Persistence of Natural Killer (NK) cell lymphocytosis with hyposplenism without development of leukaemia

BACKGROUND: Natural killer (NK) cell lymphocytosis usually has an indolent course and can progress into massive lymphocytosis with development of cytopenias and neoplastic diseases. NK-cells usually express one or more "NK-associated" antigens (CD16, CD56, CD57). Reactive expansions are seen in autoimmune diseases, viral infections, solid tumours and non-Hodgkin's lymphoma. CASE PRESENTATION: We report a lady with a benign clinical course over 10 years and persistent CD8+/CD3-/CD57+/CD16+ LGL proliferation with presence of Howell-Jolly bodies (functional hyposplenism), an association not previously described. CONCLUSION: We discuss the possible causes of clonal expansion and conclude that this may be part of the spectrum of immune dysregulation associated with NK-cell lymphocytosis

Boolean network simulations for life scientists

Modern life sciences research increasingly relies on computational solutions, from large scale data analyses to theoretical modeling. Within the theoretical models Boolean networks occupy an increasing role as they are eminently suited at mapping biological observations and hypotheses into a mathematical formalism. The conceptual underpinnings of Boolean modeling are very accessible even without a background in quantitative sciences, yet it allows life scientists to describe and explore a wide range of surprisingly complex phenomena. In this paper we provide a clear overview of the concepts used in Boolean simulations, present a software library that can perform these simulations based on simple text inputs and give three case studies. The large scale simulations in these case studies demonstrate the Boolean paradigms and their applicability as well as the advanced features and complex use cases that our software package allows. Our software is distributed via a liberal Open Source license and is freely accessible fro

Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice

<p>Abstract</p> <p>Background</p> <p>Signal transducer and activator of transcription 3 (STAT3) is usually constitutively activated in a variety of malignancies. Therefore, STAT3 may be a promising target for treatment of tumor cells. To explore the possibility of a double-stranded decoy oligodeoxynucleotide (ODN) targeted blocking STAT3 over-activated tumor cells, we, here, evaluate the efficacy of STAT3 decoy ODN on human lung cancer cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>A STAT3 decoy ODN was transfected into A549 lung cancer cell line <it>in vitro </it>by using lipofectamine. The flow cytometry and fluorescent microscopy were used to detect the transfection efficiency and the sub-cellular localization of STAT3 decoy ODN in A549 cells. Cell proliferation was determined by counting cell numbers and [³H]-thymidine uptake. Cell apoptosis was examined with Annexin V and propidum iodide by flow cytometry. The expression levels of STAT3 target genes were identified by RT-PCR and immunoblot. For <it>in vivo </it>experiment, A549 lung carcinoma-nude mice xenograft was used as a model to examine the effect of the STAT3 decoy by intratumoral injection. At the end of treatment, TUNEL and immunohistochemistry were used to examine the apoptosis and the expression levels of bcl-xl and cyclin D1 in tumor tissues.</p> <p>Results</p> <p>STAT3 decoy ODN was effectively transfected into A549 lung cancer cells and mainly located in nucleus. STAT3-decoy ODN significantly induced apoptosis and reduced [³H]-thymidine incorporation of A549 cells as well as down-regulated STAT3-target genes <it>in vitro</it>. STAT3 decoy ODN also dramatically inhibited the lung tumor growth in xenografted nude mice and decreased gene expression of bcl-xl and cyclin D1.</p> <p>Conclusion</p> <p>STAT3 decoy ODN significantly suppressed lung cancer cells <it>in vitro </it>and <it>in vivo</it>, indicating that STAT3 decoy ODN may be a potential therapeutic approach for treatment of lung cancer.</p

IPSS-independent prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes

Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (interleukin (IL)-2R, IL-8, IL-12, IL-15 and C–X–C motif chemokine 10 (CXCL10)) and large-cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). To examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex enzyme-linked immunosorbent assay to measure 30 plasma cytokines in 78 patients with primary MDS. Compared with normal controls (n=35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (P<0.01), IL-7 (P=0.02) and IL-6 (P=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the International Prognostic Scoring System, age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (P<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (P=0.01). Comparison of plasma cytokines between MDS (n=78) and primary myelofibrosis (n=127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically relevant plasma cytokine signatures in hematological malignancies

Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

<p>Abstract</p> <p>Background</p> <p>Persistent high risk HPV infection can lead to cervical cancer, the second most common malignant tumor in women worldwide. NK cells play a crucial role against tumors and virus-infected cells through a fine balance between activating and inhibitory receptors. Expression of triggering receptors NKp30, NKp44, NKp46 and NKG2D on NK cells correlates with cytolytic activity against tumor cells, but these receptors have not been studied in cervical cancer and precursor lesions. The aim of the present work was to study NKp30, NKp46, NKG2D, NKp80 and 2B4 expression in NK cells from patients with cervical cancer and precursor lesions, in the context of HPV infection.</p> <p>Methods</p> <p>NKp30, NKp46, NKG2D, NKp80 and 2B4 expression was analyzed by flow cytometry on NK cells from 59 patients with cervical cancer and squamous intraepithelial lesions. NK cell cytotoxicity was evaluated in a 4 hour CFSE/7-AAD flow cytometry assay. HPV types were identified by PCR assays.</p> <p>Results</p> <p>We report here for the first time that NK cell-activating receptors NKp30 and NKp46 are significantly down-regulated in cervical cancer and high grade squamous intraepithelial lesion (HGSIL) patients. NCRs down-regulation correlated with low cytolytic activity, HPV-16 infection and clinical stage. NKG2D was also down-regulated in cervical cancer patients.</p> <p>Conclusion</p> <p>Our results suggest that NKp30, NKp46 and NKG2D down-regulation represent an evasion mechanism associated to low NK cell activity, HPV-16 infection and cervical cancer progression.</p

Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6

BACKGROUND: AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta). The authors concluded that TGF-beta acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6) may represent a counteracting positive influence in their growth regulation. METHODS: Growth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3. RESULTS: Results confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines differed in their responsiveness to TGF-beta1 and IL-6. Analysis of a recently derived AIDS-NHL cell line, UMCL01-101, indicated that it represents immunoblastic AIDS-DLCBL. Like LCL-8664, UMCL01-101 was sensitive to TGF-beta1-mediated inhibition, rescued partially by IL-6, and demonstrated rapid STAT3 activation following IL-6 treatment even in the presence of TGF-beta1. CONCLUSION: These studies indicate that the sensitivity of immunoblastic AIDS- or SAIDS-DLBCL to TGF-beta1-mediated growth inhibition may be overcome through the stimulation of proliferative and anti-apoptotic signals by IL-6, particularly through the rapid activation of STAT3