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1.
George Z Rassidakis Georgios V Georgakis Mauricio Oyarzo Anas Younes L Jeffrey Medeiros 《Modern pathology》2004,17(8):946-953
c-Kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells and has been reported to be expressed in CD30+ lymphomas such as Hodgkin's disease and anaplastic large-cell lymphoma. Imatinib mesylate, a well-established inhibitor of bcr-abl tyrosine kinase, and currently used for the treatment of patients with chronic myeloid leukemia, also inhibits c-kit receptor kinase activity. In view of the possible use of imatinib as experimental therapy for patients with c-kit-positive tumors, we assessed c-kit expression in CD30+ cell lines and lymphomas. The cell lines were assessed using multiple methods (RT-PCR, flow cytometry, and Western blot). c-Kit expression was also immunohistochemically assessed in 168 CD30+ lymphomas including 87 classical Hodgkin's disease, 63 anaplastic large-cell lymphoma, and 15 cutaneous anaplastic large-cell lymphoma. We also studied 18 cases of lymphomatoid papulosis, a CD30+ lesion closely related to cutaneous anaplastic large-cell lymphoma. Neither c-kit mRNA nor protein was detected in any of the cell lines assessed. Furthermore, treatment with imatinib did not inhibit proliferation of cell lines in vitro. Using immunohistochemistry, only one of 183 (0.5%) lesions was positive for c-kit, the positive case being an ALK-negative anaplastic large-cell lymphoma. Our data demonstrate that expression of c-kit receptor is exceedingly rare among CD30+ lymphomas and lymphomatoid papulosis, suggesting that c-kit receptor is unlikely to be an appropriate target for therapeutic options such as imatinib in patients with these tumors. 相似文献
2.
Zumel-Marne Angela Kundi Michael Castaño-Vinyals Gemma Alguacil Juan Petridou Eleni Th Georgakis Marios K. Morales-Suárez-Varela Maria Sadetzki Siegal Piro Sara Nagrani Rajini Filippini Graziella Hutter Hans-Peter Dikshit Rajesh Woehrer Adelheid Maule Milena Weinmann Tobias Krewski Daniel ′t Mannetje Andrea Momoli Franco Lacour Brigitte Mattioli Stefano Spinelli John J. Ritvo Paul Remen Thomas Kojimahara Noriko Eng Amanda Thurston Angela Lim Hyungryul Ha Mina Yamaguchi Naohito Mohipp Charmaine Bouka Evdoxia Eastman Chelsea Vermeulen Roel Kromhout Hans Cardis Elisabeth 《Journal of neuro-oncology》2020,147(2):427-440
Journal of Neuro-Oncology - We used data from MOBI-Kids, a 14-country international collaborative case–control study of brain tumors (BTs), to study clinical characteristics of the tumors in... 相似文献
3.
OBJECTIVE: Heat shock protein 90 (HSP90) chaperones and maintains the molecular integrity of a variety of signal transduction proteins, including the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein, a genetic abnormality that is frequently observed in anaplastic large cell lymphoma (ALCL) cells. Here we demonstrate that HSP90 is overexpressed in primary and cultured ALK-positive and ALK-negative ALCL cells, and we evaluate the potential role of the small molecule inhibitor of HSP90, 17-allylamino-17-demethoxygeldanamycin (17-AAG) in treating ALCL. METHODS: The antiproliferative effect of 17-AAG-cultured cells was determined by MTS assay. Apoptosis and cell-cycle arrest were determined by Annexin-V/propidium iodide and propidium iodide staining, respectively, and fluorescein-activated cell sorting analysis. Expression of HSP90 was evaluated by immunohistochemistry, and molecular changes were determined by Western blot. RESULTS: Treatment of cultured ALCL cells with 17-AAG induced cell-cycle arrest and apoptosis, irrespective of ALK expression. At the molecular level, 17-AAG induced degradation of ALK and Akt proteins, dephosphorylated extracellular signal-regulated kinase, and degraded the cell-cycle regulatory protein cyclin D1 and its cyclin-dependent kinases, CDK4 and CDK6, but had a differential effect on p27 and p53 proteins. Inhibition of extracellular signal-regulated kinase phosphorylation by the mitogen activated protein kinase inhibitor U0126 induced cell death in all ALCL cell lines, and sublethal concentration 17-AAG showed synergistic antiproliferative effects when combined with U0126 or doxorubicin. CONCLUSION: Our data demonstrate that targeting HSP90 function by 17-AAG may offer a novel therapeutic strategy for ALCL, either as single-agent activity or by combining 17-AAG with conventional or targeted therapeutic schemes. 相似文献
4.
