Molecular basis of multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by clonal expansion of malignant plasma cells in the bone marrow. The disease is accompanied by various clinical manifestations, such as bone lesions, anemia, hypercalcemia, and renal insufficiency. However, despite significant advances in treatment over the last two decades, the disease remains challenging to treat, and most patients relapse. Although its pathogenesis has not yet been elucidated, it is clear that genomic instability plays a key role in its develop-ment or resistance to treatment. In some instances, the cause of this instability is chromothripsis, a form of complex genomic rearrangement that involves shattering and subsequent haphazard reassembly of chromosomes within a single catastrophic event. The resulting rearrangements involve a variety of structural changes, including deletions, duplications, inversions, and translocations, that lead to genome disruption. Specifically, these changes may result in alteration or inactivation of tumor suppressor genes (TP53 and CDKN2C), activation of oncogenes (MAF, FGFR3, and CCND1) or genes involved in key cellular processes. Unraveling the mechanisms that result in chromothripsis provides opportunities to identify critical genes and pathways involved in MM pathogenesis. These findings may serve as a basis for improved dia-gnostic approaches. PURPOSE: The goal of this review is to summarize the common primary and secondary chromosomal aberrations in MM with a particular focus on introducing complex chromosomal aberrations, especially chromothripsis in MM.

The endoplasmic reticulum and its signaling pathways - a novel target for multiple myeloma treatment.

BACKGROUND: The endoplasmic reticulum (ER), an organelle composed of a system of cisternae and tubules, is essential for many cellular processes, including protein synthesis and transport. When misfolded proteins accumulate in the ER lumen, ER stress is induced, and the subsequent response to the disruption of homeostasis is the activation of the unfolded protein response (UPR). The purpose of this process is to restore homeostasis by increasing the capacity of the ER and its ability to fold proteins. Activation of the homeostatic UPR occurs via one of three transmembrane proteins, inositol-requiring enzyme 1a (IRE1a), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Failure of the attempt to restore homeostasis, on the other hand, leads to the development of terminal UPR and apoptosis via hyperactivation of the same proteins. Activation of UPR has been described in many malignancies, including multiple myeloma (MM), which is characterized by malignant transformation of plasma cells and increased monoclonal immunoglobulin synthesis, where the role of the ER is of particular importance. Despite advances in the treatment of MM, the disease remains difficult to treat and targeting signaling pathways associated with the UPR could, for example, enhance the effect of proteasome inhibitors. PURPOSE: This review intends to present the molecular response to ER stress under physiological circumstances and in the context of cancer, particularly with regard to potential therapeutic targets in MM.

Erdheim-Chester disease.

Erdheim-Chester disease is a rare inflammatory myeloid clonal disease which is classified into histiocytoses. It is characterized by excessive production and accumulation of foamy histiocytes and Touton giant cells in various tissues and organs. Foamy histiocytes and Touton giant cells produce proinflammatory cytokines and chemokines and contain somatic mutations in genes activating the MAPK/ERK signaling pathway, but also in genes activating the PI3K/AKT signaling pathway. BRAFV600E is the most common somatic mutation. Furthermore, somatic mutations in the MAP2K1, KRAS, NRAS, ARAF or PIK3CA genes are abundant. Erdheim-Chester dis-ease is a multisystemic disease in which any organ can be affected, especially the long bones of the lower extremities, but also the cardiovascular system, retroperitoneum, endocrine system, central nervous system, lungs, skin or orbit. The dia-gnosis is difficult because of the various manifestations of this disease. The disease occurs mainly in adults and is more common in men than in women. Targeted treatment by kinase inhibitors, interferon a, cytokine blockers or cladribine is used for the treatment.

Waldenström macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is a hematological malignancy; it is a monoclonal gammopathy, a disease characterized by presence of a monoclonal immunoglobulin in serum and/or urine. The median age at dia-gnosis is 71 years. WM is not an aggres-sive disease and patients with this dia-gnosis can live for several years. Infiltration of the bone marrow with lymphoplasmacytoid cells causes anemia, leading to various problems, mainly fatigue. Hepatomegaly, splenomegaly and lymphadenopathy can also occur. Hyperviscosity syndrome can appear and is caused by excessive production of immunoglobulin M. A mutation in MYD88 gene is detected in almost every WM patient, and in almost one third of them, a mutation in CXCR4 gene is detected. The detection of MYD88 mutation is important for a correct therapeutic strategy, since a Brutons tyrosine kinase inhibitor, ibrutinib, is most effective in patients with mutated MYD88 and wt CXCR4. The therapy is started when first symptoms occur. PURPOSE: The aim of this study is to summarize current knowledge about this disease, its dia-g-nostics, molecular basis and treatment.

Role of exosomes in malignancies.

BACKGROUND: Extracellular vesicles are closed structured surrounded by a lipid membrane that are secreted by almost all types of cells; their function is information delivery during cell-to-cell communication. They are most commonly divided into three categories - exosomes, microvesicles and apoptotic bodies. Exosomes are small vesicles with the size of 30-100 nm, and they are found in almost all body fluids, including peripheral blood, urine, breast milk, saliva and others. They are able to deliver their content to target cells and change their behavior. Cancer cells are able to secrete more exosomes and also contain different proteins and RNA species than the exosomes from healthy cells. Due to their specific composition that is connected to the cell of origin, exosomes could be used as bio-markers of various diseases in the future. PURPOSE: The aim of this work is to summarize current knowledge about exosomes and their role in various processes connected to resistance in tumors. This work was supported by grant of the Ministry of Health of the Czech Republic AZV 17-29343A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

The effect of colesevelam treatment on bile acid and lipid metabolism and glycemic control in healthy men.

