Sphingosine-1-phosphate is a bioactive lipid that is mitogenic for human glioma cell lines by signaling through its G protein-coupled receptors. We investigated the role of sphingosine-1-phosphate receptors and the enzymes that form sphingosine-1-phosphate, sphingosine kinase (SphK)-1, and -2 in human astrocytomas. Astrocytomas of various histologic grades expressed three types of sphingosine-1-phosphate receptors, S1P1, S1P2, and S1P3; however, no significant correlation with histologic grade or patient survival was detected. Expression of SphK1, but not SphK2, in human astrocytoma grade 4 (glioblastoma multiforme) tissue correlated with short patient survival. Patients whose tumors had low SphK1 expression survived a median 357 days, whereas those with high levels of SphK1 survived a median 102 days. Decreasing SphK1 expression using RNA interference or pharmacologic inhibition of SphK significantly decreased the rate of proliferation of U-1242 MG and U-87 MG glioblastoma cell lines. Surprisingly, RNA interference to knockdown SphK2 expression inhibited glioblastoma cell proliferation more potently than did SphK1 knockdown. SphK knockdown also prevented cells from exiting G1 phase of the cell cycle and marginally increased apoptosis. Thus, SphK isoforms may be major contributors to growth of glioblastoma cells in vitro and to aggressive behavior of glioblastoma multiforme.
Purpose: This study describes SMN1 deletion frequency, carrier studies, and the effect of the modifying SMN2 gene on the spinal muscular atrophy (SMA) phenotype. A novel allele-specific intragenic mutation panel increases the sensitivity of SMN1 testing. Methods: From 1995 to 2001, 610 patients were tested for SMN1 deletions and 399 relatives of probands have been tested for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. A fluorescent allele-specific polymerase chain reaction (PCR) -based strategy detected intragenic mutations in potential compound heterozygotes and was used on 366 patients. Results: Less than half of the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the seven most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients. Conclusions: SMN1 molecular testing is essential for the diagnosis of SMA and allows for accurate carrier testing.Screening for intragenic mutations in SMN1 increases the sensitivity of diagnostic testing. Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information. Genet Key Words: spinal muscular atrophy, SMN, polymerase chain reactionSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by homozygous mutation of the SMN1 gene 1 on chromosome 5q13. 2-12 5q-SMA has an incidence of 1/10,000 with an estimated carrier frequency of 1/50. [13][14][15][16][17] Deletion and gene conversion events result in a 95% to 98% rate of homozygous loss of the SMN1 gene in patients with classic SMA. 1,18 -31 A further 1% to 3% of well-characterized SMA cases are the result of compound heterozygosity with an intragenic mutation and a deletion. 31,32 Clinically, SMA patients are classified as type I, II, or III, based on the severity of the disease and the age of onset. 33,34 SMA type I, also known as Werdnig-Hoffmann disease, 35,36 is the most severe presentation. Type I infants are hypotonic and have severe proximal muscle wasting due to a lack of ␣-motor neurons in the anterior horn of the spinal cord. These patients are diagnosed prenatally or within 6 months after birth. They never sit unaided and usually die within the first 2 years, most often due to respiratory muscle weakness. Patients with intermediate SMA type II develop the disease before 18 months of age. They are able to sit unaided, but do not stand or walk. SMA type III, also called Kugelberg-Welander disease, is less severe. 37,38 Type III patients are diagnosed after 18 months, are able to walk, can have children, and often live at least into the second or third decade. 39 This study presents the clinical experience of 6 years of SMA testing in the Molecular Pathology Laboratory at The Ohio State University. Despite the fact that more than 95% of 5q-linked SMA patients lack any intact SMN1, it has been our experience that Ͻ43% of patients ...
A B S T R A C T PurposeMutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. Patients and MethodsIn this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. ResultsOf 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21ϩ months, four patients had SD Ն 15 months, four patients had SD Յ 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed. ConclusionSorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib.
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