mTOR signaling in pediatric acute lymphoblastic leukemia and its clinical consequences

Ważnym kierunkiem badań, które mają na celu optymalizację stratyfikacji i leczenia ostrej białaczki limfoblastycznej u dzieci (ALL), jest poszukiwanie nowych molekularnych i genetycznych czynników prognostycznych oraz możliwości wprowadzenia do terapii leków biologicznych, ukierunkowanych na wewnątrzkomórkowe szlaki regulacyjne związane z nowotworzeniem. Ssaczy cel rapamycyny (mTOR), kinaza treoninowo-serynowa, stanowi kluczowy regulator kontroli proliferacji, różnicowania, wzrostu i przeżycia komórek. Uważa się, że odgrywa ona istotną rolę w procesie leukemiogenezy i że może mieć wpływ na przebieg kliniczny ALL u dzieci. W ostatnich latach na szeroką skalę prowadzone są badania nad ewentualnym zastosowaniem inhibitorów kinazy mTOR (MTI) w terapii ALL. W niniejszej pracy podsumowano dotychczasowe doniesienia naukowe dotyczące znaczenia aktywności kinazy mTOR w ALL u dzieci oraz potencjalnej skuteczności jej inhibitorów w terapii ALL.Extensive research has been conducted to identify more precise molecular and cytogenetic markers to improve risk stratification scheme and develop new targeted biological drugs in pediatric acute lymphoblastic leukemia (ALL). Activity of serine/threonine protein kinase mTOR plays a cardinal role in cell proliferation, differentiation, growth and survival. Dysregulation of mTOR signaling pathway is considered to be significant in the pathogenesis and clinical course of childhood ALL. Efficacy of mTOR inhibitors (MTI) in pediatric acute lymphoblastic leukemia has been evaluated in numerous studies. This review summarises the current knowledge of clinical relevance of mTOR signaling in childhood ALL and its potential therapeutic significance

Effect of regulated deficit irrigation on growth, flowering and physiological responses of potted Syringa meyeri ‘Palibin’

The aim of this study was to analyze the physiological and morphological response of Syringa meyeri ‘Palibin’ to different levels of irrigation and to evaluate regulated deficit irrigation (RDI) as a possible technique for saving water in nursery production and promoting of flowering. Plants were grown in 3 liter containers in an unheated greenhouse and were subjected to six irrigation treatments for 18 weeks from the be- ginning of June to mid-October 2011. A drip irrigation system was used. Irrigation treatments were established on the basis of evapotranspiration (ETp). Three constant irrigation treatments were used: 1) 1 ETp; 2) 0.75 ETp; 3) 0.5 ETp, while the other three with irrigation varying between phases were as follows: 4) 1–0.5–1; 5) 1–0.25–1; and 6) 0.5–1–0.5 ETp. The 0.75 ETp and 0.5 ETp irrigation regimes adversely affected the growth and visual quality index of plants as well as they resulted in reduced leaf conductance, transpiration, maximum quantum efficiency of photosystem II (Fv/Fm) and CCI (chlorophyll content index). Plants grown under the 1–0.5–1 ETp regime had the same morphological parameters as plants grown under the 0.5 ETp treatment. A further reduction of water quantity supplied to plants in the 1–0.25–1 ETp regime resulted in further deterioration of the visual quality index of plants. In this study, the quality index of plants exposed to 0.5–1–0.5 ETp was similar to control plants (1 ETp). These plants were lower, more compact, and had smaller leaves than control plants. The irrigation regimes imposed in this study had no significant effect on the number of floral buds formed in relation to the control regime, except for 1–0.25–1 ETp where this number decreased

eRAMZES – a new web-based tool for reactive moulding simulations

This paper describes a unique multiphysics simulation tool allowing one to analyse and optimize the reactive moulding process used for the production of epoxy resin based electrical insulation in many power products. The presented methodology offers fully automated numerical computations of the mentioned process excluding the requirement for high knowledge and experience of the tool end-user in the area of computer simulations

Progressive arthropathy in the course of immune tolerance induction failure in a child with hemophilia A and FVIII inhibitor – a case report

We present the case of an 18.5-year-old boy with hemophilia A and FVIII inhibitor detected at the age of 8 months. No persistent inhibitor eradication was achieved, despite three attempts of immune tolerance induction (ITI) with temporary inhibitor resolution and subsequent administration of 11 doses of rituximab. In spite of hemostatic treatment, rehabilitation, and radiosynovectomy, the patient suffered from recurrent bleeding episodes into almost all major joints, which resulted in the development of progressive hemophilic arthropathy. Currently, due to high frequency of bleeding episodes, the patient is being treated prophylactically and receives prophylaxis with activated prothrombin complex concentrate (aPCC)

Hemophilic arthropathy - pathogenesis, clinical symptoms and diagnostic possibilities

