Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease.

T-cell receptor (TCR)-transgenic models of acute graft-versus-host disease (aGvHD) offer a straightforward and highly controlled approach to study the mechanisms and consequences of T-cell activation following allogeneic hematopoietic stem cell transplantation (aHSCT). Here, we report that aHSCT involving OT-I mice as donors, carrying an ovalbumin-specific CD8+ TCR, and Act-mOVA mice as recipients, expressing membrane-bound ovalbumin driven by the β-actin promoter, induces lethal aGvHD in a CD8+ T-cell-dependent, highly reproducible manner, within 4-7 days. Tracking of UBC-GFP/OT-I graft CD8+ T cells disclosed heavy infiltration of the gastrointestinal tract, liver, and lungs at the onset of the disease, and histology confirmed hallmark features of gastrointestinal aGVHD, hepatic aGvHD, and aGvHD-associated lymphocytic bronchitis in infiltrated organs. However, T-cell infiltration was virtually absent in the skin, a key target organ of human aGvHD, and histology confirmed the absence of cutaneous aGVHD, as well. We show that the model allows studying CD8+ T-cell responses in situ, as selective recovery of graft CD45.1/OT-I CD8+ T cells from target organs is simple and feasible by automated tissue dissociation and subsequent cell sorting. Assessment of interferon-gamma production by flow cytometry, granzyme-B release by ELISA, TREC assay, and whole-genome gene expression profiling confirmed that isolated graft CD8+ T cells remained intact, underwent clonal expansion, and exerted effector functions in all affected tissues. Taken together, these data demonstrate that the OT-I/Act-mOVA model is suitable to study the CD8+ T-cell-mediated effector mechanisms in a disease closely resembling fatal human gastrointestinal and hepatic aGVHD that may develop after aHSCT using HLA-matched unrelated donors

Magyar Tanítóképző 48 (1935) 2

Magyar Tanítóképző A Tanítóképző-intézeti Tanárok Országos Egyesületének folyóirata 48. évfolyam, 2. szám Budapest, 1935. februá

Gyermekkori központi idegrendszeri daganatok érújdonképződés-gátló kezelésének magyarországi eredményei a Kieran-sémával

In Hungary a new oral antiangiogenic treatment was introduced in cases of primary chemoresistant or recurrent pediatric CNS tumors, called Kieran schedule. The early results of this treatment were analyzed. From 2010 at Semmelweis University on individual decisions a daily combined per oral treatment was introduced in pediatric patients with recurrent or progressive CNS tumor (Kieran schedule: thalidomid, celecoxib, etoposid and cyclophosphamid). Efficacy of therapy was analyzed in terms of demographic data, histology, side effects and tolerability in a retrospective manner. From 2010 through 2013, twenty patients were treated with Kieran schedule (medulloblastoma: 3, ependymoma: 5, anaplastic astrocytoma: 2, GBM: 4, plexus choroideus carcinoma: 1, central primitive neuroectodermal tumor: 1, optic glioma: 2, brainstem tumor: 2). Median treatment time and median progression-free survival were 0.60 and 0.61 years, respectively. Based on the preliminary analysis of a limited cohort of patients, the therapy was efficient in those cases of medulloblastoma, ependymoma, high-grade and optic gliomas, where the expected survival time was more than 3 months at start of treatment. Side effects were slight myelosuppresion in terms of previous therapy, 16% transient ischemic attack (TIA)-like episodes. During therapy patients could live their everyday life. Kieran schedule was well-tolerable and efficient with good quality of life in certain cases of pediatric CNS tumors

Compilers

Dynamic program slicing methods are very attractive for debugging because many statements can be ignored in the process of localizing a bug. Although language interoperability is a key concept in modern development platforms, current slicing techniques are still restricted to a single language. In this paper a cross-language dynamic program slicing technique is introduced for the.NET environment. The method is utilizing the CLR Debugging Services API, hence it can be applied to large multi-language applications

Normal tissue sparing using different techniques for prostate irradiation

AimThe aim of this study was to investigate normal tissue sparing through dosimetric parameters of normal tissue volumes using different irradiation techniques for conventional (CFRT) and simultaneously integrated boost (SIB) schedules.BackgroundSeveral dose-escalation studies for localized prostate cancer (PCa) have shown advanced biochemical relapse-free (bRFS) rates and also better local control for higher total doses using either CFRT or SIB schedules. Besides the most important organs-at-risk, absorbed dose reduction of other surrounding normal tissues are also preferable. In order to analyse the normal tissue sparing, dosimetric parameters of different normal tissue volumes were examined.Materials and methodsTreatment plans for 15 high risk prostate cancer patients were created using RapidArc (RA), Sliding Window (SW) IMRT and 4-field box (3D-CRT) technique. In order to evaluate normal tissue sparing, the volume of pelvic region was divided into six normal tissue cylinders with 1cm wall thickness, located in each other.ResultsAll plans met the criteria of target coverage (V95%>95%). All techniques provided the same results for OARs except 3D-CRT for rectum and bilateral femoral heads. The values of V5, V10 and V15 increased in cases which included RapidArc technique and decreased for V20 and V30.ConclusionsThe dosimetric parameters for the cylindrical normal tissue volumes show that using RapidArc technique gives equal or slightly better normal tissue sparing and SIB provided the same normal tissue sparing as CFRT planned with RapidArc

mTOR Pathway As a Potential Target In a Subset of Human Medulloblastoma.

As mammalian Target of Rapamycin (mTOR) plays role in protein synthesis and metabolism, mTOR pathway activation is involved in the pathogenesis of several types of tumors. Our aim was to elucidate its role in medulloblastoma in terms of prognosis and as a therapeutic target. Members of activated mTOR complex 1 (mTORC1) pathway, phospho-mTOR (p-mTOR) and phospho-S6 (p-S6) were examined by immunohistochemistry in formalin fixed paraffin embedded samples of 40 patients with medulloblastoma, and results were compared to clinical features and survival of patients. In proliferation assays, Daoy and UW228-2 medulloblastoma cell lines were tested by rapamycin, an mTORC1 inhibitor, and NVP-BEZ235, a dual mTOR and phosphatidylinositol 3-kinase (PI3K) inhibitor, each in monotherapy and in combination with cytostatic drugs (cisplatin, etoposide). Components of mTORC1 and mTORC2 complexes were also examined in these cell lines. Neither presence of p-mTOR (32.5 %) nor p-S6 (32.5 %) correlated with age, gender or histological subtype. In 22.5 % of cases simultaneous expression of p-mTOR and p-S6 was shown. Kaplan-Meier analysis showed inferior survival of patients expressing both marker proteins, but it was not statistically significant, probably due to low case number. UW228-2 cells had greater sensitivity to mTOR inhibitors, possibly due to its higher mTORC1 specific protein expression levels, compared to Daoy cells. In both cell lines antiproliferative effect of cytostatic drugs was significantly enhanced by mTOR inhibitors (p < 0.05). Based on our in vitro and clinicopathological studies mTOR inhibitors may have a role in the future treatment of a subset of patients with medulloblastoma