Ewing's Sarcoma.

In 1920, during a meeting of the New York Pathological Society, James Ewing described an unusual tumor in a 14-year-old girl as a “diffuse endothelioma of bone.”1 The tumor had initially been diagnosed as an osteosarcoma, but its architecture, the morphologic features of its cells, and its marked sensitivity to radiation therapy led Ewing to consider it as a distinct entity, going so far as to hypothesize an endothelial-cell origin.1 He later reported similar tumors in other adolescents, which pathologists variously referred to as Ewing’s sarcoma, Askin’s tumor, and peripheral primitive neuroectodermal tumor, on the basis of their shared morphologic and immunohistochemical features. The first landmark discovery toward unequivocally diagnosing Ewing’s sarcoma was made more than 70 years later, when the most frequent of the chromosomal translocations that define the tumor was identified.2 A century after Ewing’s seminal observation, the cancer that bears his name has become a paradigm for solid-tumor development after a single genetic rearrangement. In this review, we discuss the clinical features and pathogenesis of Ewing’s sarcoma, along with current and experimental therapeutic approaches. From the mechanistic point of view, we review the way in which a unique chromosomal translocation harnesses the epigenetic machinery of permissive cells to rewire their transcriptome and initiate a heterogeneous cancer that can elude even the most intensive conventional therapy available

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer.

IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMP1-3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth

Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis.

Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth

Soft tissue sarcomas: introduction to the Virchows Archiv review issue

Molecular tumour pathology - and tumour genetic

5-Hydroxymethylcytosine Loss in Conjunctival Melanoma.

Conjunctival and cutaneous melanoma partially share similar clinical and molecular backgrounds. As 5-hydroxymethylcytosine (5-hmC) loss has been demonstrated in cutaneous melanoma, we decided to assess if similar changes were occurring in conjunctival melanoma. 5-methylcytosine (5-mC), 5-hmC and TET2 were respectively identified by immunohistochemistry and RNA ISH in 40 conjunctival nevi and 37 conjunctival melanomas. Clinicopathological correlations were established. 5-mC, TET2 and 5-hmC were respectively identified in 67.5%, 95% and 100% of conjunctival nevi and in 81.1%, 35.1% and 54% of conjunctival melanomas. A significant 5-hmC and TET2 loss was identified in conjunctival melanoma comparing to nevus, as well as a significant correlation between TET2 and 5-hmC expression. In the melanomas, 5-hmC expression was only significantly associated with local lymphatic invasion, but not with other clinicopathological parameters. There was a correlation between TET2 expression and the localization of the tumors. 5-mC expression was not associated with any clinicopathological parameters. We identified a significant 5-hmC loss in conjunctival melanoma similar to cutaneous melanoma. This loss may possibly be attributed to TET2 loss or IDH1 mutations. 5-hmC loss in conjunctival melanoma may help in the differential diagnosis between atypical conjunctival nevus and conjunctival melanoma

Approccio metodologico per l’ individuazione di siti potenzialmente inquinati attraverso l’integrazione di dati multiparametrici, in ambiente GIS: un esempio di applicazione al Comune di Marigliano (Napoli)

In the most recent year, the environmental monitoring is became important for managing of territory and mitigation of the geo-environmental risks. The integration of the current geo-technologies and geomorphologic, geological, geochemical and geophysical parameters is fundamental for excellent results. In this paper we describe a methodology of study to identify environmental anomalies (illegal buried waste) of the Marigliano town, in province of Naples, brownfield of national interest for the reclamation. Particularly we have been described the use of satellite imagines in several years that has been the goal of this research. Brownfields not known potential contaminated have been identified and managing in GIS system to give a base for realization of a control support system

Synovial sarcoma: when epigenetic changes dictate tumour development.

Synovial sarcoma is a highly aggressive soft tissue malignancy that often affects adolescents and young adults. It is associated with a unique chromosomal translocation that results in the formation and expression of the fusion gene SS18-SSX, which underlies its pathogenesis. Although SS18-SSX provides a potentially unique therapeutic target, all attempts to neutralise it have been unsuccessful thus far. When complete surgical removal of the tumour fails, therapy is limited to largely ineffective cytotoxic drug regimens. Nevertheless, recent discoveries about the mechanisms of SS18-SSX protein function have provided insight into potential alternative therapeutic strategies. SS18-SSX displays oncogenic activity through protein-protein interactions and participation in chromatin remodelling complexes. This review summarises our current understanding of the function of SS18-SSX and the mechanisms by which it alters the epigenetic landscape of permissive cells to induce transformation and the subsequent development of synovial sarcoma

The polarization mode of the auroral radio emission from the early-type star HD142301

We report the detection of the auroral radio emission from the early-type magnetic star HD142301. New VLA observations of HD142301 detected highly polarized amplified emission occurring at fixed stellar orientations. The coherent emission mechanism responsible for the stellar auroral radio emission amplifies the radiation within a narrow beam, making the star where this phenomenon occurs similar to a radio lighthouse. The elementary emission process responsible for the auroral radiation mainly amplifies one of the two magneto-ionic modes of the electromagnetic wave. This explains why the auroral pulses are highly circularly polarized. The auroral radio emission of HD142301 is characterized by a reversal of the sense of polarization as the star rotates. The effective magnetic field curve of HD142301 is also available making it possible to correlate the transition from the left to the right-hand circular polarization sense (and vice-versa) of the auroral pulses with the known orientation of the stellar magnetic field. The results presented in this letter have implications for the estimation of the dominant magneto-ionic mode amplified within the HD142301 magnetosphere.Comment: 5 pages, 4 figures; accepted to MNRAS Letter

IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells

The EWS-FLI-1 fusion protein is associated with 85-90% of Ewing's sarcoma family tumors (ESFT), the remaining 10-15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin. To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS-ERG expression and none could express FUS-ERG for more than 3-5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression. Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.

Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy