admitted to NICU. This prospective cohort study was conducted at NICU, Minia, and Alexandria University Children's Hospital. Screening of 886 patients admitted to NICU over one year with different clinical presentations, patients were classified into the thrombotic and non-thrombotic groups based on the presence or absence of thrombosis. Thrombosis was diagnosed based on clinical, laboratory and different radiologic assessments. Genetic testing for factor V Leiden mutations G1691A, prothrombin mutation G20210A, protein C, protein S, and antithrombin III gene mutations were performed for patients with a family history of thrombosis. Out of a total of 886 neonatal admissions, 36 patients were diagnosed with evident thrombosis (40 per 1000 NICU admissions). The sites of venous thrombosis detection were Portal vein thrombosis in 11 patients (30.6%), superior vena cava thrombosis in 7 patients (19.4%), deep venous thrombosis in 5 patients (13.9%), central venous thrombosis in 5 patients (13.9%), intra-cardiac thrombosis in 3 patients (8.3%) and necrotic skin patches in one patient (2.8%). Only 69% of enrolled thrombosis patients showed genetic mutations the most common of which was factor V Leiden mutation (52.3%). Sepsis, central venous line (CVL) insertion, C reactive protein (CRP), and duration of NICU admission were significantly more common in the thrombotic group (p < 0.001) and were associated with a higher risk of thrombosis (ORs: 1.02, 7.7, and 1.11, respectively) (p < 0.001). Higher mortality occurred in thrombosis neonates compared with a non-thrombotic group (52.8% versus 17.4%) (p < 0.001). NICU-admitted neonates are exposed to multiple overlapped risk factors, the detection of which is important for preventing potential thrombosis and improving the patient's outcomes. The complexity of sepsis pathogenesis and management could potentiate multiple acquired risk factors. inherited thrombophilia detection is required for prevention of further morbidities. [ABSTRACT FROM AUTHOR]

The article announces the winners of the Eberhard F. Mammen Young Investigator Awards, which recognize outstanding presentations or meeting abstracts in the fields of thrombosis and hemostasis. The winners receive a cash prize and are selected by the Senior Editors of Seminars in Thrombosis & Hemostasis. The article also provides a list of previous award winners and their resulting publications. Additionally, the article lists various articles published in the journal Seminars in Thrombosis and Hemostasis, covering topics such as primary immune thrombocytopenia, heparin-induced thrombocytopenia, hemophilia, von Willebrand disease, platelet function, and anticoagulant therapy. The articles offer insights into the causes, diagnosis, and treatment of these conditions. [Extracted from the article]

Although inherited thrombophilias are lifelong risk factors for a first thrombotic episode, progression to thrombosis is multifactorial and not all individuals with inherited thrombophilia develop thrombosis in their lifetimes. Consequently, indiscriminate screening in patients with idiopathic thrombosis is not recommended, since presence of a thrombophilia does not necessarily predict recurrence or influence management, and testing should be selective. It follows that a decision to undertake laboratory detection of thrombophilia should be aligned with a concerted effort to identify any significant abnormalities, because it will inform patient management. Deficiencies of antithrombin and protein C are rare and usually determined using phenotypic assays assessing biological activities, whereas protein S deficiency (also rare) is commonly detected with antigenic assays for the free form of protein S since available activity assays are considered to lack specificity. In each case, no single phenotypic assay is capable of detecting every deficiency, because the various mutations express different molecular characteristics, rendering thrombophilia screening repertoires employing one assay per potential deficiency, of limited effectiveness. Activated protein C resistance (APCR) is more common than discrete deficiencies of antithrombin, protein C, and protein S and also often detected initially with phenotypic assays; however, some centres perform only genetic analysis for factor V Leiden, as this is responsible for most cases of hereditary APCR, accepting that acquired APCR and rare F5 mutations conferring APCR will go undetected if only factor V Leiden is evaluated. All phenotypic assays have interferences and limitations, which must be factored into decisions about if, and when, to test, and be given consideration in the laboratory during assay performance and interpretation. This review looks in detail at performance and limitations of routine phenotypic thrombophilia assays. [ABSTRACT FROM AUTHOR]

The factor V Leiden (FVL) polymorphism is known as the most common inherited risk factor for venous thrombosis. In turn, FVL is the leading cause of an activated protein C resistance (APCR) phenotype, in which the addition of exogenous activated protein C to plasma does not result in the expected anticoagulant effect. In the routine laboratory approach to the formal diagnosis of FVL, an initial positive screening plasma-based method for APCR is often performed, and only if needed, this is followed by a confirmatory DNA-based assay for FVL. Multiple methods with accepted sensitivity and specificity for determining an APCR/FVL phenotype are commonly categorized into two separate groups: (1) screening plasma-based assays, including qualitative functional clot-based assays, for APCR, and (2) confirmatory DNA-based molecular assays, entailing several tests and platforms, including polymerase chain reaction-based and non-PCR-based techniques, for FVL. This review will describe the methodological aspects of each laboratory test and prepare suggestions on the indication of APCR and FVL testing and method selection. [ABSTRACT FROM AUTHOR]

The article in the British Journal of Haematology offers guidelines for healthcare professionals in the UK regarding the measurement of non-coumarin anticoagulants and their effects on laboratory assays. It includes a comprehensive table of licensed anticoagulants, their measurement methods, and potential laboratory tests. The document stresses the importance of monitoring direct oral anticoagulants (DOACs) in specific situations, such as renal impairment or suspected overdose, and discusses the challenges and variability in monitoring unfractionated heparin (UFH) therapy. The text provides detailed information on monitoring various anti-coagulant therapies, highlighting the significance of using specific assays for accurate monitoring and addressing potential adverse events associated with these medications. [Extracted from the article]

This article discusses the need for a dedicated classification system for fetal intraventricular hemorrhage (IVH) and periventricular hemorrhagic venous infarction (PVHI). These conditions are major causes of mortality and morbidity in preterm newborns and can lead to long-term neurodevelopmental issues. The article highlights the differences between fetal and postnatal IVH, the risk factors associated with fetal IVH, and the use of ultrasound and MRI for diagnosis. It also emphasizes the need for further research on the outcomes of fetal IVH and the development of a classification system to improve prenatal counseling and guide treatment decisions. The authors propose a classification system based on fetal neurosonography and MRI that includes various parameters such as location, extent, and laterality of parenchymal involvement, as well as the presence of posterior fossa involvement. They suggest that this classification system could serve as a reliable prognostic tool for accurate parental counseling. The authors also outline a research timeline for the development and evaluation of this classification system. [Extracted from the article]

