Quantitative analysis of mutant subclones in chronic myeloid leukemia : comparison of different methodological approaches

Identification and quantitative monitoring of mutant BCR-ABL1 subclones displaying resistance to tyrosine kinase inhibitors (TKIs) have become important tasks in patients with Ph-positive leukemias. Different technologies have been established for patient screening. Various next-generation sequencing (NGS) platforms facilitating sensitive detection and quantitative monitoring of mutations in the ABL1-kinase domain (KD) have been introduced recently, and are expected to become the preferred technology in the future. However, broad clinical implementation of NGS methods has been hampered by the limited accessibility at different centers and the current costs of analysis which may not be regarded as readily affordable for routine diagnostic monitoring. It is therefore of interest to determine whether NGS platforms can be adequately substituted by other methodological approaches. We have tested three different techniques including pyrosequencing, LD (ligation-dependent)-PCR and NGS in a series of peripheral blood specimens from chronic myeloid leukemia (CML) patients carrying single or multiple mutations in the BCR-ABL1 KD. The proliferation kinetics of mutant subclones in serial specimens obtained during the course of TKI-treatment revealed similar profiles via all technical approaches, but individual specimens showed statistically significant differences between NGS and the other methods tested. The observations indicate that different approaches to detection and quantification of mutant subclones may be applicable for the monitoring of clonal kinetics, but careful calibration of each method is required for accurate size assessment of mutant subclones at individual time points

System size and centrality dependence of the balance function in A + A collisions at sqrt s NN = 17.2 GeV

Electric charge correlations were studied for p+p, C+C, Si+Si and centrality selected Pb+Pb collisions at sqrt s_NN = 17.2$ GeV with the NA49 large acceptance detector at the CERN-SPS. In particular, long range pseudo-rapidity correlations of oppositely charged particles were measured using the Balance Function method. The width of the Balance Function decreases with increasing system size and centrality of the reactions. This decrease could be related to an increasing delay of hadronization in central Pb+Pb collisions

TAX POLICY ISSUES - TAXATION OF HUNGARIAN AGRICULTURAL ACTIVITY

In modern market economies the majority of state revenues is derived from taxation. Since 1988 the Hungarian regulations on taxation follow the practices of developed countries. The system of burdening is focused/based more and more on consumption instead of production as a result of tax reforms. The different types of enterprises and their activities are subjected to various taxation rules. Unfavourable conditions in agriculture (higher risk, lower profitability) are controlled through the adjustments or reduced tax rates and application of various kinds of tax allowances. The study examines both the theoretical and practical elements of income taxation in the enlarged Europe, particularly the tax schemes employed in Hungary’s agriculture in the period around the EU ac-cession. These investigations are focused also on prospective changes and their consequences for the near future in this regard. In new member states lower in-come tax rates are applied, and agriculture is a distinguished sector in this regard of the economy. XXXXXXXXXXXXXXXXXXXXXXXXXXXX A modern piacgazdaságok esetében az állami bevételek jelentős része az adókból származik. 1988 óta az adórendszer szabályozása Magyarországon a fejlett országok gyakorlatát követi. Az adóztatás súlypontja a termelést terhelő adókról a fogyasztást terhelő adókra helyeződött át. Az egyes vállalkozási formákra, az eltérő gazdasági tevékenységekre más és más adózási szabályok vannak érvényben. A mezőgazdaság kedvezőtlen adottsá-gait (pl. a magasabb kockázat, alacsonyabb jövedelmezőség) a szabályozórend-szer alacsonyabb adókulcsokkal, illetve különféle adókedvezményekkel igyekszik kompenzálni. A tanulmány a jövedelemadózás elméleti és gyakorlati kérdéseinek elemeit vizsgálja a kibővült Európai Unióban, különös tekintettel a magyar me-zőgazdaságra vonatkozó adózási gyakorlatra. A vizsgálatok kiterjednek a közeli jövőben várható változásokra, esetleges következményekre egyaránt

Is profession associated with fear of death?

Publisher’s version of article deposited according to Akademiai Kiado Optional Open Access agreement http://akkrt.hu/196/journals/for_authors/optional_open_access/ July 8, 2015.Introduction: There are relatively few data on the relationship between professions and fear of death. Aim: The aim of the authors was to examine the association between profession and fear of death. Method: Physicians, medical students and other healthcare workers, priests, psychologists and non-healthcare workers (N = 1062) were asked about their attitude to death by means of the Multidimensional Fear of Death Scale. Results: Significant differences were found in the total and some factor scores among the study groups. Priests showed the lowest fear of death values. Scores on the Fear of the Dead Factor was the highest in psychologists and non-healthcare workers who had no contact with the dead and dying. Conclusions: Fear of death seems rather to be present in professions dealing less directly with the dead and dying. Orv. Hetil., 2014, 155(31), 1236–1240.Ye

Multistep pathogenesis of chronic myelomonocytic leukemia in patients

Background: A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients. ----- Methods: Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14). ----- Results: Median survival was 90, 45, and 9 months, respectively (p = .001). Whereas no patient in the T and TS group transformed into acute myeloid leukemia (AML), 6/14 patients in the TSN group had AML at study entry or transformed during follow-up. Leukocyte counts, blast cell counts, and LDH levels were significantly higher in TSN vs. TS and T, respectively, whereas hemoglobin and platelet values were not significantly different. Increased growth factor-independent myeloid colony formation was restricted to TSN but not found in T and TS, respectively. The proportion of patients showing in vitro myelomonocytic skewing in T, TS, and TSN was 0%, 56%, and 100%, respectively (p = .010). ----- Conclusion: Our results demonstrate that the model of multistep pathogenesis in CMML can be recapitulated in patients regarding clinical, phenotypic, and biologic features

Additional file 2: of cFinder: definition and quantification of multiple haplotypes in a mixed sample

Archive containing test data. Include annotations and exemplary alignment files from AVA and CLC for sample 5, as well as simulated test reads for overlapping amplicons

Impact of age on the cumulative risk of transformation in patients with chronic myelomonocytic leukaemia

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia - A Retrospective Analysis in 337 Patients

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies