Dziecioł J

BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma

Tumour necrosis factor alpha (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the TNF-α family. Vascular endothelial growth factor (VEGF), on the other hand, is one of the most characteristic pro-angiogenic cytokines produced by multiple cell types in multiple myeloma (MM). We have analysed BAFF and APRIL concentrations in parallel with pro-angiogenic cytokines in serum and trephine biopsy, and the bone marrow microvascular density (MVD) in 50 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of BAFF, APRIL and TNF-α, as well as VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. A statistically positive correlation between the concentration of TNF-α and the expression of VEGF was demonstrated, and so was a positive link between BAFF, APRIL, MVD and lactate dehydrogenase (LDH). Furthermore, we observed a significant decrease in all studied cytokines after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with stable disease. It was also established that APRIL, but not BAFF, correlated with pro-angiogenic cytokines such as VEGF with its receptor, MVD and syndecan-1. Finally, our results showed that serum BAFF and APRIL levels could be useful biomarkers of MM disease activity and its progression which suggests that APRIL could be a possible novel therapeutic target in MM.

Evaluation of TNF superfamily molecules in multiple myeloma patients: Correlation with biological and clinical features

B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis inducing ligand (TRAIL) are members of the tumour necrosis factor (TNF) family. They are the main survival factors for immature, naive and activated B cells. We have analysed BAFF, APRIL and TRAIL serum concentrations in 52 patients with newly diagnosed IgG multiple myeloma and 20 healthy volunteers. The values were significantly higher in the studied patients and advanced diseases, decreasing after chemotherapy, compared to the control group. It was established that BAFF as APRIL (but not TRAIL) correlated with adverse prognostic factors such as IL-6 and lactate dehydrogenase. Furthermore, higher concentrations of APRIL and BAFF (but not TRAIL) predicted a shorter progression free survival, suggesting thereby an important prognostic marker and a possible therapeutic target in myeloma.

Angiogenesis in gliomas.

Brain gliomas are characterized by invasive growth and neovascularisation potential. Angiogenesis plays a major role in the progression of gliomas and its determination has a great prognostic value. The aim of the study was to assess the vascularisation of chosen brain gliomas and to estimate how it is correlated with tumour histological type, malignancy grade, location and size, and with age and sex of patients. Tumour vascularisation analysis was based on the determination of microvascular proliferation (MVP) and microvessel density (MVD). Microvascular proliferation was measured with immunohistochemical methods using mouse monoclonal antibodies to detect cell proliferation antigens. The following antibodies were used Ki-67 and PCNA (DAKO). Identification of vessels was performed by CD31 antibody and anti-human von Willebrand factor (DAKO). The highest microvascular proliferation and microvascular density were observed in multiform glioblastomas and the lowest in oligodendrogliomas. Significant correlation was observed between the vascularisation and malignancy grade.

The role of Interleukin-17A and Interleukin-17E in multiple myeloma patients

Summary Background Tumor growth in multiple myeloma (MM) is regulated by the cytokine networks which are produced by myeloma cells and the microenvironment of the bone marrow. Interleukin-17 (IL-17) is implicated in the increased angiogenesis in the bone marrow of MM. Recent studies reported elevated levels of interleukin 17A (IL-17A) in the sera of patients with advanced stages according to Durie-Salmon classification. Material/Methods We compared the concentration of IL-17A and IL-17E in the blood serum of 34 newly diagnosed MM patients with healthy subjects’ sera. We also evaluated the concentration of IL-17A and IL-17E in the blood serum of MM patients and the relation to the percentage of plasma cells and other clinical parameters. The concentration of IL-17E and IL-17A of healthy subjects and patients with MM was assessed by enzyme-linked immunosorbent assay (ELISA). Results Our data confirm that IL-17A and IL-17E serum levels were significantly higher in all MM patients and also in patients with advanced stage compared with healthy subjects. We found the correlation between serum levels of IL-17A in MM patients and percentage of plasma cells. Our results also showed that if serum levels of IL-17E were higher in MM patients, the percentage of plasma cells and beta-2-microglobulin levels were lower. Conclusions The IL-17 family of cytokines may suppress or promote tumor growth. There seems to be some balance between the effects of IL-17A and IL-17E. The role of increased levels of IL-17E needs further investigation to understand its role in the pathobiology of MM.

