ABSTRACT
The nearby Supernova 1987A was accompanied by a burst of neutrino emission, which indicates that a compact object (a neutron star or black hole) was formed in the explosion. There has been no direct observation of this compact object. In this work, we observe the supernova remnant with JWST spectroscopy, finding narrow infrared emission lines of argon and sulfur. The line emission is spatially unresolved and blueshifted in velocity relative to the supernova rest frame. We interpret the lines as gas illuminated by a source of ionizing photons located close to the center of the expanding ejecta. Photoionization models show that the line ratios are consistent with ionization by a cooling neutron star or a pulsar wind nebula. The velocity shift could be evidence for a neutron star natal kick.
ABSTRACT
Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination. We previously showed that CYR61/CCN1 expression in osteosarcoma cells is correlated to aggressiveness both in vitro and in vivo in mouse models, as well as in patients. In this study, we found that CYR61 is a critical contributor to the vascularization of primary tumor. We demonstrate that silencing CYR61, using lentiviral transduction, leads to a significant reduction in expression level of pro-angiogenic markers such as VEGF, FGF2, PECAM and angiopoietins concomitantly to an increased expression of major anti-angiogenic markers such as thrombospondin-1 and SPARC. Matrix metalloproteinase-2 family member expression, a key pathway in osteosarcoma metastatic capacity was also downregulated when CYR61 was downregulated in osteosarcoma cells. Using a metastatic murine model, we show that CYR61 silencing in osteosarcoma cells results in reduced tumor vasculature and slows tumor growth compared with control. We also find that microvessel density correlates with lung metastasis occurrence and that CYR61 silencing in osteosarcoma cells limits the number of metastases. Taken together, our data indicate that CYR61 silencing can blunt the malignant behavior of osteosarcoma tumor cells by limiting primary tumor growth and dissemination process.
Subject(s)
Bone Neoplasms/blood supply , Cysteine-Rich Protein 61/genetics , Neovascularization, Pathologic/genetics , Osteosarcoma/blood supply , Animals , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Cell Proliferation/genetics , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, Transgenic , Neoplasm Invasiveness , Neoplasm Metastasis , Osteosarcoma/genetics , Osteosarcoma/pathology , RNA Interference , Tumor Cells, CulturedABSTRACT
Osteosarcoma is the most common primary tumor of bone occurring in children and adolescents. The histological response to chemotherapy represents a key clinical factor related to survival. We previously showed that statins exhibit antitumor effects in vitro, inducing apoptotic cell death, reducing cell migration and invasion capacities and strengthening cytotoxic effects in combination with standard drugs. Comparative transcriptomic analysis between control and statin-treated cells revealed strong expression of several genes, including metallothionein (MT) 2A. MT2A overexpression by lentiviral transduction reduced bioavailable zinc levels, an effect associated with reduced osteosarcoma cell viability and enhanced cell differentiation. In contrast, MT2A silencing did not modify cell viability but strongly inhibited expression of osteoblastic markers and differentiation process. MT2A overexpression induced chemoresistance to cytotoxic drugs through direct chelation of platinum-containing drugs and indirect action on p53 zinc-dependent activity. In contrast, abrogation of MT2A enhanced cytotoxic action of chemotherapeutic drugs on osteosarcoma cells. Finally, clinical samples derived from chemonaive biopsies revealed that tumor cells expressing low MT2A levels correspond to good prognostic (good responder patients with longer survival rate), whereas high MT2A levels were associated with adverse prognosis (poor responder patients). Taken together, these data show that MT2A contributes to chemotherapy resistance in osteosarcoma, an effect partially mediated by zinc chelation. The data also suggest that MT2A may be a potential new prognostic marker for osteosarcoma sensitivity to chemotherapy.
Subject(s)
Chelating Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Metallothionein/metabolism , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Zinc/metabolism , Adolescent , Atorvastatin , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Child , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing/drug effects , Heptanoic Acids/pharmacology , Humans , Metallothionein/genetics , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoblasts/pathology , Osteosarcoma/genetics , Prognosis , Protein Conformation , Pyrroles/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/metabolismABSTRACT
Health care organizations must use research, evaluation, and enhanced management and communication strategies to effectively provide high quality care for special populations. Activities that focus on provider education, enhanced data applications, and consensus building inside and outside the organization are only some of the means by which health plans can achieve improved outcomes for persons with special health care needs.