Objectives To investigate whether circulating endothelial protein C receptor (EPCR) is associated with disease activity and inflammatory markers in rheumatoid arthritis. Methods Thirty-eight RA patients and 21 healthy controls (HC) were recruited via the A3BC biobank. Peripheral blood mononuclear cells and plasma were isolated from the blood of these participants. Plasma soluble (s)EPCR, IL-6, IL-17 and sCD14 were measured by enzyme-linked immunosorbent assay, cell membrane-associated (m)EPCR by flow cytometry; EPCR gene H3 single nucleotide polymorphism (SNP), which contributes to high plasma sEPCR levels, by PCR and DNA sequencing. Data were analysed using FlowJo10 and GraphPad Prism 10. Results RA patients had higher levels of mEPCR on T cells and plasma sEPCR compared with HC. No difference in the EPCR gene H3 SNP G genotype frequency was found between RA and HC. This SNP was significantly correlated with higher sEPCR levels in HC but not in RA patients. In RA, plasma sEPCR levels were positively correlated with IL-6, IL-17, sCD14, anti-CCP and rheumatoid factor. In contrast, mEPCR levels on T cells and natural killer cells (NK) were inversely associated with disease activity measures including 28/66 swollen joint count, 28/68 tender joint count and/or DAS28-CRP/ESR scores, and positively correlated with EPCR gene H3 SNP, which was also correlated with lower disease activity measures in RA. Conclusion Our findings suggest that EPCR may play an important role in RA, with plasma sEPCR being potentially associated with inflammatory markers and mEPCR and the EPCR gene H3 SNP possibly related to disease activity measures. [ABSTRACT FROM AUTHOR]

This article examines the risk factors and prevalence of deep vein thrombosis (DVT) in patients undergoing major surgeries. It highlights the importance of understanding factors such as age, obesity, smoking, malignancy, and medical conditions, which contribute to two-thirds of initial DVT episodes. The study conducted at a government hospital found that 24% of patients developed DVT, with males and older age groups being more prone to it. Risk factors for DVT included higher BMI, smoking, previous chemotherapy or radiotherapy, general anesthesia, and longer surgery duration. Preoperative DVT prophylaxis is crucial for high-risk patients to reduce DVT incidence post-surgery. [Extracted from the article]

Lymphedema occurs as a result of lymphatic vessel damage or obstruction, leading to the lymphatic fluid stasis, which triggers inflammation, tissue fibrosis, and adipose tissue deposition with adipocyte hypertrophy. The treatment of lymphedema is divided into conservative and surgical approaches. Among surgical treatments, methods like lymphaticovenular anastomosis and vascularized lymph node transfer are gaining attention as they focus on restoring lymphatic flow, constituting a physiologic treatment approach. Lymphatic endothelial cells form the structure of lymphatic vessels. These cells possess button-like junctions that facilitate the influx of fluid and leukocytes. Approximately 10% of interstitial fluid is connected to venous return through lymphatic capillaries. Damage to lymphatic vessels leads to lymphatic fluid stasis, resulting in the clinical condition of lymphedema through three mechanisms: Inflammation involving CD4+ T cells as the principal contributing factor, along with the effects of immune cells on the VEGF-C/VEGFR axis, consequently resulting in abnormal lymphangiogenesis; adipocyte hypertrophy and adipose tissue deposition regulated by the interaction of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ; and tissue fibrosis initiated by the overactivity of Th2 cells, leading to the secretion of profibrotic cytokines such as IL-4, IL-13, and the growth factor TGF-β1. Surgical treatments aimed at reconstructing the lymphatic system help facilitate lymphatic fluid drainage, but their effectiveness in treating already damaged lymphatic vessels is limited. Therefore, reviewing the pathophysiology and molecular mechanisms of lymphedema is crucial to complement surgical treatments and explore novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

A 58-year-old woman presented to the emergency department with progressively worsening dyspnea and dysphagia. Her symptoms had begun 22 months earlier when dyspnea on exertion had developed. She had not had an antecedent illness or prolonged period of immobilization. After symptoms had been present for 6 months, the patient saw a pulmonologist. Pulmonary function tests showed reduced diffu- sion capacity for carbon monoxide (26% of the predicted value when adjusted for hemoglobin), as well as reduced total lung capacity, vital capacity, and residual vol- ume (63%, 57°/0, and 74% of the predicted values, respectively). Computed tomo- graphic (CT) angiography of the chest showed extensive acute emboli in both lungs with evidence of right ventricular dilatation (Fig. 1). She was admitted to the hospital, where a transthoracic echocardiogram showed right ventricular dysfunction and an estimated right ventricular systolic pressure of 42 mm Hg (normal, <36 mm Hg). The N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 2522 pg per milli- liter (reference range, <300), and the troponin I level was normal. Right heart cath- eterization and advanced therapies were deferred because her condition remained hemodynamically stable, and she was discharged while receiving apixaban; her dyspnea abated substantially. The presence of lupus anticoagulant was confirmed on repeat testing performed more than 12 weeks later (after she had not taken apixaban for 1 week). Antibodies to β2-glycoprotein land anticardiolipin and factor V Leiden and prothrombin gene mutations were not identified. Levels of protein C and pro- Win S and activity of antithrombin III were normal. She received a diagnosis of antiphospholipid antibody syndrome. Warfarin therapy was offered, but apixaban was continued given her clinically stable condition. [ABSTRACT FROM AUTHOR]

Approximately one-third of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cases were unresponsive to standard first-line therapy; thus, identifying biomarkers to evaluate therapeutic efficacy and assessing the emergence of drug resistance is crucial. Through early-stage screening, long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) was found to be correlated with the R-CHOP treatment response. This study aimed to clarify the characteristics of XIST in ABC-DLBCL. The expression level of XIST in 161 patients with ABC-DLBCL receiving R-CHOP therapy was examined via RNA in situ hybridization, and the association between XIST expression and clinicopathological features, treatment response and prognosis was analyzed in the study cohort and validated in the Gene Expression Omnibus cohort. Cell biological experiments and bioinformatics analyses were conducted to reveal aberrant signaling. The proportion of complete response in patients with high XIST expression was lower than that in patients with low XIST expression (53.8% versus 77.1%) (P  = 0.002). High XIST expression was remarkably associated with the characteristics of tumor progression and was an independent prognostic element for overall survival (P  = 0.039) and progression-free survival (P  = 0.027) in ABC-DLBCL. XIST was proven to be involved in m6A-related methylation and ATF6-associated autophagy. XIST knockdown repressed ABC-DLBCL cellular proliferation by regulating Raf/MEK/ERK signaling. High XIST expression was associated with ABC-DLBCL tumorigenesis and development and contributed to R-CHOP treatment resistance. XIST may be a promising signal to predict ABC-DLBCL prognosis. [ABSTRACT FROM AUTHOR]