The treatment of hypercholesterolemia with bile acid (BA) sequestrants results in upregulation of BA synthesis through the classical pathway initiated by cholesterol 7alpha-hydroxylase (CYP7A1). To characterize the detailed dynamics of serum lipid and BA concentrations and the BA synthesis rate in response to treatment with BA sequestrants and to determine whether the -203A/C promoter polymorphism of the CYP7A1 encoding gene (CYP7A1) affects such a response, this pilot study was carried out in healthy men (8 homozygous for the -203A allele and 8 homozygous for the -203C allele of CYP7A1). The subjects were treated for 28 days with colesevelam and blood was drawn for analysis before and on days 1, 3, 7, 14 and 28 of treatment. The response of lipids, BA, fibroblast growth factor-19 (FGF19) and 7alpha-hydroxy-4-cholesten-3-one (C4) to colesevelam did not differ between carriers of -203A and -203C alleles; their data were then aggregated for further analysis. Colesevelam treatment caused immediate suppression of FGF19 concentration and a fivefold increase in CYP7A1 activity, as assessed from C4 concentration, followed by a 17 % decrease in LDL-cholesterol. Although total plasma BA concentrations were not affected, the ratio of cholic acid/total BA rose from 0.25+/-0.10 to 0.44+/-0.16 during treatment at the expense of decreases in chenodeoxycholic and deoxycholic acid.

The response of hepatic transcriptome to dietary cholesterol in Prague hereditary hypercholesterolemic (PHHC) rat.

To understand the pathogenesis of hypercholesterolemia in Prague hereditary hypercholesterolemic (PHHC) rat, we analyzed the response of hepatic transcriptome to dietary cholesterol in PHHC and control Wistar rats. Male PHHC and Wistar rats were fed chow (C), 5 % fat (palm kernel oil) (CF) or 1 % cholesterol + 5 % fat (CHOL) diet for three weeks. Hepatic transcriptome was analyzed using Affymetrix GeneChip arrays. No differences were found in the effect of both control diets (C and CF) on lipid metabolism and gene expression of 6500 genes. Therefore, these data were pooled for further analysis. Dietary cholesterol induced accumulation of cholesterol and triacylglycerols in the liver in both strains and hypercholesterolemia in PHHC rats. However, there were no differences in response of hepatic transcriptome to CHOL diet. On the other hand, several genes were found to be differently expressed between both strains independently of the diet. Two of those genes, Apof and Aldh1a7, were studied in more detail, and their role in pathogenesis of hypercholesterolemia in PHHC rats could not been corroborated. In conclusion, the hypercholesterolemia in PHHC rats is due to physiological response of hepatic transcriptome to dietary cholesterol in different genetic background.

[The "Short Physical Performance Battery" in the Czech Republic -  the pilot and validation study in older persons]. / "Krátká baterie pro testování fyzické zdatnosti senioru" -  pilotní studie a validizace testu u starsích osob v Ceské republice.

INTRODUCTION: Population ageing increases number of seniors with decline of physical capabilities and functional deficits. Targeted interventions to maintain or increase physical performance are most effective before the development of full frailty, in so-called "prefrail" period. One of the assessment tools for evaluation of the physical performance and/ or frailty in older persons is the "Short Physical Performance Battery" -  SPPB. The aim of the study was to introduce the assessment battery to clinical practice in the CR and to evaluate its selected psychometric properties. METHOD: Original English SPPB was translated into Czech language and back translated to ensure linguistic accuracy. SPPB was applied in the selected sample of older persons and validated against other performance tools for cognition, self- care and nutrition status used in CR and selected psychometric properties evaluated. RESULTS: We examined 145 older persons (108 women, i.e. 74.48 % and 37 men, i.e. 25.52 %) mean age 80.38 years (54- 101 years, SD ± 8,47). We found good physical performance in 35 (24.1 %) older persons (SPPB 10- 12 points), 21 (14.5 %) were identified as prefrail (SPPB 7- 9 points) and 89 (61.4 %) as frail in high risk of future disability or already disabled (SPPB 6 points). We found statistically significant correlation of global SPPB score with nutritional status (MNA- Short Form), activities of daily living performance (ADL) and cognitive performance (MMSE) -  (Spearman correlation ρ = 0.51; 0.53 and 0.38 respectively). The Cronbachs a for SPPB variables scored 0.821, which is consistent with good internal consistency of SPPB battery. When evaluating 3 age groups [ 75 years (n = 41), 76- 85 (n = 62) and 86- 101 years (n = 42)] the most significant correlations were found between SPPB and MNA, ADL and MMSE in the young elderly (ρ = 0.74, 0.79 and 0.64 respectively) and they diminished with increasing age. CONCLUSION: We confirmed significant correlations between SPPB and self care activities, cognitive performance and nutritional status and good internal consistency of the battery. SPPB test is simple, easy to perform, with low time and cost requirements. It could be recommended for clinical practice in both community and hospitalized older patients to evaluate their overall physical performance and identify persons at risk of frailty and disability who may profit from targeted interventions.