Retrospective study on osteosarcoma and ewing sarcoma - our experience.

INTRODUCTION: Primary bone tumors are relatively rare types of cancer. Their relative frequency is not yet well established and still there is more information needed regarding the evolution and prognosis of those patients. OBJECTIVES: We analyzed several factors (site of lesion, tumor stage, tumor volume, disease related complications, therapy related complications) that influenced the evolution of bone tumor in a lot of patients diagnosed with osteosarcoma or Ewing sarcome. MATERIAL AND METHODS: A retrospective review was conducted on hospital-based registry from the Emergency Hospital for Children "Louis Turcanu" Timisoara. Patients with newly diagnosed osteosarcoma and Ewing sarcoma, hospitalised in our clinic during a period of 10 years (1996-2006) were included. Records were analyzed for patient demographics, site of lesion, treatment and outcomes. The study group was composed of 36 patients with bone tumors, with ages betwen 3-23 years, who came from Timis and several counties around it. RESULTS: We found Ewing Sarcoma (ES) in 52.94% of cases and osteosarcoma (OS) in 47.06% of cases analyzed. We found diseases in advanced stages in 33.3% of cases in stage III and in 27.7% in stage IV. Tumoral volume had more than 200 cm3 in 53.3% of OS patients and in 21% of cases of ES. Treatment was accomplished according to the European protocols, COSS 96 in 66.6% of OS cases, EWING 99 in 73.6% of ES cases. Disease related complications were found in 26.6% of OS cases and in 51% of ES patients. CONCLUSION: In this study, the patients survival rate at 5 years after diagnosis was lower than in other studies. A possible explaination for such a high rate of mortality could be the delayed diagnosis and the advanced stage of the neoplasia, especially for Ewing sarcoma where only 16.66% of the patients were stage I or II. For the short time survival it was found a corelation with the period of time between the simptoms appearance and the moment of diagnosis, tumor stage, metastasis and severity of the complications.

ß-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma.

Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)-targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R-specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing's sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand-receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/ß-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and ß-arrestin1-dependent ERK signaling activation. Controlled ß-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further ß-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R-biased agonist: ß-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of ß-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies.

Analysis of a promoter polymorphism in the SMDF neuregulin 1 isoform in Schizophrenia.

BACKGROUND/AIMS: Neuregulin 1 (NRG1) is a positional candidate gene in schizophrenia (SZ). Two major susceptibility loci in the NRG1 gene approximately one million nucleotides apart have been identified in genetic studies. Several candidate functional allelic variants have been described that might be involved in disease susceptibility. However, the findings are still preliminary. We recently mapped active promoters and other regulatory domains in several SZ and bipolar disorder (BD) candidate genes using ChIP-chip (chromatin immunoprecipitation hybridized to microarrays). One was the promoter for the NRG1 isoform, SMDF, which maps to the 3' end of the gene complex. Analysis of the SNP database revealed several polymorphisms within the approximate borders of the region immunoprecipitated in our ChIP-chip experiments, one of which is rs7825588. METHODS: This SNP was analyzed in patients with SZ and BD and its effect on promoter function was assessed by electromobility gel shift assays and luciferase reporter constructs. RESULTS: A significant increase in homozygosity for the minor allele was found in patients with SZ (genotype distribution chi(2) = 7.32, p = 0.03) but not in BD (genotype distribution chi(2) = 0.52, p = 0.77). Molecular studies demonstrated modest, but statistically significant allele-specific differences in protein binding and promoter function. CONCLUSION: The findings suggest that homozygosity for rs725588 could be a risk genotype for SZ.

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

Synergistic interactions between interferon-gamma and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma-associated apoptosis.

Microvascular endothelial cell (MVEC) injury coupled to progression of platelet microthrombi facilitated by ADAMTS13 deficiency is characteristic of idiopathic and HIV-linked thrombotic thrombocytopenic purpura (TTP). Cytokines capable of inducing MVEC apoptosis in vitro are up-regulated in both TTP and HIV infection. However, the concentrations of these cytokines required to elicit EC apoptosis in vitro are 2- to 3-log-fold greater than present in patient plasmas. We report that clinically relevant levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon (IFN)-gamma act in synergy to induce apoptosis in dermal MVECs, but have no effect on large-vessel ECs or pulmonary MVECs. This reflects the tissue distribution of TTP lesions in vivo. Sensitivity to TTP plasma or TRAIL plus IFN-gamma is paralleled by enhanced ubiquitination of the caspase-8 regulator cellular FLICE-like inhibitory protein (c-FLIP), targeting it for proteasome degradation. c-FLIP silencing with anti-FLIP short interfering RNA (siRNA) in pulmonary MVECs rendered them susceptible to TTP plasma- and cytokine-mediated apoptosis, while up-regulation of c-FLIP by gene transfer partially protected dermal MVECs from such injury. TTP plasma-mediated apoptosis appears to involve cytokine-induced acceleration of c-FLIP degradation, sensitizing cells to TRAIL-mediated caspase-8 activation and cell death. Suppression of TRAIL or modulation of immunoproteasome activity may have therapeutic relevance in TTP.

Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus.

The role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcgammaRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G-C substitution at position -343 relative to the start of transcription) with altered FcgammaRIIb expression and function. The G-C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcgammaRIIb receptors was significantly reduced in activated B cells from (-343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in -343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.

Incorporating statistical measures of anatomical variability in atlas-to-subject registration for conformal brain radiotherapy.

Deforming a digital atlas towards a patient image allows the simultaneous segmentation of several structures. Such an intersubject registration is difficult as the deformations to recover are highly inhomogeneous. A priori information about the local amount of deformation to expect is precious, since it allows to optimally balance the quality of the matching versus the regularity of the deformation. However, intersubject variability makes it hard to heuristically estimate the degree of deformation. Indeed, the sizes and shapes of various structures differ greatly and their relative positions vary in a rather complex manner. In this article, we perform a statistical study of the deformations yielded by the registration of an image database with an anatomical atlas, and we propose methods to re-inject this information into the registration. We show that this provides more accurate segmentations of brain structures.

Grid powered nonlinear image registration with locally adaptive regularization.

Multi-subject non-rigid registration algorithms using dense deformation fields often encounter cases where the transformation to be estimated has a large spatial variability. In these cases, linear stationary regularization methods are not sufficient. In this paper, we present an algorithm that uses a priori information about the nature of imaged objects in order to adapt the regularization of the deformations. We also present a robustness improvement that gives higher weight to those points in images that contain more information. Finally, a fast parallel implementation using networked personal computers is presented. In order to improve the usability of the parallel software by a clinical user, we have implemented it as a grid service that can be controlled by a graphics workstation embedded in the clinical environment. Results on inter-subject pairs of images show that our method can take into account the large variability of most brain structures. The registration time for images of size 256 x 256 x 124 is 5 min on 15 standard PCs. A comparison of our non-stationary visco-elastic smoothing versus solely elastic or fluid regularizations shows that our algorithm converges faster towards a more optimal solution in terms of accuracy and transformation regularity.

Inhibitory Fc gamma receptors: from gene to disease.

Multiple lines of evidence have revealed a key role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) as negative modulators of innate and adaptive immune responses. Acquired and genetic factors regulate the expression of FcgammaRIIb receptors and modify their inhibitory potential. Recent advances have highlighted the importance of FcgammaRIIb receptors in influencing the development of cancer and autoimmunity. The association of increased FcgammaRIIb expression with tumor development is believed to operate at effector cell level resulting in inhibition of antitumor cytotoxicity. In autoimmune diseases, FcgammaRIIb receptors play a major role in controlling the amplitude of antibody- and immune complex-mediated reactions. Generally, FcgammaRIIb deficiency is associated with increased susceptibility and severity to organ-specific and systemic autoimmunity. This article discusses the proposed mechanisms for FcgammaRIIb deregulation associated with malignant and autoimmune pathology in animal models and human diseases.