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Piraeus, Greece

Sutton L.-A.,Uppsala University | Belessi C.,Nikea General Hospital | Darzentas N.,Masaryk University | Darzentas N.,Center for Research and Technology Hellas | And 4 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.

Ntoufa S.,National and Kapodistrian University of Athens | Vardi A.,G. Papanicolaou Hospital | Papakonstantinou N.,G. Papanicolaou Hospital | Anagnostopoulos A.,G. Papanicolaou Hospital | And 9 more authors.
Molecular Medicine | Year: 2012

Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulation of TLRs and NOD2 in 67 CLL cases assigned to different subgroups on the basis of immunoglobulin heavy variable (IGHV) gene usage, IGHV gene mutational status or B-cell receptor (BcR) stereotypy. Differences in the induction of costimulatory molecules and/or apoptosis were observed in mutated versus unmutated CLL. Different responses were also identified in subsets with stereotyped BcRs, underscoring the idea that "subset-biased" innate immunity responses may occur independently of mutational status. Additionally, differential modulation of kinase activities was induced by TLR stimulation of different CLL subgroups, revealing a TLR7-tolerant state for cases belonging to stereotyped subset #4. The distinct patterns of TLR/NOD2 functional activity in cells from CLL subgroups defined by the molecular features of the clonotypic BcRs might prove relevant for elucidating the immune mechanisms underlying CLL natural history and for defining subgroups of patients who might benefit from treatment with specific TLR ligands.

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.

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.

Papakonstantinou N.,Democritus University of Thrace | Papakonstantinou N.,Center for Research and Technology Hellas | Ntoufa S.,G. Papanicolaou Hospital | Ntoufa S.,Center for Research and Technology Hellas | And 11 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.

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