Physicochemical and Antibacterial Characterisation of a Novel Fluorapatite Coating

Peri-implantitis remains the major impediment to the long-term use of dental implants. With increasing concern over growing antibiotic resistance there is considerable interest in the preparation of antimicrobial dental implant coatings that also induce osseointegration. One such potential coating material is fluorapatite (FA). The aim of this study was to relate the antibacterial effectiveness of FA coatings against pathogens implicated in peri-implantitis to the physicochemical properties of the coating. Ordered and disordered FA coatings were produced on the under and upper surface of stainless steel (SS) discs respectively, using a hydrothermal method. Surface charge, surface roughness, wettability and fluoride release were measured for each coating. Surface chemistry was assessed by X-ray photoelectron spectroscopy and FA crystallinity by X-ray diffraction. Antibacterial activity against periodontopathogens was assessed in vitro using viable counts, confocal and scanning electron (SEM) microscopies. SEM showed that the hydrothermal method produced FA coatings predominately aligned perpendicular to the SS substrate or disordered FA coatings consisting of randomly aligned rod-like crystals. Both FA coatings significantly reduced the growth of all the examined bacterial strains in comparison to the control. The FA coatings, and especially the disordered ones, presented significantly lower charge, higher roughness and area when compared to the control, enhancing bacteria–material interactions and therefore bacterial deactivation by fluoride ions. The ordered FA layer reduced not only bacterial viability but adhesion too. Ordered FA crystals produced as a potential novel implant coating showed significant antibacterial activity against bacteria implicated in peri-implantitis which could be explained by a detailed understanding of their physicochemical properties

A study of acromegaly-associated headache with somatostatin analgesia.

To characterise somatostatin analogue responsive headache in acromegaly, hitherto not systematically documented in a significant cohort. Using the UK pituitary network, we have clinically characterised a cohort of 18 patients suffering from acromegaly-related headache with a clear response to somatostatin analogues. The majority of patients had chronic migraine (78%) as defined by the International Headache Society diagnostic criteria. Headache was present at the time of acromegaly presentation and clearly associated temporally with disease activity in all cases. Short-acting somatostatin analogues uniquely resolved pain within minutes and the mean duration of analgesia was 1-6 hours. Patients on long-acting analogues required less short-acting injections (mean 3.7 vs. 10.4 injections per day, p=0.005). 94% used somatostatin analogues to control ongoing headache pain. All patients presented with macroadenoma, most had incomplete resection (94%) and headache was ipsilateral to remnant tissue (94%). Although biochemical control was achieved in 78% of patients, headache remained in 71% of them. Patients selected for this study had ongoing headache post-treatment (mean duration 16 years after diagnosis); only 4 patients reached headache remission 26 years (mean, range 14-33) after the diagnosis. Headache in acromegaly patients can be persistent, severe, unrelieved by surgery, long-lasting and uncoupled from biochemical control. We show here that long-acting analogues allow a decrease in the number of short-acting analogue injections for headache relief. Further studies are needed to understand the mechanisms, markers and tumour tissue characteristics of acromegaly-related headache. Until then, this publication serves to provide the clinical characteristics as a reference point for further study

Comparison of three methods of DNA extraction from human bones with different degrees of degradation

There is a necessity for deceased identification as a result of many accidents and sometimes bones are the only accessible source of DNA. So far, a universal method that allows for extraction of DNA from materials at different stages of degradation does not exist. The aims of this study were: the comparison of three methods of DNA extraction from bones with different degree of degradation and an evaluation of the usefulness of these methods in forensic genetics. The efficiency of DNA extraction, the degree of extract contamination by polymerase chain reaction (PCR) inhibitors and the possibility of determining the STR loci profile were especially being compared. Nuclear DNA from bones at different states of degradation was isolated using three methods: classical, organic phenol–chloroform extraction, DNA extraction from crystal aggregates and extraction by total demineralisation. Total demineralisation is the best method for most cases of DNA extraction from bones, although it does not provide pure DNA. DNA extraction from aggregates removes inhibitors much better and is also a good method of choice when identity determination of exhumed remains is necessary. In the case of not buried bones (remains found outside) total demineralisation or phenol–chloroform protocols are more efficient for successful DNA extraction

TAuth: Verifying timed security protocols

Quantitative timing is often explicitly used in systems for better security, e.g., the credentials for automatic website logon often has limited lifetime. Verifying timing relevant security protocols in these systems is very challenging as timing adds another dimension of complexity compared with the untimed protocol verification. In our previous work, we proposed an approach to check the correctness of the timed authentication in security protocols with fixed timing constraints. However, a more difficult question persists, i.e., given a particular protocol design, whether the protocol has security flaws in its design or it can be configured secure with proper parameter values? In this work, we answer this question by proposing a parameterized verification framework, where the quantitative parameters in the protocols can be intuitively specified as well as automatically analyzed. Given a security protocol, our verification algorithm either produces the secure constraints of the parameters, or constructs an attack that works for any parameter values. The correctness of our algorithm is formally proved. We implement our method into a tool called PTAuth and evaluate it with several security protocols. Using PTAuth, we have successfully found a timing attack in Kerberos V which is unreported before.No Full Tex

A Multiset Rewriting Model for Specifying and Verifying Timing Aspects of Security Protocols

Catherine Meadows has played an important role in the advancement of formal methods for protocol security verification. Her insights on the use of, for example, narrowing and rewriting logic has made possible the automated discovery of new attacks and the shaping of new protocols. Meadows has also investigated other security aspects, such as, distance-bounding protocols and denial of service attacks. We have been greatly inspired by her work. This paper describes the use of Multiset Rewriting for the specification and verification of timing aspects of protocols, such as network delays, timeouts, timed intruder models and distance-bounding properties. We detail these timed features with a number of examples and describe decidable fragments of related verification problems

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.</p

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations