Summary
The contact system is a plasma protease cascade initiated by factor XII (FXII) that activates the proinflammatory kallikrein‐kinin system and the procoagulant intrinsic coagulation pathway. ...Anionic surfaces induce FXII zymogen activation to form proteolytically active FXIIa. Bacterial surfaces also have the ability to activate contact system proteins, indicating an important role for host defense using the cooperation of the inflammatory and coagulation pathways. Recent research has shown that inorganic polyphosphate found in platelets activates FXII in vivo and can induce coagulation in pathological thrombus formation. Experimental studies have shown that interference with FXII provides thromboprotection without a therapy‐associated increase in bleeding, renewing interest in the FXIIa‐driven intrinsic pathway of coagulation as a therapeutic target. This review summarizes how the contact system acts as the cross‐road of inflammation, coagulation, and innate immunity.
Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global ...molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function on a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signalling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic and pathologic process, somatic molecular changes and tumour biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumour molecular changes and the exposures of interest on tumour behaviour (prognosis or clinical outcome) can lead to a better understanding of tumour molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent 'molecular pathologic epidemiology', which is a multidisciplinary field of investigations of the inter-relationship between exogenous and endogenous (eg, genetic) factors, tumoural molecular signatures and tumour progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathological investigation is a promising area (GWAS-MPE approach). Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathological epidemiology has unique strengths, and can provide insights into the pathogenic process and help optimise personalised prevention and therapy. In this review, we overview this relatively new field of research and discuss measures to overcome challenges and move this field forward.
Platelet and fibrin clots occlude blood vessels in hemostasis and thrombosis. Here we report a noncanonical mechanism for vascular occlusion based on neutrophil extracellular traps (NETs), DNA fibers ...released by neutrophils during inflammation. We investigated which host factors control NETs in vivo and found that two deoxyribonucleases (DNases), DNase1 and DNase1-like 3, degraded NETs in circulation during sterile neutrophilia and septicemia. In the absence of both DNases, intravascular NETs formed clots that obstructed blood vessels and caused organ damage. Vascular occlusions in patients with severe bacterial infections were associated with a defect to degrade NETs ex vivo and the formation of intravascular NET clots. DNase1 and DNase1-like 3 are independently expressed and thus provide dual host protection against deleterious effects of intravascular NETs.
Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the 'Provocative Questions' in cancer research. ...Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the 'colorectal continuum' paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as 'epidemiology of molecular heterogeneity of disease'. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine clinical practices. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biological sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care.
Coagulation factor XII (FXII, Hageman factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII’s unique ...mechanism of activation that is induced by binding (contact) to negatively charged surfaces. Various substances have the capacity to trigger FXII contact-activation in vivo including mast cell–derived heparin, misfolded protein aggregates, collagen, nucleic acids, and polyphosphate. FXII deficiency is not associated with bleeding, and for decades, the factor was considered to be dispensable for coagulation in vivo. However, despite the fact that humans and animals with deficiency in FXII have a normal hemostatic capacity, animal models revealed a critical role of FXIIa-driven coagulation in thromboembolic diseases. In addition to its role in thrombosis, FXIIa contributes to inflammation through the activation of the inflammatory bradykinin-producing kallikrein-kinin system. Pharmacological inhibition of FXII/FXIIa interferes with thrombosis and inflammation in animal models. Thus, targeting the FXIIa-driven contact system seems to be a promising and safe therapeutic anticoagulation treatment strategy, with additional anti-inflammatory effects. Here, we discuss novel functions of FXIIa in cardiovascular thrombotic and inflammatory disorders.
We demonstrate direct coupling between phonons and diamond nitrogen-vacancy (NV) center spins by driving spin transitions with mechanically generated harmonic strain at room temperature. The ...amplitude of the mechanically driven spin signal varies with the spatial periodicity of the stress standing wave within the diamond substrate, verifying that we drive NV center spins mechanically. These spin-phonon interactions could offer a route to quantum spin control of magnetically forbidden transitions, which would enhance NV-based quantum metrology, grant access to direct transitions between all of the spin-1 quantum states of the NV center, and provide a platform to study spin-phonon interactions at the level of a few interacting spins.
A Trombocitopenia imune induzida por medicamentos é caracterizada, geralmente, por um quadro abrupto de plaquetopenia, resultante da ligação da droga a alguma proteína plaquetária com formação de um ...neoantígeno, que então desencadeia resposta imune com destruição plaquetária. Sulfonamidas, heparina e rifampicina são exemplos de drogas associadas a este mecanismo. Além disso, novos medicamentos, especialmente os “biológicos”, podem induzir plaquetopenia por outras vias e sua identificação também é de importância clínica.
