ALBERT

Description: The role of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in fibrinolysis remains unsettled. The contribution of uPA may depend on the vascular location, the physical properties of the clot, and its impact on tissue function. To study the contribution of urokinase within the pulmonary microvasculature, a model of pulmonary microembolism in the mouse was developed. Iodine 125 (125I)–labeled fibrin microparticles injected intravenously through the tail vein lodged preferentially in the lung, distributing homogeneously throughout the lobes. Clearance of125I-microemboli in wild type mice was rapid and essentially complete by 5 hours. In contrast, uPA−/− and tissue-type plasminogen activator tPA−/− mice, but not uPAR−/− mice, showed a marked impairment in pulmonary fibrinolysis throughout the experimental period. The phenotype in the uPA−/− mouse was rescued completely by infusion of single chain uPA (scuPA). The increment in clot lysis was 4-fold greater in uPA−/− mice infused with the same concentration of scuPA complexed with soluble recombinant uPAR. These data indicate that uPA contributes to endogenous fibrinolysis in the pulmonary vasculature to the same extent as tPA in this model system. Binding of scuPA to its receptor promotes fibrinolytic activity in vivo as well as in vitro. The physical properties of fibrin clots, including size, age, and cellular composition, as well as heterogeneity in endothelial cell function, may modify the participation of uPA in endogenous fibrinolysis.

Description: Simultaneous studies of the metabolism of 125I-prothrombin and 131I-fibrinogen were performed in ten patients with thrombocytosis secondary to myeloproliferative syndromes. The mean fractional catabolic rate (FCR) of prothrombin was 61.9%, differing significantly from the normal mean of 42.5% (p

Description: Introduction Oral and gastrointestinal mucositis in the context of high dose chemotherapy (CT) and/or radiotherapy (RT) remains one of the most problematic side effects that influences  quality of life (QOL). Mucositis may lead to clinical deterioration with significant weight loss and reduction of chemotherapy doses with lower effectiveness, prolongation of hospitalization and increased costs. Objectives Epidemiological characterization of mucositis secondary to CT. Prognostic impact of the type of hematologic malignancy in the mucositis' risk. Impact of conservative treatment (MASCC/ISSO) in the risk of mucositis and hospitalization days. Methods Observational study of sequencial 30 patients with acute leukemia (AL) and aggressive B-cell non-Hodgkin lymphoma (B-NHL), indicated for CT (1st or 2nd line), followed at our center between February and August 2012. Patients admitted to the study underwent daily assessment by trained nurse staff for the degree of mucositis (WHO), pain and diarrhea, according to well-established scales, and for the presence of neutrophils, need for analgesics, basic oral prophylactic care (BOC) - guidelines MASCC / ISSO - vs BOC and therapeutic treatment (Caphosol ® and/or Gelclair ®) of mucositis. The evaluation was carried out up to day 20th  of CT, or until mucositis resolved to grade ≤ 2 for 2 consecutive days or until day 12thof CT in patients who had mucositis ≤ grade 1. Patient characteristics were compared by the χ2 test for binary variables and by the Mann-Whitney test for continuous variables. Data was modeled according to longitudinal procedures, regarding continuous and multinomial dependent variables. We used R software with packages lme and VGAM. The remaining data were analyzed by using SPSS version 17.0. A p value less than 0,01 was considered to be statistically significant. Results  30 patientes were included, corresponding to 75 episodes/admissions of patients with hematologic malignancy, of which 22,7% (n = 17) developed mucositis. The median follow-up was 23 days (min.5-máx.35). 64,7% (n = 11) patients were diagnosed with AL and 35,3% (n = 6) patients diagnosed with Burkitt NHL, median age was 61 years (min.35-máx.68) and 41,5 years (min.37-máx.47), respectively. Regarding the treatment phase, 72,7% (n = 8) patients with AL were evaluated during induction, 18,2% (n = 2) during consolidation and 9,1% (n = 1) during aplasia. 33,3% (n = 2) patients with B-NHL were evaluated under CT and 66,7 (n = 4) under aplasia. Through the application of a multinomial logistic model with a longitudinal component and analyzing the variation of the degree of mucositis over time we found that, in patients with AL, the period of greatest frequency of mucositis in spline curves occurs from the 10thday from starting CT, with a median time to mucositis development of 12 days (mín.0-máx.24). In patients with B-NHL, the frequency of mucositis is higher in the first 10 days of treatment, the median time until installation of mucositis was 5 days (min.1-máx.12). In both diagnostic groups, few patients had grade 3 mucositis (18,2% in AL and 16,7% in B-NHL), since most patients with B-NHL and AL show grade 1 mucositis. The risk of developing grade 1 mucositis is higher in AL vs B-NHL patients (HR 0.328444, p

Description: Fibrinogen Philadelphia, a hypodysfibrinogenemia described in a family with a history of bleeding, is characterized by prolonged thrombin time, abnormal fibrin polymerization, and increased catabolism of the abnormal fibrinogen. Turbidity studies of polymerization of purified fibrinogen under different ionic conditions reveal a reduced lag period and lower final turbidity, indicating more rapid initial polymerization and impaired lateral aggregation. Consistent with this, scanning and transmission electron microscopy show fibers with substantially lower average fiber diameters. DNA sequence analysis of the fibrinogen genes A, B, and G revealed a T〉C transition in exon 9 resulting in a serine-to-proline substitution near the γ chain C-terminus (S378P). The S378P mutation is associated with fibrinogen Philadelphia in this kindred and was not found in 10 controls. This region of the γ chain is involved in fibrin polymerization, supporting this as the polymerization defect causing the mutation. Thus, this abnormal fibrinogen is characterized by 2 unique features: (1) abnormal polymerization probably due to a major defect in lateral aggregation and (2) hypercatabolism of the mutant protein. The location, nature, and unusual characteristics of this mutation may add to our understanding of fibrinogen protein interactions necessary for normal catabolism and fibrin formation.

Description: Telomeres are a complex of hexameric repetitive DNA sequences at the end of linear chromosomes. Telomeres erode during mitosis, and this process is accelerated in patients carrying germline pathogenic mutations in telomere-biology genes (Calado and Young, NEJM 2009). In vitro, the exposition to androgens stimulates TERT transcription and telomerase activity of lymphocytes and bone marrow CD34+ cells (Calado et al. Blood 2009). In a phase 1-2 prospective trial, the use of danazol led to telomere elongation in patients with telomeropathies (Townsley et al. NEJM 2016). The hematological response was observed in 79% of evaluable patients. Here, we describe a phase 1-2 single-center prospective study assessing the safety and the effect of the male hormone nandrolone decanoate on telomere erosion in patients with telomere diseases (ClinicalTrials.gov Identifier: NCT02055456). Entry criteria comprised patients older than two-year-old with age-adjusted mean telomere length below the 1st percentile ± identified mutations in telomerase complex genes, associated with at least one cytopenia and/or diagnosis of idiopathic pulmonary fibrosis (IPF). Patients were treated with nandrolone decanoate intramuscular at a dose of 5 mg/kg every 14 days for 24 months. The primary efficacy end point was a 20% decrease in the annual rate of telomere erosion, and the incidence of toxic effects was the primary safety end point. Secondary endpoints were hematologic response and pulmonary response. Flow-FISH was used to determine the telomere length of peripheral blood leukocytes. From May 2014 to October 2017, 20 consecutive patients were eligible for participation, and 17 were enrolled. The median age was 36 years (range, 4 - 59 years), and five patients were female. In all but one patient germline pathogenic mutations were identified (TERT, 7; RTEL1, 4; TERC, 2; WRAP53, 1; TINF2, 1; and SAMD9, 1). Eleven patients were diagnosed with bone marrow failure (9 with moderate and one with severe AA, and one with myelodysplasia). Four patients were diagnosed with IPF, and 2 patients had both moderate AA and IPF. One patient diagnosed with IPF had received an allogeneic bone marrow transplant before enrollment. Four patients had additional hepatic involvement, and 5 displayed cutaneous features of dyskeratosis congenita. The most common adverse events associated with drug were elevations in liver enzyme levels in 88%, acne in 59%, and virilization in 59%. Severe adverse events possibly related to drug occurred in six instances. Dose reductions were necessary in 5 patients due to severe or moderate adverse events. Seven patients withdrew from the study before 2 years: two patients discontinued therapy due to grade 3 adverse events (depression and acne); one patient sought alternative therapies; and four patients died during the study period, two due progressive IPF and two due intracranial hemorrhage. Out the 17 patients enrolled, a total of 15 reached 12 months of treatment and 13 were evaluable (one patient was transplanted and telomere length not evaluated; and for one patient the telomere sample was missing). Ten patients met the primary efficacy end point, showing telomere elongation. As of July 2019, nine patients reached 24 months of treatment and telomere length measured for seven patients at this time-point; all of them met end point criteria and showed telomere elongation at two years. The average increase in telomere length at 12 months was 1,119 bp (95% CI, 180-2,059 bp; P

Description: The role of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in fibrinolysis remains unsettled. The contribution of uPA may depend on the vascular location, the physical properties of the clot, and its impact on tissue function. To study the contribution of urokinase within the pulmonary microvasculature, a model of pulmonary microembolism in the mouse was developed. Iodine 125 (125I)–labeled fibrin microparticles injected intravenously through the tail vein lodged preferentially in the lung, distributing homogeneously throughout the lobes. Clearance of125I-microemboli in wild type mice was rapid and essentially complete by 5 hours. In contrast, uPA−/− and tissue-type plasminogen activator tPA−/− mice, but not uPAR−/− mice, showed a marked impairment in pulmonary fibrinolysis throughout the experimental period. The phenotype in the uPA−/− mouse was rescued completely by infusion of single chain uPA (scuPA). The increment in clot lysis was 4-fold greater in uPA−/− mice infused with the same concentration of scuPA complexed with soluble recombinant uPAR. These data indicate that uPA contributes to endogenous fibrinolysis in the pulmonary vasculature to the same extent as tPA in this model system. Binding of scuPA to its receptor promotes fibrinolytic activity in vivo as well as in vitro. The physical properties of fibrin clots, including size, age, and cellular composition, as well as heterogeneity in endothelial cell function, may modify the participation of uPA in endogenous fibrinolysis.

Description: Ischemic cerebrovascular disease (ICD) is a multi-factorial entity whose anatomopathologic substrate is atherosclerosis. The inflammatory cells migrate to vascular endothelium and release chemokines such as interleukin 6 (IL6), resulting in the atheroma plaque development. The IL6 production induces acute phase proteins synthesis such as fibrinogen. Objective. The purpose of this case-control study is to analyze the ICD risk associated to the polymorphisms IL6-174 G/C and beta chain of fibrinogen-455 G/A (fibri-β-455). The association of these polymorphisms, classic vascular risks factors and ICD subtypes according to TOAST classification has also been explored. Methods and patients. A total of 159 ICD diagnosed patients (82 female and 77 male; mean age 67.7±15) were analysed. They were matched for age (±5 years) and sex with a control group (65.6±14) without thrombotic history. AHT, DM, dyslipidaemia and smoking habit data were collected for each group. Polymorphisms were analysed by PCR-RFLP. Serum IL6 was measured by ELISA and fibrinogen by Clauss method. Statistic analysis was made with the SAS v9 software. Results. Genotype analysis showed a significant higher prevalence of the genotypes G/G and G/C IL6 -174 in the patients (OR: 1.49, IC 95%: 0.95–2.34, p: 0.049). By contrast, the fibri-β-455 genotypes were not different in patients and controls (p= 0.230). When the stroke subtypes were analysed, we found that IL6-174 G/C genotype was more frequent in cardioembolic (60.0%) and atherothrombotic ICD subtypes (58.3%). In relation to fibri-β-455 G/A, the A allele showed a increased prevalence in atherothrombotic stroke (43.2%) (p= 0.049). We observed an association between the dyslipidaemia and IL6-174 G/C polymorphism (p= 0.034) and smoking habit with fibri-β-455G/A (p= 0.072). No synergic relation were found between IL6-174 G/C and fibri-β-455 G/A. The G allele IL6-174 G/C carriers group presented higher serum IL6 levels than C allele carriers, 5.85 pg/ml (2.9–34.5) vs. 4.94pg/ml (2.5–11.4). Also, allele A fibri-β-455 G/A was associated with a higher fibrinogen levels than G allele, 329 mg/dl (210–686) versus 280 mg/dl (107–783). Conclusion. There is an association between-174 IL6 G/C polymorphism and ischemic stroke. By contrast, we did not find any association between fibri-β-455 G/A, and ICD. Besides, the analysis performed by ICD subtypes showed an association of this polymorphism and atherothrombotic subtype. These results suggest a relation between smoking habit and fibri-β-455 G/A, and dislypidaemia and-174 IL6 G/C polymorphism.

Description: Multiple myeloma (MM) is a genetically unstable malignancy of postgerminal center B-cells. Almost 40% of intramedullary MM tumors show primary translocations that affect immunoglobulin heavy chain (IgH) gene. These include t(4;14)(p16;q32) which results in the dysregulated expression of two potential oncogenes, MMSET on der(4) and FGFR3 on der(14), and has been associated with poor outcome. The main goals of this study were to determine the incidence and clinical significance of t(4;14) among our MM patients. Therefore, we studied bone marrow specimens from 65 patients with MM by fluorescence in situ hybridization (FISH). All cases were screened for IgH rearrangements, t(4;14), t(11;14), and 13q14 deletions using the locus-specific probes LSI IgH dual color, break apart, LSI IGH/FGFR3, LSI IGH/CCND1, and LSI D13S319 (Vysis). FISH analysis revealed 35 cases (54%) involving IgH locus. 8 patients (12.3%) had a t(4;14), and 13 cases (20%) showed a t(11;14). In the remaining 14 samples (21.5%), IgH rearrangements were observed, but the translocation partner was not one of the loci for we tested. Furthermore, 13q14 deletions were more frequent among patients with t(4;14) than among those with t(11;14) (62.5% vs 30.7% respectively, p=0.03). Regarding clinical parameters, presence of t(4;14) was significantly associated with anemia (mean value: 9.0 g/dl, p=0.049), elevated LDH levels (mean value: 535.4 U/l, p=0.05), Durie III stage (p=0.049), and number of lytic bone lesions 〉2 (p=0.007). Finally, the survival median of patients with t(4;14) was 23 months vs 48 months for the group without this abnormality. Cases with t(11;14) did not show adverse correlation with survival. Based on these data, FISH is a successful technique to detect translocations affecting telomeric localization of both chromosomal partner loci. In addition, we confirmed t(4;14) as an important factor of poor prognostic in MM. Its detection is essential to lead a correct evaluation of patients at diagnosis.