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Sutton L.-A.,Uppsala University | Belessi C.,Nikea General Hospital | Darzentas N.,Masaryk University | Darzentas N.,Center for Research and Technology Hellas | And 5 more authors.
Seminars in Cancer Biology | Year: 2013

While signaling through the B cell receptor (BcR) facilitates B cell development and maintenance, it also carries intertwined risks for the development of lymphomas since malignant B cells can exploit these pathways in order to trigger and fuel clonal expansion. This corruption of the normal B cell response to antigens, leading to sustained BcR signaling, has given great impulse to investigate in detail the role of antigen in lymphomas. Suffice it to conclude from such studies, largely immunogenetics based, that the evidence implicating antigens (exogenous or self) in lymphoma development is substantial and that lymphomagenesis is functionally driven and dynamic, rather than a simple stochastic process. As the paradigm of antigen-driven lymphoma evolves, further investigation will be paramount to the identification of the inciting agent(s) that may be responsible for immunoproliferative neoplasms and also for the development of therapeutic agents targeting effectors of the BcR signaling pathway. © 2013 Elsevier Ltd.


Psychari S.N.,Nikea General Hospital | Chatzopoulos D.,Nikea General Hospital | Iliodromitis E.K.,National and Kapodistrian University of Athens | Apostolou T.S.,Nikea General Hospital | Kremastinos D.T.,National and Kapodistrian University of Athens
Angiology | Year: 2011

Aims: We investigated the role of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and N-terminal pro-brain natriuretic peptide (NTpro-BNP), in atrial fibrillation (AF) recurrence rate. Methods: A total of 80 patients with first AF episode were studied prospectively. Echocardiography (ECG), Holter ECG, and measurements of hsCRP, IL-6, and NTproBNP were performed immediately post conversion and at 1 month. Results: Recurrence was positively related to left atrial volume (P <.001), with no difference in NTpro-BNP, hsCRP, and IL-6. Decreased NTpro-BNP was observed in all at 1 month (P <.001, F = 63.4) and was positively related to left atrial volume (P <.01). In the lone AF subgroup, NTpro-BNP was lower and dropped significantly at 1 month (interaction F = 6.53, P <.01). Conclusions: Atrial volume was related to AF recurrence, whereas hsCRP, IL-6, and NTpro-BNP were not reliable for AF relapse. Relation of NTpro-BNP to left atrial volume could indicate a role in the atrial remodeling process. © The Author(s) 2011.


Polydorou A.,National and Kapodistrian University of Athens | Vezakis A.,National and Kapodistrian University of Athens | Fragulidis G.,National and Kapodistrian University of Athens | Katsarelias D.,Mediterraneo Hospital | And 2 more authors.
Journal of Gastrointestinal Surgery | Year: 2011

Background: The management of endoscopic retrograde cholangiopancreatography (ERCP)-related perforations remains controversial. The aim of the study was to determine the incidence of perforations following ERCP, their characteristics, operative and non-operative management options and clinical outcome. Methods: A retrospective review of ERCP-related perforations, during a 21-year period, was performed. Each perforation was categorized into types I to IV according to the location, mechanism and radiographic evaluation of the injury. Comparisons were made between patients treated operatively and non-operatively. Results: Forty-four perforations (0. 4%) occurred in 9,880 procedures. They were mainly caused by the passage of the endoscope (type I) in 7 (16%) and sphincterotomy (type II) in 30 (68%) patients. The management was non-operative in 32 (72%) and operative in 12 patients. In multivariate analysis, only the type of perforation (type I: endoscope-related) was found significant for predicting operative treatment. The hospital stay was longer for patients requiring an operation (median, 24 vs 9 days). The overall mortality was 2/44 (4. 5%). There was no death in the non-operative group. Conclusions: The need for immediate operative intervention should be based on the type of injury and clinical findings. Patients with type I perforations should be treated surgically and primary repair should be tried. Patients with type II injuries may be treated initially non-operatively. Delayed operative intervention will be required in a minority of these patients. © 2011 The Society for Surgery of the Alimentary Tract.


Vardi A.,G Papanicolaou Hospital | Agathangelidis A.,San Raffaele Scientific Institute | Sutton L.-A.,Uppsala University | Chatzouli M.,Nikea General Hospital | And 12 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Immunoglobulin G-switched chronic lymphocytic leukemia (G-CLL) is a rare variant of CLL, whose origin and ontogenetic relationship to the common IgM/IgD (MD-CLL) variant remains undefined. Here, we sought for clues about the ontogeny of G-CLL versus MD-CLL by profiling the relevant IG gene repertoires. Experimental Design: Using purpose-built bioinformatics methods, we performed detailed immunogenetic profiling of a multinational CLL cohort comprising 1,256 cases, of which 1,087 and 169 expressed IG mu/delta and gamma heavy chains, respectively. Results: G-CLL has a highly skewed IG gene repertoire that is distinct from MD-CLL, especially in terms of (i) overuse of the IGHV4-34 and IGHV4-39 genes and (ii) differential somatic hypermutation (SHM) load. Repertoire differences were also found when comparing subgroups with similarSHMstatus and were mainly attributed to the exclusive representation in G-CLL of two major subsets with quasi-identical (stereotyped) B-cell receptors. These subsets, namely #4 (IGHV4-34/IGKV2-30) and #8 (IGHV4-39/IGKV1(D)-39), were found to display sharply contrasting SHM and clinical behavior. Conclusions: G-CLL exhibits an overall distinct immunogenetic signature from MD-CLL, prompting speculations about distinct ontogenetic derivation and/or immune triggering. The reasons underlying the differential regulation of SHM among G-CLL cases remain to be elucidated. Clin Cancer Res; 20(2); 323-30. © 2013 AACR.


PubMed | Vita-Salute San Raffaele University, Nikea General Hospital, University of Lyon, Masaryk University and 10 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.


Papakonstantinou N.,Democritus University of Thrace | Papakonstantinou N.,G Papanicolaou Hospital | Papakonstantinou N.,Center for Research and Technology Hellas | Ntoufa S.,G Papanicolaou Hospital | And 12 more authors.
Molecular Medicine | Year: 2013

Critical processes of B-cell physiology, including immune signaling through the B-cell receptor (BcR) and/or Toll-like receptors (TLRs), are targeted by microRNAs. With this in mind and also given the important role of BcR and TLR signaling and microRNAs in chronic lymphocytic leukemia (CLL), we investigated whether microRNAs could be implicated in shaping the behavior of CLL clones with distinct BcR and TLR molecular and functional profiles. To this end, we examined 79 CLL cases for the expression of 33 microRNAs, selected on the following criteria: (a) deregulated in CLL versus normal B-cells; (b) differentially expressed in CLL subgroups with distinct clinicobiological features; and, (c) if meeting (a) + (b), having predicted targets in the immune signaling pathways. Significant upregulation of miR-150, miR-29c, miR-143 and miR-223 and downregulation of miR-15a was found in mutated versus unmutated CLL, with miR-15a showing the highest fold difference. Comparison of two major subsets with distinct stereotyped BcRs and signaling signatures, namely subset 1 [IGHV1/5/7-IGKV1(D)-39, unmutated, bad prognosis] versus subset 4 [IGHV4- 34/IGKV2-30, mutated, good prognosis] revealed differences in the expression of miR-150, miR-29b, miR-29c and miR-101, all downregulated in subset 1. We were also able to link these distinct microRNA profiles with cellular phenotypes, importantly showing that, in subset 1, miR-101 downregulation is associated with overexpression of the enhancer of zeste homolog 2 (EZH2) protein, which has been associated with clinical aggressiveness in other B-cell lymphomas. In conclusion, specific miRNAs differentially expressed among CLL subgroups with distinct BcR and/or TLR signaling may modulate the biological and clinical behavior of the CLL clones.


Langerak A.W.,Rotterdam University | Davi F.,University Pierre and Marie Curie | Ghia P.,Vita-Salute San Raffaele University | Hadzidimitriou A.,Center for Research and Technology Hellas | And 6 more authors.
Leukemia | Year: 2011

Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called problematic sequences that do not fit the classic interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication. © 2011 Macmillan Publishers Limited All rights reserved.


Giannoudis P.V.,Leeds Teaching Hospitals NHS Trust | Kanakaris N.K.,Leeds Teaching Hospitals NHS Trust | Delli Sante E.,Leeds Teaching Hospitals NHS Trust | Morell D.J.,Leeds Teaching Hospitals NHS Trust | And 2 more authors.
Journal of Bone and Joint Surgery - Series B | Year: 2013

Over a five-year period, adult patients with marginal impaction of acetabular fractures were identified from a registry of patients who underwent acetabular reconstruction in two tertiary referral centres. Fractures were classified according to the system of Judet and Letournel. A topographic classification to describe the extent of articular impaction was used, dividing the joint surface into superior, middle and inferior thirds. Demographic information, hospitalisation and surgery-related complications, functional (EuroQol 5-D) and radiological outcome according to Matta's criteria were recorded and analysed. In all, 60 patients (57 men, three women) with a mean age of 41 years (18 to 72) were available at a mean follow-up of 48 months (24 to 206). The quality of the reduction was 'anatomical' in 44 hips (73.3%) and 'imperfect' in 16 (26.7%). The originally achieved anatomical reduction was lost in12 patients (25.8%). Radiologically, 33 hips (55%) were graded as 'excellent', 11 (18.3%) as 'good', one (1.7%) as 'fair' and 15 (25%) as 'poor'. A total of 11 further operations were required in 11 cases, of which six were total hip replacements. Univariate linear regression analysis of the functional outcome showed that factors associated with worse pain were increasing age and an inferior location of the impaction. Elevation of the articular impaction leads to joint preservation with satisfactory overall medium-term functional results, but secondary collapse is likely to occur in some patients. © 2013 The British Editorial Society of Bone & Joint Surgery.


Darzentas N.,Center for Research and Technology Hellas | Hadzidimitriou A.,Center for Research and Technology Hellas | Hadzidimitriou A.,G Papanicolaou Hospital | Murray F.,Uppsala University | And 14 more authors.
Leukemia | Year: 2010

Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, stereotyped B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of stereotyped cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first (30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells. © 2010 Macmillan Publishers Limited All rights reserved.

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