Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21)

p53 is frequently wild type (wt) in diffuse large B-cell lymphoma (DLBCL) associated with t(14;18)(q32;q21) that overexpresses BCL2. Nutlin-3a is a small molecule that activates the p53 pathway by disrupting p53–MDM2 interaction. We show that nutlin-3a activates p53 in DLBCL cells associated with t(14;18)(q32;q21), BCL2 overexpression and wt p53, resulting in cell cycle arrest and apoptosis. Nutlin-3a treatment had similar effects on DLBCL cells of activated B-cell phenotype with wt p53. Cell cycle arrest was associated with upregulation of p21. Nutlin-3a-induced apoptosis was accompanied by BAX and PUMA upregulation, BCL-XL downregulation, serine-70 dephosphorylation of BCL2, direct binding of BCL2 by p53, caspase-9 upregulation and caspase-3 cleavage. Cell death was reduced when p53-dependent transactivation activity was inhibited by pifithrin-α (PFT-α), or PFT-μ inhibited direct p53 targeting of mitochondria. Nutlin-3a sensitized activation of the intrinsic apoptotic pathway by BCL2 inhibitors in t(14;18)-positive DLBCL cells with wt p53, and enhanced doxorubicin cytotoxicity against t(14;18)-positive DLBCL cells with wt or mutant p53, the latter in part via p73 upregulation. Nutlin-3a treatment in a xenograft animal lymphoma model inhibited growth of t(14;18)-positive DLBCL tumors, associated with increased apoptosis and decreased proliferation. These data suggest that disruption of the p53–MDM2 interaction by nutlin-3a offers a novel therapeutic approach for DLBCL associated with t(14;18)(q32;q21)

The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms

Feline low-grade alimentary lymphoma: an emerging entity and a potential animal model for human disease

Background: Low-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions. Results: A total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Conclusions: The pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine

The activation of Lycabettus hill

Το θέμα της διπλωματικής εργασίας είναι ο λόφος του Λυκαβηττού. Ο λόφος αποτέλεσε τόπο επίσκεψής μας για χρόνια. Οι βόλτες μας όμως, περιορίζονταν στην κορυφή γύρω από το ναό του Αγίου Γεωργίου και το χώρο του υπαίθριου παρκινγκ, έξω από το θέατρο του Ζενέτου. Ο υπόλοιπος λόφος μας ήταν άγνωστος . Μπαίνοντας στο χώρο αυτό, νιώσαμε αμηχανία στο να εντοπίσουμε την ταυτότητά του. Ο λόφος είναι εγκαταλειμμένος και χωρίς ανθρώπινη παρουσία. Όμως διαθέτει κάποια στοιχεία που θα μπορούσαν να τον αναδείξουν. Ασχεδίαστα και χωρίς φροντίδα, υπάρχουν αλλά είναι σε αδράνεια. Ο Λυκαβηττός θα μπορούσε να αποκτήσει υπόσταση στη ζωή της πόλης, αντί αυτού όμως δείχνει σαν να κοιμάται. Στην επέμβασή μας βρίσκουμε σημεία –κλειδιά στο λόφο, στο υπάρχον δίκτυο μονοπατιών, τα οποία έχουν ή δύναται να αποκτήσουν στοιχεία της ταυτότητας του λόφου. Σκοπός μας είναι να μετατραπούν τα σημεία αυτά σε θύλακες ενεργοποίησης του λόφου. Τα στοιχεία που θεωρούμε ότι συνθέτουν τον τόπο αυτό είναι το νερό, η θέα, το δάσος, το φως και η διαδικασία της ανάβασης. Τα στοιχεία αυτά τα εντοπίσαμε από ιστορικές πηγές αλλά και από ανάγνωση στο πεδίο. Το δίκτυο σημείων που ορίζουμε είναι ελεύθερο για τον περιπατητή, μία περιπλάνηση. Ο στόχος της εμπειρίας κάθε φορά είναι η κατανόηση του λόφου.The subject of the project is Lycabettus hill. We used to visit the hill for years. Nevertheless, our walks there were restricted at the top of the hill, around the church of Saint George and at the parking lot near Zenetos theatre. The rest of the hill remained unfamiliar . Entering this space we were not at first able to describe its identity. The hill is abandoned, but still has some elements that can give prominence to it. But given that there are not organized or designed, these elements just lay there in inactivity. Lycabettus could be a crucial spot of the city of Athens. Though now it seems like it is in sleep mode. Our proposal locates key points of the existing network of pathways of the hill, that have or can receive elements of the identity of the hill. We aim that the points will constitute activation points of the hill. The elements that define hill’s identity are the water, the view, the forest, the light and the process of ascent. We located these elements by consulting historic resources and by recognizing them in the site. The network of points that we design is free for the walker, it is a wandering. The aim of the experience is the understanding of the hill.Μαρίνα B. ΛεβεντάκηΕλισάβετ X. Μιχαλοπούλο

Nodular lymphocyte predominant hodgkin lymphoma with clusters of lp cells, acute inflammation, and fibrosis: A syncytial variant

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has clinicopathologic, immunophenotypic, and molecular features that are distinct from classical Hodgkin lymphoma (cHL). Distinguishing these entities is usually straightforward, but unusual variants of NLPHL have been described that can be problematic diagnostically and potentially have clinical significance. We describe a case of NLPHL showing a variant histologic pattern characterized by small and large clusters of lymphocyte predominance cells within nodules defined by follicular dendritic cell meshworks, associated with numerous neutrophils and areas of internodular fibrosis. Focally, the neoplastic cells had lacunar cell-like cytologic features. The resulting combination, not previously reported, closely mimicked the syncytial variant of nodular sclerosis cHL. After chemotherapy the patient was free of disease 14 years later. In our review of the literature we identified rare cases of NLPHL that had similar histologic features, but lacked the neutrophilic infiltration. Recognition of this rare variant, facilitated by immunohistochemical studies in this case, further expands the morphologic spectrum of NLPHL. Copyright © 2009 by Lippincott Williams & Wilkins

Constitutive control of AKT1 gene expression by JUNB/CJUN in ALK plus anaplastic large-cell lymphoma: a novel crosstalk mechanism

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is an aggressive T-cell non-Hodgkin lymphoma characterized by the t(2; 5), resulting in the overexpression of nucleophosmin (NPM)-ALK, which is known to activate the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, resulting in cell cycle and apoptosis deregulation. ALK+ ALCL is also characterized by strong activator protein-1 (AP-1) activity and overexpression of two AP-1 transcription factors, CJUN and JUNB. Here, we hypothesized that a biologic link between AP-1 and AKT kinase may exist, thus contributing to ALCL oncogenesis. We show that JUNB and CJUN bind directly to the AKT1 promoter, inducing AKT1 transcription in ALK+ ALCL. Knockdown of JUNB and CJUN in ALK+ ALCL cell lines downregulated AKT1 mRNA and promoter activity and was associated with lower AKT1 protein expression and activation. We provide evidence that this is a transcriptional control mechanism shared by other cell types even though it may operate in a way that is cell context-specific. In addition, STAT3 (signal transducer and activator of transcription 3)-induced control of AKT1 transcription was functional in ALK+ ALCL and blocking of STAT3 and AP-1 signaling synergistically affected cell proliferation and colony formation. Our findings uncover a novel transcriptional crosstalk mechanism that links AP-1 and AKT kinase, which coordinate uncontrolled cell proliferation and survival in ALK+ ALCL

Expression patterns of endothelin-1 and its receptors in colorectal cancer

Background and Objectives Endothelin-1 (ET-1), a potent vasoconstricting peptide, plays an important role in carcinogenesis. Previous in vitro studies have shown that colorectal cancer cells produce ET-1. Methods: ET-1 and its receptors ET-A (ETAR) and ET-B (ETBR) were analyzed in colorectal cancer cell lines and tumors by Western blot and immunohistochemistry. Also, ET-1 levels were measured by ELISA in blood samples collected before and after tumor resection. Results: ET-1 was immunohistochemically expressed by tumor cells at a variable level in 39 cases tested. The adjacent normal mucosa was negative for ET-1 expression. Strong ETAR expression observed in the deeper infiltrating areas at the periphery of neoplastic tissue correlated significantly with tumor stage. ETBR levels were very low or undetectable. Western blot analysis in paired (normal, tumor) fresh-frozen samples of colorectal cancers and in four colon carcinoma cell lines confirmed these findings. In addition, lower levels of ET-1 in the peripheral circulation after the tumor resection were found by ELISA as compared to those observed before surgery. Conclusions: ET-1 and ETAR, but not ETBR, are expressed at a higher level in primary and cultured colon carcinoma cells as compared to normal colon mucosa cells. Further functional studies are needed to explore the role of ET-1/ETAR axis in colon carcinogenesis. J. Surg. Oncol. 2012; 105: 643-649. (C) 2011 Wiley Periodicals, Inc