Background and purpose: Cerebral sinus venous thrombosis (CSVT) is a rare but life-threatening disease and its diagnosis remains challenging. Blood biomarkers, including D-Dimer are currently not recommended in guidelines. Soluble endothelial receptor proteins (sICAM-1, sPECAM-1 and sVCAM-1) have been shown to be promising diagnostic biomarkers in deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, we examined endothelial receptor proteins as potential biomarkers for detecting CSVT. Methods: In this bi-centre, prospective study, we quantified D-Dimer as well as sICAM-1, sPECAM-1 and sVCAM-1 in plasma of patients with clinically suspected CSVT managed in the neurological emergency department (ED) of a tertiary care hospital. All patients underwent cerebral magnetic resonance imaging (MRI) and were followed up after 3, 6 and 12 months to detect thrombus resolution. Results: Twenty-four out of 75 (32%) patients with clinically suspected CSVT presenting with headache to the ED were diagnosed with acute CSVT. These patients had a mean age of 45 ± 16 years and 78% were female. In patients with CSVT, mean baseline D-dimer (p < 0.001) and sPECAM-1 (p < 0.001) were significantly higher compared to patients without CSVT. The combination of D-Dimer and sPECAM-1 yielded the best ROC-AUC (0.994; < 0.001) with a negative predictive value of 95.7% and a positive predictive value of 95.5%. In addition, higher baseline sPECAM-1 levels (> 198 ng/ml) on admission were associated with delayed venous thrombus resolution at 3 months (AUC = 0.83). Conclusion: sPECAM-1 in combination with D-Dimer should be used to improve the diagnostic accuracy of acute CSVT and sPECAM-1 may predict long-term outcome of CSVT. Confirmatory results are needed in other settings in order to show their value in the management concept of CSVT patients. [ABSTRACT FROM AUTHOR]

This article is a special issue of Seminars in Thrombosis and Hemostasis (STH) celebrating the journal's 50th anniversary. It focuses on the development of a coagulation disorders unit in Helsinki, Finland, and includes discussions on the management of hemophilia A, prophylactic treatment of hemophilia in children in Sweden, and the management of von Willebrand disease. The articles highlight advancements in technology and treatment options, but also acknowledge the challenges of access to these therapies in developing countries. Additionally, the article provides a historical review of various topics related to hemostasis and thrombosis, including tranexamic acid, diagnostics for venous thromboembolism, fibrin clots, limb ischemic necrosis, and fibrinolytic agents in thromboembolic diseases. It concludes with a letter discussing cancer-associated thrombosis from the 19th century. [Extracted from the article]

Acute respiratory distress syndrome (ARDS) is a severe form of acute respiratory failure characterised by extensive inflammatory injury to the alveolocapillary barrier leading to alveolar oedema, impaired gas exchange and, ultimately, hypoxaemia necessitating the use of supplemental oxygen combined with some degree of positive airway pressure. Although much heterogeneity exists regarding the aetiology, localisation and endotypic characterisation of ARDS, what remains largely undisputed is the role of the innate immune system, and in particular of neutrophils, in precipitating and propagating lung injury. Activated neutrophils, recruited to the lung through chemokine gradients, promote injury by releasing oxidants, proteases and neutrophil extracellular traps, which ultimately cause platelet aggregation, microvascular thrombosis and cellular death. Among various neutrophilic chemoattractants, interleukin-8/ C-X-C motif ligand 8 and related chemokines, collectively called ELR+ chemokines, acting on neutrophils through the G protein-coupled receptors CXCR1 and CXCR2, are pivotal in orchestrating the neutrophil activation status and chemotaxis in the inflamed lung. This allows efficient elimination of infectious agents while at the same time minimising collateral damage to host tissue. Therefore, understanding how CXCR1 and CXCR2 receptors are regulated is important if we hope to effectively target them for therapeutic use in ARDS. In the following narrative review, we provide an overview of the role of ELR+ chemokines in acute lung injury (ALI) and ARDS, we summarise the relevant regulatory pathways of their cognisant receptors CXCR1/2 and highlight current preclinical and clinical evidence on the therapeutic role of CXCR1 and CXCR2 inhibition in animal models of ALI, as well as in ARDS patients. [ABSTRACT FROM AUTHOR]

The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma (LUAD), and chemoresistance, however, usually results in treatment failure and limits its application in the clinic. It has been shown that microRNAs (miRNAs) play a significant role in tumor chemoresistance. In this study, miR-125b was identified as a specific cisplatin (DDP)-resistant gene in LUAD, as indicated by the bioinformatics analysis and the real-time quantitative PCR assay. The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time. MiR-125b decreased the A549/ DDP proliferation, and the multiple drug resistance- and autophagy-related protein expression levels, which were all reversed by the inhibition of miR-125b. In addition, xenografts of human tumors in nude mice were suppressed by miR-125b, demonstrating that through autophagy regulation, miR-125b could reverse the DDP resistance in LUAD cells, both in vitro and in vivo. Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L, which in turn inhibited autophagy and reversed chemoresistance. Based on these findings, miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD. [ABSTRACT FROM AUTHOR]

Background: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results: In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Cancer cells induce hypercoagulability in the tumoral microenvironment by expressing Tissue Factor (TF). We aimed to study the impact of the procoagulant signature of cancer cells on the quality and structure of fibrin network. We also studied the impact of fibrin clot shield (FCS) on the efficiency of anticancer agents and the migration of cancer cells. Pancreatic cancer cells BXPC3 and breast cancer cells MDA-MB231 and MCF7, were cultured in the presence of normal Platelet Poor Plasma (PPP), diluted 10 % in conditioning media. Their potential to induce thrombin generation and their fibrinolytic activity were assessed. The structure of fibrin network was analyzed with Scanning Electron Microscopy (SEM). Cancer cells' mobility with fibrin clot and their interactions with fibrin were observed. Cancer cells were treated with paclitaxel (PTX) or 4-hydroxy-tamoxifen (4OHTam) in the presence or absence of FCS. Cancer cells, in presence of PPP, induced fibrin network formation. High TF-expressing cancer cells (BXPC3 and MDA-MB23 cells), led to dense fibrin network with fine fibers. Low TF expressing cells MCF7 led to thick fibers. Exogenous TF enhanced the density of fibrin network formed by MCF7 cells. Cancer cells through their inherent profibrinolytic potential migrated within the fiber scaffold. The BXPC3 and MCF7 cells moved in clusters whereas the MDA-MB231 cells moved individually within the fibrin network. FCS decreased the efficiency of PTX and 4OHTam on the viability of cancer cells. The procoagulant signature of cancer cells is determinant for the quality and structure of fibrin network in the microenvironment. Original SEM images show the architecture of "bird's nest"-like fibrin network being in touch with the cell membranes and surrounding cancer cells. Fibrin network constructed by triggering thrombin generation by cancer cells, provides a scaffold for cell migration. Fibrin clot shields protect cancer cells against PTX and 4OHTam. • Cancer cells induce fibrin clot shields (FCS) formation in the microenvironment. • TF expressed by cancer cells determines the quality and structure of FCS. • FCS originates from the cell membrane and as a "bird's nest" envelop cancer cells. • FCS decreases the efficiency of the anticancer agents. • FCS offers a scaffold for the migration of cancer cells. [ABSTRACT FROM AUTHOR]

