Citations

Previous linkage analysis of an Asian population proposed possible candidate genes for mandibular prognathism, such as Matrilin-1 (cartilage matrix protein). To investigate the association between the single-nucleotide polymorphisms (SNPs) in Matrilin-1 and mandibular prognathism, we investigated three sequence variants (-158 T>C, 7987 G>A, 8572 C>T) in 164 mandibular prognathism patients and 132 control individuals with a normal occlusion. The results showed that the 8572 TT genotypes in Matrilin-1 showed increased risk of mandibular prognathism (OR = 9.28, 95% Cl = 1.19~197.57, P < 0.05), whereas the 7987 AA genotype showed a protective effect for mandibular prognathism (OR = 0.16, 95% Cl = 0.05~0.47, P < 0.05). Genotyping results showed that the Matrilin-1 polymorphism haplotype TGC (ht4; 158T, 7987G, and 8572C alleles) had a pronounced risk effect for mandibular prognathism compared with controls (OR = 5.16, 95% Cl = 2.03~13.93, P < 0.01). The results suggest that polymorphisms in Matrilin-1 could be used as a marker for genetic susceptibility to mandibular prognathism.

Abstract Ag-specific T cell tolerance plays a critical role in tumor escape. Recent studies implicated myeloid-derived suppressor cells (MDSCs) in the induction of CD8+ T cell tolerance in tumor-bearing hosts. However, the mechanism of this phenomenon remained unclear. We have found that incubation of Ag-specific CD8+ T cells, with peptide-loaded MDSCs, did not induce signaling downstream of TCR. However, it prevented subsequent signaling from peptide-loaded dendritic cells. Using double TCR transgenic CD8+ T cells, we have demonstrated that MDSC induced tolerance to only the peptide, which was presented by MDSCs. T cell response to the peptide specific to the other TCR was not affected. Incubation of MDSCs with Ag-specific CD8+ T cells caused nitration of the molecules on the surface of CD8+ T cells, localized to the site of physical interaction between MDSC and T cells, which involves preferentially only TCR specific for the peptide presented by MDSCs. Postincubation with MDSCs, only nitrotyrosine-positive CD8+ T cells demonstrated profound nonresponsiveness to the specific peptide, whereas nitrotyrosine-negative CD8+ T cells responded normally to that stimulation. MDSCs caused dissociation between TCR and CD3ζ molecules, disrupting TCR complexes on T cells. Thus, these data describe a novel mechanism of Ag-specific CD8+ T cell tolerance in cancer.

Abstract Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared with samples in chronic phase (P < .001). We identified commonly altered regions involved in disease progression including not only established targets (ETV6, TP53, and RUNX1) but also new candidate genes on 7q, 16q, 19p, and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F− cases with MPN-blast phase. Remarkably, copy number–neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (P = .01 and P = .016, respectively). Our high-density SNP-array analysis of MPN genomes in the chronic compared with leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia.

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

Purpose: Efficiency, anatomic, and histopathologic outcomes of GreenLight™ HPS™ 120-W, 532-nm lithium triborate (LBO) laser photoselective vaporization of the prostate (PVP) in a survival model of living canines were studied and compared with the outcomes of the only benchmarked survival study of 60-W 532-nm potassium-titanyl-phosphate (KTP) laser PVP in living canines. Materials and Methods: Twelve dogs underwent anterograde PVP with the 120-W LBO laser and, 4 each, were euthanized 3 hours (acute), 3 days (early), or 8 weeks (chronic) postoperatively. Laser energy and time were recorded. Prostates were sectioned, measured, and histologically analyzed after hematoxylin and eosin (H&E), triphenyltetrazolium chloride (TTC), or Gomori trichrome (GT) staining and compared with a normal control. Results: LBO laser PVP at 120 W acutely created a 6.7 ± 3.2 cm 3 cavity, hemostatically, and vaporized tissue 160% more efficiently (mean 1.3 cm 3 /min vs 0.5 cm 3 /min), 500% faster (mean 4.9 vs 29.1 min), and needed 121% less energy (mean 28.8 vs 63.6 kJ) than the 60-W KTP laser. Histologic staining with H&E and TTC demonstrated a coagulation zone of 1.5 ± 0.3 mm for the 120-W LBO laser, comparable to the 1 to 2 mm for the 60-W KTP laser. H&E- and GT-stained, healed prostates at 8-weeks postoperatively showed reepithelialized cavities with minimal submucosal fibrosis compared with an identically stained normal and the benchmarked KTP laser PVP-treated prostates. Conclusion: Our in vivo canine survival study demonstrates GreenLight HPS 120-W, 532-nm LBO laser PVP has substantially more vaporization efficiency and speed, with equally favorable tissue interaction and healing vis-à-vis those benchmarked for the 532-nm wavelength by KTP laser PVP.

Abstract The maturation of naive CD8+ T cells into effector CTLs is a critical feature of a functional adaptive immune system. Development of CTLs depends, in part, upon the expression of the transcriptional regulator eomesodermin (EOMES), which is thought to regulate expression of two key effector molecules, perforin and granzyme B. Although EOMES is important for effector CTL development, the precise mechanisms regulating CD8+ effector cell maturation remains poorly understood. In this study, we show that Notch1 regulates the expression of EOMES, perforin, and granzyme B through direct binding to the promoters of these crucial effector molecules. By abrogating Notch signaling, both biochemically as well as genetically, we conclude that Notch activity mediates CTL activity through direct regulation of EOMES, perforin, and granzyme B.

Abstract Introduction: Tissue microarrays (TMA) enable rapid analysis of biomarkers in large-scale studies involving archival tumor specimens, however, their utility in heterogeneous tumors such as ovarian cancer is limited. Methods: In this study, immunohistochemical analysis was done on TMAs comprised of epithelial ovarian cancer (EOC) to estimate the prevalence of loss of expression of three mismatch repair proteins. TMAs were initially created using cores sampled from the center of donor tissue blocks from 59 EOC cases. Full sections were subsequently created and levels of expression were compared between tissues sampled from the central portion versus the periphery. Follow-up analyses were done by obtaining cores from the periphery of up to five additional donor blocks per case. A linear mixed model for each protein was used to investigate differences between results from the initial and follow-up blocks. Results: In the original TMAs created using centrally sampled cores, loss of mismatch repair expression was noted in 17 (29%) of the 59 cases. By comparison, analyses from peripherally sampled cores revealed loss of expression in only 6 of these 17 cases. For each protein, significant differences (P &lt; 0.05) were detected between results from the initial donor block and the majority of the follow-up blocks. Conclusions: Our investigations, based on EOC, suggest that sampling variability in protein expression may result when TMAs are used. Thus, at least for EOC, it is important to preferentially sample from the periphery of tumor blocks where exposure to tissue fixatives is optimal. (Cancer Epidemiol Biomarkers Prev 2009;18(1):28–34)