A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.

BACKGROUND: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. METHODS: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. RESULTS: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95% 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95% 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95% CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. CONCLUSIONS: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients

Endonasal versus external dacryocystorhinostomy for nasolacrimal duct obstruction

BACKGROUND: A dacryocystorhinostomy (DCR) procedure aims to restore drainage of tears by bypassing a blockage in the nasolacrimal duct, through the creation of a bony ostium that allows communication between the lacrimal sac and the nasal cavity. It can be performed using endonasal or external approaches. The comparative success rates of these two approaches have not yet been established and this review aims to evaluate the relevant up-to-date research.OBJECTIVES: The primary aim of this review is to compare the success rates of endonasal DCR with that of external DCR. The secondary aim is to compare the complication rates between the two procedures.SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2016, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to 22 August 2016), Embase (January 1980 to 22 August 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to 22 August 2016), Web of Science Conference Proceedings Citation Index- Science (CPCI-S) (January 1990 to 22 August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 August 2016. We requested or examined relevant conference proceedings for appropriate trials.SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing endonasal and external DCRs.DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and extracted data on reported outcomes. We attempted to contact investigators to clarify the methodological quality of the studies. We graded the certainty of the evidence using GRADE.MAIN RESULTS: We included two trials in this review. One trial from Finland compared laser-assisted endonasal DCR with external DCR, and one trial from India compared mechanical endonasal DCR (using punch forceps) with external DCR. The trials were poorly reported and it was difficult to judge the extent to which bias had been avoided.Anatomic success was defined as the demonstration of a patent lacrimal passage on syringing, or endoscopic visualisation of fluorescein dye at the nasal opening of the anastomoses after a period of at least six months following surgery. Subjective success was defined as the resolution of symptoms of watering following surgery after a period of at least six months. Both included trials used anatomic patency demonstrated by irrigation as a measure of anatomic success. Different effects were seen in these two trials (I(2) = 76%). People receiving laser-assisted endonasal DCR were less likely to have a successful operation compared with external DCR (63% versus 91%; risk ratio (RR) 0.69, 95% confidence intervals (CI) 0.52 to 0.92; 64 participants). There was little or no difference in success comparing mechanical endonasal DCR and external DCR (90% in both groups; RR 1.00, CI 0.81 to 1.23; 40 participants). We judged this evidence on success to be very low-certainty, downgrading for risk of bias, imprecision and inconsistency. The trial from Finland also assessed subjective improvement in symptoms following surgery. Resolution of symptoms of watering in outdoor conditions was reported by 84% of the participants in the external DCR group and 59% of those in the laser-assisted endonasal DCR group (RR 0.70, CI 0.51 to 0.97; 64 participants, low-certainty evidence).There were no cases of intraoperative bleeding in any participant in the trial that compared laser-assisted endonasal DCR to external DCR. This was in contrast to the trial comparing mechanical endonasal DCR to external DCR in which 45% of participants in both groups experienced intraoperative bleeding (RR 1.00, 95% CI 0.50 to 1.98; 40 participants). We judged this evidence on intraoperative bleeding to be very low-certainty, downgrading for risk of bias, imprecision and inconsistency.There were only two cases of postoperative bleeding, both in the external DCR group (RR 0.33, 95% CI 0.04 to 3.10; participants = 104; studies = 2). There were only two cases of wound infection/gaping, again both in the external DCR group (RR 0.20, CI 0.01 to 3.92; participants = 40; studies = 1). We judged this evidence on complications to be very low-certainty, downgrading one level for risk of bias and two levels for imprecision due to the very low number of cases.AUTHORS' CONCLUSIONS: There is uncertainty as to the relative effects of endonasal and external DCR. Differences in effect seen in the two trials included in this review may be due to variations in the endonasal technique, but may also be due to other differences between the trials. Future larger RCTs are required to further assess the success and complication rates of endonasal and external DCR. Different techniques of endonasal DCR should also be assessed, as the choice of endonasal technique can influence the outcome. Strict outcome criteria should be adopted to assess functional and anatomical outcomes with a minimal follow-up of six months.</p