The impact of TNF superfamily molecules on overall survival in acute myeloid leukaemia: correlation with biological and clinical features

B cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis-inducing ligand (TRAIL) were demonstrated in several haematological diseases including acute myeloid leukemia (AML). Those cytokines are capable of activating a broad spectrum of intracellular signalling cascades that can either induce apoptosis or protect from programmed cell death. We have analysed BAFF, APRIL and TRAIL serum concentrations in 76 patients with newly diagnosed AML and 40 healthy volunteers. The values were significantly higher for APRIL and BAFF but lower for TRAIL compared to healthy volunteers. Induction therapy significantly reduced the values for BAFF and increased them for TRAIL. Moreover, the concentration of BAFF and APRIL was significantly lower and the concentration of TRAIL higher in a group of patients with complete remission compared to non-respondent AML patients. In addition, higher concentrations of BAFF and lower of TRAIL predicted a shorter overall survival, suggesting thereby an important prognostic marker and possible therapeutic target in AML.

The evaluation of angiogenesis and matrix metalloproteinase-2 secretion in bone marrow of multiple myeloma patients before and after the treatment

PURPOSE Angiogenesis appears to be a prominent feature of many hematological disorders, particularly in multiple myeloma (MM). Progression in MM also involves secretion of the metaloproteinases (MMPs). In this study, the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and its receptor, in bone marrow trephine biopsy (TB) of thirty six MM patients before and after the treatment or during progression was examined. The MMP-2 secretion was assessed from the same patients. MATERIAL/METHODS Immunohistochemical staining of bone marrow specimens for angiogenic factors and microvessel density (MVD) and bone marrow aspirates for Western blot analysis of MMP-2 expression was performed. RESULTS In active, untreated MM patients, we found statistically significant differences in the expression of angiogenic factors according to the patients after the anti-angiogenic treatment. We found statistical differences of the expression of angiogenic factors between the group of patients with a response after the treatment and the patients who had progression during the treatment. The data showed statistically significant decreased MVD after the treatment. The results showed statistically significant differences between initial secretion of MMP-2 in active, untreated MM patients and patients with a response after the treatment and patients with progression during the treatment. CONCLUSIONS We showed that not only decreased expression of angiogenic cytokines is present after the anti-angiogenic treatment but also activity of MMP-2 in MM patients who responded to the treatment. Combination therapy with the inhibition of the activity of MMPs could represent an interesting therapeutical approach in MM.

Papillary Hürthle cell tumor of thyroid : Report of a case with a cytomorphologic approach to diagnosis

BACKGROUND Hürthle cells are founded often in fine needle aspirates of the thyroid from nonneoplastic and neoplastic lesions. Papillary Hürthle cell tumors of the thyroid are composed of oxyphilic cells with a prominent papillary component. Papillary Hürthle cell carcinoma is a relatively uncommon type of thyroid carcinoma. CASE A 42-year-old man had two asymptomatic nodules (2.5 and 3.5 cm) in the left lobe and one (2.5 cm) in the right lobe of the thyroid. Fine needle aspiration biopsy of the tumor in the left lobe showed large cells in monolayers and papillary clusters with moderate to abundant eosinophilic, granular cytoplasm with sharp borders, a granular nuclear enlargement with pleomorphism and single nucleoli. Histologic examination showed capsular invasion and infiltration of vessels. CONCLUSION The cytologic appearance of papillary Hürthle cell carcinoma is not specific but can be suspected on fine needle aspiration.

The acute prothrombotic effect of aldosterone in rats is partially mediated via angiotensin II receptor type 1

INTRODUCTION We showed previously that the prothrombotic effect of one hour aldosterone (ALDO) infusion in rats was only partially mediated by the mineralocorticoid receptor (MR). Bearing in mind that ALDO potentiates the effects of angiotensin II (Ang II), in the present study we investigated the role of Ang II receptor type 1 - AT1 in acute ALDO prothrombotic action. MATERIALS AND METHODS The experiments were performed in a stasis-induced venous thrombosis model in male Wistar, normotensive rats. ALDO (30μg/kg) was infused for 1h. Valsartan (VAL; 10mg/kg), a selective AT1 receptor antagonist, was administered in a single bolus injection before ALDO infusion. Eplerenone (EPL, 100mg/kg), a selective MR receptor antagonist, was administered per os before ALDO. Thrombus weight and incidences of thrombosis were assayed. Bleeding time and platelet adhesion to collagen were evaluated as primary hemostasis parameters. The plasma levels of some coagulation and fibrinolysis parameters, and plasma NO metabolite levels were assayed. RESULTS AT1 blockade with valsartan significantly reduced ALDO-induced thrombosis expressed as a reduced thrombus mass (p<0.05 vs ALDO) and diminished the incidence of thrombosis. Valsartan reduced the ALDO-induced changes in bleeding time and platelet adhesion, as well as in coagulation, fibrinolysis, and NO metabolite levels. The effect of AT1 blockade in ALDO-induced thrombosis was similar to the effect of MR blockade. However, dual blockade of AT1 and MR showed no additional benefit. CONCLUSIONS ALDO prothrombotic action is partially mediated via AT1 receptor in the mechanism involving enhanced platelet activation, induced coagulation, impaired fibrinolysis and reduced NO bioavailability.

Changes of myocardial capillary density in progression of experimental lung emphysema

A morphometrical analysis of changes in the heart of rats with experimental lung emphysema due to single intratracheal administration of papain solution has been done. Special attention has been paid to quantitative changes of capillaries and to the cardiomyocyte diameter in respective regions of the myocardium after one, three and six months following the administration of papain. A histological and morphometrical analysis of changes in the lungs has also been carried out and partial pressures of oxygen and carbon dioxide in the arterial blood of the examined animals have been marked. It has been found that a single administration of papain caused emphysematous changes in the lungs, growing more intense until the third month of the experiment. The progression of these changes corresponded to a capillary density increase in the right ventricle, interventricular septum and in the subendocardial layer of the left ventricle. The increase in the number of capillaries was interpreted as the first adaptive stage of cor pulmonale development and explained by the occurrence of angiogenesis. The changes co-existed with a decrease in partial pressure of oxygen in the arterial blood. After six months of the experiment, a reduction in capillary density in the heart regions mentioned above and a simultaneous increase in the cardiomycyte transversal diameter were observed, being the exponents of evident myocardial hypertrophy. Development of ultrastructural changes in the hearts of rats has been analysed too. Simultaneous development of changes in the right ventricle muscle and in the subendocardial layer of the heart left ventricle myocardium was observed. The role of hypoxia as a one of essential factors responsible for the observed morphologic changes has been discussed.

ESPE Position Statement for Paediatric Endocrinology Subspecialty

Paediatric Endocrinology, under the leaderships of Lawson Wilkins in the US and of Andrea Prader in Europe, started to take shape as a subspecialty in the 1960s. Since that time, paediatric endocrinology has developed at a tremendous speed, especially during the last 30 years, in line with increasing knowledge in the field of genetics and other basic sciences, as well as improved medications and technical facilities. Endocrine conditions encountered in childhood are diverse and show a wide spectrum that is in many aspects substantially different from endocrine diseases in adults and the elderly. Children are simply not little adults. Handling of paediatric endocrine disorders requires the special attention of medical specialists with significant background training in paediatrics, to understand all aspects of human growth and development, along with specialised training in paediatric endocrinology. Developmental issues, including sex differentiation, body growth, skeletal development, pubertal maturation, and neuropsychological development from the intrauterine period to adolescence and young adulthood, are specific paediatric issues that cannot be fully understood and managed without paediatric training as the basic medical background. Recognising, classifying, diagnosing, and managing disorders of growth and development are specific tasks for fully trained paediatric endocrinologists. At the European Academy of Paediatrics (EAP), a subsection of the European Union of Medical Specialists (UEMS; formerly CESP), each paediatric subspecialty is represented by a liaison officer within the Tertiary Care Working Group (TCWG). The EAP has its own legislation/constitution (Belgian/ EU law) representing the central unifying platform for paediatric training in Europe. One of the major goals of the liaison officers is to update the current syllabus and accreditation procedures for their subspecialty, aiming at harmonisation of paediatric training throughout Europe. ESPE has recently, in 2014, revised its training program and this was approved by the General AsPublished online: July 6, 2016 HORMONE RESEARCH IN PÆDIATRICS