Benjamín Rubio-Jurado

The Clinical Significance of Posttranslational Modification of Autoantigens

Posttranslational modifications (PTMs) are defined as covalent modifications occurring in a specific protein amino acid in a time- and signal-dependent manner. Under physiological conditions, proteins are posttranslationally modified to carry out a large number of cellular events from cell signaling to DNA replication. However, an absence, deficiency, or excess in PTMs of a given protein can evolve into a target to trigger autoimmunity, since PTMs arise in the periphery and may not occur in the thymus; hence, proteins with PTMs never tolerize developing thymocytes. Consequently, when PTMs arise during cellular responses, such as inflammation, these modified self-antigens can be taken up and processed by the antigen-presenting cells (APCs). Autoreactive T cells, which recognize peptides presented by APCs, can then infiltrate into host tissue where the modified antigen serves to amplify the autoimmune response, eventually leading to autoimmune pathology. Furthermore, a PTM occurring in an amino acid residue can induce changes in the net charge of the protein, leading to conformational modifications in the tertiary and quaternary structure of the protein, especially interaction with human leukocyte antigen (HLA) molecules. Molecular mimicry (MM) was until now the prevailing hypothesis explaining generation of autoimmunity; nevertheless, experimental animal models need inflammation via infection or other immunogens to ensure autoimmunity; MM alone is not sufficient to develop autoimmunity. PTMs could arise as an additive factor to MM, which is required to start an autoimmune response. PTMs have been found to be present in different pathologic conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome, and primary biliary cirrhosis. The aim of the present review is to expose protein posttranslational modifications and the evidence suggesting their role in the generation of autoimmunity.

The Clinical Significance of Coagulation and the Inflammatory Response in Autoimmunity

Maintenance of normal blood flow requires equilibrium between procoagulant and anticoagulant factors; occasionally, procoagulant activity predominates, leading to clot formation; frequently, tissue damage is the triggering factor. Hereditary factors, primary or acquired, play a role in the development of thrombosis. Primary thrombophilia is associated with hereditary factors, which promote hypercoagulability because natural anticoagulants are not exerting their activity. On the other hand, acquired thrombophilia may occur associated to autoimmune diseases, cancer, surgical procedures, pregnancy, postpartum period, and obesity. Activation of the coagulation system is characterized by the co-participation of inflammatory response components, factors related to the subjacent disease, and other procoagulant factors. The study of patients with thrombosis should include both inflammatory and autoimmune response markers.

WNT receptors profile expression in mature blood cells and immature leukemic cells: RYK emerges as a hallmark receptor of acute leukemia.

Wnt signaling induces a plethora of intracellular responses that dictate normal or abnormal cellular behavior. Abnormal WNT signaling has been related to the development of leukemogenic processes. In this regard, it is important to know the expression profile of WNT receptors in normal and malignant cells, in order to understand the WNT mechanisms that control the cell behavior. This work aimed to determine the WNT receptors expression profile in normal and leukemia cells.

Obesity, Thrombotic Risk, and Inflammation in Cancer

Neoplasms exhibits a high incidence and mortality rates due to their complex and commonly overlapping clinical, biochemical, and morphologic profiles influenced by acquired or inherited molecular abnormalities, cell of origin, and level of differentiation. Obesity appears related to ~20% of cancers including endometrial, esophageal, colorectal, postmenopausal breast, prostate, and renal. Several factors other than obesity, i.e., insulin, insulin-like growth factor, sexual hormones, and adipokines may play a potential role in neoplasia. Cancer-associated hypercoagulable and thrombotic states are influenced by abnormalities in the vascular wall and susceptibility to invasion, interference in blood flow and increase in circulating tissue factor and thrombin, activation of cell growth factors, the presence of a central catheter, chemotherapies, neoplasm type, and surgery. In cancer, thromboembolic complications are the second most frequent cause of death with pulmonary thromboembolism in ~50% of cases postmortem. Thrombosis worsens prognosis as demonstrated with a survival rate as low as 12% per year vs 36% in nonthrombic patients. Deep vein thrombosis is the most frequent thromboembolic complication in cancer. It is usually detected at diagnosis and within the first 3 months of chemotherapy. The underlining mechanisms of this association should be further studied to identify patients at higher risk and develop adequate prevention, diagnostic, and treatment measures. The D-dimer test can be successfully used to assess the fibrinolytic phase of coagulation and as such is routinely used in suspected cases of deep vein thrombosis and pulmonary thromboembolism. In addition, significant advances have been made in understanding the composition and functional capabilities of the gut microbiota in the inflammatory process, obesity, and its roles in cancer; however, the intricate balance that exists within the microbiota may not only affect the host directly, it can also disrupt the entire microbial community. CONCLUSIONS Cancer is a prothrombotic and inflammatory state in which the activation of coagulation is related to tumor growth, angiogenesis, and metastasis. It is important to identify the relationship between body mass index with these processes and clarify their importance in cancer prognosis. Future research should answer the question if manipulation of resident microbial communities could potentially improve prognosis and treatment outcome.

Circulating Levels of Urokinase-Type Plasminogen Activator Receptor and D-Dimer in Patients With Hematological Malignancies

BACKGROUND Patients with cancer exhibit changes in their hemostatic mechanisms. The D-dimer (D-D) is the most important subproduct of fibrinolysis, and urokinase plasminogen activator receptor (uPAR) is related to invasiveness and metastases, and is overexpressed in neoplastic cells. The objective of this study was to identify in patients with hematological neoplasia, the serum levels of uPAR and D-D, and to determine their effects on outcome. PATIENTS AND METHODS A cross-sectional study was performed. Clinical and demographic data were obtained from the clinical chart. Determination of uPAR in serum (pg/L) was performed using an enzyme-linked immunosorbent assay, and D-D (μg/dL) using nephelometry. RESULTS We included 42 patients (35 with lymphomas). Statistically significant differences were found in D-D (P < .001) and uPAR (P < .01) between patients and control participants. Response was an accumulated clinical outcome. We observed statistical differences between groups (P < .001). D-D was positive in 70% of cases. CONCLUSION We found differences in D-D serum levels and soluble uPAR between control participants and patients with lymphoma. These results indicate that D-D serum levels and soluble uPAR should be considered biomarkers of response and survival in patients with lymphoma.