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Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.

The borderline between necrosis and apoptosis is indistinct, but that between types of cell death is important because necrosis may lead to local inflammation, whereas apoptosis usually does not. In certain autoimmune disorders, inhibition of cell death is crucial, since macromolecules released from the dead cells may accelerate the autoimmune processes. We have used various cell death inhibitors to block cell death induced by 4HPR [N-(4-hydroxyphenil)-retinamide] the BL41 and U937 cell lines. VD-FMK, a general caspase inhibitor, inhibited DNA fragmentation induced by 4HPR, but not PI (propidium iodide) uptake and necrosis. Interestingly heparin, a serine-protease inhibitor, lowered the PI fluorescence of the dead cell population and increased the sub-G1 population as measured by flow cytometry. Regarding these changes, we found that heparin failed to increase DNA fragmentation, but merely liberated high molecular mass DNA fragments from dead cells. The exact mechanism is unclear, but heparin during secondary necrosis might enter the cells, bind RNPs (ribonucleoproteins), and pull them out with the attached DNA, where they would be sensitive to enzymatic degradation. Thus, the results suggest that heparin treatment helps in the clearance of cell debris and decreases the immunogenity of secondary necrotic cells.

The traditional ritual year which was characterized by Christian feasts for centuries on one hand, and the cosmological, agrarian (economic), individual, family, and local communal holidays on the other, has been rapidly changing between 1945 and 1956 during the first Socialist/Communist years. A new system of the ritual year was established according to the new ideology and power situation: the so-called Socialist ritual year. It was characterized by international, Soviet and national-communist feasts, refusing the religious holidays. Some softening were introduced only after the 1956 Hungarian revolution. The main Christian feasts were again accepted (Christmas, Easter). This Socialist period with its Socialist feasts lasted for 45 years when in 1989/1990 the legal power system was changed.After the elction in 1990 the totalitarian Socialist ideology with its symbolic holidays has mostly disappeared. New national feasts were created e.g. the memorial day of the 1956 revolution which was a prohibited alt...

Introduction: Subunit A of blood coagulation factor XIII (FXIIIA) may be expressed in leukemic B-cell precursor (BCP) lymphoblasts in addition to platelets, megakaryocytes, monocytes and macrophages (Kiss F. et al Thromb Haemost 2006;96:172-82.). In a retrospective single-center cohort of children with acute lymphoblastic leukemia (ALL) treated with the BFM ALL-IC 2002 protocol, expression of FXIIIA was correlated with statistically significant survival advantage (Kárai B et al. Pathol Oncol Res 2018; 24:345-52.). Our aim was to investigate the impact of FXIIIA expression pattern on EFS and its correlation with known clinical and genetic prognostic factors in a multi-center pilot study within the frames of the BFM ALL-IC 2009 clinical trial (EuDract: 2010-019722-13). Patients and Methods: We examined 317 children with BCP-ALL between 2011 and 2018 at institutions in Poland (n=188), Hungary (n=116), and Slovakia (n=13). Patients with Down-syndrome, t(9;22), and infants ( Results: We observed 3 different patterns of FXIIIA expression in leukemic lymphoblasts: negative pattern (80%). Evaluation of FC histograms of the moderate positive pattern showed that FXIIIA expression increased continuously which excluded the existence of distinct FXIIIA negative and FXIIIA positive subpopulations within the moderate positive expression group (Fig.1). In contrast to the previous single-center retrospective cohort, EFS of patients with FXIIIA positive BCP-ALL was not significantly different from that of patients of FXIIIA negative BCP-ALL (Fig.2A). However, a significant EFS advantage of patients with moderate FXIIIA positivity was demonstrated when compared with patients with FXIIIA negative BCP-ALL (p=0.019), and with patients with FXIIIA strong positive BCP-ALL (p=0.001) (Fig.2B). The 3 different FXIIIA expression patterns did not correlate significantly with either risk stratification according to BFM ALL-IC 2009 or FC MRD categories. Intermediate genetic risk categories (low hyperdiploidy, t(1;19), and "B-other") were significantly more prevalent (p=0.042) among patients with FXIIIA negative BCP-ALL than among patients with strong FXIIIA positive BCP-ALL. The "B-other" subgroup was also significantly more prevalent (p=0.022) among patients of the above 2 groups (Table 1). Distribution of the "B-other" genetic group and the prednisone response differed significantly between the FXIIIA positive and negative groups. Intermediate genetic risk group is mostly made up of patients assigned to the "B-other" group explaining the significant difference between the FXIIIA positive and negative groups, in terms that FXIIIA negative patients had 50% lower chance of facing low instead of intermediate genetic risk compared to FXIIIA positive patients. The multivariate logistic regression analysis confirmed the association between the FXIIIA characteristics and the intermediate genetic risk group. This association persisted after adjusting for categorical variables, i.e. gender, age, WBC, and BFM ALL-IC 2009 stratification (Table 2). High risk copy number alterations were detected in 4/7 samples of the FXIIIA negative group and in 1/17 of the FXIIIA positive group. Conclusions: FXIIIA expression status of leukemic lymphoblasts can easily be determined by FC. Patients with FXIIIA negative lymphoblasts should be further investigated with sophisticated and more expensive genetic and molecular methods. Grant sponsor: OTKA K108885. Disclosures No relevant conflicts of interest to declare.

Introduction Long non-coding RNAs (lncRNAs) contribute to different cancers including colorectal cancer (CRC). Previous studies have shown altered LINC00152 expression in CRC, but the detailed mechanism of its effects during CRC development and progression is not well studied. We aimed to study the effects of LINC00152 silencing on the cell cycle regulation and whole transcriptome in colon carcinoma cells. We also analysed the DNA methylation alterations caused by LINC00152 knockdown. Material and methods LINC00152 were silenced in SW480 colon carcinoma cells using Stealth siRNAs. Flow cytometric cell cycle analysis was performed using propidium-iodide DNA staining. Cyclin D1 protein expression was detected using flow cytometry after labelling with anti-cyclin D1 antibody. The effect of LINC00152 silencing to genome-wide gene expression was studied on Human Transcriptome Array 2.0 microarrays. DNA methylation alterations after LINC00152 knockdown were evaluated using Reduced Representation Bisulfite Sequencing (RRBS) method using NextSeq500 device. Results and discussions Silencing of LINC00152 significantly suppressed cell growth compared to negative control cells (p 1). Using RRBS, DNA methylation alterations after LINC00152 silencing could be detected genome-widely including hypomethylation in SFRP2 and ALDH1A3 gene promoters. Conclusion Our results suggest that LINC00152 lncRNA can contribute to CRC pathogenesis by facilitating cell proliferation through up-regulation of several oncogenes/metastatic genes in WNT, Notch and TP53 pathways and of cyclin D1 cell cycle progression gene, furthermore, by affecting the promoter methylation status of certain CRC associated genes.

3090Background: Cancer mortality correlates with metastatic progression where genetic/epigenetic changes in the cancer are important. Recent data indicate, however, that the host thrombotic and inf...

The effect and possible timing of nonradiolabeled somatostatin analogue octreotide are still not determined in the treatment of medulloblastoma, while the presence of somatostatin receptor type-2 (SSTR2) is proved in the majority of medulloblastoma by several authors.Daoy, SSTR2A positive medulloblastoma cell culture was tested with octreotide in monotherapy and combined with cisplatin, etoposide, and vincristine. Daoy medulloblastoma mice xenograft was treated with octreotide alone.In monolayer cell culture high-dose octreotide (44 microM) resulted in mitotic inhibition with parallel increment of apoptosis. Combination with cytostatic drugs did not result in additive or synergistic effect, but vincristine was partially antagonized. In medulloblastoma xenograft, octreotide monotherapy (100 microg/kg/day for 10 days) resulted in partial tumor growth inhibition.High concentration of nonradiolabeled octreotide may have role in the treatment of medulloblastoma by long-term administration. Concomitant administration of octreotide with widely used cytostatic drugs against medulloblastoma will not have beneficial impact.

Flow cytometric analysis of CD23 expression in CD5-positive B-cells is a widely applied method in the differential diagnosis of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). According to the most accepted criteria, the leukaemic cell population is CD19/CD5/CD23 triple positive in CLL but CD23-negative in MCL. Recently, several groups have reported CD23-positive MCL cases; however, these studies mostly analysed only CD23 positivity but not intensity. To determine the role and the cut-off levels of CD23 positivity and intensity in the differential diagnosis of CLL and MCL, 26 cases of MCL and 84 cases of CLL were compared using flow cytometric analysis. Our results suggest that high values of CD23 positivity (>92.5%) and/or high fluorescence intensity (>44.5 mean fluorescence intensity (MFI)) of CD23 are related to CLL, whereas low CD23 positivity (

The sacred space of a place of pilgrimage and its objects: Mariaradna . From the turn of the 17th to the 18th century Mariaradna was a place of pilgrimage for the Catholic inhabitants (Hungarians, Germans, Bulgarians and others) in a vast region of South-east Hungary. Since the First World War the area of its attraction has belonged to the territory of three countries, Hungary, Romania and Serbia. In the second half of the 19th century and before the First World War the people of settlements visiting the place of pilgrimage erected chapels, columns with sacred images, stations of the cross and statues on the hillside behind the church using concrete, a modern building material at that time. The article examines these structures. They clearly reflect the strong Franciscan influence (Saint Francis, Saint Anthony, Saint Elizabeth of Hungary), as well as the devotional trends of the previous century (Sacred Heart, Heart of Mary, Virgin Mother of Lourdes) in the religious practice of the region.

Mycophenolic acid (MPA)/mycophenolate mofetil (MMF), a powerful immunosuppressive agent was tested on human B-lymphoma cells (Epstein-Barr virus +/-) in vitro and in SCID mouse xenograft model. Proliferation, apoptotic activity and tumor volume were evaluated. MPA inhibited lymphoma cell proliferation and induced apoptosis (50-60% at 72 h). In vivo, oral administration significantly inhibited subcutaneous tumor growth. Immunohistochemistry showed significantly decreased proliferation rate and higher apoptotic activity in tumors treated with MMF. Xenografted lymphoma cells remained sensitive to MPA. Our results suggest that MPA may be recommended as an additional component of lymphoma chemotherapeutical regimens, with special considerations to post-transplant lymphomas.

