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The expression patterns and prognostic significance of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) protein in the neoplastic Hodgkin and Reed Sternberg (HRS) cells of Hodgkin lymphoma (HL) were investigated in a cohort of 154 patients with HL treated with standard regimens. SAMHD1 expression was assessed by immunohistochemistry using diagnostic lymph node biopsies obtained prior to treatment. Using an arbitrary 20% cut-off, SAMHD1 was positive in HRS cells of 48/154 (31·2%) patients. SAMHD1 expression was not associated with clinicopathologic parameters, such as age, gender, stage or histologic subtype. In 125 patients with a median follow-up of 90 months (7–401 months), SAMHD1 expression in HRS cells significantly correlated with inferior freedom from progression (FFP) (P = 0·025), disease-specific survival (DSS) (P = 0·013) and overall survival (OS) (P = 0·01). Importantly, in multivariate models together with disease stage, histology subtype and type of treatment as covariates, SAMHD1 expression retained an independent significant association with unfavourable FFP (P = 0·005) as well as DSS (P = 0·022) and OS (P = 0·018). These findings uncover the significance of a novel, adverse prognostic factor in HL that may have therapeutic implications since SAMHD1 inhibitors are now available for clinical use. © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Background: Anastomosing hemangioma (AH) is a very rare vascular tumor mimicking angiosarcoma, predominately observed in kidney and less frequently in other organs. We present two new renal cases of AH at opposite ends of the clinical presentation spectrum, provide review of the literature and compare the epidemiological, clinical and pathological profiles of renal and non-renal cases. Case presentation: The first occurred in a 64-year-old woman presented with back pain and the second, a multifocal lesion, in a 47-year-old man with end stage renal disease (ESRD). Histology disclosed a vascular tumor with striking anastomosing pattern, minimal nuclear atypia and locally infiltrative pattern, mimicking superficially angiosarcoma. Extramedullary hematopoiesis, extensive perirenal fat entrapment and increased number of mast cells were additional features in the second lesion. Both patients are well, without disease, 25 and 14 months after diagnosis. Conclusion: Comprehensive review and analysis of the published literature show that the growing number of non-renal AHs exhibits similar epidemiologic, clinical, biologic and histologic characteristics with renal AHs and most mild differences vanish after exclusion of cases associated with ESRD. Better understanding of AH pathogenesis will contribute to optimal treatment choices. © 2017 The Author(s).

Mass spectrometry-based quantitative proteomics specifically applied to comprehend the pathogenesis of lymphoma has incremental value in deciphering the heterogeneity in complex deregulated molecular mechanisms/pathways of the lymphoma entities, implementing the current diagnostic and therapeutic strategies. Essential global, targeted and functional differential proteomics analyses although still evolving, have been successfully implemented to shed light on lymphoma pathogenesis to discover and explore the role of potential lymphoma biomarkers and drug targets. This review aims to outline and appraise the present status of MS-based quantitative proteomic approaches in lymphoma research, introducing the current state-of-the-art MS-based proteomic technologies, the opportunities they offer in biological discovery in human lymphomas and the related limitation issues arising from sample preparation to data evaluation. It is a synopsis containing information obtained from recent research articles, reviews and public proteomics repositories (PRIDE). We hope that this review article will aid, assimilate and assess all the information aiming to accelerate the development and validation of diagnostic, prognostic or therapeutic targets for an improved and empowered clinical proteomics application in lymphomas in the nearby future. © 2016 Elsevier B.V.

Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in rheumatoid arthritis (RA) and plays a pivotal role in disease pathogenesis. However, the mechanism through which NETs shape the autoimmune response in RA remains elusive. In this study, we demonstrate that inhibition of peptidylarginine deiminases activity in collagen-induced arthritis (CIA) mouse model significantly reduces NET formation, attenuates clinical disease activity, and prevents joint destruction. Importantly, peptidylarginine deiminase 4 blocking markedly reduces the frequency of collagen-specific IFN-γ-producing T helper 1 (Th1) cells in the draining lymph nodes of immunized mice. Exposure of dendritic cells (DCs) to CIA-derived NETs induces DC maturation characterized by significant upregulation of costimulatory molecules, as well as elevated secretion of IL-6. Moreover, CIA-NET-treated DCs promote the induction of antigen-specific Th1 cells in vitro. Finally, NETs from RA patients show an increased potential to induce the maturation of DCs from healthy individuals, corroborating the findings obtained in CIA mouse model. Collectively, our findings delineate an important role of NETs in the induction and expansion of Th1 pathogenic cells in CIA through maturation of DCs and reveal a novel role of NETs in shaping the RA-autoimmune response that could be exploited therapeutically. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

c-JUN N-terminal Kinase (JNK) is activated/phosphorylated by upstream MAPK kinases (MKK), and, in turn, phosphorylates and activates its major substrate c-JUN, a member of the activator protein-1 (AP-1) transcription factors. c-JUN is overexpressed and activated in Hodgkin and Reed Sternberg cells (HRS) of classical Hodgkin lymphoma (cHL), however, the mechanism of its activation remains unknown. JNK activation was immunohistochemically assessed in 60 cases of HL and in a control group of 151 B-cell non-Hodgkin lymphomas. The biologic effects of JNK activation in cultured HRS cells were investigated using colony formation, cell growth and viability assays and cell cycle analysis by flow cytometry. Western blotting was used to assess protein levels. p-JNK was expressed in 90% of HL, 83% of Burkitt lymphomas, 28% of mantle cell lymphomas, 23% of diffuse large B-cell lymphomas, 19% of follicular lymphomas, and 18% of extranodal marginal zone lymphomas of MALT type. None of the 48 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma and 18 cases of plasma cell myeloma showed JNK phosphorylation (P < 001, Kruskall-Wallis test). Pharmacological inhibition of JNK activity in cultured HRS cells resulted in a significant decrease of cell growth, which was associated with cell cycle arrest at the G2/M phase. The cell cycle effects were linked to deactivation of c-JUN and upregulation of its known target, the cyclin-dependent kinase inhibitor p21. JNK is highly activated in HRS cells, and may contribute to uncontrolled cell cycle progression and proliferation of tumor cells in cHL. © 2014 Elsevier Inc. All rights reserved.

Summary: Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL. © 2014 John Wiley & Sons Ltd.

Fas-associated death domain protein is a key component of the extrinsic apoptotic pathway. In addition, in animal models, Fas-associated death domain protein phosphorylation at serine 194 has been shown to affect cell proliferation, especially in T lymphocytes. The importance of Fas-associated death domain protein phosphorylation at serine 194 for the proliferation of B lymphocytes, however, is uncertain. Here we show in reactive lymph nodes that serine 194 phosphorylated Fas-associated death domain protein is expressed predominantly in the dark (proliferative) zone of germinal centers. In B-cell non-Hodgkin lymphoma cell lines, serine 194 phosphorylated Fas-associated death domain protein levels are substantially higher in highly proliferating cells and lower in serum-starved cells. We also used immunohistochemical analysis to assess Fas-associated death domain protein phosphorylation at serine 194 expression in 122 B-cell non-Hodgkin-type lymphomas. The mean percentage of serine 194 phosphorylated Fas-associated death domain protein positive tumor cells was 81% in Burkitt lymphoma, 41% in diffuse large B-cell lymphoma, 18% in follicular lymphoma, 18% in plasma cell myeloma, 12% in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, 11% in mantle cell lymphoma, and 2% in chronic lymphocytic leukemia/small lymphocytic lymphoma (P

Background: Hypothermia has a detrimental effect on hemostatic mechanism. The purpose of this experimental study was to investigate the effect of graded hypothermia on markers of the anticoagulant system (antithrombin III and protein C) and fibrinolytic system (plasminogen, α 2-antiplasmin), and on vascular wall and other tissue specimens. Materials and methods: Ten New Zealand rabbits were subjected to mild and then moderate core hypothermia of 32°C for 60 min. Blood samples were obtained at normothermic (T 1), mild (T 2), and moderate (T 3) hypothermic conditions. Chromogenic assay methods were used to determine quantitatively (%) the activity of antithrombin III, protein C, plasminogen, and α 2-antiplasmin. Hypothermic values were compared with the normothermic values. Tissue and vessel wall specimens were examined under light microscope. Results: Reduction of activity (%) from normothermia (T 1) to mild (T 2) and moderate (T 3) hypothermia was found for antithrombin III (103.40 ± 12.54, 87.40 ± 13.50, and 82.70 ± 20.78, respectively, with statistically significant difference between T 1-T 3: P=0.03), for protein C (70.1 ± 7.51, 56.30 ± 8.34, and 53.1 ± 7.34, with statistically significant difference between T 1-T 2 and T 1-T 3: P=0.015 for both comparisons) and α 2-antiplasmin (97 ± 9.63, 80.60 ± 11.73, and 83.70 ± 13.94, with statistically significant difference between T 1-T 2: P=0.006). Plasminogen activity was increased (14.50 ± 0.52, 16.30 ± 1.63, and 17.30 ± 2.45, with statistically significant difference between T 1-T 2 and T 1-T 3: P=0.033 for both comparisons). Histologic examination revealed no significant lesions on tissue and vessel wall specimens. Conclusions: The results of our study suggest that even though the hypothermia period was relatively short, the processes of coagulation and fibrinolysis were altered with simultaneous changes. © 2011 Elsevier Inc. All rights reserved.

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). © 2011 Macmillan Publishers Limited All rights reserved.

Jun activation domain-binding protein 1 (JAB1) is a multifunctional protein that participates in the control of cell proliferation and the stability of multiple proteins. JAB1 overexpression has been implicated in the pathogenesis of human cancer. JAB1 regulates several key proteins and thereby produces varied effects on cell cycle progression, genome stability and cell survival. However, the biological significance of JAB1 activity in these cellular signaling pathways is unclear. Therefore, we developed mice that were deficient in Jab1 and analyzed the null embryos and heterozygous cells. This disruption of Jab1 in mice resulted in early embryonic lethality due to accelerated apoptosis. Loss of Jab1 expression sensitized both mouse primary embryonic fibroblasts and osteosarcoma cells to γ-radiation-induced apoptosis, with an increase in spontaneous DNA damage and homologous recombination (HR) defects, both of which correlated with reduced levels of the DNA repair protein Rad51 and elevated levels of p53. Furthermore, the accumulated p53 directly binds to Rad51 promoter, inhibits its activity and represents a major mechanism underlying the HR repair defect in Jab1-deficient cells. These results indicate that Jab1 is essential for efficient DNA repair and mechanistically link Jab1 to the maintenance of genome integrity and to cell survival. © 2010 Macmillan Publishers Limited All rights reserved.

Activating mutations of the FLT3 gene mediate leukemogenesis, at least in part, through activation of PI3K/AKT. The mammalian target of rapamycin (mTOR)-Raptor signaling pathway is known to act downstream of AKT. Here we show that the mTOR effectors, 4EBP1, p70S6K and rpS6, are highly activated in cultured and primary FLT3-mutated acute myeloid leukemia (AML) cells. Introduction of FLT3-ITD expressing constitutively activated FLT3 kinase further activates mTOR and its downstream effectors in BaF3 cells. We also found that mTOR signaling contributes to tumor cell survival, as demonstrated by pharmacologic inhibition of PI3K/AKT/mTOR, or total silencing of the mTOR gene. Furthermore, inhibition of FLT3 kinase results in downregulation of mTOR signaling associated with decreased survival of FLT3-mutated AML cells. These findings suggest that mTOR signaling operates downstream of activated FLT3 kinase thus contributing to tumor cell survival, and may represent a promising therapeutic target for AML patients with mutated-FLT3. © 2010 Chen et al; licensee BioMed Central Ltd.

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.

p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-α, or when pifithrin-was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip S/L, and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK ALCL patients. © 2009 Macmillan Publishers Limited All rights reserved.

The mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients. © 2008 Cambridge University Press.

Background: The kidney is one of the most frequently injured intraabdominal organs. In this study, we investigated the efficacy and safety of radiofrequency ablation (RFA) as a kidney-preserving hemostatic technique for grade IV renal trauma. Methods: A grade IV injury was induced in the right kidney of 12 Landrace pigs. Then RFA was applied around the injury in 10 animals until hemostasis was achieved; two animals were not treated (control group). The treated animals were killed humanely on days 0, 3, 7, 14 and 21 and examined. The kidneys were subjected to histologic and radiologic examination. Results: The two untreated animals died from hypovolemic shock. Hemostasis was achieved in all treated animals. We had no operative deaths and no morbidity. No blood, pus, urine, or other fluid was found at the time of death. In one animal, a fistulous lesion leading to the collecting system was identified, but no urine leakage was observed. At histology, the ablated areas were found to consist of three zones: an inner necrotic one, a zone of neutrophils digesting necrotic tissue, and an outer zone with possibly reversible damage. Conclusions: Radiofrequency ablation is an efficient and safe hemostatic method for grade IV renal trauma. Further study is needed to investigate the possible application of this method to humans and its percutaneous or laparoscopic use.

Background: Splenic salvage is the ultimate goal of the treatment for splenic injury. We experimentally investigated a spleen salvage technique after spleen injury using radiofrequency ablation technology. Methods: A grade IV spleen trauma was produced in 10 white male Landrace pigs (the lower pole of the spleen was sharply divided at the level where the lower hilar vessel enters the organ) under general anesthesia. A Radionics Cooltip Radio Frequency needle was used to stop the bleeding in every case. The electrode was inserted in four to six different sites and each session lasted for 2 to 6 minutes. Results: All bleeding sites were controlled intraoperatively with no additional means. Postoperatively, all animals appeared clinically healthy, and at the time the animals were killed, no blood, pus, or other fluid was identified in the abdomen or chest. Subcapsular or perisplenic hematomas were not found either. Conclusion: We believe that radiofrequency ablation may be used in splenic injury to stop bleeding, especially when blood transfusion or surgery is indicated. This procedure may reduce the frequency of open surgery for repair of the injury, the number of splenectomies, and the amount of blood transfusion required. The advantage of use under ultrasound or computed tomographic guidance or laparoscopically makes it even more appealing. Thus, we suggest that further study in human subjects is required to validate our results.

Aims: To report a case of pyothorax-associated lymphoma in a non-immunocompromised 78-year-old man with a 45-year history of tuberculous pleuritis and left pleural effusion. Pyothorax-associated lymphoma is a high-grade non-Hodgkin’s lymphoma occurring in 2% of patients with long-standing tuberculous pleuritis and pyothorax. Pyothorax-associated lymphoma is frequently Epstein-Barr virus (EBV)-associated, mainly reported in Japan but exceedingly rare in western countries. Methods and results: Histology revealed a high-grade, diffuse large B-cell lymphoma with immunoblastic and plasmacytoid features and marked angiocentricity with focal destruction of the vessel walls. Immunohistochemistry revealed a post germinal B-cell phenotype. RNA in-situ hybridization and molecular analysis showed a latent EBV infection and absence of human herpes virus-8 (HHV-8). Conclusions: Pyothorax-associated lymphoma represents a rare but distinctive type of diffuse large B-cell lymphoma, with characteristic clinico-epidemiological, immunohistological, and biological features.