Applying selective breeding for 10 years we established the MeLiM (Melanoblastoma-bearing Libechov Minipigs) strain. Melanoblastoma (MB) in this strain shows a hereditary occurrence. Cutaneous tumours are usually nodular, multiple and distributed on various parts of body. They appear in darkly pigmented animals already at the birth or during two months thereafter (57% of all animals). Numerous organ metastases mainly into the spleen, lymph nodes and lungs are regularly ascertained in animals with cutaneous MB. Tumour cells were surprisingly found also in the inner organs of phenotypically healthy minipigs in which no cutaneous MBs were observed visually (27% of all animals). About 34% of all affected piglets die during the first 2 months of age. These features document a malignancy of this tumour in the MeLiM strain. Original surgical technique was applied in more than 40 affected minipigs at 1-2 months of age. It consists in a devitalization (ischemization) of one of cutaneous tumours by the mattress sutures conducted around the tumour base without any excision of tumour tissue. This simple procedure causes a total destruction of MB cells in all cutaneous tumours as well as in all organ metastases during 4-6 months. Animals treated by this technique were fully healed of tumour cells and no relapses were observed. This technique could bring similar positive results also in therapy of human MB.

• MeSH
• antigeny nádorové analýza   imunologie   MeSH
• barva vlasů genetika   MeSH
• chov MeSH
• dědičné nádorové syndromy genetika   imunologie   patologie   MeSH
• dominantní geny MeSH
• fenotyp MeSH
• geny recesivní MeSH
• hlavní histokompatibilní komplex genetika   MeSH
• ligace MeSH
• melanocyty imunologie   MeSH
• melanom experimentální krevní zásobení   vrozené   genetika   imunologie   patologie   chirurgie   MeSH
• metastázy nádorů MeSH
• miniaturní prasata genetika   MeSH
• nádorové kmenové buňky patologie   MeSH
• nádory kůže krevní zásobení   vrozené   genetika   patologie   chirurgie   MeSH
• nádory plic krevní zásobení   vrozené   genetika   patologie   chirurgie   MeSH
• nádory sleziny krevní zásobení   vrozené   genetika   patologie   chirurgie   MeSH
• pigmentace kůže genetika   MeSH
• pigmentový névus vrozené   genetika   patologie   MeSH
• prasata MeSH
• šicí techniky MeSH
• spontánní remise MeSH
• vnitřnosti patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH

• MeSH
• antigeny nádorové analýza   MeSH
• buněčná adheze MeSH
• imunofenotypizace MeSH
• leukemie metabolismus   patologie   MeSH
• lidé MeSH
• lymfom metabolismus   patologie   MeSH
• molekuly buněčné adheze metabolismus   MeSH
• myelodysplastické syndromy metabolismus   patologie   MeSH
• nádorové buňky kultivované MeSH
• nádorové kmenové buňky metabolismus   MeSH
• nádorové proteiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antigeny nádorové MeSH
• molekuly buněčné adheze MeSH
• nádorové proteiny MeSH

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells. These cells have an unlimited self-renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC-derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.

• Klíčová slova
• ARSACS, 3D organoids, ataxia, cerebellum, disease modelling, induced pluripotent stem cells,
• MeSH
• indukované pluripotentní kmenové buňky MeSH
• lidé MeSH
• mozeček patologie   MeSH
• nemoci mozečku patologie   terapie   MeSH
• spinocerebelární ataxie vrozené   patologie   terapie   MeSH
• svalová spasticita patologie   terapie   MeSH
• teoretické modely MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte-macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.

• MeSH
• aktivace transkripce účinky léků   MeSH
• azacytidin farmakologie   terapeutické užití   MeSH
• buněčná diferenciace účinky léků   genetika   MeSH
• chromatin genetika   MeSH
• faktory stimulující kolonie farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• myelodysplastické syndromy farmakoterapie   genetika   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• protinádorové antimetabolity farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• regulační oblasti nukleových kyselin účinky léků   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• trans-aktivátory genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• chromatin MeSH
• faktory stimulující kolonie MeSH
• protinádorové antimetabolity MeSH
• proto-oncogene protein Spi-1 MeSH Prohlížeč
• protoonkogenní proteiny MeSH
• trans-aktivátory MeSH

To evaluate the preclinical efficacy and safety of human mesenchymal stem cells (hMSC) rapidly expanded in growth medium for clinical use with human serum and recombinant growth factors, we conducted a controlled, randomized trial of plasma clots with hMSC vs. plasma clots only in critical segmental femoral defects in rnu/rnu immunodeficient rats. X-ray, microCT and histomorphometrical evaluation were performed at 8 and 16 weeks. MSC were obtained from healthy volunteers and patients with lymphoid malignancy. Human MSC survived in the defect for the entire duration of the trial. MSC from healthy volunteers, in contrast to hMSC from cancer patients, significantly improved bone healing at 8, but not 16 weeks. However, at 16 weeks, hMSC significantly improved vasculogenesis in residual defect. We conclude that hMSC from healthy donors significantly contributed to the healing of bone defects at 8 weeks and to the vascularisation of residual connective tissue for up to 16 weeks. We found the administration of hMSC to be safe, as no adverse reaction to human cells at the site of implantation and no evidence of migration of hMSC to distant organs was detected.

• MeSH
• dospělí MeSH
• femur diagnostické zobrazování   fyziologie   MeSH
• hojení ran fyziologie   MeSH
• krysa rodu Rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezenchymální kmenové buňky fyziologie   MeSH
• náhodné rozdělení MeSH
• osteogeneze fyziologie   MeSH
• počítačová rentgenová tomografie metody   MeSH
• potkani nazí MeSH
• senioři MeSH
• syndromy imunologické nedostatečnosti diagnostické zobrazování   imunologie   terapie   MeSH
• transplantace mezenchymálních kmenových buněk metody   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• krysa rodu Rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The impact of classification, prognostic factors and treatment on survival and rate of leukemic transformation was analysed in 197 patients with primary myelodysplastic syndrome (MDS) treated in the Institute of Hematology and Blood Transfusion in the years 1980-2000. METHODS AND RESULTS: The patients were classified according to the FAB criteria and divided into risk groups according to the International Prognostic Scoring System (IPSS). A separate evaluation of 34 patients who underwent stem cell transplantation and of 163 of those not transplanted was performed. Median survival of not transplanted patients with RAEB (10.0 months) and RAEB-T (12.0 months) was significantly shorter than survival of RA (62.4 months) and RARS (48.1 months, P < 0.001) patients as well as survival of patients included in intermediate II. (13.8 months) and high (10.8 months) risk subgroups when compared to those with low (74.9 months) and intermediate I. risk (56.0 months, P < 0.001). A similar difference was observed in percentage of patients evolving towards acute leukemia and in estimated 3 years survival (EFS). EFS of RA patients was 57% in contrast to 4% in RAEB-T group (P < 0.001) in the same way, EFS in low risk subgroup was 79% vs. 3% in high risk patients (P < 0.001). Chemotherapy alone did not significantly affect median survival of patients with advanced MDS when compared with supportive care. On the contrary, median survival of transplanted patients with RAEB and RAEB-T was 38.4 months in comparison to 11.5 months in those not transplanted (P < 0.001) and 36.8 months vs. 12.0 months in transplanted and not transplanted patients with intermediate II. and high risk (P = 0.05). The difference in survival between transplanted and not transplanted patients with RA and in patients in low and intermediate I. risk subgroups was not statistically significant. CONCLUSIONS: We confirmed an adverse effect of excess of blasts on prognosis of patients with primary MDS. Stem cell transplantation had a significant beneficial effect on survival of patients with RAEB or RAEB-T as well as of patients included in intermediate II. or high risk subgroups. The impact of stem cell transplantation on survival of patients with RA or with low or intermediate I. risk was not significant. Therefore, further criteria should be taken in account for indication of stem cell transplantation in these subgroups of patients.

• MeSH
• leukemie etiologie   MeSH
• lidé MeSH
• myelodysplastické syndromy * klasifikace   komplikace   terapie   MeSH
• prognóza MeSH
• rizikové faktory MeSH
• transplantace kmenových buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH

The heterogeneous nature of myelodysplastic syndrome (MDS) brings a very variable prognosis of patients with the need for individualized treatment. The prognosis and treatment depend on the conventional determination of IPSS (International Prognostic Scoring System) and its revised form IPSS-R, which divides patients into lower and higher risk groups. Treatment of patients with lower risk of MDS include the improvement of cytopenia, especially anemia. The goal of treatment in patients with higher risk of MDS is delaying disease progression and improve patient survival. The only curative method for therapy of MDS is allogeneic hematopoietic stem cell transplantation (HSCT), howewer it is rarely applicable due to the age and comorbidities of patients.

• Klíčová slova
• azacitidin, erythropoiesis-stimulating agents, lenalidomid, lenalidomide, myelodysplastic syndromes, treatment, type 2 diabetes,
• MeSH
• lidé MeSH
• myelodysplastické syndromy * MeSH
• prognóza MeSH
• progrese nemoci MeSH
• riziko MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• lidé MeSH
• myelodysplastické syndromy * terapie   MeSH
• nádory * MeSH
• příprava pacienta k transplantaci MeSH
• retrospektivní studie MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

Granulocytic precursors of the granulopoietic proliferating compartment (GPC) were investigated in patients suffering from refractory anemia (RA) of myelodysplastic syndrome (MDS) to provide an information on the number of nucleoli and incidence of main nucleolar types in these cells stained with the simple cytochemical procedure for the demonstration of RNA. The results demonstrated that the incidence of main nucleolar types in all stages of the granulopoietic proliferating compartment in RA patients of MDS generally did not differ in comparison with that of control patients without a disturbed granulopoiesis. In contrast, the number of nucleoli expressed by the values of the nucleolar coefficient in all stages of GPC in RA patients was significantly smaller than in control persons. In addition, the values of the nucleolar coefficient of myeloblasts in patients with RA of MDS were close to those in patients with acute myeloid leukemias.

• MeSH
• anemie etiologie   patologie   MeSH
• buněčné dělení MeSH
• buněčné jadérko patologie   MeSH
• buňky kostní dřeně patologie   MeSH
• granulocyty patologie   MeSH
• hematopoetické kmenové buňky patologie   MeSH
• lidé MeSH
• myelodysplastické syndromy patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Low-density blood cells from patients with refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T) release a high molecular weight inhibitory substance that reduces the entry of normal progenitor cells of granulocytes and macrophages (CFU-GM) into the S-phase. Out of 20 patients with refractory anemia (RA and RAS) only 3 were positive. One patient with CMML was negative. Serial examination of 3 patients (two RA and one CMML) revealed that the production of the inhibitory activity preceded the development of the disease into RAEB, RAEB-T, or AML. With one exception, the inhibitory activity in positive cases was neutralized by antiserum against human placental ferritin.

• MeSH
• ferritiny fyziologie   MeSH
• granulocyty fyziologie   MeSH
• hematopoetické kmenové buňky fyziologie   MeSH
• hematopoéza * MeSH
• lidé MeSH
• lymfokiny biosyntéza   MeSH
• makrofágy fyziologie   MeSH
• myelodysplastické syndromy komplikace   metabolismus   MeSH
• refrakterní anemie etiologie   MeSH
• vyšetřování kostní dřeně MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ferritiny MeSH
• lymfokiny MeSH
• stem cell inhibitory factor MeSH Prohlížeč