Microscopy imaging has enabled us to establish the presence of fibrin(ogen) amyloid (fibrinaloid) microclots in a range of chronic, inflammatory diseases. Microclots may also be induced by a variety of purified substances, often at very low concentrations. These molecules include bacterial inflammagens, serum amyloid A, and the S1 spike protein of severe acute respiratory syndrome coronavirus 2. Here, we explore which of the properties of these microclots might be used to contribute to differential clinical diagnoses and prognoses of the various diseases with which they may be associated. Such properties include distributions in their size and number before and after the addition of exogenous thrombin, their spectral properties, the diameter of the fibers of which they are made, their resistance to proteolysis by various proteases, their cross-seeding ability, and the concentration dependence of their ability to bind small molecules including fluorogenic amyloid stains. Measuring these microclot parameters, together with microscopy imaging itself, along with methodologies like proteomics and imaging flow cytometry, as well as more conventional assays such as those for cytokines, might open up the possibility of a much finer use of these microclot properties in generative methods for a future where personalized medicine will be standard procedures in all clotting pathology disease diagnoses. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. Methods: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. Results: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). Conclusion: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy (DAPT) is standard treatment for endoluminal stent insertion, and complete resistance to DAPT is rare. A case of in-stent thrombosis occurring 3 hours after stent-assisted coiling of internal carotid artery aneurysm is presented despite compliance with DAPT. Platelet function tests (PFTs) revealed complete clopidogrel and prasugrel resistance. [ABSTRACT FROM AUTHOR]

Background: The Y-box-binding proteins (YBX) act as a multifunctional role in tumor progression, metastasis, drug resistance by regulating the transcription and translation process. Nevertheless, their functions in a pan-cancer setting remain unclear. Methods: This study examined the clinical features expression, prognostic value, mutations, along with methylation patterns of three genes from the YBX family (YBX1, YBX2, and YBX3) in 28 different types of cancer. Data used for analysis were obtained from Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. A novel YBXs score was created using the ssGSEA algorithm for the single sample gene set enrichment analysis. Additionally, we explored the YBXs score's association with the tumor microenvironment (TME), response to various treatments, and drug resistance. Results: Our analysis revealed that YBX family genes contribute to tumor progression and are indicative of prognosis in diverse cancer types. We determined that the YBXs score correlates significantly with numerous malignant pathways in pan-cancer. Moreover, this score is also linked with multiple immune-related characteristics. The YBXs score proved to be an effective predictor for the efficacy of a range of treatments in various cancers, particularly immunotherapy. To summarize, the involvement of YBX family genes is vital in pan-cancer and exhibits a significant association with TME. An elevated YBXs score indicates an immune-activated TME and responsiveness to diverse therapies, highlighting its potential as a biomarker in individuals with tumors. Finally, experimental validations were conducted to explore that YBX2 might be a potential biomarker in liver cancer. Conclusion: The creation of YBXs score in our study offered new insights into further studies. Besides, YBX2 was found as a potential therapeutic target, significantly contributing to the improvement of HCC diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: Cuproptosis, programmed cell death by intracellular copper-mediated lipoylated protein aggregation, is involved in various tumorigenesis and drug resistance abilities by mediating the tumor microenvironment. Previous studies have demonstrated that serum copper levels are higher in OC patients than in normal subjects. However, the exact relationship between cuproptosis and ovarian cancer progression remains to be further elucidated. Methods: The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) datasets were utilized to establish a cuproptosis-related prognostic signature in ovarian cancer. Subsequently, the bulk RNA-seq analysis and single-cell RNA-seq analysis were used to identify the relationship between signature with immune cell infiltration, chemotherapy, and cuproptosis-related scoring (CuRS) system. Finally, the potential biological functional roles of target genes in cuproptosis were validated in vitro. Results: By using LASSO-Cox regression analysis to establish the cuproptosis-related prognostic model, our works demonstrated the accuracy and efficiency of our model in the TCGA (583 OC patients) and GEO (260 OC patients) OC cohorts, and the high-scoring groups showed worse survival outcomes. Notably, there were substantial differences between the high and low-risk groups in extensive respects, such as the activating transcription factors, cell pseudotime features, cell intercommunication patterns, immunocytes infiltration, chemotherapy response, and potential drug resistance. KIF26B was selected to construct a prognostic model from the identified 33 prognosis-related genes, and high expression of KIF26B predicted poorer prognosis in ovarian cancer. Ultimately, further in vitro experiments demonstrated that KIF26B participated in the proliferation and cisplatin resistance of OC cells. Knockdown of KIF26B increased the sensitivity of OC cells to elesclomol, a cuproptosis agonists. Conclusion: This study constructed a new cuproptosis-related gene signature that has a good prognostic capacity in assessing the outcome of OC patients. This study enhances our understanding of cuproptosis associated with ovarian cancer aggressiveness, cross-talk with immunocytes, and serves as a novel chemotherapy strategy. [ABSTRACT FROM AUTHOR]

Endothelial Protein C Receptor (EPCR) is a key regulator of the activated protein C anti-coagulation pathway due to its role in the binding and activation of this protein. EPCR also binds to other ligands such as Factor VII and X, γδ T-cells, plasmodium falciparum erythrocyte membrane protein 1, and Secretory group V Phospholipases A2, facilitating ligand-specific functions. The functions of EPCR can also be regulated by soluble (s)EPCR that competes for the binding sites of membrane-bound (m)EPCR. sEPCR is created when mEPCR is shed from the cell surface. The propensity of shedding alters depending on the genetic haplotype of the EPCR gene that an individual may possess. EPCR plays an active role in normal homeostasis, anti-coagulation pathways, inflammation, and cell stemness. Due to these properties, EPCR is considered a potential effector/mediator of inflammatory diseases. Rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus are autoimmune/inflammatory conditions that are associated with elevated EPCR levels and disease activity, potentially driven by EPCR. This review highlights the functions of EPCR and its contribution to rheumatic diseases. [ABSTRACT FROM AUTHOR]

Background: Despite pregnancy's hypercoagulable state, the correlation between inherited thrombophilia and thrombotic adverse pregnancy outcomes remains uncertain. The objective of this study was to determine the prevalence of inherited thrombophilic polymorphisms among asymptomatic pregnant individuals and to examine their potential correlation with adverse perinatal outcomes. Methods: in this single-center prospective study, 105 healthy pregnant women were included. Genotyping was conducted for factor V Leiden (FVL), prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and plasminogen activator inhibitor-1 (PAI-1), alongside the assessment of protein C (PC), protein S (PS), and antithrombin (AT) levels. The study analyzed the association between inherited thrombophilic polymorphisms and pregnancy complications linked to placental insufficiency, such as gestational hypertension (GH), preeclampsia (PE), intrauterine death (IUD), fetal growth restriction (FGR), and placental abruption. Results: The prevalence of identifiable thrombophilic polymorphism mutations was 61.9% (95% confidence interval—CI 52.4–70.8%), with the most common single mutation being PAI-1 4G/5G (12/105, 11.4%, 95% CI 6.4–18.5). The most frequent combined mutation was heterozygosity for MTHFR C677T and PAI-1 (12/105, 11.4%, 95% CI 6.4–18.5). Notably, no FVL homozygous carriers or single homozygous and heterozygous carriers for prothrombin polymorphisms were found. Additionally, no deficiencies in PC and AT were detected among participants. Except for homozygosity for PAI-1, none of the studied polymorphisms demonstrated a significant association with pregnancy complications linked to placental insufficiency. Conclusions: The asymptomatic carriers of inherited thrombophilic polymorphisms do not have an increased risk of adverse perinatal outcomes. [ABSTRACT FROM AUTHOR]

