Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: An immunohistological study

<p>Abstract</p> <p>Background</p> <p>Human β-defensins (hBD) are antimicrobial peptides that are an integral part of bone innate immunity. Recently, it could be shown that expression of hBD-1, -2 and -3 were upregulated in cases of osteomyelitis of the jaws. In order to gain insight into the possible impairment of hBD metabolism in bisphosphonate-associated osteonecrosis of the jaws (BONJ), the present exploratory study was designed so as to determine the qualitative and quantitative expression of afore mentioned hBDs in BONJ and infected osteoradionecrosis (ORN), both of which represent inflammatory bone diseases.</p> <p>Methods</p> <p>Bone samples were collected from patients with BONJ (n = 20) and ORN (n = 20). Non-infected healthy bone samples (n = 20) were included as controls. Immunohistological staining in an autostainer was carried out by the (Strept-ABC)-method against hBD-1,-2,-3. Specific positive vs. negative cell reaction of osteocytes (labeling index) near the border of bony resection was determined and counted for quantitative analysis. Number of vital osteocytes vs. empty osteocytes lacunae was compared between groups.</p> <p>Results</p> <p>hBD-1,-2 and -3 could be detected in BONJ as well as ORN and healthy bone samples. Immunoreactivity against hBD-2 and -3 was significantly higher in BONJ than in ORN and healthy jaw bone samples. Number of empty osteocyte lacunae was significantly higher in ORN compared with BONJ (<it>P </it>= 0.001).</p> <p>Conclusion</p> <p>Under the condition of BONJ an increased expression of hBD-1,-2,-3 is detectable, similarly to the recently described upregulation of defensins in chronically infected jaw bones. It remains still unclear how these findings may relate to the pathoetiology of these diseases and whether this is contributing to the development of BONJ and ORN or simply an after effect of the disease.</p

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The Nurses’ Health Studies would like to thank the participants and staff of the Nurses' Health Study and Nurses' Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, UM1-CA186107, UM1-CA176726 and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; Eve Appeal; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital ‘Womens Health Theme’ and the Royal Marsden Hospital; and WorkSafeBC 14. Investigator-specific funding: G.C.P receives scholarship support from the University of Queensland and QIMR Berghofer. Y.L. was supported by the NHMRC Early Career Fellowship. G.C.T. is supported by the National Health and Medical Research Council. S.M. was supported by an ARC Future Fellowship

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.Other Research Uni

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Funder: Funding details are provided in the Supplementary MaterialAbstractPolygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.</jats:p

Comparative investigation of the expression of antimicrobial peptides (human ß-defensins 1-3) at bisphosphonate-associated osteonecrosis and osteoradionecrosis

Humane ß-Defensine (hBD) sind antimikrobielle Peptide, die einen Teil der Immunkompetenz des Knochens vermitteln. Es konnte kürzlich gezeigt werden, dass humane ß-Defensine 1-3 am entzündlichen Kieferknochen verstärkt exprimiert werden. Derzeit ist über die Expression von humanen Defensinen bei bisphosphonat-assoziierter Knochennekrose (BONJ) nur wenig bekannt. Es war Ziel der Studie, die Expression von hBD -1, -2 und -3 bei der bisphosphonat-assoziierten Knochennekrose mit der infizierten Osteoradionekrose (ONJ) und gesunden Kieferknochenproben zu vergleichen. Jeweils 20 Knochenbiopsien von Patienten mit BONJ, infizierter ONJ und gesundem Kieferknochen, der bei Dysgnathieeingriffen anfiel, wurden herangezogen. Von den Formalin fixierten und in Paraffin eingebetteten Proben wurden 2-4 µm starke Mikrotomschnitte angefertigt. Anschließend erfolgte die immunhistochemische Behandlung durch die Inkubation mit Kaninchenantiseren gegen hBD-1, -2 und -3 nach der Strept-ABC Methode. Als Positivkontrolle diente Haut. Die Ergebnisse wurden statistisch mit dem Mann-Whitney-U-Test auf signifikante Unterschiede getestet. Alle 3 getesteten humanen ß-Defensine wurden von Osteozyten der untersuchten Proben exprimiert. Die positive Zellreaktion auf hBD-1 und -2 lag bei der BONJ höher als bei der ONJ und beim gesunden Knochen (bei hBD-2 P<0,05). Signifikant höhere Expression von hBD-3 zeigten sich bei der BONJ gegenüber der ONJ (P=0,003) und dem gesunden Knochen (P=0,0002). Bei der bisphosphonat-assoziierten Knochennekrose und der Osteoradionekrose kommt es zu der sonst bei chronischen Infektionen des Knochens beschriebenen Steigerung der Defensinexpression. Zukünftig muss geklärt werden, ob ein Zusammenhang zwischen dem Maß der Defensinexpression und der Ausdehnung der bisphosphonat-assoziierten Knochennekrose besteht.Human ß-defensins (hBD) are antimicrobial peptides that are an integral part of bone innate immunity. It could be shown recently that human ß-defensins 1-3 become increasingly expressed in the inflammatory jaw bone. There is currently little-known about the expression of human defensins at bisphosphonate-associated osteonecrosis of the jaw (BONJ). The aim of the present study was to assess the expression of hBD-1, -2 and -3 in bisphosphonate-associated osteonecrosis of the jaws (BONJ) in comparison with infected osteoradionecrosis (ONJ) and healthy bone. Bone samples were collected from patients with BONJ (n=20) and ONJ (n=20). Non-infected healthy bone samples (n=20) were included as controls. Immunohistological staining in an autostainer was carried out by the Strept-ABC method against hBD-1, -2 and -3. Specific positive vs. negative cell reaction of osteocytes (labeling index) near the border of bony resection was determined and counted for quantitative analysis. The results were tested statistically with the Mann-Whitney-U-Test for significant differences. hBD-1, -2 and -3 could be detected in BONJ as well as ONJ and healthy bone samples. The positive cell reaction to hBD-1 and -2 was in BONJ higher than in ONJ and in healthy jaw bone samples (at hBD-2 P<0,05). A significantly higher expression of hBD-3 appeared in BONJ compared to ONJ (P=0,003) and healthy jaw bone (P=0,0002). Under the condition of BONJ an increased expression of hBD-1, -2 and -3 is detectable, similarly to the recently described upregulation of defensins in chronically infected jaw bones. It remains still unclear how these findings may relate to the pathoetiology of these diseases and whether this is contributing to the development of BONJ or simply a side effect of the disease

Effects of risk factors for ovarian cancer in women with and without endometriosis.

ObjectiveTo evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis.DesignPooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium.SettingPopulation-based.Patient(s)We included 8,500 women with ovarian cancer, 13,592 control women.Intervention(s)Ten well-established ovarian cancer risk factors.Main outcome measure(s)Risk of ovarian cancer for women with and without endometriosis.Result(s)Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-&lt;30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-&lt;25 kg/m2; an&nbsp;increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively).Conclusion(s)The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology

La recherche universitaire, vecteur du développement endogène régional : le cas de l'Université du Québec à Chicoutimi au Saguenay-Lac-Saint-Jean

Le contexte économique et socio-politique actuel de dévitalisation des régions du Québec et de désengagement de l'État introduit une nouvelle approche du développement territorial. Ce changement de perspective se fonde sur les postulats du développement endogène en suggérant entre autres de prendre appui sur le potentiel humain. Cette vision des choses interpelle tous les acteurs individuels, organisationnels et institutionnels et au premier chef le système scolaire en raison notamment de sa responsabilité à l'égard du capital humain. Dans ce contexte, il se dégage une pertinence sociale et scientifique d'améliorer la compréhension du rôle de l'éducation dans la dynamique du développement régional endogène. En particulier, c'est la contribution qui revient de manière spécifique à l'institution d'enseignement universitaire qui retient ici l'attention. C'est que le champ d'intervention des universités sises en région périphérique du Québec est fortement questionné sur la place publique. Les institutions d'enseignement sont traditionnellement perçues comme des agents économiques au sens où elles génèrent des injections monétaires dans leur environnement. On reconnaît par ailleurs au système éducatif un rôle socio-culturel de formation de la main d'oeuvre et d'amélioration de la qualité de vie tributaire de l'augmentation de la scolarité. En revanche, peu d'études scientifiques se sont penchées sur le thème de la spécificité du rapport que l'université entretient avec la dynamique du développement régional. En l'occurrence, deux volets complémentaires de la mission universitaire sont interpellés à savoir l'effort de recherche de même que la production de connaissances régionales sur le milieu et transférées au milieu. C'est donc la question de l'apport exclusif de la recherche universitaire au développement économique et socio-culturel régional qui retient ici l'attention. En référence à un modèle d'analyse de la recherche universitaire emprunté à Godin (1997), la conclusion qui se dégage de cette étude de cas démontre que l'effort de recherche mis en oeuvre au Saguenay?Lac-Saint-Jean par l'Université du Québec à Chicoutimi est considérable. De nombreux exemples ont été recensés en regard d'intrants, d'extrants et d'activités de recherche dont la portée régionale est manifeste. De même, des impacts scientifiques, socio-culturels et politiques ont été constatés. Par contre, un constat de réponse partielle des résultats de cette étude s'impose. En effet, des limites associées aux modèles conceptuels actuels permettent difficilement de quantifier ou de qualifier l'influence effective de ces retombées de nature économique et socio-culturelle sur la dynamique de développement du Saguenay?Lac-Saint-Jean. En outre, l'analyse des résultats montre que l'Université du Québec à Chicoutimi est un vecteur du développement endogène de sa région environnante. En définitive, les retombées régionales de l'effort de recherche universitaire peuvent constituer à maints égards des impulsions endogènes dont la dynamique socioéconomique et culturelle régionale pourrait tirer davantage profit. En fin de compte, l'université régionale pourrait constituer le moteur même du changement paradigmatique attendu dans l'optique du développement par la base. Car elle contribue certes à forger une culture scientifique et technologique propice à l'innovation dans des domaines associés à l'économie du savoir