Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP.

Glioblastoma is the most common primary brain tumor with a very poor prognosis, calling for novel treatment strategies. Here, we provide first evidence that histone deacetylase inhibitors (HDACI) prime glioblastoma cells for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis at least in part by c-myc-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP). Pretreatment with distinct HDACI (MS275, suberoylanilide hydroxamic acid, valproic acid) significantly enhances TRAIL-induced apoptosis in several glioblastoma cell lines. Monitoring a panel of apoptosis-regulatory proteins revealed that MS275 reduces the expression of cFLIP(L) and cFLIP(S). This leads to decreased recruitment of cFLIP(L) and cFLIP(S) and increased activation of caspase-8 to the TRAIL death-inducing signaling complex, resulting in enhanced cleavage of caspase-8, -9 and -3 and caspase-dependent apoptosis. Also, MS275 promotes TRAIL-triggered processing of Bid, activation of Bax, loss of mitochondrial membrane potential and release of cytochrome c. MS275-mediated downregulation of cFLIP occurs at the mRNA level independent of proteasome- or caspase-mediated degradation, and is preceded by upregulation of nuclear levels of c-myc, a transcriptional repressor of cFLIP. Notably, MS275 causes increased binding of c-myc to the cFLIP promoter and reduces cFLIP promoter activity. Indeed, knockdown of c-myc partially rescues cFLIP(L) from MS275-inferred downregulation and significantly decreases TRAIL- and MS275-induced apoptosis. Also, overexpression of cFLIP(L) or cFLIP(S) significantly reduces MS275- and TRAIL-induced apoptosis. Importantly, MS275 sensitizes primary cultured glioblastoma cells towards TRAIL and cooperates with TRAIL to reduce long-term clonogenic survival of glioblastoma cells and to suppress glioblastoma growth in vivo underscoring the clinical relevance of this approach. Thus, these findings demonstrate that HDACI represent a promising strategy to prime glioblastoma for TRAIL-induced apoptosis by targeting cFLIP.

[Intraocular epithelial downgrowth - report on 14 cases from 1986 to 2000]. / Intraokulare Epithelimplantation - Bericht über 14 Patienten 1986 - 2000.

BACKGROUND: Diffuse and cystic epithelial downgrowth occur rarely, but they represent a mostly preventable potential cause of blindness as sequels to trauma and surgery. The aim of this study is to report on the etiology and course of disease in patients with histologically verified epithelial downgrowth. PATIENTS AND METHODS: From 1986 until 2000 the ophthalmopathological laboratory of the University Eye Hospital Hamburg-Eppendorf received 13 (4 external) referrals. Ten patients with cystic of diffuse intraocular epithelial downgrowth were treated and 9 eyes were operated on in the Hospital. RESULTS: At presentation 4/10 patients had a visual acuity of < or = 0.1, and 2/10 had no light perception. A cystic epithelial downgrowth was verified histologically in 9/13, and a diffuse form in 4/13 patients. Mucin production was proven histochemically in 1/9 intraocular epithelial downgrowth sections. In one case a spontaneous iris cyst was detected by the immunohistological examinations. Trauma (10/14) and surgery (3/14) were the most frequent causes and were symptomatic on average 17 years after the primary event. A curative surgery was done in 13/14 patients (5 x en bloc excision, 2 x penetrating keratoplasty, 1 x iridectomy, 2 x enucleations, 3 x external) resulting in no recurrences during the follow-up of 4(1/2) years (1 - 12 years). The postoperative visual acuity was ameliorated in 5/9, worsened in 2 patients, and 2 were enucleated. CONCLUSIONS: Epithelial downgrowth is a rare but preventable cause of blindness. The most important prophylaxis is meticulous primary surgery including a sufficient wound closure. The visual outcome depends on the preoperative conditions.

The representations of the arithmetic operations include functional relationships.

Current theories of mathematical problem solving propose that people select a mathematical operation as the solution to a problem on the basis of a structure mapping between their problem representation and the representation of the mathematical operations. The structure-mapping hypothesis requires that the problem and the mathematical representations contain analogous relations. Past research has demonstrated that the problem representation consists of functional relationships, or principles. The present study tested whether people represent analogous principles for each arithmetic operation (i.e., addition, subtraction, multiplication, and division). For each operation, college (Experiments 1 and 2) and 8th grade (Experiment 2) participants were asked to rate the degree to which a set of completed problems was a good attempt at the operation. The pattern of presented answers either violated one of four principles or did not violate any principles. The distance of the presented answers from the correct answers was independently manipulated. Consistent with the hypothesis that people represent the principles, (1) violations of the principles were rated as poorer attempts at the operation, (2) operations that are learned first (e.g., addition) had more extensive principle representations than did operations learned later (multiplication), and (3) principles that are more frequently in evidence developed more quickly. In Experiment 3, college participants rated the degree to which statements were indicative of each operation. The statements were either consistent or inconsistent with one of two principles. The participants' ratings showed that operations with longer developmental histories had strong principle representations. The implications for a structure-mapping approach to mathematical problem solving are discussed.

Research designs and statistical techniques used in the Journal of Learning Disabilities, 1989-1993.

One hundred seventy-four research articles published in the Journal of Learning Disabilities from 1989 through 1993 were analyzed and coded by the type of research design and statistical technique used. Eighty percent of the research designs employed were identified as nonintervention methods. Fifty-five percent of all statistical techniques in the research articles reviewed were coded as primary, 32% were found to be intermediate, and the remaining 14% were considered advanced. The most frequently reported designs and analyses were those that are typically taught in most introductory and intermediate courses in research methods and statistics. Thus, the study indicates that readers would need at least a strong conceptual understanding of basic and intermediate statistical procedures to interpret research reported in the Journal of Learning Disabilities.