Estetrol (E4) represents a novel estrogen of interest to relieve vasomotor symptoms. E4 activates the nuclear estrogen receptor α (ERα) but antagonizes the estradiol ERα-dependent membrane-initiated steroid signaling pathway. The distinct pharmacological properties of E4 could explain its low impact on hemostasis. This study aimed to assess the effect of E4 on coagulation in postmenopausal women, using the thrombin generation assay (TGA). Data were collected from a multicenter, randomized, placebo-controlled, dose-finding study in postmenopausal women (NCT02834312). Oral E4 (2.5 mg, n = 42; 5 mg, n = 29; 10 mg, n = 34; or 15 mg, n = 32) or placebo (n = 31) was administered daily for 12 weeks. Thrombograms and TGA parameters were extracted for each subject at baseline and after 12 weeks of treatment. After 12 weeks of treatment, all treatment groups showed a mean thrombogram (±95% confidence interval [CI] of the mean) within the reference ranges, that is, the 2.5th–97.5th percentile of all baseline thrombograms (n = 168), as well as for TGA parameters. The intake of E4 15 mg for 12 weeks led to significant but not clinically relevant changes compared to baseline as the mean values (±95% CI of the mean) remained within reference ranges, demonstrating a neutral profile of this estrogen on hemostasis. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome. [ABSTRACT FROM AUTHOR]

Underlying mechanisms for bleeding and impaired thrombin generation (TG) and plasma clot formation (PCF) in patients with mild to moderate bleeding disorders (MBDs) are still to be elucidated, especially in bleeding disorder of unknown cause (BDUC). The role of the natural anticoagulants activated protein C (APC) and free protein S (PS) has not yet been investigated in this patient population. To analyze antigen levels of APC and PS in patients with MBDs and BDUC and investigate associations to clinical bleeding phenotype and severity as well as and hemostatic capacity. Antigen levels of APC and free PS were measured in 262 patients from the Vienna Bleeding Biobank (VIBB), a single-center cohort study, by ELISA and compared to 61 healthy controls (HC). Antigen levels of APC were higher in MBD patients than in HC when adjusted for age, sex and BMI (median (IQR) 33.1 (20.6–52.6) and 28.6 (16.4–47.2) ng/mL). This was most pronounced in patients with BDUC (35.3 (21.7–54.3) ng/mL). No differences in PS antigen levels between patients and HC were seen overall, or according to specific diagnoses. Further, no association between APC or PS and bleeding severity or global tests of hemostasis or TG were identified, while paradoxically APC weakly correlated with shorter lag time and time to peak of PCF in BDUC. Our data demonstrate increased antigen levels of APC in BDUC, which might contribute to the bleeding tendency in some patients and could be a future therapeutic target in BDUC. [Display omitted] • Influence of APC and protein S on hemostatic capacity in BDUC patients is unclear. • APC antigen levels were higher in BDUC patients than in healthy controls. • No association between APC/protein S and bleeding severity was identified. • APC might contribute to hemostatic impairment and could be a therapeutic target. [ABSTRACT FROM AUTHOR]

This article discusses the rare condition of spontaneous pampiniform venous plexus (PVP) thrombosis, which can cause chronic scrotal pain. PVP thrombosis is a rare condition, with less than 30 reported cases to date. The most common symptom is acute scrotal pain, but it is often misdiagnosed due to its rarity. The article presents a case study of a 19-year-old male with PVP thrombosis and discusses the management and treatment options for this condition. It emphasizes the importance of ruling out underlying coagulopathies and considering mental health evaluations for patients with persistent pain. [Extracted from the article]

Hemophilia patients have a deficiency in or dysfunction of clotting factors, which can lead to a bleeding tendency. However, paradoxically, some hemophilia patients may also be at an increased risk of developing thrombotic events such as deep vein thrombosis or pulmonary embolism. The pathophysiology of thrombosis in hemophilia patients is not fully understood, but it is thought to involve a complex interplay of various factors, including the severity of the hemophilia, the presence of other risk factors such as obesity, smoking, or the use of hormonal therapies, and the presence of certain genetic mutations that increase the risk of thrombosis. In addition, it has been suggested that the use of clotting factor replacement therapy, which is a standard treatment for hemophilia, may also contribute to the development of thrombosis in some cases. [ABSTRACT FROM AUTHOR]

Macrophages constitute a major part of tumor microenvironment, and most of existing data demonstrate their ruling role in the development of anti-drug resistance of cancer cell. One of the most powerful protection system is based on heat shock proteins whose synthesis is triggered by activated Heat Shock Factor-1 (HSF1); the inhibition of the HSF1 with CL-43 sensitized A549 lung cancer cells to the anti-cancer effect of etoposide. Notably, analyzing A549 tumor xenografts in mice we observed nest-like pattern of co-localization of A549 cells demonstrating enhanced expression of HSF1 with macrophages, and decided to check whether the above arrangement has a functional value for both cell types. It was found that the incubation of A549 or DLD1 colon cancer cells with either human monocytes or THP1 monocyte-like cells activated HSF1 and increased resistance to etoposide. Importantly, the same effect was shown when primary cultures of colon tumors were incubated with THP1 cells or with human monocytes. To prove that HSF1 is implicated in enhanced resistance caused by monocytic cells, we generated an A549 cell subline devoid of HSF1 which did not respond to incubation with THP1 cells. The pharmacological inhibition of HSF1 with CL-43 also abolished the effect of THP1 cells on primary tumor cells, highlighting a new target of tumor-associated macrophages in a cell proteostasis mechanism. [ABSTRACT FROM AUTHOR]

Currently, limited information is available in the literature regarding the relationships between PROC mutations and clinical features in Chinese individuals. We aimed to characterize severe congenital Protein C deficiency in 22 unrelated Chinese families in a tertiary hospital by analyzing its clinical manifestation, associated risk factors, and gene mutations. We measured protein C activity and antigen levels for all participants, screened them for mutations in the PROC gene, and analyzed the clinical features of each family to identify commonalities and differences. The analysis revealed a total of 75 individuals with PCD and 16 different PROC mutations, including 12 missense mutations and 4 deletion mutations. Among them, 11 who were compound heterozygotes or homozygotes for mutations tended to develop symptoms at a younger age without any clear triggers. In contrast, the remaining 64 individuals who were heterozygotes for mutations often had clear triggers for their symptoms and experienced a milder course of the disease. It is worth noting that the mutation c.565C > T occurred most frequently, being identified in 8 out of 22 families (36%). Our team also reported five novel mutations, including c.742-744delAAG, c.383G > A, c.997G > A, c.1318C > T, and c.833T > C mutations. The identification of five novel mutations adds to the richness of the Human Genome Database. Asymptomatic heterozygotes are not uncommon, and they are prone to develop symptoms with obvious triggers. The evidence presented strongly suggest that asymptomatic individuals with family history of protein C deficiency can benefit from mutational analysis of PROC gene. [ABSTRACT FROM AUTHOR]

Background: t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30–50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive. Methods: Chromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO. Results: Here we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells. Conclusion: Our work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C. [ABSTRACT FROM AUTHOR]

EGFR tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutated non-small cell lung carcinoma (NSCLC); however, therapeutic resistance remains a clinical challenge. Acquired secondary EGFR mutations that increase ATP affinity and/or impair inhibitor binding are well-described mediators of resistance. Here we identify a de novo EGFR Y891D secondary alteration in a NSCLC with EGFR L858R. Acquired EGFR Y891D alterations were previously reported in association with resistance to first generation EGFR TKIs. Functional studies in Ba/F3 cells demonstrate reduced TKI sensitivity of EGFR L858R + Y891D, with the greatest reduction observed for first and second generation TKIs. Unlike other EGFR mutations associated with TKI resistance, Y891D does not significantly alter ATP affinity or promote steric hindrance to inhibitor binding. Our data suggest that the Y891D mutation destabilizes EGFR L858R, potentially generating a population of misfolded receptor with preserved signaling capacity but reduced sensitivity to EGFR inhibitors. These findings raise the possibility of protein misfolding as a mechanism of resistance to EGFR inhibition in EGFR-mutated NSCLC. [ABSTRACT FROM AUTHOR]

Background: Although the exact origin of portal vein thrombosis (PVT) is unknown, many studies have linked it to systemic factors like protein C, protein S as well as antithrombin III deficiencies. Other studies have linked it to the elevation of D-dimer and international normalized ratio (INR). Aim: To evaluate the role of serum protein C, D-dimer and INR as predictors of portal vein thrombosis among cirrhotic patients without hepatocellular carcinoma (HCC). Patients and Methods: This cross-sectional study was conducted on 60 cirrhotic patients, 30 cirrhotic patients without PVT (Group I) and 30 cirrhotic patients with PVT (Group II), who were collected from patients who attended at the outpatient clinic and inpatient of The Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, University of Benha. Levels of protein C, D dimer and INR were assessed among all participants. Results: This present study showed that protein C level was lower in group II than in group I. In contrast D-dimer and INR levels were higher in group II than in group I. Positive correlation was found between D-dimer, INR, alanine transaminase (ALT), aspartate transaminase (AST), serum creatinine and total bilirubin with severity of liver disease (Child score) especially with cirrhotic patients with PVT. Negative correlation was found between protein C, platelets and serum albumin with severity of liver disease (Child score) especially with cirrhotic patients with PVT. Conclusion: Decreased protein C, increased D-dimer and increased INR were considered risk factors for formation of PVT among cases with liver cirrhosis. So, it is important to conduct specific imaging techniques in order to confirm the diagnosis and start treatment early. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a severe, long‐term condition characterised by disruptions in glucolipid and energy metabolism. Autophagy, a fundamental cellular process, serves as a guardian of cellular health by recycling and renewing cellular components. To gain a comprehensive understanding of the vital role that autophagy plays in T2DM, we conducted an extensive search for high‐quality publications across databases such as Web of Science, PubMed, Google Scholar, and SciFinder and used keywords like 'autophagy', 'insulin resistance', and 'type 2 diabetes mellitus', both individually and in combinations. A large body of evidence underscores the significance of activating autophagy in alleviating T2DM symptoms. An enhanced autophagic activity, either by activating the adenosine monophosphate‐activated protein kinase and sirtuin‐1 signalling pathways or inhibiting the mechanistic target of rapamycin complex 1 signalling pathway, can effectively improve insulin resistance and balance glucolipid metabolism in key tissues like the hypothalamus, skeletal muscle, liver, and adipose tissue. Furthermore, autophagy can increase β‐cell mass and functionality in the pancreas. This review provides a narrative summary of autophagy regulation with an emphasis on the intricate connection between autophagy and T2DM symptoms. It also discusses the therapeutic potentials of natural products with autophagy activation properties for the treatment of T2DM conditions. Our findings suggest that autophagy activation represents an innovative approach of treating T2DM. [ABSTRACT FROM AUTHOR]

Airway epithelial cell injury plays a crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, a novel form of Cu‐induced programmed cell death known as cuproptosis has not yet been thoroughly investigated in the context of COPD. Clinical reports have suggested that high copper exposure may increase the risk of COPD. In this study, we aimed to determine the expression and potential functions of cuproptosis‐related genes and genes associated with copper metabolism in COPD. We initially identified 52 copper metabolism‐related genes based on a review of the literature. Subsequently, we calculated the expression levels of these genes using data from four GEO datasets. To gain insights into the activated signalling pathways and underlying mechanisms in COPD patients, we conducted Gene Ontology (GO) and KEGG pathway analyses, examined protein–protein interactions, and performed weighted correlation network analysis. Our findings revealed that 18 key copper metabolism‐related genes, including 5 cuproptosis‐related genes, were significantly enriched in signalling pathways and biological processes associated with the development of COPD. Further analysis of clinical data and animal experiments confirmed the high expression of certain cuproptosis key regulators, such as DLD and CDKN2A, in both healthy smokers and COPD smokers. Additionally, these regulators exhibited abnormal expression in a COPD rat model. Notably, copper content was found to be elevated in the lung tissues of COPD rats, suggesting its potential involvement in cuproptosis. These findings provide an experimental foundation for further research into the role of cuproptosis in COPD. Targeting copper metabolism‐related genes may represent an effective approach for the treatment of COPD. [ABSTRACT FROM AUTHOR]

Adult glioma progresses rapidly and has a poor clinical outcome. The focal adhesion protein Kindlin-3 (encoded by the FERMT3 gene) participates in tumor development, drug resistance, and progression. However, the relationship between Kindlin-3 and glioma prognosis or immune microenvironment is poorly understood. We comprehensively analyzed the expression, prognostic value, mutation landscape, functional enrichment, immune infiltration, and therapeutic role of FERMT3 in glioma using multiple datasets and validated Kindlin-3 expression in clinical tissue specimens by immunohistochemistry and multiple immunofluorescence staining. FERMT3 is an independent predictor of glioma prognosis and is highly expressed in glioblastoma tissues. Functional enrichment analyses indicated that FERMT3 participates in multiple immune-related pathways such as immune response and cytokine production. Furthermore, FERMT3 expression was positively correlated with the infiltration of several immune cells, immune scores, and the expression of genes related to immune checkpoints. Further analyses revealed that overexpression of FERMT3 was linked to a better response to anti-PD1 therapy. Data from single-cell RNA-seq reveal that FERMT3 was largely expressed in microglial cells and tissue-resident macrophages. Multiple immunofluorescence staining confirmed the overexpression of Kindlin-3 in the glioma-associated microglia/macrophages (GAMs). The findings of this study provide a new perspective on the role of Kindlin-3 in glioma and may have a significant impact on the discovery of novel biomarkers and targeting of GAMs in the future. [ABSTRACT FROM AUTHOR]

Background: Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism. Methods: MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage. Results: Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group. Conclusion: Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Hepatic encephalopathy (HE) symptoms associated with liver insufficiency are linked to the neurotoxic effects of ammonia and other toxic metabolites reaching the brain via the blood–brain barrier (BBB), further aggravated by the inflammatory response. Cumulative evidence documents that the non-coding single-stranded RNAs, micro RNAs (miRs) control the BBB functioning. However, miRs' involvement in BBB breakdown in HE is still underexplored. Here, we hypothesized that in rats with acute liver failure (ALF) or rats subjected to hyperammonemia, altered circulating miRs affect BBB composing proteins. Methods: Transmission electron microscopy was employed to delineate structural alterations of the BBB in rats with ALF (thioacetamide (TAA) intraperitoneal (ip.) administration) or hyperammonemia (ammonium acetate (OA) ip. administration). The BBB permeability was determined with Evans blue dye and sodium fluorescein assay. Plasma MiRs were profiled by Next Generation Sequencing (NGS), followed by in silico analysis. Selected miRs, verified by qRT-PCR, were examined in cultured rat brain endothelial cells. Targeted protein alterations were elucidated with immunofluorescence, western blotting, and, after selected miR mimics transfection, through an in vitro resistance measurement. Results: Changes in BBB structure and increased permeability were observed in the prefrontal cortex of TAA rats but not in the brains of OA rats. The NGS results revealed divergently changed miRNA-ome in the plasma of both rat models. The in silico analysis led to the selection of miR-122-5p and miR-183-5p with their target genes occludin and integrin β1, respectively, as potential contributors to BBB alterations. Both proteins were reduced in isolated brain vessels and cortical homogenates in TAA rats. We documented in cultured primary brain endothelial cells that ammonia alone and, in combination with TNFα increases the relative expression of NGS-selected miRs with a less pronounced effect of TNFα when added alone. The in vitro study also confirmed miR-122-5p-dependent decrease in occludin and miR-183-5p-related reduction in integrin β1 expression. Conclusion: This work identified, to our knowledge for the first time, potential functional links between alterations in miRs residing in brain endothelium and BBB dysfunction in ALF. [ABSTRACT FROM AUTHOR]

A 43-year-old woman with a recent history of confirmed hepatitis B presented with yellow sclera and dyspnea. Clinically, she had tachycardia and tachypnea as well as signs of jaundice and right upper quadrant pain. She was in sinus rhythm with a normal aspect of cardiac examination. She was treated with corticosteroids and her symptoms were partially relieved, however, her mild fever remained unchanged and a transthoracic echocardiogram (TTE) and transesophageal echocardiography (TEE) were done to rule out embolic or in situ infective endocarditis. Images from the TEE and TTE showed a ping-pong-like clot in the left atrium with a normal cardiac function and a normal mitral valve function. The mitral leaflets appeared to be normal with no regurgitation, and no clot was noted in other chambers or valves, including the atrial appendages. A differential diagnosis of infective vegetations, clots, or tumors was considered. The three subsequent blood cultures were negative. A complete thrombophilia assay revealed a severe reduced protein C factor, however, the IgG anti cardiolipin and lupus anticoagulant were normal. The woman's anti-nuclear antibody and anti-double-stranded DNA were negative, confirming the diagnosis of acquired protein C deficiency. The patient underwent an open surgical removal of the clot and postoperative treatment with steroids, warfarin, and heparin. The postoperative course was uneventful, and the patient was discharged on the 13th day of operation in good condition. This case was interesting because we did not find any mitral valve pathology such as mitral stenosis, or arrhythmia like atrial fibrillation. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the most common malignant and aggressive hematologic tumors, and risk stratification is indispensable to ensure proper treatment. But immune-related long noncoding RNAs (ir-lncRNAs) pairs prognostic risk models used to stratify AML have yet to be reported. In this study, we established a prognostic risk model based on eight ir-lncRNAs pairs using LASSO-penalized Cox regression analysis and successfully validated the model in an independent cohort. According to risk scores, patients were divided into a high-risk group and a low-risk group. High-risk patients presented more tumor mutation frequency and higher expression of human leukocyte antigen (HLA)-related genes and immune checkpoint molecules. Gene Set Enrichment Analysis (GSEA) indicated that the transforming growth factors β (TGFβ) pathway was activated in the high-risk group; meanwhile, we found that TGFβ1 mRNA levels were significantly elevated in AML patients and correlated with poor prognosis, which is closely related to drug resistance. Consistently, in vitro studies found that exogenous TGFβ1 can protect AML cells from chemotherapy-induced apoptosis. Collectively, we developed an ir-lncRNA prognostic model that helps predict the prognosis of AML patients and provides valuable information about their response to immune checkpoint inhibitors, and we found that increased TGFβ1 levels resulting in chemoresistance may be one of the leading causes of treatment failure in high-risk AML patients. [ABSTRACT FROM AUTHOR]

Neuropilin 1 (NRP1) is a single-channel transmembrane glycoprotein whose role and mechanism in renal fibrosis remain incompletely elucidated. Therefore, we investigated the effect of NRP1 on renal fibrosis and its potential mechanism. NRP1 expression in the renal sections from patients with chronic kidney disease (CKD) and a unilateral ureteral obstruction (UUO) mouse model was detected. Nrp1 overexpression or knockdown plasmid was transfected into mice, TKPTS mouse kidney proximal tubular epithelial cells (TECs), and rat kidney fibroblasts, after which pathological injury evaluation and fibrosis marker detection were conducted. The direct interaction of the receptor of activated protein C kinase 1 (RACK1) with NRP1 was validated by immunoprecipitation and Western blot analysis. We found that the upregulated renal NRP1 expression in patients with CKD was located in proximal TECs, consistent with the degree of interstitial fibrosis. In the UUO mouse model, NRP1 expression was upregulated in the kidney, and overexpression of Nrp1 increased the mRNA and protein expression of fibronectin (Fn) and α-smooth muscle actin (α-SMA), whereas Nrp1 knockdown significantly reduced Fn and α-SMA expression and downregulated the inflammatory response. NRP1 promoted transforming growth factor β1 (TGF-β1)-induced profibrotic responses in the TKPTS cells and fibroblasts, and Nrp1 knockdown partially reversed these responses. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry verified that NRP1 can directly bind to RACK1, and Rack1 knockdown reversed the NRP1-induced fibrotic response. In summary, NRP1 may enhance the TGF-β1 pathway by binding to RACK1, thus promoting renal fibrosis. NEW & NOTEWORTHY Although a few studies have confirmed the correlation between neuropilin 1 (NRP1) and renal diseases, the mechanism of NRP1 in renal fibrosis remains unclear. Here, we investigated the effects of NRP1 on renal fibrosis through in vitro and in vivo experiments and explored the possible downstream mechanisms. We found that NRP1 can stimulate the TGF-β1 signaling pathway, possibly by binding to RACK1, thereby promoting renal fibrosis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Purpura fulminans is a severe coagulation disorder that often leads to death in neonates. Mutations in the protein C (PROC) gene can cause protein C deficiency, leading to this disorder. This study aimed to investigate a family with a history of coagulopathies, particularly those related to protein C deficiency. The primary objective was to identify any genetic mutations in the PROC gene responsible for the coagulopathies. The study focused on a male neonate with purpura fulminans who ultimately died at 2 months of age. The patient had low protein C activity levels (6%). The entire PROC gene of the patient and his family was analyzed using next‐generation sequencing to identify any genetic mutations. Segregation analysis was conducted to determine if the mutation followed an autosomal dominant inheritance pattern. In silico analysis was also conducted to evaluate the pathogenicity of the identified mutation. Analysis revealed a novel homozygous c.1243T>G variant PROC gene. The mutation resulted in a Phe415Val substitution. The mutation was found in at least three generations of the family. Carrier family members had lower protein C activity levels than wild‐type homozygotes. Additionally, the mutation may account for the observed reduction in protein C enzyme activity. [ABSTRACT FROM AUTHOR]