Zheng B Fiumara P Li YV Georgakis G Snell V Younes M Vauthey JN Carbone A Younes A 《Blood》2003,102(3):1019-1027
The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD. 相似文献
5.
Bhavaraju K Georgakis A Jin J Gartner TK Tomiyama Y Nurden A Nurden P Kunapuli SP 《Platelets》2010,21(8):604-609
Antiplatelet therapy for the management of patients with cardiovascular risks often includes a combination therapy of aspirin and clopidogrel, acting through inhibition of thromboxane generation and blockade of G(i)-coupled P2Y?? receptor, respectively. We hypothesized that ADP acting through P2Y?? regulates physiological thromboxane levels. The serum thromboxane levels in mice (n?=?3) dosed with clopidogrel and prasugrel were decreased by 83.1?±?5.3% and 94.26?±?1.75% respectively compared to untreated mice. Pre-treatment of human blood (n?=?3) ex vivo with active metabolites of clopidogrel or prasugrel led to a reduction in thromboxane levels to 16.3?±?3.2% and 4.9?±?0.8% respectively, compared to untreated human serum. We also evaluated serum thromboxane levels in P2Y receptor null mice (n?=?4). Whereas serum thromboxane levels in P2Y? null mice were similar to those in wild type littermates, those in the P2Y?? null mice were inhibited by 83.15?±?3.8%. Finally, in a pilot study, serum thromboxane levels were reduced by 76.05?±?8.41% in healthy human volunteers (n?=?6) upon dosing with clopidogrel, compared to the levels before dosing. In conclusion, P2Y?? antagonism alone can decrease physiological thromboxane levels. Thus, this study could pave way the for newer/modified treatment regimens for the management of patients with thrombotic complications who are allergic or non-responsive to aspirin. 相似文献
6.
Bei Zheng Georgios V Georgakis Yang Li Alok Bharti David McConkey Bharat B Aggarwal Anas Younes 《Clinical cancer research》2004,10(9):3207-3215
PURPOSE: The malignant Hodgkin and Reed-Sternberg cells of Hodgkin disease (HD) are known to constitutively express high levels of activated nuclear factor kappaB (NF-kappaB), which plays an important role in their survival. The proteasome inhibitor PS-341 has been recently shown to modulate tumor cell proliferation and survival by inhibiting NF-kappaB and modulating critical cellular regulatory proteins, but its activity in cells carrying IkappaBalpha gene mutations has not been reported previously. Experimental Design: The activity of PS-341 in four well-characterized, HD-derived cell lines. Cell proliferation and apoptosis were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium (MTS) and Annexin-V binding methods, respectively. Cell cycle analysis was determined by flow cytometry. Intracellular protein levels were determined by Western blot. RESULTS: PS-341 demonstrated a strong antiproliferative activity, which was irrespective of the status of mutations in IkappaBalpha and even the presence of CD30, CD40, or RANK receptor activation. This effect was attributable to the induction of apoptosis and cell cycle arrest at the G(2)-M phase. PS-341 not only inhibited nuclear localization of NF-kappaB but also activated the caspase cascade, increased p21 and Bax levels, and decreased Bcl-2 levels. Furthermore, PS-341 enhanced the effect of gemcitabine chemotherapy and potentiated the effect of tumor necrosis factor-related apoptosis-inducing ligand/APO2L and two agonistic antibodies to tumor necrosis factor-related apoptosis-inducing ligand death receptors R1 and R2. CONCLUSIONS: The in vitro activity of PS-341 against HD-derived cell lines suggests that PS-341 may have a therapeutic value for the treatment of HD. 相似文献
7.
Neuroblastoma among children in Southern and Eastern European cancer registries: Variations in incidence and temporal trends compared to US 下载免费PDF全文
Marios K. Georgakis Nick Dessypris Margarita Baka Maria Moschovi Vassilios Papadakis Sophia Polychronopoulou Maria Kourti Emmanuel Hatzipantelis Eftichia Stiakaki Helen Dana Evdoxia Bouka Luis Antunes Joana Bastos Daniela Coza Anna Demetriou Domenic Agius Sultan Eser Raluca Gheorghiu Mario Sekerija Maciej Trojanowski Tina Zagar Anna Zborovskaya Anton Ryzhov Athanassios Tragiannidis Paraskevi Panagopoulou Eva Steliarova‐Foucher Eleni Th. Petridou 《International journal of cancer. Journal international du cancer》2018,142(10):1977-1985
Neuroblastoma comprises the most common neoplasm during infancy (first year of life). Our study describes incidence of neuroblastoma in Southern–Eastern Europe (SEE), including – for the first time – the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM‐ST)/Greece, compared to the US population, while controlling for human development index (HDI). Age‐adjusted incidence rates (AIR) were calculated for 1,859 childhood (0–14 years) neuroblastoma cases, retrieved from 13 collaborating SEE registries (1990–2016), and were compared to those of SEER/US (N = 3,166; 1990–2012); temporal trends were assessed using Poisson regression and Joinpoint analyses. The overall AIR was significantly lower in SEE (10.1/million) compared to SEER (11.7 per million); the difference was maximum during infancy (43.7 vs. 53.3 per million, respectively), when approximately one‐third of cases were diagnosed. Incidence rates of neuroblastoma at ages <1 and 1–4 years were positively associated with HDI, whereas lower median age at diagnosis was correlated with higher overall AIR. Distribution of primary site and histology was similar in SEE and SEER. Neuroblastoma was slightly more common among males compared to females (male‐to‐female ratio: 1.1), mainly among SEE infants. Incidence trends decreased in infants in Slovenia, Cyprus and SEER and increased in Ukraine and Belarus. The lower incidence in SEE compared to SEER, especially in infants living in low HDI countries possibly indicates a lower level of overdiagnosis in SEE. Hence, increases in incidence rates in infancy noted in some subpopulations should be carefully monitored to avoid the unnecessary costs health impacts of tumors that could potentially spontaneously regress. 相似文献
8.
Chrissidis T Saliangas K Economou A Nikoloudis N Andreadis E Prodromou K Georgakis K 《Techniques in coloproctology》2004,8(Z1):s193-s195
Colorectal cancer (CRC) is the second leading cause of cancer-related morbidity and mortality in Europe and the United States. Planning for a CRC screening began in co-operation with local authorities (Pella Prefecture sponsored test kits). Our aims were to develop a screening programme for colorectal cancer using the faecal occult blood test (FOBT) in Almopea province, and to investigate the compliance of local farmers population. Cancer statistics data from Almopea have been analysed and they showed higher colorectal cancer incidence compared to the rest of Greece. We designed a one-time FOBT screening programme on the Surgery Department computer Network, in which we listed 8963 subjects, over 50 years of age. From them, 4189 underwent 3 days FOBT, and the rest were our control group. The method of successive visits to each community by the medical team and educational meeting was chosen. For allocation and gathering of tests, teams of volunteers have been organised. In case of positive FOBT (176 subjects), total colonoscopy was performed. Seventeen (17) polypoids (in 15 patients) and 20 cases of diverticulosis were detected. The compliance of FOBT group was 49% (from 4189). Colonoscopy accepted 89% from 176 patients with positive test. We concluded that our study shows poor compliance of screening population. There is a need for co-operation of medical services, local authorities, media and volunteers support organising. 相似文献
9.
Mantle cell lymphoma (MCL), a distinct type of non-Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17-allylamino-17-demethoxy-geldanamycin (17-AAG), a HSP90 small molecule inhibitor, induced G(0/1) cell cycle arrest and cell death in a dose- and time-dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17-AAG may have a potential therapeutic value in patients with MCL. 相似文献
10.
Marios K. Georgakis Maria A. Karalexi Domenic Agius Luis Antunes Joana Bastos Daniela Coza Anna Demetriou Nadya Dimitrova Sultan Eser Margareta Florea Anton Ryzhov Mario Sekerija Tina Žagar Anna Zborovskaya Snezana Zivkovic Evdoxia Bouka Prodromos Kanavidis Helen Dana Emmanuel Hatzipantelis Maria Kourti Maria Moschovi Sophia Polychronopoulou Eftichia Stiakaki Μaria Kantzanou Apostolos Pourtsidis Eleni Th. Petridou 《Cancer causes & control : CCC》2016,27(11):1381-1394