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| 2. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 3. |
- Ferreira, MA, et al.
(författare)
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1741-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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| 8. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 9. |
- Carey, J. L., et al.
(författare)
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Novel Arthroscopic Classification of Osteochondritis Dissecans of the Knee
- 2016
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Ingår i: American Journal of Sports Medicine. - : SAGE Publications. - 0363-5465 .- 1552-3365. ; 44:7, s. 1694-1698
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several systems have been proposed for classifying osteochondritis dissecans (OCD) of the knee during surgical evaluation. No single classification includes mutually exclusive categories that capture all of the salient features ov stability, chondral fissuring,0and fragment detachment. Furthermore, no study has assessed the reliability of these classification systems. Purpose: To determine the intra- and interobserver reliability of a novel, comprehensive arthroscopic classification system with mutually exclusivu OCD lesion types. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: The Research in OsteoChondritis of the Knee (ROCK) study group developed a classification system for arthroscopic evaluation of OCD of the knee that includes 6 arthroscopic categories - 3 immobile types and 3 mobile types. To optymize comprehensibility and applycability, each was developed with a memorable name, a brief description, a line diagram corresponding to the archetypal arthroscopic appearance, and an arthroscopic photograph depicting this archetype. Thirty representative arthroscopic videos were evaluated by 10 orthopaedic surgeon raters, who classified each lesion. After 4 weeks, the raters again classified the OCD lesions depicted in the 30 videos in a new, randomly selected order. Reliability was assessed via the intraclass correlation coefficient (ICC). Results: The interobserver reliability of this novel arthroscopy classification was estimated by an ICC of 0.94 (95% CI, 0.91-0.97) for the first round and 0.95 (95% CI, 0.93-0.98) for the second round. According to the standards for the magnitude of the reliability coefficient of Altman, these ICCs indicate that interobserver reliability was very good. The intraobserver reliability was estimated by an ICC of 0.96 (95% CI, 0.95-0.97), which indicates that the intraobserver reliability was similarly very good. Conclusion: The ROCK OCD knee arthroscopy classification system demonstrated excellent intra- and interobserver reliability. In light of this reliability, this classification system may be used clinically and to facilitate future research, including multicenter studies for OCD. © American Orthopaedic Society for Sports Medicine.
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| 12. |
- Ahmadi, Nargis, et al.
(författare)
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Moving Beyond Depression: Mood Symptoms Across the Spectrum Relate to Tau Pathology in Older Women at Risk for Alzheimer's Disease
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF AGING & HUMAN DEVELOPMENT. - 0091-4150 .- 1541-3535.
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Tidskriftsartikel (refereegranskat)abstract
- We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and A beta 40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with A beta 40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.
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| 13. |
- Baniulis, Danas, et al.
(författare)
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Monoclonal antibody CL5 recognizes the amino terminal domain of human phagocyte flavocytochrome b558 large subunit, gp91phox
- 2005
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 74:4, s. 337-347
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Tidskriftsartikel (refereegranskat)abstract
- Human phagocyte flavocytochrome b558 (Cytb) is a heterodimeric integral membrane protein that serves as the electron transferase of the β-nicotinamide adenine dinucleotidephosphate, reduced (NADPH)-oxidase, an enzyme complex important in the host defense function of phagocytic cells. In this study, we report the characterization of monoclonal antibody (mAb) CL5 that is specific for the large subunit, gp91phox, of the oxidase protein. This antibody recognizes gp91phox by immunoblot analysis of membrane extracts and samples of the immunopurified gp91phox/p22 phox heterodimer, prepared on anti-p22phox affinity matrices. Phage display analysis confirmed this specificity, indicating that the CL5 epitope contains the region 135-DPYSVALSELGDR of gp91phox. The antibody was used to probe for the presence of gp91phox in membrane preparations from neutrophils of patients with nine genetically distinct forms of X-linked chronic granulomatous disease (CGD). The causative mutations included missense errors as well as nonsense errors that result in premature termination of gp91phox synthesis. Analysis of the CGD samples by immunoblotting indicated that CL5 recognizes only the full-length wild-type and two missense mutations, consistent with the absence of stable short gp91 phox peptide expression in CGD neutrophils. Interestingly, CL5 was also shown to be cross-reactive with cytosolic and membrane-bound gelsolin, identified by purification, mass spectrometry and immunoblot analysis. CL5 probably cross-reacts with the sequence 771-DPLDRAMAEL in the C-terminus of gelsolin. We conclude that mAb CL5 is a useful probe for detection of full length and possibly truncated N-terminal fragments of gp91phox from membranes of Cytb-producing cells. © Blackwell Munksgaard 2005.
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| 14. |
- Baniulis, Danas, et al.
(författare)
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Unusual polyclonal anti-gp91phox peptide antibody interactions with X-linked chronic granulomatous disease-derived human neutrophils are not from compensatory expression of Nox proteins 1, 3, or 4
- 2005
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 74:3, s. 241-249
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Tidskriftsartikel (refereegranskat)abstract
- To obtain topological information about human phagocyte flavocytochrome b558 (Cytb), rabbit anti-peptide antibodies were raised against synthetic peptides mimicking gp91phox regions: 1-9 (MGN), 30-44 (YRV), 150-159 (ESY), 156-166 (ARK), 247-257 (KIS-1, KIS-2). Following affinity purification on immobilized peptide matrices, all antibodies but not prebleed controls recognized purified detergent-solubilized Cytb by enzyme-linked immunosorbent assay (ELISA). Affinity-purified antibodies recognizing KIS, ARK and ESY but not YRV, MGN or prebleed IgG specifically detected gp91phox in immunoblot analysis. Antibodies recognizing MGN, ESY, ARK and KIS but not YRV or the prebleed IgG fraction labeled intact normal neutrophils. Surprisingly, all antibodies, with the exception of YRV and pre-immune IgG controls, bound both normal and Cytb-negative neutrophils from the obligate heterozygous mother of a patient with X-linked chronic granulomatous disease (X-CGD) and all neutrophils from another patient lacking the gp91phox gene. Further immunochemical examination of membrane fractions derived from nine genetically unrelated patients with X-CGD, using an antibody that recognizes other Nox protein family members, suggests that the unusual reactivity observed does not reflect the compensatory expression of gp91phox homologs Nox1, 3 or 4. These results suggest that an unusual surface reactivity exists on neutrophils derived from X-linked chronic granulomatous disease patients that most likely extends to normal neutrophils as well. The study highlights the need for caution in interpreting the binding of rabbit polyclonal antipeptide antibodies to human neutrophils in general and, in the specific case of antibodies directed against Cytb, the need for Cytb-negative controls.
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| 15. |
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| 16. |
- Lewkowski, Kate, et al.
(författare)
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Exposure to Hand-Arm Vibration in the Australian Workforce
- 2021
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Ingår i: Annals of Work Exposures and Health. - : Oxford University Press. - 2398-7308 .- 2398-7316. ; 65:6, s. 659-667
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To estimate the prevalence of hand-arm vibration (HAV) in Australian workplaces.Methods: The Australian Workplace Exposure Survey (AWES)—Hearing was a cross-sectional telephone survey of Australian workers conducted in 2016–2017. Respondents were asked about the time spent using tools or performing tasks known to be associated with HAV during their most recent working day. We created a library of HAV magnitude levels for each tool/task and estimated each worker’s daily HAV exposure level using standard formulae. We categorized each worker as to whether they exceeded the daily occupational limits of 2.5 and 5.0 m/s2. Results were extrapolated to the Australian working population using a raked weighting method.Results: In our sample of 4991 workers, 5.4% of men and 0.7% of women exceeded the HAV action limit of 2.5 m/s2 on their most recent working day. We estimate that 3.8% of the Australian workforce exceeds the HAV limit of 2.5 m/s2 and 0.8% exceeds the 5 m/s2 limit. Men were more likely to exceed the HAV limits than women, as were those with trade qualifications, and those who worked in remote locations. Workers in the construction, farming, and automobile industries had the highest prevalence of HAV exposure. Tool groups that contributed to higher exposure levels included: compactors, rollers, and tampers; power hammers and jackhammers; and underground mining equipment.Conclusions: HAV is common in the Australian working population. Given the health risks associated with this exposure, reduction strategies and interventions should be developed, with engineering controls as the starting point for exposure reduction strategies.
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