Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness ...characters and tumorigenicity of glioma initiating cells. Consultation of publicly available TCGA database indicated that high OPN expression correlated with poor survival in GBM patients. In this study, we explored the role of OPN in GBM radioresistance using an OPN-depletion strategy in U87-MG, U87-MG vIII and U251-MG human GBM cell lines. Clonogenic experiments showed that OPN-depleted GBM cells were sensitized to irradiation. In comet assays, these cells displayed higher amounts of unrepaired DNA fragments post-irradiation when compared to control. We next evaluated the phosphorylation of key markers of DNA double-strand break repair pathway. Activating phosphorylation of H2AX, ATM and 53BP1 was significantly decreased in OPN-deficient cells. The addition of recombinant OPN prior to irradiation rescued phospho-H2AX foci formation thus establishing a new link between DNA repair and OPN expression in GBM cells. Finally, OPN knockdown improved mice survival and induced a significant reduction of heterotopic human GBM xenograft when combined with radiotherapy. This study reveals a new function of OPN in DNA damage repair process post-irradiation thus further confirming its major role in GBM aggressive disease.
Background Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-Beta1 has been identified as a ...key driving force behind metastatic breast cancer, with promising therapeutic implications. Methods and Findings Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1Beta, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-Beta1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. Conclusions Our data show that asporin is a stroma-derived inhibitor of TGF-Beta1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving ...force behind metastatic breast cancer, with promising therapeutic implications. Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
Cytochrome c oxidase (COX) deficiency is one of the most common respiratory chain deficiencies. A woman was presented at the age of 18y with acute loss of consciousness, non-convulsive status ...epilepticus, slow neurological deterioration, transient cortical blindness, exercise intolerance, muscle weakness, hearing loss, cataract and cognitive decline. Muscle biopsy revealed ragged-red fibers, COX negative fibers and a significant decreased activity of complex IV in a homogenate. Using next generation massive parallel sequencing of the mtDNA, a novel heteroplasmic mutation was identified in MTCO1, m.7402delC, causing frameshift and a premature termination codon. Single fiber PCR showed co-segregation of high mutant load in COX negative fibers. Mutation in mitochondrially encoded complex IV subunits should be considered in mitochondrial encephalomyopathies and COX negative fibers after the common mtDNA mutations have been excluded.
Bone mass of the calvarium Simoni, Paolo; Stulko, Jennifer; Ben Mustapha, Selma ...
Skeletal radiology,
08/2013, Letnik:
42, Številka:
8
Journal Article
Regulatory T cells (TR cells) play a crucial role in the regulation of intestinal inflammation. To examine the pathogenetic relevance of TR cells in inflammatory bowel disease (IBD), we evaluated ...their frequency in peripheral blood and inflamed and noninflamed mucosae of pediatric patients with IBD and age-matched controls without IBD; we also characterized the immune profile of the inflammatory infiltrate in the different phases of the disease.
Circulating TR cells were investigated on peripheral blood mononuclear cells by fluorescence-activated cell sorting analysis; mucosal TR cells and inflammatory cell populations were investigated by immunohistochemistry on bioptic specimens. FOXP3 messenger RNA expression levels were confirmed using real-time polymerase chain reaction.
FOXP3+ TR cells were significantly increased in the intestinal lesions of patients with active IBD, and returned to normal levels in posttherapy remission phase. At variance, circulating TR cell frequency was elevated in patients with IBD independently of disease activity, as it persisted in the remission phase. A selective imbalance in the frequency of CD4+ T and natural killer cell subsets characterized the abundant inflammatory infiltrate of active intestinal lesions, and also persisted, at a lower level, in noninflamed mucosae of patients in the remission phase.
TR cell frequency is differently regulated in mucosal tissues and at the systemic level during the distinct phases of pediatric IBD. The inactive stage of pediatric IBD is characterized by an incomplete normalization of the immune profile, independently of the clinical efficacy of the therapy. The pediatric, early-onset condition may represent a privileged observatory to dissect the immune-mediated pathogenetic mechanisms at the basis of the disease.
Multiple choroid plexus papillomas (CPPs) are rare. Usually, they correspond to villous hypertrophy or metastasis occurring during cerebrospinal dissemination. Multiple CPPs have rarely been reported ...as synchronous tumors.
Three synchronous CPPs were resected in a 59-year-old female 6 years after their first imaging description. Pathology showed mucus-producing CPP in all 3, 1 of the 3 presenting some signs of atypia. No p53 or hSNF5/INI1 mutation, or signs of polyoma viruses infection were found.
Although no clear cause for the multifocality was found, the simultaneous presence of the three tumors and their benign histology suggest that they were synchronous and not metastatic. The issue of differentiating synchronous CPPs from metastatic CPP is discussed.
Unusual presentation of osteopoikilosis Simoni, P; Denut, J; Ben Mustapha, S ...
JBR-BTR : organe de la Societe royale belge de radiologie (SRBR) = orgaan van de Koninklijke Belgische Vereniging voor Radiologie (KBVR),
2013 Nov-Dec, Letnik:
96, Številka:
6
Journal Article
Recenzirano
Odprti dostop
We present a case of osteopoikilosis in a 74-year-old woman with hip pain, presenting multiple osteoblastic lesions of the axial skeleton including an osteoblastic large lesion of her left femur. The ...imaging findings on X-rays and computed tomography are provided along with the discussion of the differential diagnosis on the basis of the recent literature.
PDF