Long-term humoral immunity is mediated by short-lived plasma cells (replenished by memory B cells) and long-lived plasma cells. Their relative contributions are uncertain for immunity to SARS-CoV-2, especially given the widespread use of novel mRNA vaccines. Yet, this has far-reaching implications in terms of the need for regular booster doses in the general population and perhaps even revaccination in patients receiving B cell-depleting therapy. We aimed to characterise anti-SARS-CoV-2 antibody titres in patients receiving Rituximab following previous SARS-CoV-2 vaccination. We recruited 10 fully vaccinated patients (age: 16.9 ± 2.52 years) with childhood-onset nephrotic syndrome, not in relapse, receiving Rituximab for their steroid/calcineurin-inhibitor sparing effect. Antibodies to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins were measured immediately prior to Rituximab and again ~6 months later, using the Roche Elecys® Anti-SARS-CoV-2 (S) assay. All ten patients were positive for anti-S antibodies prior to Rituximab, with six patients (60%) having titres above the upper limit of detection (>12,500 U/mL). Following Rituximab therapy, there was a reduction in anti-S titres (p = 0.043), but all patients remained positive for anti-S antibodies, with five patients (50%) continuing to have titres >12,500 U/mL. Six patients (60%) were positive for anti-N antibodies prior to Rituximab. Following Rituximab therapy, only three of these six patients remained positive for anti-N antibodies (p = 0.036 compared to anti-S seroreversion). Humoral immunity to SARS-CoV-2 is likely to be mediated in part by long-lived plasma cells. [ABSTRACT FROM AUTHOR]

Excessive productions of inflammatory cytokines and free radicals are involved in spinal cord injury (SCI). Fibroblast growth factor 5 (FGF5) is associated with inflammatory response and oxidative damage, and we herein intend to determine its function in SCI. Lentivirus was instilled to overexpress or knockdown FGF5 expression in mice. Compound C or H89 2HCl were used to suppress AMP‐activated protein kinase (AMPK) or protein kinase A (PKA), respectively. FGF5 level was significantly decreased during SCI. FGF5 overexpression mitigated, while FGF5 silence further facilitated inflammatory response, oxidative damage and SCI. Mechanically, FGF5 activated AMPK to attenuate SCI in a cAMP/PKA‐dependent manner, while inhibiting AMPK or PKA with pharmacological methods significantly abolished the neuroprotective effects of FGF5 against SCI. More importantly, serum FGF5 level was decreased in SCI patients, and elevated serum FGF5 level often indicate better prognosis. Our study identifies FGF5 as an effective therapeutic and prognostic target for SCI. [ABSTRACT FROM AUTHOR]

This letter, published in the journal Neurological Sciences, describes a case of corpus callosum bilateral infarction in a patient with Sneddon syndrome. The patient, a 59-year-old man, presented with left hemiparesis and a history of behavioral changes and cognitive decline. Imaging revealed acute ischemic areas in the corpus callosum, along with chronic infarcts in multiple vascular territories. The patient was ultimately diagnosed with Sneddon syndrome based on skin biopsy results and the presence of livedo racemosa. The letter highlights the importance of considering Sneddon syndrome as a potential cause of callosal infarction and suggests that a single antiplatelet regimen may be the preferred treatment for aPL-negative patients. [Extracted from the article]

This article discusses a case of secondary livedoid vasculopathy (LV) following a SARS-CoV-2 infection. The patient, a 30-year-old male, presented with skin lesions on his ankles after being diagnosed with COVID-19. The physical examination revealed ulcers, hyperpigmentation, and atrophy. The patient was treated with pentoxifylline and showed improvement after three months. LV is a rare vaso-occlusive disease characterized by thrombosis of dermal venules. The article suggests that the hypercoagulation observed in COVID-19 patients may be similar to the pathophysiology of LV. [Extracted from the article]

Hemostasis impairment represents the most threatening consequence of Viperidae envenoming, notably with Bothrops genus. In the French departments of America, B. atrox envenomation in French Guiana may lead to bleeding while B. lanceolatus envenomation in Martinique to thrombosis. Bleeding related to B. atrox envenomation is attributed to vascular damage mediated by venom metalloproteinases and blood uncoagulable state resulting from thrombocytopenia and consumptive coagulopathy. Thrombosis related to B. lanceolatus envenomation are poorly understood. We aimed to compare the effects of B. atrox and B. lanceolatus venoms in the rat to identify the determinants of the hemorrhagic versus thrombotic complications. Viscoelastometry (ROTEM), platelet count, plasma fibrinogen, thrombin generation assay, fibrinography, endothelial (von Willebrand factor, ADAMTS13 activity, ICAM-1, and soluble E-selectin), and inflammatory biomarkers (IL-1β, IL-6, TNF-α, MCP-1, and PAI-1) were determined in blood samples obtained at H3, H6, and H24 after the subcutaneous venom versus saline injection. In comparison to the control, initial fibrinogen consumption was observed with the two venoms while thrombocytopenia and reduction in the clot amplitude only with B. atrox venom. Moreover, we showed an increase in thrombin generation at H3 with the two venoms, an increase in fibrin generation accompanied with hyperfibrinogenemia at H24 and an increase in inflammatory biomarkers with B. lanceolatus venom. No endothelial damage was found with the two venoms. To conclude, our data support two-sided hemostasis complications in Bothrops envenoming with an initial risk of hemorrhage related to platelet consumption and hypocoagulability followed by an increased risk of thrombosis promoted by the activated inflammatory response and rapid-onset fibrinogen restoration. Author summary: Bothrops venoms contain toxins targeting hemostasis, a physiological process aiming stopping bleeding in case of injury. Envenomation by B. atrox in French Guiana leads to hemorrhage while envenomation by B. lanceolatus in Martinique results in thrombosis. To understand the mechanisms involved in these opposite manifestations related to the two venoms, we designed a comparative rat study of hemostasis based on a comprehensive approach including blood measurement of initiation time and size of the clot, platelet count, plasma fibrinogen, thrombin and fibrin generation, and various inflammatory and endothelial biomarkers. We showed that B. atrox venom induces more marked platelet and fibrinogen consumption, promoting the risk of hemorrhage, while B. lanceolatus venom induces an initial fibrinogen consumption followed by a secondary increase in combination to an enhanced inflammatory reaction resulting in increased thrombosis risk. Interestingly, the two venoms exhibited no endothelial toxicity. [ABSTRACT FROM AUTHOR]