Toll-like receptor 3 activation is required for normal skin barrier repair following UV damage.

UV damage to the skin leads to the release of noncoding RNA (ncRNA) from necrotic keratinocytes that activates Toll-like receptor 3 (TLR3). This release of ncRNA triggers inflammation in the skin following UV damage. Recently, TLR3 activation was also shown to aid wound repair and increase the expression of genes associated with permeability barrier repair. Here, we sought to test whether skin barrier repair after UVB damage is dependent on the activation of TLR3. We observed that multiple ncRNAs induced expression of skin barrier repair genes, that the TLR3 ligand Poly (I:C) also induced expression and function of tight junctions, and that the ncRNA U1 acts in a TLR3-dependent manner to induce expression of skin barrier repair genes. These observations were shown to have functional relevance as Tlr3-/- mice displayed a delay in skin barrier repair following UVB damage. Combined, these data further validate the conclusion that recognition of endogenous RNA by TLR3 is an important step in the program of skin barrier repair

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism

Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health

Current Dyspnea Among Long-Term Survivors of Early-Stage Non-small Cell Lung Cancer

IntroductionDyspnea is common among lung cancer patients. As most studies of dyspnea have reviewed patients with active cancer or immediately after treatment, its prevalence during the longer-term period once treatment has been completed is not well characterized. This study quantifies the prevalence of dyspnea among lung cancer survivors and identifies potential correlates that may be amenable to intervention.MethodsCross-sectional survey of 342 patients with disease-free, stage I, non-small cell lung cancer, assessed 1 to 6 years after surgical resection. Dyspnea was quantified using the Baseline Dyspnea Index. Any moderate/strenuous physical activity was measured using the Godin Leisure-Time Exercise Questionnaire. Mood disorder symptoms were assessed using the Hospital Anxiety and Depression Scale. Multiple regression analyses were used to examine demographic, medical, and health-related correlates of dyspnea.ResultsMean age was 68.9 years. Average predicted preoperative forced expiratory volume in 1 second was 89.0%. Current dyspnea, defined by a Baseline Dyspnea Index score of 9 or less, existed among 205 (60%) individuals. For 133 (65%) of these patients, dyspnea was absent preoperatively. Multivariate correlates of current dyspnea included preoperative dyspnea (odds ratio [OR] = 5.31), preoperative diffusing capacity (OR = 0.98), lack of moderate/strenuous physical activity (OR = 0.41), and the presence of clinically significant depression symptoms (OR = 4.10).ConclusionsDyspnea is common 1 to 6 years after lung cancer resection, and is associated with the presence of preoperative dyspnea, reduced diffusing capacity, clinically significant depression symptoms, and lack of physical activity. Further research is needed to test whether strategies that identify and treat patients with these conditions attenuate dyspnea among lung cancer survivors

Degenerate recognition of MHC class I molecules with Bw4 and Bw6 motifs by a killer cell Ig-like receptor 3DL expressed by macaque NK cells

The killer cell immunoglobulin-like receptors (KIRs) expressed on the surface of natural killer (NK) cells recognize specific major histocompatibility complex class I (MHC-I) molecules and regulate NK cell activities against pathogen-infected cells and neoplasia. In human immunodeficiency virus (HIV) infection, survival is linked to host KIR and MHC-I genotypes. In the simian immunodeficiency virus (SIV) macaque model, however, the role of NK cells is unclear due to the lack of information on KIR-MHC interactions. Here, we describe the first characterization of a KIR-MHC interaction in pig-tailed macaques (Macaca nemestrina). Initially, we identified three distinct subsets of macaque NK cells that stained ex vivo with macaque MHC-I tetramers loaded with SIV peptides. We then cloned cDNAs corresponding to 15 distinct KIR3D alleles. One of these, KIR049-4, was an inhibitory KIR3DL that bound MHC-I tetramers and prevented activation, degranulation and cytokine production by macaque NK cells after engagement with specific MHC-I molecules on the surface of target cells. Furthermore, KIR049-4 recognized a broad range of MHC-I molecules carrying not only the Bw4 motif but also Bw6 and non-Bw4/Bw6 motifs. This degenerate, yet peptide-dependent, MHC reactivity differs markedly from the fine specificity of human KIRs

Genetic Variation in VEGF Does Not Contribute Significantly to the Risk of Congenital Cardiovascular Malformation

Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95–1.17]); rs1570360 (OR 1.17 [95% CI 0.99–1.26]); and rs2010963 (OR 1.04 [95% CI 0.93–1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility

Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls

Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ∼1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9-107.6); P = 2.2 × 10−7], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4-22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100-200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8-64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locu

New standards for reducing gravity data: The North American gravity database

The North American gravity database as well as databases from Canada, Mexico, and the United States are being revised to improve their coverage, versatility, and accuracy. An important part of this effort is revising procedures for calculating gravity anomalies, taking into account our enhanced computational power, improved terrain databases and datums, and increased interest in more accurately defining long-wavelength anomaly components. Users of the databases may note minor differences between previous and revised database values as a result of these procedures. Generally, the differences do not impact the interpretation of local anomalies but do improve regional anomaly studies. The most striking revision is the use of the internationally accepted terrestrial ellipsoid for the height datum of gravity stations rather than the conventionally used geoid or sea level. Principal facts of gravity observations and anomalies based on both revised and previous procedures together with germane metadata will be available on an interactive Web-based data system as well as from national agencies and data centers. The use of the revised procedures is encouraged for gravity data reduction because of the widespread use of the global positioning system in gravity fieldwork and the need for increased accuracy and precision of anomalies and consistency with North American and national databases. Anomalies based on the revised standards should be preceded by the adjective “ellipsoidal” to differentiate anomalies calculated using heights with respect to the ellipsoid from those based on conventional elevations referenced to the geoid

Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls

Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ∼1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9–107.6); P = 2.2 × 10−7], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4–22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100–200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8–64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus

Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TO