The Living Rosary Association, a renewed form of the rosary confraternity, was principally an association of the peasantry and lower social strata in Hungary. The paper presents and interprets the confraternity practice of a settlement (Kunszentmarton, Jasz-Nagykun-Szolnok County on the Hungarian Great Plain), through confraternity minutes (1851-1940), the fraternity's religious literature and journal, interviews and comparison with other fraternities. The rosary was principally a form of female devotion. However, up to the 1940s the leaders were men. The high degree of feminisation can be interpreted in the frame of the process of secularisation. In the course of the processes of economic, social and cultural modernisation, the tasks of the private sphere within the family (running the household, raising children) fell to women. Within this frame they also provided for the family's sacral world. Until the 1940s the rosary confraternity preserved its character as a women's mass movement. At the turn of th...

Chronic lymphocytic leukemia (CLL) is characterized by a neoplastic B-cell population coexpressing CD5 and CD23; however, the expression of CD23 is variable. In human, two isotypes of CD23 have been identified and related to different functions. The aim of our study was to investigate the relative expression of the two CD23 isotypes in CLL and find possible correlation with other prognostic factors. The expression of CD23 isotypes was analyzed in 54 cases of CLL by polymerase chain reaction (PCR) and quantitative real-time PCR. The immunophenotype of CLL cells was characterized by flow cytometry. We demonstrated a higher CD23a than CD23b expression of CLL cells. Our results also revealed two subsets of CLL cases with a distinct CD23 isotype expression pattern. Thirty-two percent of the cases (group CLL1) showed both low mRNA level of CD23 isotypes and high protein levels of CD20 and CD38 in contrast to group CLL2 with high CD23 mRNA levels. By correlating these results to the presence of prognostic factors determined by fluorescence in situ hybridization, we found that the majority of the cases of group CLL1 (14/17) carried trisomy 12. In summary, our results confirm a high CD23a/CD23b ratio of the CLL cells and demonstrate that in a subset of CLL cases, low CD23 expression together with high CD20 and CD38 expressions may serve as a surrogate for trisomy 12. Copyright © 2015 John WileySons, Ltd.

Transforming growth factor beta1 (TGF beta1) has antiproliferative and/or apoptotic effect on lymphoid cells. In certain lymphomas exogenous TGF beta1 is able to induce apoptosis, however many lymphoid malignancies are resistant to the endogenous TGF beta1 production. We studied the expression and the activity of TGF beta1 signalling components in B cell lymphoma cell lines (e.g. HT 58 cells) and in isolated human peripheral mononuclear cells (PBMCs) from healthy individual's and B-CLL patient's blood. We found that all signal transducer Smads (Smad2,-3; Smad4) and at least one of the inhibitory Smads (Smad6,-7) were expressed in non-treated lymphoma cells, but the inhibitory Smads did not in normal/control PBMCs. However, after TGF beta1 treatment Smad6 disappeared, while the expression of Smad7 increased in HT 58 cells. The activity of Smad signals was proved by phosphorylation of Smad2, nuclear translocation of Smad2/3, and the increased expression of Smad-dependent gene, TIEG in TGF beta1 treated lymphoma cells. These results showed that Smad signaling is available in certain different human lymphoma cells, however ISmads expression could inhibit the signal transmission. This findings indicates that the lost sensitivity of lymphoma cells toward a physiological regulatory factor could be reversed.

In Hungary in the last 20-30 years the traditional mass pilgrimages, mainly by bus, organised by parishes within village or town frames have almost disappeared. A special form of pilgrimage can now be observed: pilgrimages made on foot by small groups from narrower social, age or occupational groups. The recent paper examines two of these pilgrimages and groups, on the basis of interviews conducted with the leaders and written sources. The first one is a youth pilgrimage and is organised and led by Franciscans between August 15-20. The other pilgrimage on foot is organised by a group of highly qualified, middle-aged Budapest intellectuals. They do not reach the goal by walking continuously but in stages of 18-25 km covered on every second Saturday of the month. Pilgrimage on foot brings together people. Self-restraint plays a big role in the Franciscan youth pilgrimage. Community building is important for both groups. These pilgrimages can become the most important compensative rites of man today.

Sandor Balint was an important representative of ethnography in Hungary in the 20th century. In many respects his work is unique: in its themes and from the geographical and methodological viewpoin...

2-methoxyestradiol (2ME2) is an endogenous metabolite of estradiol with estrogen-receptor-independent antitumor and antiangiogenic activity. We examined the effects of 2ME2 on the cellular proliferation of 8 human melanoma cell lines. We show that 2ME2 inhibited cell proliferation by inducing apoptosis and an arrest in the G2/M phase, and the mechanism of action involved microtubules, mitochondrial damage and caspase activation. In male SCID mice, 2ME2 was effective in reducing primary tumor weight and the number of liver metastases after intrasplenic injection of human melanoma cells. In the metastases, we found a significantly higher rate of apoptotic cells after 2ME2 treatment. These findings on the antitumor effect of 2ME2 in cell culture as well as in an animal model may have implications for designing alternative treatment options for patients with advanced malignant melanoma. © 2004 Wiley-Liss, Inc.

The paper is dealing with new forms of writings. The inscription books, found in a hospital in Budapest, contain shorter or longer texts of patients who say thanks to doctors and nurses for helping in regaining their health. The inscription books and their texts are regarded by the author as special form of communication, ritualized way of thanksgiving. The motivation of the rite can be found in a search for safety and stability, in a feeling of compensation.