Artropatia hemofilowa jest jednym z najistotniejszych problemów klinicznych u pacjentów z ciężką postacią hemofilii, a zwłaszcza u pacjentów z obecnością inhibitora. Początkowe krwawienia dostawowe występują w pierwszych latach życia i dotyczą najczęściej stawów kolanowych, łokciowych i skokowych. W patogenezie artropatii główną rolę odgrywają przerost błony maziowej oraz bezpośredni toksyczny wpływ składników krwi na chrząstkę stawową. Charakterystyczne dla artropatii są krwawienia dostawowe, prowadzące do stopniowego ograniczenia ruchów, deformacji, zaników mięśniowych, upośledzenia funkcji stawów i ograniczenia aktywności pacjenta. Do typowych zmian radiologicznych należą: zanik kostny, przerost nasad, nieregularna powierzchnia warstwy podchrzęstnej kości, zwężenie szpary stawowej, torbiele podchrzęstne, brzeżna erozja powierzchni stawowych oraz nierówności powierzchni stawowych oraz deformacja kątowa stawu lub/i jego podwichnięcia. Do dokładnej oceny wczesnych zmian w stawach coraz szerzej wykorzystuje się badanie rezonansu magnetycznego i badanie ultrasonograficzne.Hemophilic arthropathy is a fundamental clinical problem in patients with severe hemophilia, particularly in patients with inhibitor. Initial intraarticular bleeds occur in first years of life and concern mainly knee, elbow and ankle joints. Overgrowth of synovium and direct toxic effect of blood components on the cartilage are major underlying factors of arthropathy pathogenesis. Typical symptoms include intraarticular bleeds leading to gradual loss of range of motion, joint deformity, muscular atrophia, loss of function and limitation of patient’s activity. Radiological signs of hemophilic arthropathy comprise osteopenia, epiphyseal overgrowth, irregular subchondral layer, erosions and incongruity of articular surfaces, subluxation or/ and angular deformity of the joint. There is growing interest in the use of magnetic resonance imaging and ultrasonography in the diagnosis of early stages of hemophilic arthropathy

PILOT STUDY OVER SECONDARY TASK COGNITIVE WORKLOAD INDUCED ON DRIVERS IN AS 1200-6 SIMULATOR

Modern cars are increasingly equipped not only with the driver assisting systems, but also in multimedia devices allowing to track the information, use the Internet or send and receive e-mail. This type of activity can cause dangerous situations by inducing various forms of distraction to the driver. In order to identify the effects caused by performing additional tasks while driving, two types of secondary tasks were proposed.The following article presents the results of a pilot study that uses two additional tasks to induce the driver with cognitive load not related to driving. At the same time, in the course of the experiment, both the driving performance and the quality of performing additional tasks was observed. The article describes selected results of the conducted study

Lower expression of mRNA for interferon-gamma in T helper cells of children with newly diagnosed lymphomas

The complex interactions between cancer and host cells are far from being fully elucidated. Assessment of Th1/Th2/Th3/Tr1 balance is an interesting approach to explain immunological disturbances in lymphomas. The aim of our study was to assess mRNA for pro- and anti-inflammatory cytokines in T-cells in 20 children with Hodgkin- and non-Hodgkin lymphomas. CD4+ and CD8+ cells were isolated from whole peripheral blood and four different cytokine mRNA levels (IFN-γ, IL-10, IL-4, TGF-β) were determined by real-time PCR technique. Comparing to the control group, we found lower expression of mRNA for IFN-gamma in CD4+ cells at the time of lymphoma diagnosis. It may be one of the pathogenetic mechanisms of impaired immunity in these patients

Cross-resistance to five glucocorticoids in childhood acute lymphoblastic and non-lymphoblastic leukemia samples tested by the MTT assay : preliminary report

In vitro antileukemic activity of five glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and non-lymphoblastic leukemia were determined by means of the MTT assay in 25 leukemia cell samples of childhood acute leukemias. The equivalent antileukemic concentrations of the drugs tested were: 34 μM hydrocortisone (HC), 8 μM prednisolone (PRE), 1.5 μM methylprednisolone (MPR), 0.44 μM dexamethasone (DX) and 0.22 μM betamethasone (BET). In comparison with initial ALL cell samples, the relapsed ALL group was more resistant to PRE (38-fold, p = 0.044), DX (> 34-fold, p = 0.04), MPR (38-fold), BET (45-fold) and HC (33-fold). The AML cell samples were even more resistant to: PRE (>85-fold, p=0.001), DX (> 34-fold, p = 0.004), MPR (> 69-fold, p = 0.036), BET (> 69-fold, p = 0.038) and HC (54-fold, p = 0.059) when compared with ALL on initial diagnosis. A significant cross-resistance among all the glucocorticoids used was found. Only in some individual cases the cross-resistance was less pronounced

In vitro activity of oxazaphosphorines in childhood acute leukemia : preliminary report

Glufosfamide (β-D-glucosyl-ifosfamide mustard) is a new agent for cancer chemotherapy. Its pharmacology is similar to commonly used oxazaphosphorines, but it does not require activation by hepatic cytochrome P-450 and preclinically demonstrates lower nephrotoxicity and myelosuppression than ifosfamide. The aim of the study was a comparison of the drug resistance profiles of glufosfamide and other oxazaphosphorines in childhood acute leukemias. Leukemic cells, taken from children with ALL on diagnosis (n = 41), ALL on relapse (n = 12) and AML on diagnosis (n= 13) were analyzed by means of the MTT assay. The following drugs were tested: glufosfamide (GLU), 4-HOO-ifosfamide (IFO), 4-HOO-cyclophosphamide (CYC) and mafosfamide cyclohexylamine salt (MAF). In the group of initial ALL samples median cytotoxicity values for GLU, IFO, CYC and MAF were 15.5, 33.8, 15.7 and 7.8 μM, respectively. In comparison with initial ALL samples, the relative resistance for GLU and IFO in relapsed ALL samples was 1.9 (p = 0.049) and 1.3 (ns), and in initial AML samples 31 (p < 0.001) and 5 (p = 0.001), respectively. All oxazaphosphorines presented highly significant cross-resistance. Glufosfamide presented high activity against lymphoblasts both on diagnosis and on relapse