A surrogate method for comparison analysis of salivary concentrations of Xylitol-containing products

Background: Xylitol chewing gum has been shown to reduce Streptococcus mutans levels and decay. Two studies examined the presence and time course of salivary xylitol concentrations delivered via xylitol-containing pellet gum and compared them to other xylitol-containing products. Methods: A within-subjects design was used for both studies. Study 1, adults (N = 15) received three xylitol-containing products (pellet gum (2.6 g), gummy bears (2.6 g), and commercially available stick gum (Koolerz, 3.0 g)); Study 2, a second group of adults (N = 15) received three xylitol-containing products (pellet gum, gummy bears, and a 33% xylitol syrup (2.67 g). For both studies subjects consumed one xylitol product per visit with a 7-day washout between each product. A standardized protocol was followed for each product visit. Product order was randomly determined at the initial visit. Saliva samples (0.5 mL to 1.0 mL) were collected at baseline and up to 10 time points (~16 min in length) after product consumption initiated. Concentration of xylitol in saliva samples was analyzed using high-performance liquid chromatography. Area under the curve (AUC) for determining the average xylitol concentration in saliva over the total sampling period was calculated for each product. Results: In both studies all three xylitol products (Study 1: pellet gum, gummy bears, and stick gum; Study 2: pellet gum, gummy bears, and syrup) had similar time curves with two xylitol concentration peaks during the sampling period. Study 1 had its highest mean peaks at the 4 min sampling point while Study 2 had its highest mean peaks between 13 to 16 minutes. Salivary xylitol levels returned to baseline at about 18 minutes for all forms tested. Additionally, for both studies the total AUC for the xylitol products were similar compared to the pellet gum (Study 1: pellet gum - 51.3 [micro]g.min/mL, gummy bears - 59.6 [micro]g.min/mL, and stick gum - 46.4 [micro]g.min/mL; Study 2: pellet gum - 63.0 [micro]g.min/mL, gummy bears - 55.9 [micro]g.min/mL, and syrup - 59.0 [micro]g.min/mL). Conclusion: The comparison method demonstrated high reliability and validity. In both studies other xylitol-containing products had time curves and mean xylitol concentration peaks similar to xylitol pellet gum suggesting this test may be a surrogate for longer studies comparing various products.NIDCR-NIH U54 DE14254; Head Start, HRSA 90YD0188/03; and MCHB, HRSA R40MC03622-03

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials

Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ

The recently characterised 299-residue human XLF/Cernunnos protein plays a crucial role in DNA repair by non-homologous end joining (NHEJ) and interacts with the XRCC4–DNA Ligase IV complex. Here, we report the crystal structure of the XLF (1–233) homodimer at 2.3 Å resolution, confirming the predicted structural similarity to XRCC4. The XLF coiled-coil, however, is shorter than that of XRCC4 and undergoes an unexpected reverse in direction giving rise to a short distorted four helical bundle and a C-terminal helical structure wedged between the coiled-coil and head domain. The existence of a dimer as the major species is confirmed by size-exclusion chromatography, analytical ultracentrifugation, small-angle X-ray scattering and other biophysical methods. We show that the XLF structure is not easily compatible with a proposed XRCC4:XLF heterodimer. However, we demonstrate interactions between dimers of XLF and XRCC4 by surface plasmon resonance and analyse these in terms of surface properties, amino-acid conservation and mutations in immunodeficient patients. Our data are most consistent with head-to-head interactions in a 2:2:1 XRCC4:XLF:Ligase IV complex

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist