The interplay between critical transcription factors and microRNAs in the control of normal and malignant myelopoiesis

Myelopoiesis is a complex process driven by essential transcription factors, including C/EBPα, PU.1, RUNX1, KLF4 and IRF8. Together, these factors are critical for the control of myeloid progenitor cell expansion and lineage determination in the development of granulocytes and monocytes/macrophages. MicroRNAs (miRNAs) are expressed in a cell type and lineage specific manner. There is increasing evidence that miRNAs fine-tune the expression of hematopoietic lineage-specific transcription factors and drive the lineage decisions of hematopoietic progenitor cells. In this review, we discuss recently discovered self-activating and feed-back mechanisms in which transcription factors and miRNAs interact during myeloid cell development. Furthermore, we delineate how some of these mechanisms are affected in acute myeloid leukemia (AML) and how disrupted transcription factor-miRNA interplays contribute to leukemogenesis

Synergistic effects of TNF-alpha and melphalan in an isolated limb perfusion model of rat sarcoma: a histopathological, immunohistochemical and electron microscopical study.

Isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF-alpha) and melphalan has shown impressive results in patients with irresectable soft tissue sarcomas and stage III melanoma of the extremities. The mechanisms of the reported in vivo synergistic anti-tumour effects of TNF-alpha and melphalan are not precisely understood. We have developed an ILP model in the rat using a non-immunogenic sarcoma in which similar in vivo synergy is observed. The aim of this present study was to analyse the morphological substrate for this synergistic response of TNF-alpha in combination with melphalan to shed more light on the pathomechanisms involved. Histology of the tumours from saline- (n = 14) and melphalan-treated (n = 11) rats revealed apparently vital tumour cells in over 80% of the cross-sections. Interstitial oedema and coagulation necrosis were observed in the remaining part of the tumour. Haemorrhage was virtually absent. TNF-alpha (n = 22) induced marked oedema, hyperaemia, vascular congestion, extravasation of erythrocytes and haemorrhagic necrosis (20-60% of the cross-sections). Oedema and haemorrhage suggested drastic alterations of permeability and integrity of the microvasculature. Using light and electron-microscopy, we observed that haemorrhage preceded generalised platelet aggregation. Therefore, we suggest that the observed platelet aggregation was the result of the microvascular damage rather than its initiator. Remarkably, these events hardly influenced tumour growth. However, perfusion with the combination of TNF-alpha and melphalan (n = 24) showed more extensive haemorrhagic necrosis (80-90% of the cross-sections) and revealed a prolonged remission (mean 11 days) in comparison with the other groups of rats. Electron microscopical analysis revealed similar findings as described after TNF-alpha alone, although the effects were more prominent at all time points after perfusion. In conclusion, our findings suggest that the enhanced anti-tumour effect after the combination of TNF-alpha with melphalan results from potentiation of the TNF-alpha-induced vascular changes accompanied by increased vascular permeability and platelet aggregation. This may result in additive cytotoxicity or inhibition of growth of residual tumour cells

miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia

T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3

MicroRNA-139, an Emerging Gate-Keeper in Various Types of Cancer

Mounting data show that MIR139 is commonly silenced in solid cancer and hematological malignancies. MIR139 acts as a critical tumor suppressor by tuning the cellular response to different types of stress, including DNA damage, and by repressing oncogenic signaling pathways. Recently, novel insights into the mechanism of MIR139 silencing in tumor cells have been described. These include epigenetic silencing, inhibition of POL-II transcriptional activity on gene regulatory elements, enhanced expression of competing RNAs and post-transcriptional regulation by the microprocessor complex. Some of these MIR139-silencing mechanisms have been demonstrated in different types of cancer, suggesting that these are more general oncogenic events. Reactivation of MIR139 expression in tumor cells causes inhibition of tumor cell expansion and induction of cell death by the repression of oncogenic mRNA targets. In this review, we discuss the different aspects of MIR139 as a tumor suppressor gene and give an overview on different transcriptional mechanisms regulating MIR139 in oncogenic stress and across different types of cancer. The novel insights into the expression regulation and the tumor-suppressing activities of MIR139 may pave the way to new treatment options for cancer

MicroRNA-139, an Emerging Gate-Keeper in Various Types of Cancer

Mounting data show that MIR139 is commonly silenced in solid cancer and hematological malignancies. MIR139 acts as a critical tumor suppressor by tuning the cellular response to different types of stress, including DNA damage, and by repressing oncogenic signaling pathways. Recently, novel insights into the mechanism of MIR139 silencing in tumor cells have been described. These include epigenetic silencing, inhibition of POL-II transcriptional activity on gene regulatory elements, enhanced expression of competing RNAs and post-transcriptional regulation by the microprocessor complex. Some of these MIR139-silencing mechanisms have been demonstrated in different types of cancer, suggesting that these are more general oncogenic events. Reactivation of MIR139 expression in tumor cells causes inhibition of tumor cell expansion and induction of cell death by the repression of oncogenic mRNA targets. In this review, we discuss the different aspects of MIR139 as a tumor suppressor gene and give an overview on different transcriptional mechanisms regulating MIR139 in oncogenic stress and across different types of cancer. The novel insights into the expression regulation and the tumor-suppressing activities of MIR139 may pave the way to new treatment options for cancer

Synergistic antitumor effect of recombinant human tumor necrosis factor alpha with melphalan in isolated limb perfusion in the rat

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Assment of role of neutrofiles on the antitumor effect of TNF-alpha in an in vivo isolated limb perfusion model in sarcoma bearing brown norway rats

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Parameters of selected levels in 35 Cl

Parameters of selected levels in 35 Cl have been determined by means of several techniques, including proton elastic scattering studies, angular distribution measurements, calibration of the excitation energies by a cascade/crossover method and resonance absorption experiments. For the E = 1375, 1683 and 2791 keV resonances we found J π = 5 2 + , while the assignments for the E p = 1354, 1893, 1974 and 2541 keV resonances were 3 2 − , 1 2 + , 1 2 − and 7 2 − , respectively. The parity of the E p = 1891 keV resonance is positive; a J = 5 2 assignment is tentatively made for this level. Values for the proton width were determined. The excitation energies of these resonances and also of 18 bound levels were measured with sub-keV precision. The absolute resonance strength in the E p = 1891 keV resonance has been determined to be 4.1 ± 0.5 eV, in agreement with recent thick-target γ-ray yield measurements

Adjuvant cytokeratin staining in Mohs micrographic surgery for basal cell carcinoma

Mohs micrographic surgery (MMS) is a technique that offers excellent cure rates in the treatment of basal cell carcinoma (BCC). One of the reasons for its success is the 100% visualization of the resection margins. Still, recurrences do occur in 2% to 5% of the treated BCCs. It has been suggested that BCC cells in frozen sections stained with hematoxylin and eosin (H&E) may be missed. To determine whether an additional immunohistochemical staining with a cytokeratin marker (MNF 116) indicates BCC cells in sections in which the H&E-stained frozen sections were negative. The Mohs procedure was performed under standard conditions in which H&E-stained slides were judged by the Mohs surgeon and the pathologist. After the H&E slides where judged negative, an extra slide was stained using immunohistochemistry and a monoclonal antibody against cytokeratin (MNF 116). A total of 143 complete slides were stained and judged by two Mohs surgeons and a pathologist. One of the 143 slides stained with MNF 116 showed positive staining where the H&E slides were negative, which is 0.7% of the slides. However, this single slide represents a failure of nearly 2% of the treated patients. Frozen sections stained with H&E in MMS offer enough security in detecting BCC cells during surgery; however, adjuvant cytokeratin staining can be useful in very selected cases of aggressive growing BC

Synergistic antitumour effect of recombinant human tumour necrosis factor α with melphalan in isolated limb perfusion in the rat

textabstractThe efficacy of isolated limb perfusion (ILP) for 'in-transit' metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) α. A rat sarcoma tumour model was, therefore, developed to evaluate the effects of TNF-α, melphalan and the combination of these drugs in the treatment of sarcoma. In BN rats bearing the non-immunogenic BN 175 sarcoma ILPs were performed with perfusate only, TNF-α, melphalan alone, or in combination when tumours had grown to approximately 15 cm in diameter. All rats treated with sham perfusion or perfusion with 50 μg TNF-α showed progressive disease. After perfusion with 40 μg melphalan no change in tumour diameter was observed in any rats at 4 days. After a combined perfusion with 40 μg melphalan and 50 μg TNF-α complete remission was noted in 12 of 16 rats. This synergistic effect in vivo between relatively ineffective doses of TNF-α and melphalan was not observed in vitro