Mikroaaltoavusteisen MP-AES-menetelmän soveltuvuus Hugger-murskaimella tuotettujen mineraalipartikkeleiden analysoimiseen

Tiivistelmä. Maapallon raaka-ainevarojen kestävään hyödyntämiseen tarvitaan uusia ja innovatiivisia menetelmiä. Kaivos- ja rikastusteollisuudessa käytetyt malmien hienonnusmenetelmät kuluttavat suurimman osan energiasta ja tuottavat eniten jätteitä metallien ja mineraalien arvoketjussa. Myös hienonnustuotteiden ja -jätteiden kemialliset analyysit kuluttavat arvokkaita luonnonvaroja reagenssien ja suojakaasujen muodossa. Tässä opinnäytetyössä tarkastellaan uuden ja innovatiivisen Hugger-murskauksen toimintaperiaatetta. Hugger-murskaus perustuu ”free crushing” -ilmiöön, jossa malminkappaleiden hienonnus tapahtuu niiden sisältämien mineraalien luonnollisia raerajoja pitkin. Tavoitteena on tuottaa mahdollisimman puhtaita mineraalipartikkeleita kuluttamalla mahdollisimman vähän energiaa, vettä ja kemikaaleja. Hugger-murskaustekniikka on nykyisin aktiivisen menetelmäkehityksen kohteena, mutta sen toimintaperiaatteen taustalla olevat fysikaaliset ilmiöt on tunnettu jo 1950-luvulta asti. Tässä opinnäytetyössä tarkastellaan myös mikroaaltoavusteisen hajotuksen, mikroaaltoplasma-atomiemissiospektrometrin (MP-AES) ja röntgenfluoresenssi-spektroskopian (XRF) käyttöä malmien hienonnustuotteiden analyyseissä. Nämä hajotus- ja analyysimenetelmät ovat paitsi nopeita myös edullisia, sillä ne kuluttavat mahdollisimman vähän hajotus- ja analyysireagensseja. Lisäksi MP-AES-menetelmässä käytetyn laitekohtaisen typpigeneraattorin tuottama typpikaasu tekee siitä huomattavasti edullisemman vaihtoehdon muihin plasmaemissiotekniikoihin verrattuna. Opinnäytetyössä osoitetaan edellä mainittujen Hugger-murskaus-, mikroaaltohajotus-, XRF- ja MP-AES-tekniikoiden soveltuvuus rinnakkaiskäyttöön.Applicability of microwave-assisted MP-AES method for the analysis of mineral particles produced by the Hugger crusher. Abstract. New and innovative methods are needed for the sustainable utilisation of the earth’s raw materials. The ore grinding methods used in the mining and beneficiation industry consume most of the energy and produce the most waste in the value chain of metals and minerals. Chemical analyses of comminution products and waste also consume valuable natural resources in the form of reagents and shielding gases. This thesis examines the operating principle of the new and innovative Hugger crushing. Hugger crushing is based on the "free crushing" phenomenon, where ore bodies are crushed along the natural grain boundaries of the minerals they contain. The goal is to produce the purest possible mineral particles by consuming as little energy, water, and chemicals as possible. Hugger crushing technology is currently the subject of active method development, but the physical phenomena underlying its operating principle have been known since the 1950s. This thesis also examines the use of microwave-assisted digestion, microwave plasmaatomic emission spectrometer (MP-AES) and X-ray fluorescence spectroscopy (XRF) in the analysis of ore crushing products. These digestion and analysis methods are not only fast but also inexpensive, as they consume as little digestion and analysis reagents as possible. In addition, the nitrogen gas produced by the device-specific nitrogen generator used in the MP-AES method makes it a significantly more affordable alternative compared to other plasma emission techniques. In this thesis, the suitability of the Hugger crushing, microwave digestion, MP-AES, and XRF techniques for parallel use is demonstrate

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C&gt;T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

INTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are