Introduction: In the progression of colorectal cancer, metastasis is a critical step in the development of systemic disease. Early diagnosis of metastatic progression, however, is not available. We present a novel approach to detect metastatic predisposition early, from patient blood. Background: Metastasis is disseminated by cancer stem cells. They rapidly adapt to hypoxia, they prefer hypoxic metabolism, which is also a major factor in clinical therapy-resistance and dissemination. By studying cancer stem cell differentiation we found that they readily form spheroids (small multicellular clusters or organoids) with hypoxic centers. Hypothesis: We propose that cancer stem cells develop hypoxic spheroids to provide a protected hypoxic micro-niche for survival. Based on the fact that spheroid formation is universally found in vitro, we asked whether cancer stem cells may also form spheroids in vivo, when they enter circulation. Our hypothesis is that in vivo circulating tumorspheres carry cancer stem cells and contribute to metastatic dissemination. To investigate the possibility of circulating cancer spheroids in colorectal and other cancers, we worked out the methodology to detect and characterize them from patient blood. Experimental Procedures: Blood samples were collected from 20 colorectal and 86 mixed cancer cases. 16 of the 20 colorectal and 62 of the 86 mixed cancers were metastatic, respectively. We also tested 44 controls. The samples were analyzed by flow cytometry using forward scatter and SYTO16 fluorescent labels. For spheroid capture we used simple nylon mesh filters (10 um and 20 um pore size). From the collected spheroids RNA was isolated and gene expression assays were performed for stem cell, hypoxia and epithelial markers. We also studied the role of inflammation and immune check point mechanisms in dissemination. Results: We found that spheroids with epithelial lineage develop hypoxia and carry stem cells. By using Partec and Beckman-Coulter flow cytometers we detected circulating spheroids in patient blood. In the majority of colorectal cancer cases (56%) spheroids in blood indicated metastasis, while the controls were all negative. Furthermore, in half of the mixed cancer cases spheroids in blood also correlated with metastasis. All healthy samples and non-metastatic cases were negative. A subset of spheroids was positive for immune checkpoint and platelet markers suggesting immune/inflammation mechanisms in dissemination. Follow-up clinical studies will investigate the prospective significance of the results. Conclusions: We showed that cancer stem cells form spheroid clusters in vivo and can be detected in circulation. We found significant correlation between spheroids in blood (spheremia) and metastasis in colorectal and other cancers. The most critical new finding of our studies is that systemic dissemination of cancer involves a novel spheroid mechanism. Based on this observation we developed a simple blood test that may detect metastatic predisposition early in colon cancer progression. Citation Format: Viktoria Denes, Laszlo Graf, Gabor Barna, Balint Tegze, Pal Jakso, Peter Geck. Blood test of metastatic predisposition in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B03.

Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in α-smooth muscle actin positive than α-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in neoplastic stromal cells are associated with the clinical progression and worse prognosis in GCTB.

TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells. Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor. These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.

Hairy cell leukemia is a rare chronic lymphoproliferative disorder with indolent but progressive clinical course. Patients require treatment when they have significant cytopenia or recurrent infections. The gold standard treatment are purine nucleoside analogues (cladribine and pentostatine), with these agents the rate of complete remission can approach even 95 %. The differential diagnosis between classical hairy cell leukemia and other, rare splenic lymphomas that can mimic this disease might be really challenging. Splenic lymphoma with villous lymphocytes and other new, provisional WHO entities share some, but not all immunophenotypical features with hairy cell leukemia. The correct diagnosis is of an extreme importance as these entities require different treatment. Thus further investigation in the pathogenesis of hairy cell leukemia is required in order to solve this challenge. Discovery of the BRAF V600E mutation as a disease-defining genetic event in hairy cell leukemia can be helpful in both differential diagnosis and treatment of this disease. We report the case of three hairy cell leukemia patients, whose diagnosis or treatment was based on this newly discovered somatic mutation, but the treatment results and side effects were individual.

The paper deals bascally wth the mutual interference of politcs and relgon. It gives a short historical overview based on European and Hungarian examples and tries to shape the dominance of them in different ages and fields (heretic movements, Reformation, Counter-Reformation, spiritual movements, Christian politics, political Cathol cism, etc.). It describes how religious symbols or quasireligious symbols can be/are used in politics as expressions for social and power efforts. It s deal ng with the role of religion in naton-building in the past and present, with the role and format on of religous parties, of national and politcal myths.

Places of Pilgrimage in Hungary to Images of Mary said to Shed Tears - Ideological Instruments of the Catholic Restoration and the Church Union - Miraculous tears or drops of blood shed by paintings or statues are found at the origin of a few Marian places of pilgrimage in Hungary. Contemporary souces recorded nine cases in the late 17th to early 18th centuries. Four of these are Greek Catholic (Uniate) places, such as Mariapocs, the famous place of pilgrimage in Eastern Hungary. These miraculous events are linked to the situation of the country and the church at that time. This was the period when the Turks were driven out of Hungary, the time of the Counter-Reformation, the wars of independence against the Habsburgs and of civil wars. The tears were inter-preted at the time to mean that Mary was sorrowing for the people's sufferings and for the division of Christendom, longing for the restoration of Christian unity and reorganisation of the Catholic Church. The miraculous happenings also had an anti-Pro...

INTRODUCTION Metastasis is the turning point in the progression of most cancers. The prognosis of systemic, disseminated cancer is usually negative, but methods for early metastasis detection are not available in the clinical practice. We present a novel approach that may have the potential to detect metastatic predisposition early from patient blood. BACKGROUND It is almost universally accepted that metastases are disseminated by cancer stem cells. It is also known that hypoxia in a cancer is a major factor in therapy-resistance and dissemination. The findings are consistent with other observations that stem cells rapidly adapt to hypoxia and prefer hypoxic metabolism. We studied cancer stem cell differentiation and found that most stem cells (cancer and normal) readily form spheroids in suspension culture in vitro. Further studies showed that these spheroids develop hypoxic centers and are positive for stem cell markers. HYPOTHESIS These observations suggest that in vitro spheroid formation may reflect a fundamental biological feature of cancer stem cells and they may find a perfect niche in the hypoxic microenvironments in spheroids. The fact that spheroid formation is universally found in vitro raised the possibility that stem cells may also form spheroids in vivo, and by providing a “portable” hypoxic milieu, circulating tumorspheres may be critical in metastatic dissemination. We investigated, therefore, whether cancer spheroids can enter circulation and worked out the methodology to detect them in blood. EXPERIMENTAL PROCEDURES Blood samples were collected from 106 patients, 62 metastatic and 44 controls. The samples were analyzed by flow cytometry using forward scatter and fluorescent labels. For spheroid capture we used simple nylon mesh filters (10 um and 20 um pore size). From the collected spheroids total RNA was isolated and gene expression studies were performed for stem cell, hypoxia and other markers. Both the collected spheroids and in vitro spheroid models were analyzed by immunohistochemistry. RESULTS We found that spheroids show complex metabolic architecture with hypoxia, stem and other markers. We tested several flow cytometers and found that the wide scatter of spheroids was not optimal in some instruments, but performed well in Partec and Beckman-Coulter systems. In our pool almost half of the metastatic samples were spheroid positive, while all healthy samples were negative. Follow up clinical studies will investigate the prospective significance of the results. CONCLUSIONS Our data demonstrate significant correlation between cancer spheroid positivity in blood and metastasis. The results suggest that circulating in vivo spheroids may be involved in the dissemination of metastatic cancer stem cells and can be used as a new prognostic/diagnostic approach. Citation Format: Viktoria Denes, Laszlo Graf, Gabor Barna, Balint Tegze, Pal Jakso, Eva Pallinger, Peter Geck. Metastasis blood test by in vivo tumorsphere detection. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1545.

In the second half of the 20th century, a new generation of believers reached back to an older religious practice, thus embracing a tradition of earlier generations and adapting it to new social and church circumstances. Tradition has been given a new function and a new social role. In Gyongyos, a small town in Northern Hungary, the Franciscan fathers who care for the place of pilgrimage were able to revive the pilgrimage feast of Our Mother of Sorrows by announcing a gathering of portable procession statues and images of the Carpathian Basin for the feast. In this way, the feast of Our Mother of Sorrows became a cheerful festival of young people. My paper takes this example to examine why this innovation was successful. The most spectacular characteristic of the process is the festivalisation, the creation of a lively, mass public celebration rich in events, that is, in external appearances. V drugi polovici 20. stoletja je nova generacija vernikov posegla po starejsi praksi, pri cemer je zaobjela izrocilo starejsih rodov in ga prilagodila novim družbenim in cerkvenim razmeram. Tradicija je dobila novo funkcijo in novo družbeno vlogo. V mestecu Gyongyos na severu Madžarske so franciskanski brati, ki skrbijo za romarski kraj, oživili romarski praznik Žalostne Matere Božje. Za praznovanje so napovedali procesijo s prenosnimi figurami in podobami z obmocja karpatskega bazena. V clanku je predstavljen ta zgled, da bi preucili, zakaj je bila ta inovacija uspesna. Najvelicastnejsa znacilnost je festivalizacija, stvaritev živahnega množicnega javnega praznovanja, bogatega z dogodki, tj. zunanjimi oblikami.

Tissue-specific migration of immune cells involved both in physiological and pathological immune responses is a current research subject for medical science. Several homing molecules have been identified orchestrating extravasation of immune cells to certain peripheral non-lymphoid tissues such as gut, lung and skin. Regarding lymphocyte homing to skin, the first-line defense of human body cutaneous lymphocyte associated antigen (CLA) and a group of chemokine-chemokine receptor pairs are considered to be of crucial importance. The aim of the present review is to summarize existing knowledge about skin- and tumor-specific migration of immune cells playing a major pathogenetic role in host immune responses induced by non-lymphoid malignant skin tumors as well as in the development of primary cutaneous T-cell lymphomas (CTCL). Melanoma malignum, squamous and basal cell carcinoma evoke host immune responses and consequently a subset of reactive immune cells is recruited to site of the tumor. Regarding migratory process and exact functional role of these cells a growing number of data is available in literature. On the other hand tissue-specific immune cell homing is regarded as a key process in the pathogenesis of CTCL where malignant T-lymphocytes can be found in circulation and symptomatic skin. Hereby homing mechanism of malignant T-cells in mycosis fungoides and Sezary-syndrome as separate clinical entities of CTCL is discussed. A precise insight into the molecular background of skin- and tumor-specific immune cell migration can contribute to developing efficient vaccine therapies in non-lymphoid malignant skin tumors and beneficial treatment modalities in CTCL.

Growth factors and mitogens influence signaling pathways and often induce the activity of p70S6 kinase (p70S6K), which in turn phosphorylates the ribosomal S6 protein (S6). Although recent data are rather conflicting, the overall view suggests that phosphorylated S6 is a regulator of global protein synthesis, cell proliferation, cell size and glucose homeostasis. In the present work, emphasis was given to cell cycle-dependent activation of S6 focusing mainly on human lymphoid and lymphoma cells. Paraffin-embedded human tissue blocks from lymph node and different tumor biopsies as well as in vitro cell lines were investigated by immunohistochemistry, immunocytochemistry, flow cytometry and Western blotting using antibodies directed against phospho-S6, phospho-mTOR, phospho-p70S6K and phospho-Histone H3. To enrich the cell number in different phases of the cell cycle, nocodazole, staurosporine or rapamycin were used in cell cultures. We observed strong phospho-S6 positivity by immunostainings in the dividing lymphoid cells of reactive lymph nodes and in lymphoma cells cultured in vitro. Phospho-S6 protein levels were shown to be elevated throughout mitosis in lymphoma cells; however, the high expression of phospho-S6 in mitotic cells was not a general hallmark of tumor cell types studied so far: phospho-S6-negative mitotic cells were detected in several carcinoma and sarcoma biopsies. These observations may have practical implications as they raise the possibility to consider p70S6K and/or S6 as a potential therapeutic target—besides mTOR—in certain lymphomas and perhaps in clinical immunosuppression.

Dipeptidyl peptidase-4 (DPP-4) is involved in the metabolism of peptide hormones, T-cell activation and proliferation. In type 1 diabetes mellitus (T1DM) β-cell destruction involves a number of dysregulated T-cells. Our aim was to assess the serum DPP-4 activity and the lymphocyte membrane bound CD26 expression in patients with type 1 diabetes and healthy controls. Ninety-eight (T1DM: 48, F/M = 20/28, mean age: 34.4y; control: 50, F/M = 39/11 mean age: 32,4y) individuals were included. Fasting serum DPP-4 enzymatic activity, plasma glucose (FPG), CD26 expression on CD3+, CD4+ and CD8+ lymphocytes, HbA1c and body mass index (BMI) were assessed. ICA and GAD antibodies were assessed in the T1DM group. DPP-4 enzymatic activity was determined by kinetic enzyme assay, ICA and GAD were assessed by ELISA. Determination of the CD26 expression on CD3+, CD4+ and CD8+ lymphocytes was performed by flow-cytometric analysis. We found higher serum DPP-4 activity (Mean: T1DM: 30.069 U/L, control: 22.62 U/L, p < 0.0001) and decreased CD26 lymphocyte expression on all lymphocyte subpopulations in T1DM. Fasting serum DPP-4 activity was independent from the ICA or GAD status of patients with T1DM. Here we first present that the serum DPP-4 activity is increased and the lymphocyte membrane bound CD26 expression is decreased in type 1 diabetes. Decreased lymphocyte membrane bound CD26 expression in T1DM might be a novel part of the T-lymphocyte regulatory dysfunction observed in type 1 diabetes mellitus. These results might provide some basis for the clinical implication of DPP-4 inhibition in patients with T1DM.

Recent studies have identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) on the surface of chronic lymphoid leukaemia (CLL) cells. In order to determine whether ROR1 expression is a suitable surrogate marker for the diagnosis of CLL we analysed the mRNA level of ROR1 in different types of non-Hodgkin lymphomas (NHL), and detected elevated levels of ROR1 compared to control peripheral mononuclear cells in several entities (CLL ≥ mantle cell lymphoma (MCL) > marginal zone lymphoma (MZL) >> diffuse large B-cell lymphoma > follicular lymphoma). ROR1 protein was expressed intensely on the cell surface of lymphoma cells with leukaemic blood count detected by three colour immunofluorescence. Our results indicate that ROR1 expression is not limited to CLL cases, but it is more prevalent in NHLs, mainly in MCL where it is expressed intensely and MZL where it is expressed moderately, suggesting a general role of ROR1 in lymphoma genesis and/or maintenance. Copyright © 2010 John Wiley & Sons, Ltd.

The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesions sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.

The antiproliferative effect of 5-fluorouracil (5-FU) in the presence of low dose non-steroidal anti-inflammatory drugs (NSAIDs) on high cyclooxygenase-2 (COX-2)-expressing HCA-7 and low COX-2-expressing HT-29 colon carcinoma cell lines was investigated. Pharmacogenetic parameters were studied to characterize the 5-FU sensitivity of the two cell lines. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms were determined by PCR analysis. Cell proliferation was measured by SRB assay, cell cycle distribution and apoptosis by FACS analysis. Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy. Prostaglandin E(2) (PGE(2)) levels were investigated with ELISA kit. The HT-29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for MTHFR 677 polymorphisms predicting high 5-FU sensitivity (IC(50): 10 microM). TS 3R homozygosity, TS 1496del6 and MTHFR 677CT heterozygosity may explain the modest 5-FU sensitivity (IC(50): 1.1 mM) of the HCA-7 cell line. Indomethacin and NS-398 (10 microM and 1.77 microM, respectively) reduced the PGE(2) level in HCA-7 cells (>90%). Low concentrations of NSAIDs without antiproliferative potency increased the S-phase arrest and enhanced the cytotoxic action of 5-FU only in HCA-7 cells after 48-hours treatment. The presented data suggested that the enhancement of 5-FU cytotoxicity by indomethacin or NS-398 applied in low dose is related to the potency of NSAIDs to modulate the cell-cycle distribution and the apoptosis; however, it seems that this effect might be dependent on cell phenotype, namely on the COX-2 expression.

Before and after the Second World War ethnography, ethnology and folklore were taught in Hungary within largely similar frames. Education and research attached importance to the study of Hungarian peasant culture from a retrospective historical viewpoint. From the 1970s until 1980s, demands led to changes in both research and teaching. The teaching of Hungarian ethnology was re-organised at Szeged University, Pécs University and in Kolozsvár (Cluj-Napoca, Transylvania, Romania). From the 1970s a paradigm shift occurred in ethnology. The most important indication of this is that, in place of peasant society, ethnology now studies the entire society and all cultural phenomena, including many current social problems. Within the framework of the Bologna Agreement, students at the BA level at Szeged learn specific introductory subjects and general and specific methodology. Studies in only one specialist field begin at this level: studies in folklore and the anthropology of dance. The anthropology of dance continues at the MA level; which is also planned in English, in international co-operation. Studies in ethnology and anthropology of religion also appear at the MA level, as well as studies in cultural heritage. The content of both the BA and MA stages and of doctoral studies is largely determined by the fact that ethnology has come under strong influence of cultural and social anthropology., U desetljećima nakon Drugoga svjetskog rata etnografija, etnologija i folkloristika predavale su se u Mađarskoj na dva sveučilišta – Sveučilištu u Budimpešti i Sveučilištu u Debrecenu, unutar sličnih disciplinarnih okvira. U podučavanju i istraživanju važnost se pridavala proučavanju mađarske seljačke kulture iz povijesne retrospektive, u cilju njezine rekonstrukcije. Međutim, kao posljedica disciplinarnog, međunarodnog i interdisciplinarnog utjecaja, tijekom 1970-ih i 1980-ih stvorili su se uvjeti za velike paradigmatske promjene kako u istraživanju, tako i u predavanjima. Najvažniji pokazatelj te promjene bila je činjenica da je etnologija umjesto seljačkog društva počela istraživati društvo u cjelini, sve kulturne fenomene i mnoge suvremene probleme. Na institucionalnoj razini podučavanje etnologije je reorganizirano s ponovnom uspostavom predavanja iz etnologije na Sveučilištu u Szegedu, osnivanjem novog odsjeka na Sveučilištu u Pečuhu i ponovnim uvođenjem predavanja na temu mađarske etnologije u Kolozsváru (Cluj-Napoca, Transilvanija, Rumunjska). Slične promjene provedene su i na Odsjeku za etnologiju u Szegedu. Prvo smo proširili tradicionalne etnološke teme na podučavanje i istraživanje novih tema. Od 1998. godine uveli smo predavanja iz etnologije religije unutar područja specijalističkih znanja. U segedskoj školi etnologije folkloristika, materijalna kultura i kulturna antropologija podučavaju se unutar jednog područja i unutar istog odsjeka. U skladu s odredbama Bolonjskog sporazuma, na dodiplomskom studiju studenti slušaju temeljne/uvodne kolegije i dobivaju uvid u opću i specifičnu metodologiju. Na toj razini započinjemo samo jedan specijalistički program – folkloristiku i antropologiju plesa – u kojem studenti stječu osnovna teoretska znanja o narodnim plesovima. Antropologija plesa predaje se i na diplomskome studiju gdje postoje i kolegiji iz etnologije i antropologije religije, zajedno s onima koji se bave kulturnom baštinom. U Mađarskoj postoji velika potreba za predavačima etnologije. Pedagogija i metodologija predavanja etnologije također se predaju na diplomskoj razini. No, općenito, diplomski je studij podijeljen na tri dominantna specijalistička modula. Opći i specijalistički programi pripremaju studente za razna područja istraživanja, za područje obrazovanja, obrazovanja odraslih, javnih muzejskih zbirki, turizma, telekomunikacija te za rad u mnogim segmentima državne administracije i lokalnih vlasti. Studentima je na raspolaganju ekstenzivna međunarodna razmjena putem programa Erasmus/Socrates i CEEPUS, kao i studentski međunarodni ljetni seminar u Szegedu (Seminarium Ethnologicum Szegediense). Sadržaj preddiplomskoga, diplomskoga i poslijediplomskog studija uvelike je određen činjenicom da je etnologija sada pod snažnim utjecajem kulturne i socijalne antropologije.

The theme of the conference of the SIEF Commission for Folk Religion (9–12 September 2006, Celje, Slovenia) was based on two pillars. One was the sensual perception of reality and within this the place of the five human senses (sight, hearing, smell, touch, and taste), and the other was religion as a process of cognition, in which the role of sensual perception may differ from one age and one culture to another. Osnovna tema konference Komisije za ljudsko religijo SIEF (9.–12. september 2006 - Celje, Slovenija) je slonela na dveh temeljih. Prvi pomeni cutno percepcijo resnicnosti in znotraj nje mesto petih cutov (vid, sluh, vonj, dotik in okus), drugi pa religijo kot proces spoznavanja, v katerem se vloga cutnega dojemaja lahko razlikuje od ene dobe do druge in ene kulture do druge.

