Citations

AbstractBackground: Laboratory testing in suspected α-1-antitrypsin (A1AT) deficiency involves analysis of A1AT concentrations and identification of specific alleles by genotyping or phenotyping. The purpose of this study was to define and evaluate a strategy that provides reliable laboratory evaluation of A1AT deficiency.Methods: Samples from 512 individuals referred for A1AT phenotype analysis were analyzed by quantification, phenotype, and genotype. A1AT concentrations were measured by nephelometry. Phenotype analysis was performed by isoelectric focusing electrophoresis. The genotype assay detected the S and Z deficiency alleles by a melting curve analysis.Results: Of the 512 samples analyzed, 2% of the phenotype and genotype results were discordant. Among these 10 discordant results, 7 were attributed to phenotyping errors. On the basis of these data we formulated an algorithm, according to which we analyzed samples by genotyping and quantification assays, with a reflex to phenotyping when the genotype and quantification results were not concordant. Retrospective analyses demonstrated that 4% of samples submitted for genotype and quantitative analysis were reflexed to phenotyping. Of the reflexed samples, phenotyping confirmed the genotype result in 85% of cases. In the remaining 15%, phenotyping provided further information, including identifying rare deficiency alleles and suggesting the presence of a null allele, and allowed for a more definitive interpretation of the genotype result.Conclusions: The combination of genotyping and quantification, with a reflex to phenotyping, is the optimal strategy for the laboratory evaluation of A1AT deficiency.

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele–dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

Abstract OBJECTIVE: Intravascular ultrasound (IVUS) imaging has been used extensively in coronary artery interventions and has provided invaluable information for the understanding and treatment of coronary arterial disease. We present here the first description, to our knowledge, of IVUS-guided intracranial arterial interventions in the clinical setting. CLINICAL PRESENTATION: Two patients underwent intracranial angioplasty and stent placement with the assistance of IVUS for the evaluation of their lesions. One patient underwent stenting to treat an occlusive dissection of the left internal carotid artery that occurred during arteriovenous malformation embolization. Another patient underwent angioplasty and stenting for high-grade restenosis of a basilar artery atherosclerotic lesion. RESULTS: Both patients underwent successful revascularization procedures. The patient with the dissection had a small intraventricular and parenchymal hemorrhage documented by computed tomography 4 hours after treatment, but did not develop hydrocephalus or further hemorrhage. Both patients did well clinically and had no permanent neurological deficits. IVUS provided important information in terms of lesion evaluation, stent selection, and stent placement in each case. CONCLUSION: IVUS of the intracranial circulation may assist the performance of intracranial angioplasty and stenting. It provides useful information that can affect clinical decisions. It may prove to be a valuable tool in clinical use and enhance our understanding of vascular disease of the intracranial circulation, as it has in the coronary circulation.

Abstract The phosphatidylinositol 3-kinases (PI3K) are a family of enzymes that relay important cellular growth control signals. Recently, a large-scale mutational analysis of eight PI3K and eight PI3K-like genes revealed somatic mutations in PIK3CA, which encodes the p110α catalytic subunit of class IA PI3K, in several types of cancer, including glioblastoma multiforme. In that report, 4 of 15 (27%) glioblastomas contained potentially oncogenic PIK3CA mutations. Subsequent studies, however, showed a significantly lower mutation rate ranging from 0% to 7%. Given this disparity and to address the relation of patient age to mutation frequency, we examined 10 exons of PIK3CA in 73 glioblastoma samples by PCR amplification followed by direct DNA sequencing. Overall, PIK3CA mutations were found in 11 (15%) samples, including several novel mutations. PIK3CA mutations were distributed in all sample types, with 18%, 9%, and 13% of primary tumors, xenografts, and cell lines containing mutations, respectively. Of the primary tumors, PIK3CA mutations were identified in 21% and 17% of pediatric and adult samples, respectively. No evidence of PIK3CA gene amplification was detected by quantitative real-time PCR in any of the samples. This study confirms that PIK3CA mutations occur in a significant number of human glioblastomas, further indicating that therapeutic targeting of this pathway in glioblastomas is of value. Moreover, this is the first study showing PIK3CA mutations in pediatric glioblastomas, thus providing a molecular target in this important pediatric malignancy. (Mol Cancer Res 2006;4(10):709–14)

AbstractThe underlying mechanisms by which tumor cells are resistant to CTL-mediated apoptosis are not clear. Using a human model of B-cell non-Hodgkin's lymphoma (B-cell NHL), we show that intratumoral Treg cells inhibit the proliferation and granule production of activated autologous infiltrating CD8+ T cells. Our results also show that degranulation and subsequent cytotoxic activity of infiltrating CD8+ T cells exposed to lymphoma B cells is completely attenuated by the presence of intratumoral Treg cells. Furthermore, we show that increased numbers of intratumoral Treg cells correlates with the number of CD8+ T cells in biopsy specimens from patients with B-cell NHL, supporting the in vitro findings that intratumoral Treg cells inhibit proliferation of infiltrating CD8+ T cells. Taken together, these data indicate that human lymphoma B cells are sensitive to autologous CTL-mediated cell death but are protected by the inhibitory function of intratumoral Treg cells. (Cancer Res 2006; 66(20): 10145-52)

Abstract Combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma. The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell medium, we cultured a few tumors. Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in 2 North Central Cancer Treatment Group (NCCTG) low-grade glioma trials. Interphase fusion of CEP1 and 19p12 probes detected the t(1;19). 1p/19q deletions were evaluated by fluorescence in situ hybridization. Upon culture, one oligodendroglioma contained an unbalanced 45,XX,t(1;19)(q10;p10). CEP1/19p12 fusion was observed in all metaphases and 74% of interphase nuclei. Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81%. Among NCCTG patients, CEP1/19p12 fusion prevalence was 55%, 47%, and 0% among the oligodendrogliomas, mixed oligoastrocytomas, and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with 1p/19q deletion and 12% without 1p/19q deletion had CEP1/19p12 fusion (P < 0.001, χ2 test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients. (Cancer Res 2006; 66(20): 9852-61)

This study examined how information obtained from an adolescent screening instrument administered in a medical clinic is affected by the method of data collection and knowledge that a summary report would be given to the provider. The Adolescent Health Review (AHR) was administered to 610 adolescent patients randomly assigned to 1 of 3 conditions to test the effect of mode of administration (paper vs. computer) and disclosure of results to the provider versus only to researchers (using the computer version). The AHR obtained information on mental health, sexual experiences, and use of psychoactive substances. Response patterns varied by mode of administration, with the paper version generally eliciting higher, and arguably more accurate, rates of disclosure. Knowing that the results would be provided to the doctor further attenuated disclosure. Results suggest that the paper version's higher rates of reporting must be weighed against the computer version's benefits of automated scoring and reporting.