Evaluation of precipitation forecasts by polarimetric radar

Over the last years, weather services have developed a new generation of high resolution mesoscale numerical weather prediction (NWP) models with the aim to explicitly predict convection. New methods are required to validate the representation of precipitation processes in these NWP models against observations. Polarimetric radar systems are especially suited for model validation as they provide information on the intensity and the microphysical characteristics of a precipitation event at a high temporal and spatial resolution. However, the observations can not be directly employed for model evaluation as polarimetric radar systems do not explicitly measure the parameters represented in microphysical parameterization schemes. In order to establish a relationship and allow for a direct comparison between the model parameters and the observations, the polarimetric radar forward operator SynPolRad (Synthetic Polarimetric Radar) has been developed. SynPolRad simulates synthetic polarimetric radar quantities out of model forecasts which permits an evaluation in terms of observed quantities. In a first step, the synthetic reflectivity, LDR, and ZDR are computed from predicted bulk water quantities and in a second step, the beam propagation in the model domain is simulated under consideration of refractivity and attenuation effects. In order to successfully employ SynPolRad for model evaluation purposes, the link between the forward operator and the mesoscale model has to conform as closely as possible to the model assumptions. However, in the case of a polarimetric radar forward operator not all the input parameters are defined by the model. Within this work, these free parameters are derived on theoretical terms accordingly to the model assumptions such that the polarimetric quantities match the thresholds of a hydrometeor classification scheme. Furthermore, special care is given to the representation of brightband signatures. The application of SynPolRad on two case studies proves the potential of the new method. A stratiform and a convective case study are chosen to assess the ability of mesoscale models to represent precipitation in different dynamical regimes. LMK (Lokal-Modell-Kürzestfrist) and MesoNH (Mesoscale Non-Hydrostatic Model) simulations considering different microphysical parameterization schemes are evaluated. The evaluation concentrates on the representation of life cycle, intensity, and the spatial distribution of synthetic reflectivity, LDR, and ZDR. Furthermore, hydrometeor types derived from the observed and synthetic polarimetric quantities employing a classification scheme are compared. Large discrepancies are found between the model simulations and the observations. However, the consideration of an additional ice hydrometeor category in the 3 component scheme significantly improves the performance of the LMK

Comparison of Chimerism and Minimal Residual Disease Monitoring for Relapse Prediction after Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia

AbstractLittle data are available on the relative merits of chimerism and minimal residual disease (MRD) monitoring for relapse prediction after allogeneic hematopoietic stem cell transplantation (HCT). We performed a retrospective analysis of serial chimerism assessments in 101 adult HCT recipients with acute lymphoblastic leukemia (ALL) and of serial MRD assessments in a subgroup of 22 patients. All patients had received myeloablative conditioning. The cumulative incidence of relapse was significantly higher in the patients with increasing mixed chimerism (in-MC) compared with those with complete chimerism, low-level MC, and decreasing MC, but the sensitivity of in-MC detection with regard to relapse prediction was only modest. In contrast, MRD assessment was highly sensitive and specific. Patients with MRD positivity after HCT had the highest incidence of relapse among all prognostic groups analyzed. The median time from MRD positivity to relapse was longer than the median time from detection of in-MC, but in some cases in-MC preceded MRD positivity. We conclude that MRD assessment is a powerful prognostic tool that should be included in the routine post-transplantation monitoring of patients with ALL, but chimerism analysis may provide additional information in some cases. Integration of these tools and clinical judgment should allow optimal decision making with regard to post-transplantation therapeutic interventions

Częstość występowania mutacji somatycznych RAS w raku rdzeniastym tarczycy — analiza populacji polskiej

Introduction: Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations.Material and methods: Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing.Results: RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations.Conclusions: RAS mutations constitute a frequent molecular event in RET-negative sporadic medullary thyroid carcinoma in Polish patients. However, their role in MTC tumorigenesis remains unclear. (Endokrynol Pol 2015; 66 (2): 121–125)Wstęp: Somatyczne mutacje proto-onkogenu RET wykrywane są w trzech czwartych wszystkich sporadycznych raków rdzeniastych tarczycy (MTC). Ostatnie badania wykazały, że mutacja genu RAS jest również częstym wydarzeniem w sporadycznych guzach MTC, co może oznaczać, że mutacje genów z rodziny RAS są alternatywnym wydarzeniem molekularnym w kancerogezie sporadycznej postaci tego raka. Z tego względu celem niniejszej pracy było oszacowanie częstości występowania mutacji genów RAS w sporadycznym raku rdzeniastym tarczycy w populacji polskiej i odniesieniu częstości ich występowania do obecności mutacji somatycznych proto-onkogenu RET.Materiał i metody: Materiał do badań stanowiło 78 fragmentów guza raka rdzeniastego tarczycy (57 próbek postaci sporadycznej i 21 dziedzicznej MTC). Analizowano mutacje genu RET, H-RAS, K-RAS i N-RAS metodą bezpośredniego sekwencjonowania a także 3 próbki raka sporadycznego, wybrane losowo, zostały zeskwencjonowane metodą głębokiego sekwencjonowania (Illumina).Wyniki: Mutację genów RAS wykryto w 26,5% z 49 przeanalizowanych guzów sporadycznej postaci MTC. Natomiast, gdy tylko brano pod uwagę próbki RET-negatywne, częstość występowania mutacji genów RAS wynosiła 68,7% w porównaniu z 6% obserwowanych w guzach RET-pozytywnych. Nie wykryto, w żadnej z próbek, mutacji genu N-RAS. Najczęściej wykrywaną mutacją była zmiana w kodonie 61 genu H-RAS (72%). Nie wykryto mutacji genów RAS w żadnej z próbek dziedzicznego guza raka tarczycy.Wnioski: Mutacje somatyczne genów RAS są częstym wydarzeniem obserwowanym w RET-negatywnych sporadycznych rakach rdzeniastych tarczycy w populacji polskiej. Jednakże rola tych mutacji w rozwoju rdzeniastego raka tarczycy nie jest do końca poznana. (Endokrynol Pol 2015; 66 (2): 121–125

Unsupervised analysis of follicular thyroid tumours transcriptome by oligonucleotide microarray gene expression profiling

Wstęp: Rak pęcherzykowy tarczycy (FTC) jest nowotworem którego podłoże molekularne jest mało zbadane. W podjętej analizie transkryptomuoceniono możliwość dyskryminacji raka i gruczolaka pęcherzykowego tarczycy (FTA) na podstawie badań profilu ekspresjigenów metodą tzw. nienadzorowaną (tzn. na podstawie dominujących źródeł zmienności). Analizę tę prowadzono by sprawdzić czyzłośliwość guza jest rzeczywiście czynnikiem dominującym dla profilu ekspresji genów w nowotworach pęcherzykowych.Materiał i metody: Podstawowy zbiór guzów pęcherzykowych obejmował 52 próbki (27 FTC i 25 FTA), z których wyizolowano całkowityRNA i poddano badaniu na mikromacierzach HG-U133 Plus 2.0. Otrzymany zbiór normalizowano za pomocą RMA i GC-RMA. Identyfikacjigłównych źródeł zmienności dokonano metodą analizy głównych składowych (PCA).Wyniki: Analizę funkcji biologicznej genów przeprowadzono dla pierwszych 6 składowych głównych. Geny skorelowane z pierwsząskładową pozwalały wyodrębnić 2 klastry próbek: jeden złożony głównie z gruczolaków, z wysoką ekspresją między innymi transkryptówtarczycowo-swoistych, drugi zaś, zawierający większość raków, wykazywał zwiększoną, ale heterogenną ekspresję genów związanychz odpowiedzią immunologiczną, a obniżoną ekspresję genów tarczycowych. Geny odpowiedzi immunologicznej stwierdzono wśród transkryptów skorelowanych przebiegiem pierwszej, trzeciej i szóstej głównej składowej; w istotny sposób wpływały one na rozróżnieniemiędzy FTC i FTA.Wnioski: W analizie nienadzorowanej stwierdzono, że złośliwość (inwazyjność) nowotworu pęcherzykowego może być jednymz głównych źródeł zmienności w transkryptomie tych guzów. Jednak, genomiczna odległość między grupami FTC i FTA jest niewielka,a wyodrębnione w analizie nienadzorowanej klastry nakładają się, stąd sama analiza nienadzorowana nie jest wystarczającym narzędziemdo celów klasyfikacji tych guzów.(Endokrynol Pol 2013; 64 (5): 329–334)Introduction: Mechanisms driving the invasiveness of follicular thyroid cancer (FTC) are not fully understood. In our study, we undertookan unsupervised analysis of the set of follicular thyroid tumours (adenomas (FTA) and carcinomas) to verify whether the malignantphenotype influences major sources of variability in our dataset.Material and methods: The core set of samples consisted of 52 tumours (27 FTC, 25 FTA). Total RNA was analysed by oligonucleotidemicroarray (HG-U133 Plus 2.0). Principal Component Analysis (PCA) was applied as a main method of unsupervised analysis.Results: An analysis of biological character of genes correlated to the first six PCs was performed. When genes correlated to the first PCwere used to cluster FTC and FTA, they appeared in two branches; one, relatively enriched in adenomas, with homogenous expressionof subset of genes, and the other containing mainly carcinomas, with down-regulation of these genes and heterogeneous up-regulationin a smaller cluster of transcripts. Genes highly up-regulated in adenomas included some thyroid-specific transcripts. The second clusterof genes, up-regulated in carcinomas, contained mainly immunity-related transcripts. Immune response genes were found in the first,third and sixth principal components, improving the discrimination between carcinomas and adenomas.Conclusions: Our unsupervised analysis indicates that invasiveness of follicular tumours might be considered as the major source of variabilityin transcriptome analysis. However, the distance between both groups is small and the clusters are overlapping, thus, unsupervisedanalysis is not sufficient to properly classify them. (Endokrynol Pol 2013; 64 (5): 328–334

The Methanothermobacter thermautotrophicus ExoIII homologue Mth212 is a DNA uridine endonuclease

The genome of Methanothermobacter thermautotrophicus, as a hitherto unique case, is apparently devoid of genes coding for general uracil DNA glycosylases, the universal mediators of base excision repair following hydrolytic deamination of DNA cytosine residues. We have now identified protein Mth212, a member of the ExoIII family of nucleases, as a possible initiator of DNA uracil repair in this organism. This enzyme, in addition to bearing all the enzymological hallmarks of an ExoIII homologue, is a DNA uridine endonuclease (U-endo) that nicks double-stranded DNA at the 5′-side of a 2′-d-uridine residue, irrespective of the nature of the opposing nucleotide. This type of activity has not been described before; it is absent from the ExoIII homologues of Escherichia coli, Homo sapiens and Methanosarcina mazei, all of which are equipped with uracil DNA repair glycosylases. The U-endo activity of Mth212 is served by the same catalytic center as its AP-endo activity

A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML

Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as a potential mechanism of resistance to blinatumomab therapy

The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19–) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19– malignant progenitor cells. We present 2 BCR-ABL1 fusion–positive BCP-ALL patients with CD19– myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1–positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19– precursors should be targeted to avoid CD19– relapses in patients with BCR-ABL1–positive ALL