Impact of anakinra treatment on cytokine and lymphocytes/ monocytes profile of an Erdheim-Chester patient.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans cells histiocytosis associated with intense immune activation. In our clinical center, an ECD patient was treated with anakinra, IL1RA (interleukin1 receptor antagonist), resulting in clinical improvement and major decrease of pathological fatigue. The aim of the study was to evaluate changes in cytokine profile and shift of immune cells estimated by flow cytometric analysis of ECD patient before, during initial stages of anakinra treatment as well as after treatment ceased in comparison to healthy donors. METHODS: Singleplex reactions of 19 individual cytokines from serum of ECD patient were measured by FACS array. Flow cytometric analyses were performed on peripheral blood cells. RESULTS: The most striking result is substantial decrease of IL6 immediately after anakinra treatment started suggesting a major role of IL1 pathway in ECD pathophysiology. As for flow cytometric analysis, increased number of CD16+ monocytes before treatment is a new finding. CONCLUSION: Our results suggest that IL6 may be a marker of early treatment response of ECD patients treated with anakinra.

[Cytokine profiles of multiple myeloma and Waldenström macroglobulinemia]. / Cytokinové profily mnohocetného myelomu a Waldenströmovy makroglobulinemie.

Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are malignant disorders of B lymphocytes. These diseases are characterized by monoclonal immunoglobulin production and bone marrow infiltration, which further lead to disease manifestation mainly via osteolytic lesions and disruption of hematopoiesis. The bone marrow microenvironment plays a crucial role in pathogenesis of both of these diseases, as it is well known that interaction between malignant cells and bone marrow cells facilitates both survival and growth of these tumor cells. The interactions are mediated by several different factors, including cytokines. Their production leads to tumor cell growth, proliferation and survival contributing to pathogenesis of MM and WM. In this review, we focus on function of the most important cytokines in both these diseases.

[Cyclins D in regulation and dysregulation of the cell cycle in multiple myeloma]. / Cykliny D v regulaci a dysregulaci bunecného cyklu u mnohocetného myelomu.

Multiple myeloma is the second most common hematooncological disease characterized by clonal proliferation of plasma cells and monoclonal immunoglobulin production. It is a heterogenous disease; however, dysregulation of cyclins D seems to be an early unifying pathogenic event in multiple myeloma. In almost all patients, there is increased expression level of at least one of the cyclins D. Nevertheless, the mechanism of this increase is unknown in many cases. Next to wellknown roles of cyclins D in the cell cycle, they have many other functions contributing to tumor cell progression. Cyclins D are prognostic markers and are also used for subclassification of multiple myeloma. In this review, we focus on significance of cyclins D in multiple myeloma.

[Degradation of proteins by ubiquitin proteasome pathway]. / Degradace proteinu ubikvitinproteazomovou dráhou.

All intracellular and some extracellular proteins are continually degraded and replaced by synthesis of new proteins. Both these processes need to stay in equilibrium since their balance may lead to emergence of diseases. Cells contain many proteolytic systems that ensure highly specific and controlled degradation of proteins. One of these systems is the proteasome, a very complex molecular engine allowing degradation of proteins conjugated to ubiquitin. Since the first isolation of proteasome in 1968, many details about its function have been uncovered. In 2004, Nobel Prize for chemistry was awarded for these discoveries. In our review article, we aimed to summarize information about the mechanism of highly selective degradation of proteins by the ubiquitin proteasome pathway. Individual parts of the paper summarize current knowledge about highly selective degradation of proteins by the ubiquitin proteasome system, mechanisms of protein degradation regulation and bio-logical effects of proteasome inhibitors.

[Proteasome inhibitors in treatment of multiple myeloma]. / Inhibitory proteazomu v lécbe mnohocetného myelomu.

Multiple myeloma, a plasma cell malignancy, still remains a hard-to-treat hematological disease that desperately needs new therapy targeting plasmocytes but also the bone marrow microenvironment. Clonal plasmocytes are characterized by increased regulation of ubiquitin-proteasome pathway which augments their sensitivity to proteasome inhibitors. Treatment strategies based on proteasome inhibitors belong to the era of new drugs, and they have become increasingly important for treatment of multiple myeloma in recent years. Bortezomib became the first proteasome inhibitor approved for the treatment of multiple myeloma and showed remarkable anti-myeloma activity. However, despite its high efficiency, a large proportion of patients have became bortezomib resistant. The second generation of proteasome inhibitors - carfilzomib, marizomib and MLN9708 - were developed in an effort to overcome bortezomib-resistance and find proteasome inhibitors with a better toxic profile. These drugs brought a chance that multiple myeloma would become a chronic disease.

[Implication of bone marrow microenvironment in pathogenesis of multiple myeloma]. / Význam mikroprostredí kostní drene v patogenezi mnohocetného myelomu.

Multiple myeloma is a hematooncological disease characterized by malignant proliferation of plasma cells. These cells accumulate in the bone marrow where they suppress physiological hematopoiesis; at the same time, these cells interact with a wide variety of cytokines, growth factors and adhesion molecules. It is obvious that the bone marrow microenvironment plays an important role in disease pathogenesis as well as treatment resistance.

[Molecular basis of Waldenström macroglobulinemia]. / Molekulární podstata Waldenströmovy makroglobulinemie.

Waldenström macroglobulinemia is a rare lymphoproliferative disease that is currently classified into lymphomas with incidence of 3 cases per million. This disease comprises about 1-2% of hematological malignancies and is characterized by infiltration of malignant B cells into the bone marrow and presence of monoclonal immunoglobulin IgM in serum. WM is still an incurable disease with median survival of 5 years. Molecular basis of this disease remains unclear even though deletion of 6q, trisomy of chromosomes 4 and 8, deletion of 13q and increased expression of IL-6 seem to be typical for this disease. The most important changes of microRNA are increased expression of miR-155 and decreased expression of miR-9*. This work aims to describe current knowledge about the molecular basis of this disease.