Relatamos dois casos de trombocitopenia medicamentosa onde destaca-se a importância do diagnóstico e acompanhamento clínico-laboratorial para o tratamento adequado do paciente.
Paciente 50 anos, feminino previamente hígida com contagem normal de plaquetas apresentou quadro de petéquias em membros inferiores. Hemograma: Leucócitos totais = 4.840/mm3, Hb= 13,2g/dL, RDW=13,4%, e Plaquetas=2.000/mm³. No esfregaço sanguíneo confirmou-se a plaquetopenia (ausência de grumos e de macrotrombócitos). Paciente encontrava-se em uso de sulfametoxazol/trimetoprina há cerca de 15 dias por infecção de partes moles. Sete dias após a suspensão da medicação a contagem plaquetária estava em 430.000/mm3, estável há cerca de 9 meses.
Paciente de 2 anos, masculino, realizou hemograma que evidenciou Leucócitos = 9.780/mm3, Hb= 11,4 g/dl, RDW 14,1 %, Plaquetas = 79.000/mm³, VPM = 10,4 fL. No esfregaço observou-se a redução do número de plaquetas e raros macrotrombócitos. O paciente fizera, há 4 dias, uso do medicamento ZolgensmaR (Onasemnogene abeparvovec), medicamento do tipo biológico usado como terapia genética para o tratamento da atrofia muscular espinhal (AME), doença genética rara que acomete 1/10.000 nascidos vivos. Cerca de 7 dias após, as plaquetas estavam em 150.000/mm3, estável há 6 meses.
A trombocitopenia induzida por drogas pode ser de caráter não imune (supressão medular/toxicidade) ou de fundo imune. Esta ocorre geralmente pela formação de neoantígenos, tem início abrupto, pode acarretar plaquetas < 20.000/mm3 e ser sintomática. Apesar de raro, algumas medicações são classicamente relacionadas a este quadro, como as sulfonamidas, descrita no primeiro caso. Exceto pela relação com uso de medicamentos, esta condição pode ser de difícil diferenciação em relação à púrpura trombocitopenica imune. O caso 2 trata-se de uma criança com AME em uso de ZolgensmaR, terapia gênica que utiliza um vetor viral para introduzir material genético modificado no organismo (gene SMN1, sem o qual há perda de neurônios motores no tronco cerebral e medula espinhal). O capsídeo viral induz importante reação inflamatória e a plaquetopenia é comum (>90% dos casos), apesar de raramente <50.000/mm3. Supõe-se a etiologia imune, mas por atividade do complemento e não por atividade do tipo antígeno-anticorpo. Quando de fundo imune, a recuperação da trombocitopenia fármaco induzida começa entre 1-2 dias após a suspensão do medicamento e os níveis de plaquetas geralmente se normalizam em 1-2 semanas, apenas com esta medida. Raramente, o uso de corticosteroides é necessário, com eficácia > 90%.
Summary
Background
Acute thrombotic microangiopathies (TMAs) are characterized by excessive microvascular thrombosis and are associated with markers of neutrophil extracellular traps (NETs) in ...plasma. NETs are composed of DNA fibers and promote thrombus formation through the activation of platelets and clotting factors.
Objective
The efficient removal of NETs may be required to prevent excessive thrombosis such as in TMAs. To test this hypothesis, we investigated whether TMAs are associated with a defect in the degradation of NETs.
Methods and Results
We show that NETs generated in vitro were efficiently degraded by plasma from healthy donors. However, NETs remained stable after exposure to plasma from TMA patients. The inability to degrade NETs was linked to a reduced DNase activity in TMA plasma. Plasma DNase1 was required for efficient NET degradation and TMA plasma showed decreased levels of this enzyme. Supplementation of TMA plasma with recombinant human DNase1 restored NET‐degradation activity.
Conclusions
Our data indicate that DNase1‐mediated degradation of NETs is impaired in patients with TMAs. The role of plasma DNases in thrombosis is, as of yet, poorly understood. Reduced plasma DNase1 activity may cause the persistence of pro‐thrombotic NETs and thus promote microvascular thrombosis in TMA patients.
Background: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular ...chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). Objective: To explore the source and role of extracellular chromatin in DVT. Methods: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). Results: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham‐operated mice. Immunohistochemical staining revealed the presence of Gr‐1‐positive neutrophils in both red (RBC‐rich) and white (platelet‐rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs’ structure, was present only in the red part of thrombi and was frequently associated with the Gr‐1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. Conclusions: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.
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