Abstract
Inherited genetics are increasingly being identified as a significant factor that contributes to both treatment outcome and treatment-associated toxicities in cancer patients undergoing ...therapy. The specific SNPs and genes involved are, however, still poorly understood. In this study, we exploited the unique advantages of a linkage disequilibrium-based approach to examine the relationship between genetic diversity in regions of DNA repair and GST genes with survival in adults with anaplastic astrocytoma and glioblastoma multiforme treated on temozolomide and carmustine-based protocols. We genotyped a subset of 1,267 tagging SNPs within or near haplotype blocks of 27 genes in 301 patients. The SNPs were selected to be in high LD with and, thus, to be predictive of the diversity of the target region containing the gene and 20 kb flanking 3′ and 5′ of it. Genotyping was conducted on a high-throughput customized Affymetrix platform. Associations between genotypes and survival was performed using the Fisher's exact test, after testing for Hardy-Weinberg conformity and gender mismatches. The results identified several tSNPs in and around the loci of 11 genes (EXO1, DDB2, LIG1, MGMT, MSH2, MSH4, PAN3, RAD52, TDG, XRCC1, and XRCC5) to be highly associated with survival. Several other SNPs showing a statistical tendency to be associative. Although, a number of SNPs/genes was associated with survival in both anaplastic astrocytoma and GBM, a subset of genes and SNPs were associative in GBMs but not in AAs and vice versa. We then examined 28 SNPs in all eight members of the GST family (A1, M1, M3, P1, O1, S1, T and Z) allowing the identification of seven specific SNPs that were highly associated with treatment outcome/survival. The identification of highly polymorphic regions associated with the loci of DNA repair and GST genes as determinants of alkylating agent-based therapy in malignant gliomas is consistent with the established role of enhanced DNA repair and drug metabolism in tumor resistance to these agents. Ongoing studies are directed at these associative SNPs to gain insight into the biology underlying their association with treatment outcome.
Supported by grants RO1 CA 153050, RO1 CA127872, RO1 CA 112519 and P30-CA114236 from the NIH, USA.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL07-01.
OBJECTIVE To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure ...(25%), to evaluate autonomic indices that distinguish MSA from PD. METHODS We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale UMSARS I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis. RESULTS We report the results of a study on 52 patients with MSA (mean SD, age, 61.1 7.8 years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 4.6; Hoehn-Yahr grade, 3.2 0.9; UMSARS I score, 21.5 7.4; and UMSARS II score, 22.7 9.0) and 29 patients with PD, including PD with autonomic failure (mean SD, age, 66.0 8.1 years; body mass index, 26.6 5.5; Hoehn-Yahr grade, 2.2 0.8; UMSARS I score, 10.4 6.1; and UMSARS II score, 13.0 5.9). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 1.9 vs 3.3 2.3, respectively), Composite Autonomic Symptom Scale (54.4 21.8 vs 24.7 20.5, respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% 35.2% vs 9.9% 17.7%, respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD. CONCLUSIONS The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.Arch Neurol. 2009;66(6):742-750-->
Abstract Glioma-associated epilepsy is associated with excessive glutamate signaling. We hypothesized that perampanel, an amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate ...receptor antagonist, would treat glioma-related epilepsy. We conducted a single-arm study of adjunctive perampanel for patients with focal-onset glioma-associated seizures. The most common related adverse events were fatigue and dizziness. Three out of 8 participants had self-reported seizure reduction and an additional 3 reported improved control. Of these 6, 5 had isocitrate dehydrogenase 1 mutant gliomas. We conclude that perampanel is safe for patients with glioma-related focal-onset epilepsy. Further study into the association between AMPA signaling, IDH1 status and seizures is warranted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Calf venous compliance in multiple system atrophy LIPP, A; SANDRONI, P; AHLSKOG, J. Eric ...
American journal of physiology. Heart and circulatory physiology,
2007, Volume:
62, Issue:
1
Journal Article
Inhibitory natural killer receptors (NKRs) such as killer cell immunoglobulin-like receptors (KIRs) in humans and Ly49 molecules in mice are expressed on NK cells and recognize multiple major ...histocompatibility (MHC) class I proteins. In humans and mice, a subset of CD8 super(+) T cells also expresses NKRs and harbors a memory phenotype. Using mice that are transgenic for KIR2DL3 and its cognate HLA-Cw3 ligand, we show that engagement of inhibitory NKRs selectively drives the in vivo accumulation of a subset of memory-phenotype CD8 super(+) T cells that express the beta chain of the interleukin 2 receptor. In vitro, recognition of MHC class I molecules by inhibitory NKRs on T cells down-regulated activation-induced cell death. These results unveil an MHC class I-dependent pathway that promotes the survival of a subset of memory-phenotype CD8 super(+) T cells and also reveal an unexpected biological function for inhibitory NKRs on T cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We study the pressure evolution of the 4functionof electrons in elemental praseodymium metal compressed through several crystallographic phases, including the large volume-collapse transition at 20 ...GPa. Using resonant x-ray emission, we directly and quantitatively measure the development of multiple electronic configurations with differing 4functionof occupation numbers, the key quantum observable related to the delocalization of the strongly correlated 4functionof electrons. These results provide a high-fidelity test of prior predictions by dynamical mean-field theory, and support the hypothesis of a strong connection between electronic and structural degrees of freedom at the volume-collapse transition.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
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