Citations

Abstract MUC1 (MUC1 in human and Muc1 in nonhumans) is a membrane-tethered mucin that interacts with Pseudomonas aeruginosa (PA) through flagellin. In this study, we compared PA pulmonary clearance and proinflammatory responses by Muc1−/− mice with Muc1+/+ littermates following intranasal instillation of PA or flagellin. Compared with Muc1+/+ mice, Muc1−/− mice showed increased PA clearance, greater airway recruitment of neutrophils, higher levels of TNF-α and KC in bronchoalveolar lavage fluid, higher levels of TNF-α in media of flagellin-stimulated alveolar macrophages, and higher levels of KC in media of tracheal epithelial cells. Knockdown of MUC1 enhanced flagellin-induced IL-8 production by primary human bronchial epithelial cells. Expression of MUC1 in HEK293T cells attenuated TLR5-dependent IL-8 release in response to flagellin, which was completely ablated when its cytoplasmic tail was deleted. We conclude that MUC1/Muc1 suppresses pulmonary innate immunity and speculate its anti-inflammatory activity may play an important modulatory role during microbial infection.

Abstract Previously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-α. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.

Background/Purpose:Genome‐wide association studies have identified susceptibility loci for many autoimmune diseases, including rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). About 5% of children with JIA have rheumatoid factor positive arthritis that is phenotypically similar to adult seropositive RA, thus representing childhood onset RA (CORA). To understand the genetic architecture of CORA risk relative to other autoimmune diseases, we genotyped CORA cases and controls on the Immunochip, a custom array designed by the Immunochip Consortium to fine map autoimmune disease‐associated loci shared across 11 autoimmune phenotypes.Methods:Genotyping was completed on 340 CORA cases (mean onset age: 10.2 ± 4.2 yrs) and 11624 controls. Standard SNP and sample QC was performed (e.g., removing samples with call rate <98%, admixture outliers). To test for SNP association with CORA a logistic regression model was computed with Caucasian admixture proportions (ADMIXTURE) as covariates (SNPLash). False discovery rate (FDR) adjusted p‐values (PFDR) are reported to account for the actual number of tests computed.Results:SNP rs3129769, near HLA DRB1 was the most significantly associated (PFDR <3×10‐25), and is in linkage disequilibrium with the HLA DRB1 SNP reported in RA (rs660895, PFDR <1×10‐24). Outside the HLA region, 28 regions had ≥1 SNP meeting genome‐wide significance (PFDR<0.05). The best signal of association was on 22q13 (rs9610687, OR = 0.57, PFDR < 0.0002) near IL2RB, followed by the PTPN22 locus (rs6679677, OR = 1.83, PFDR < 0.0005), an intergenic SNP on chromosome 4 (rs970036, OR = 1.78, PFDR < 0.002) and an intronic SNP (19p13, rs3787016 PFDR < 0.002) in the POLR2E gene, which encodes a subunit of RNA polymerase II. Some loci which have previously been implicated in RA had evidence of association including MMEL (rs751358 PFDR < 0.003), IRF5 (rs4731531 PFDR < 0.006) and CCR6 (rs11575078 PFDR < 0.03). In addition using the FDR‐based threshold we identified several potential SNPs (rs10918214, 1q23; rs28491312, 14q31) not previously implicated in RA.Conclusion:Immunochip analysis of the largest cohort of CORA investigated to date has confirmed the HLA DRB1 association and identified several other loci associated with CORA. Comparisons among loci associated with CORA and those identified in RA and other forms of JIA are underway and will help delineate the unique genetic factors for CORA susceptibility.

Abstract Background: Melanoma cases may exist in pancreatic cancer kindreds, whereas there is increased risk of pancreatic cancer in familial melanoma. The two cancers may share genetic susceptibility variants in common. Methods: Three dbGaP (datasets in Genotypes and Phenotypes)-deposited GWAS (genome-wide association study) datasets (MD Anderson melanoma, PanScan 1, and PanScan 2 for pancreatic cancer) were used. Thirty-seven melanoma susceptibility variants in 22 genomic regions from published GWAS, plus melanoma-related genes and pathways were examined for pancreatic cancer risk in the PanScan datasets. Conversely, nine known pancreatic cancer susceptibility variants were examined for melanoma risk in the MD Anderson dataset. Results: In the PanScan data, initial associations were found with melanoma susceptibility variants in NCOA6 [rs4911442; OR, 1.32; 95% confidence interval (CI), 1.03–1.70; P = 0.03], YWHAZP5 (rs17119461; OR, 2.62; 95% CI, 1.08–6.35; P = 0.03), and YWHAZP5 (rs17119490; OR, 2.62; 95% CI, 1.08–6.34; P = 0.03), TYRP1 (P = 0.04), and IFNA13 (P = 0.04). In the melanoma dataset, two pancreatic cancer susceptibility variants were associated: NR5A2 (rs12029406; OR, 1.39; 95% CI, 1.01–1.92; P = 0.04) and CLPTM1L-TERT (rs401681; OR, 1.16; 95% CI, 1.01–1.34; P = 0.04). None of these associations remained significant after correcting for multiple comparisons. Conclusion: Reported variants of melanoma genes and pathways do not play a role in pancreatic cancer predisposition. Reciprocally, pancreatic cancer susceptibility variants are not associated with melanoma risk. Impact: Known melanoma-related genes and pathways, as well as GWAS-derived susceptibility variants of melanoma and pancreatic cancer, do not explain the shared genetic etiology of these two cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1121–4. ©2014 AACR.

AbstractPurposeThe goals of part 2 of the study presented here were 1) to assess whether there is a difference in failure mode of different thicknesses (2.0, 1.5, 1.0, and 0.5 mm) of anatomically standardized full contour monolithic lithium disilicate restorations for posterior teeth, and 2) to assess if there is a difference among various crown thicknesses when these restorations are subjected to dynamic load forces common for posterior teeth.Materials and MethodsFour groups (n = 10), each with a different thickness of anatomically appropriate all‐ceramic crowns, were to be tested as established from the statistical analysis of the preliminary phase. Group 1: 2.0 mm; group 2: 1.5 mm; group 3: 1.0 mm; group 4: 0.5 mm. The specimens were adhesively luted to the corresponding die, and underwent dynamic cyclic loading (380 to 390 N) completely submerged in an aqueous environment until a failure was noted by graphic recording and continuous monitoring.ResultsThere was a statistically significant difference of the fatigue cycles to failure among four groups (p < 0.001; Kruskal‐Wallis test). The mean number of cycles to fail for 2.0 mm specimens was 17 times more than the mean number of cycles to fail for 1.0 mm specimens and 1.5 times more than the mean number of cycles to fail for 1.5 mm specimens. The 0.5 mm specimens failed with one cycle of loading. A qualitative characteristic noted among the 2.0 mm specimens was wear of the area of indenter contact followed by shearing of the material and/or crack propagation.ConclusionBased on the findings of this study, it may be reasonable to consider a crown thickness of 1.5 mm or greater for clinical applications of milled monolithic lithium disilicate crowns for posterior single teeth.