Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome

Background: Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear. Results: MacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis. Conclusions: Together, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies

Using gene co-expression network analysis to predict biomarkers for chronic lymphocytic leukemia

<p>Abstract</p> <p>Background</p> <p>Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is a highly heterogeneous disease, and can be divided roughly into indolent and progressive stages based on classic clinical markers. Immunoglobin heavy chain variable region (IgV_H) mutational status was found to be associated with patient survival outcome, and biomarkers linked to the IgV_H status has been a focus in the CLL prognosis research field. However, biomarkers highly correlated with IgV_H mutational status which can accurately predict the survival outcome are yet to be discovered.</p> <p>Results</p> <p>In this paper, we investigate the use of gene co-expression network analysis to identify potential biomarkers for CLL. Specifically we focused on the co-expression network involving ZAP70, a well characterized biomarker for CLL. We selected 23 microarray datasets corresponding to multiple types of cancer from the Gene Expression Omnibus (GEO) and used the frequent network mining algorithm CODENSE to identify highly connected gene co-expression networks spanning the entire genome, then evaluated the genes in the co-expression network in which ZAP70 is involved. We then applied a set of feature selection methods to further select genes which are capable of predicting IgV_H mutation status from the ZAP70 co-expression network.</p> <p>Conclusions</p> <p>We have identified a set of genes that are potential CLL prognostic biomarkers IL2RB, CD8A, CD247, LAG3 and KLRK1, which can predict CLL patient IgV_H mutational status with high accuracies. Their prognostic capabilities were cross-validated by applying these biomarker candidates to classify patients into different outcome groups using a CLL microarray datasets with clinical information.</p

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management

Державна підтримка підприємців та доступність фінансових ресурсів: оцінка студентів Чехії, Польщі і Словаччини

У статті проаналізовано залежність готовності випускників університетів починати підприємницьку діяльність від таких трьох факторів: національність респондентів, державна підтримка підприємництва в країні, рівень доступу підприємців до фінансових ресурсів. Результати показали, що відношення студентів до започаткування власної справи залежать від країни їх походження. Підґрунтям дослідження стали результати анкетування 1352 студентів: 409 з чотирнадцяти університетів Чеської Республіки, 375 з трьох університетів Польщі та 568 з восьми університетів Словаччини. Методичним інструментарієм дослідження стали статистичні методи: критерій узгодженості Пірсона (chi–squared test) та z–оцінка, результати анкетування були згруповані та проаналізовані з використанням інструменту обробки даних – зведених таблиць. Найбільший інтерес до підприємницької діяльності виявлено у студентів з Польщі (38,1% респондентів), середній – у студентів зі Словаччини (35,7% респондентів), а найменший інтерес продемонстрували студенти з Чехії (26,9% респондентів). У статті доведено суттєвий вплив національності студентів на вибір тих факторів, які виявилися для них найбільш важливими при прийняття рішення щодо започаткування власної справи. Так, наприклад, такі два фактори як доступ до фінансових ресурсів та необхідність дотримання відповідної розрахунково–платіжної дисципліни виявилися важливими для 27,4% опитаних студентів з Чехії, 22,4% студентів зі Словаччини та 19,5% студентів з Польщі. Правові умови ведення бізнесу виявилися важливими для 25,9% респондентів з Чехії та 17,4% респондентів зі Словаччини. Стаття містить результати аналізу не лише двох основних факторів впливу на готовність студентів - випускників університетів до підприємництва (державна підтримка та доступ до фінансових ресурсів), а ряду додаткових, найбільш важливими з яких виявилися наступні: соціальне середовище в країні (сім'я, суспільство, політика, засоби масової інформації); макроекономічне середовище (ВВП, зайнятість, інфляція); якість ділового середовища (адміністративний тягар для підприємців, покращення становища суб'єктів господарювання порівняно з ситуацією в діловому середовищі 5 років тому); якість вищої освіти (система університетської освіти, набуті знання та їх подальше застосування) тощо.The article’s aim is to find out whether student's nationality influences the assessment of access to financial resources, state support for entrepreneurship, and students’ inclination to start a business after graduating from college. The questionnaire was completed by 1352 students: 409 from 14 CR universities; 375 from 3 PL universities and 568 from 8 universities in SR. To meet the goal of the article, mathematical statistics such as chi–squared test, pivot tables, z–score, and descriptive statistics were used. One of the most significant findings is that there were significant differences between the students of different nationalities when assessing access to financial resources. The most significant interest in after graduation entrepreneurship was seen in students from Poland (38.1%), then from Slovakia (35.7%), and the least interest was demonstrated by the students from Czech Republic (26.9%). Students from Czech Republic (25.9%) and Slovak Republic (17.4%) had significantly different views on the quality of legal conditions for entrepreneurship in their countries. Students from Czech Republic evaluated access to external resources and payment discipline as being the worst (27.4%), as compared to the ratings by the students from Slovakia (22.4%) and Poland (19.5%). In addition to state support and access to financial resources, other essential factors are: the social environment in the country (family, society, politicians, the media); macroeconomic environment (statistical indicators – GDP, employment, inflation); quality of the business environment (administrative burden on entrepreneurs, improving the situation of business entities compared to the situation in the business environment 5 years ago); quality of higher education (university education system, acquired knowledge and their subsequent application), etc

Preferences of people with disabilities on wheelchairs in relation to forest trails for recreational in selected European countries

The article presents the results of the survey on the preferences of disabled people in wheelchairs for selected features recreational trails in the woods. The study was conducted in 2015, including a sample of 130 people older than 18 years, in Poland, the Czech Republic and Slovakia (52 interviews in Poland, 21 in the Czech Republic and 57 in Slovakia). Respondents were interviewed both at the premises of the organisation as well as by email. The questions in the survey were designed to determine the preferences of the respondents in terms of recreational trails in the forests concerned: the optimal length of the route, recreational and educational points along the distribution routes of and usability of different types of forest roads. The results show that there is quite a lot of differences between the preferences of respondents from each of the analysed countries. Respondents from the Poland and Slovakia prefer shorter routes for recreation in forests, with a greater incidence of recreational and educational points along the route, whilst respondents in the Czech Republic prefer far longer routes, with a relatively larger distance between recreational points. In all the analysed countries, people with disabilities attributed highest usefulness to asphalt surfaces, concrete surfaces or surfaces made of cobblestones. The surface evaluated lowest for usability was made of wood

Preferences of disabled on wheelchairs in relation to forest recreation in Poland and Czech Republic

The article presents the results of the survey on the preferences of disabled people on wheelchairs for selected features of recreation in forests. The study was conducted in 2015, including a sample of 108 people over the age of 18 interviewed simultaneously in the Poland and Czech Republic (52 interviews in Poland, 56 in the Czech Republic). Respondents were questioned both at the premises of the activation organizations as well as activation by email. The questions in the survey were designed to determine the preferences of the respondents in terms of the frequency and duration of the rest in the forests, the size of forest users groups, the choice of means of transport and certain equipment of forest recreation management. The results show that there is quite a lot of differences between the preferences of respondents from both of the analyzed countries. The statistic differences relate mainly to the choice of the means of transport enabling the rest of the forest, the frequency of recreation visits in the forests and the scope of necessary recreational infrastructure in the forests. The results indicate also significant differences in the profile of the respondents. They were associated with the place of residence, time of moving on a wheelchair and the use of a particular type of wheelchair

Preferences of people with disabilities on wheelchairs in relation to forest trails for recreational in selected European countries

The article presents the results of the survey on the preferences of disabled people in wheelchairs for selected features recreational trails in the woods. The study was conducted in 2015, including a sample of 130 people older than 18 years, in Poland, the Czech Republic and Slovakia (52 interviews in Poland, 21 in the Czech Republic and 57 in Slovakia). Respondents were interviewed both at the premises of the organisation as well as by email. The questions in the survey were designed to determine the preferences of the respondents in terms of recreational trails in the forests concerned: the optimal length of the route, recreational and educational points along the distribution routes of and usability of different types of forest roads. The results show that there is quite a lot of differences between the preferences of respondents from each of the analysed countries. Respondents from the Poland and Slovakia prefer shorter routes for recreation in forests, with a greater incidence of recreational and educational points along the route, whilst respondents in the Czech Republic prefer far longer routes, with a relatively larger distance between recreational points. In all the analysed countries, people with disabilities attributed highest usefulness to asphalt surfaces, concrete surfaces or surfaces made of cobblestones. The surface evaluated lowest for usability was made of wood