B-lymphoid tumor cells are often less sensitive than their normal counterparts or insensitive to transforming growth factor beta1 (TGFb) effects. We studied the apoptotic effect of exogenous TGFb in B-lymphoma cells, focusing on the activity and the role of Smad and protein phosphatase/kinase signals. Recombinant TGFb treatment and Smad4 siRNA transfection were used in HT58 B-NHL lymphoma cells in vitro. Gene expression and apoptosis were detected by RT–PCR, Western blot analysis and flow cytometry. The role of MEK1 kinase and PP2A activity – measured with a phosphatase assay – were assessed with the help of specific inhibitors. Smad4 siRNA treatment completely abolished TGFb-induced early gene upregulation, indicating the absence of the rapid activation of Smad signaling. Moreover, functional inhibition of Smad4 had no influence on TGFb-induced apoptosis, but it was dependent on PP2A phosphatase activation, ERK1/2 and JNK inactivation in lymphoma cells. The results prove that exogenous TGFb uses Smad4-independent, alternative (PP2A/PP2A-like dependent) signaling pathways for apoptosis induction in lymphoma cells. Further studies are needed to clarify the possible role and involvement of Smad4-independent effects of TGFb in normal and malignant lymphoid cells and in cells of the tumor microenvironment.

All-trans-retinoic acid (ATRA) and its synthetic analog fenretinide (4HPR) are potent anticancer drugs. Only a few reports are available about the effects of retinoids on B lymphoma cells. In our study, non-Hodgkin lymphoma cells (HT58) were treated with ATRA and 4HPR. Both agents induced cell death time- and dose-dependently. Reactive oxygen species (ROS) production was elevated in 4HPR-treated cells, but not in ATRA-treated cells. The depolarization of the mitochondrial membrane occured earlier after ATRA than after 4HPR treament. Z-VAD-fmk, the general caspase inhibitor, decreased the DNA fragmentation in ATRA-treated cells, but simultaneously increased necrosis. However, z-VAD-fmk did not influence the DNA fragmentation in 4HPR-treated cells. Endonuclease G was released from the mitochondria during 4HPR treatment, which could be an inducer for caspase-independent DNA fragmentation. Our results suggest that natural (ATRA) and synthetic (4HPR) retinoids induce different apoptotic pathways in B lymphoma cells, which is particularly relevant for their potential use in leukemia treatment.

2-methoxyestradiol (2ME(2)) is an endogenous metabolite of estradiol with estrogen-receptor-independent antitumor and antiangiogenic activity. We examined the effects of 2ME(2) on the cellular proliferation of 8 human melanoma cell lines. We show that 2ME(2) inhibited cell proliferation by inducing apoptosis and an arrest in the G(2)/M phase, and the mechanism of action involved microtubules, mitochondrial damage and caspase activation. In male SCID mice, 2ME(2) was effective in reducing primary tumor weight and the number of liver metastases after intrasplenic injection of human melanoma cells. In the metastases, we found a significantly higher rate of apoptotic cells after 2ME(2) treatment. These findings on the antitumor effect of 2ME(2) in cell culture as well as in an animal model may have implications for designing alternative treatment options for patients with advanced malignant melanoma.

Statins have been used successfully in the treatment of hypercholesterinaemia. Moreover, in vitro studies have shown that statins can trigger apoptosis in a variety of tumor cell lines. In the present study we analysed the effect of mevastatin--a novel inhibitor of HMG-COA reductase, the rate-limiting enzyme of the mevalonate pathway--on U266 human myeloma cells. Apoptosis induced by mevastatin was associated with increased caspase activity and depolarisation of the mitochondrial membrane. Expression of Bcl-2 mRNA and protein was down-regulated, with no change in Bax or Bcl-XL protein production. The mitochondrial program was supported by caspase-8 and cleaved-Bid activity. None of the antibodies neutralizing the death-ligand/death-receptor pathway--TRAIL-R2Fc, anti-TNF-alpha, anti-FASL(NOK-1)--influenced the mevastatin-induced apoptosis. Mevastatin also stimulated shedding of syndecan-1 from the surface of myeloma cells. The apoptosis inducing effect of mevastatin could be considered as a potential participant in a complex antitumor protocol.

Statins have been used successfully in the treatment of hypercholesteremia. Moreover, in vitro studies have shown that statins can trigger apoptosis in a variety of tumor cell lines. In the present study we analysed the effect of mevastatin -- a novel inhibitor of HMG-COA reductase, the rate-limiting enzyme of the mevalonate pathway -- on U266 human myeloma cells. Apoptosis induced by mevastatin was associated with increased caspase activity and depolarisation of mitochondrial membrane. Expression of BCL-2 mRNA and protein was down-regulated, with no change in BAX or BCLxL protein production. The mitochondrial program was supported by caspase-8 and cleaved BID activity. None of the antibodies neutralising death-ligand/death-receptor pathway -- TRAIL-R2Fc, anti-TNF-a, anti FASL (NOK-1) -- influenced the mevastatin-induced apoptosis. Mevastatin also stimulated shedding of syndecan-1 from the surface of myeloma cells.

Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments.