Abstract
Previous studies suggest that the association between mammographic density (MD) and breast cancer risk might be modified by other breast cancer risk factors. In this study, we assessed ...multiplicative interactions between MD measures and established risk factors on the risk of invasive breast cancer overall and according to menopausal and estrogen receptor status. We used data on 2,137 cases and 4,346 controls from a nested case-control study within the Nurses’ Health Study (1976–2004) and Nurses’ Health Study II (1989–2007), whose data on percent mammographic density (PMD) and absolute area of dense tissue and nondense tissue (NDA) were available. No interaction remained statistically significant after adjusting for number of comparisons. For breast cancer overall, we observed nominally significant interactions (P < 0.05) between nulliparity and PMD/NDA, age at menarche and area of dense tissue, and body mass index and NDA. Individual nominally significant interactions across MD measures and risk factors were also observed in analyses stratified by either menopausal or estrogen receptor status. Our findings help provide further insights into potential mechanisms underlying the association between MD and breast cancer.
Purpose of the Review
Increasing access to large-scale genetic datasets in population-based studies allows for genetic association studies as a means to examine previously known and novel ...relationships among complex traits. In this review, we discuss two widely used approaches to leverage genetic data to study the links between traits: Genome-wide genetic correlation and Mendelian Randomization (MR) studies.
Recent Findings
Both genetic correlation and MR studies have provided important novel insights. However, although they are less sensitive to many sources of bias present in traditional, observational epidemiology, they still rely on assumptions that in practice might be difficult to assess. To overcome this, development of novel methods less sensitive to these assumptions is an active area of research.
Summary
We believe that as population-based genetic datasets grow larger and novel methods allowing for weaker forms of current assumptions become available, genetic correlation and MR studies will become an integral part of genetic epidemiology studies.
Previous literature has suggested that identifying putative differences in health care seeking patterns before death by suicide depending on age and gender may facilitate more targeted suicide ...preventive approaches. The aim of this study is to map health care utilisation among individuals in the two years prior to suicide in Sweden in 2015 and to examine possible age and gender differences.
Design: A retrospective explorative study with a medical record review covering the two years preceding suicide.
All health care units located in 20 of Sweden's 21 regions.
All individuals residing in participating regions who died by suicide during 2015 (n = 949).
Almost 74% were in contact with a health care provider during the 3 months prior to suicide, and 60% within 4 weeks. Overall health care utilisation during the last month of life did not differ between age groups. However, a higher proportion of younger individuals (< 65 years) were in contact with psychiatric services, and a higher proportion of older individuals (≥ 65 years) were in contact with primary and specialised somatic health care. The proportion of women with any type of health care contact during the observation period was larger than the corresponding proportion of men, although no gender difference was found among primary and specialised somatic health care users within four weeks and three months respectively prior to suicide.
Care utilisation before suicide varied by gender and age. Female suicide decedents seem to utilise health care to a larger extent than male decedents in the two years preceding death, except for the non-psychiatric services in closer proximity to death. Older adults seem to predominantly use non-psychiatric services, while younger individuals seek psychiatric services to a larger extent.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HER2 (human epidermal-growth-factor receptor-2; ErbB2) and EGFR (epidermal-growth-factor receptor) are overexpressed in various forms of cancer, and the co-expression of both HER2 and EGFR has been ...reported in a number of studies. The simultaneous targeting of HER2 and EGFR has been discussed as a strategy with which to potentially increase efficiency and selectivity in molecular imaging and therapy of certain cancers. In an effort to generate a molecule capable of bispecifically targeting HER2 and EGFR, a gene fragment encoding a bivalent HER2-binding affibody molecule was genetically fused in-frame with a bivalent EGFR-binding affibody molecule via a (G4S)3 (Gly4-Ser)3-encoding gene fragment. The encoded 30 kDa affibody construct (ZHER2)2-(G4S)3-(ZEGFR)2, with potential for bs (bispecific) binding to HER2 and EGFR, was expressed in Escherichia coli and characterized in terms of its binding capabilities. The retained ability to bind HER2 and EGFR separately was demonstrated using both biosensor technology and flow-cytometric analysis, the latter using HER2- and EGFR-overexpressing cells. Furthermore, simultaneous binding to HER2 and EGFR was demonstrated in: (i) a sandwich format employing real-time biospecific interaction analysis where the bs affibody molecule bound immobilized EGFR and soluble HER2; (ii) immunofluorescence microscopy, where the bs affibody molecule bound EGFR-overexpressing cells and soluble HER2; and (iii) a cell-cell interaction analysis where the bs affibody molecule bound HER2-overexpressing SKBR-3 cells and EGFR-overexpressing A-431 cells. This is, to our knowledge, the first reported bs affinity protein with potential ability for the simultaneous targeting of HER2 and EGFR. The potential future use of this and similar constructs, capable of bs targeting of receptors to increase the efficacy and selectivity in imaging and therapy, is discussed.
Flow cytometry and microscopy are perhaps the two most commonly used techniques for analyzing single cells. Both techniques are typically robust and provide a high throughput analysis of living ...and/or fixed cells. The techniques are often combined with fluorescent labeling of cells, using for example antibodies. This chapter is a short introductory review where some of the possible applications using flow cytometry and microscopy are discussed.
Objective
This study aimed to uncover genetic contributors to adiposity in early life.
Methods
A genome‐wide association study of childhood body fatness in 34,401 individuals within the Nurses’ ...Health Studies and the Health Professionals Follow‐up Study was conducted. Data were imputed to the 1000 Genomes Phase 3 version 5 reference panel.
Results
A total of 1,354 single‐nucleotide polymorphisms (P < 10−4) were selected for replication in a previously published genome‐wide association study of childhood BMI. Nineteen significant genome‐wide (P < 5 × 10−8) regions were observed, fourteen of which were previously associated with childhood obesity and five were novel: BNDF (P = 7.58 × 10−13), PRKD1 (P = 1.43 × 10−10), 20p13 (P = 2.05 × 10−10), FHIT (P = 1.77 × 10−8), and LOC101927575 (P = 3.22 × 10−8). The BNDF, FHIT, and PRKD1 regions were previously associated with adult BMI. LOC101927575 and 20p13 regions have not previously been associated with adiposity phenotypes. In a transcriptome‐wide analysis, associations for POMC at 2p23.3 (P = 3.36 × 10−6) and with TMEM18 at 2p25.3 (P = 3.53 × 10−7) were observed. Childhood body fatness was genetically correlated with hip (rg = 0.42, P = 4.44 × 10−16) and waist circumference (rg = 0.39, P = 5.56 × 10−16), as well as age at menarche (rg = −0.37, P = 7.96 × 10−19).
Conclusions
Additional loci that contribute to childhood adiposity were identified, further explicating its genetic architecture.
BACKGROUND:Recent studies of breast cancer and common genetic markers have failed to identify pervasive gene–gene and gene–environment interactions. Theoretical considerations also suggest that the ...contribution of modest interactions to risk discrimination in the general population is likely small. However, the clinical utility of common breast cancer risk markers may nonetheless differ across strata defined by known risk factors, such as age.
METHODS:We examined the age-specific per-allele odds ratios of 15 common single nucleotide polymorphisms (SNPs) found to be associated with breast cancer in 1142 breast cancer cases and 1145 controls from the Nurses’ Health Study. We calculated the age-specific discriminatory ability of risk models incorporating these SNPs. We then conducted simulation studies to explore how hypothetical underlying genetic models may fit the observed results.
RESULTS:Although all individual SNP-by-age interactions were modest, we found a negative interaction effect between age and a genetic risk score defined by the sum of risk alleles (P = 0.04). We also observed a decrease in discriminatory ability, as measured by the area under the curve (AUC), of the SNPs with age (P = 0.04). Simulation studies revealed models where the AUC can differ by strata defined by a risk factor without the presence of interactions; however, our study suggests that the observed differences in AUC are explained by the age-specific effect of the SNPs.
CONCLUSION:The identification of risk factors that alter the effect of multiple genetic variants can help to explain the genetic architecture of multifactorial diseases and identify subgroups of persons who may benefit from genetic screening.
A recent genome-wide association study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to ...replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry.
We genotyped five single-nucleotide polymorphism (SNP): rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22), and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the National cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed whether associations differed with respect to disease severity and age of onset.
Four SNPs (rs13385191, rs12653946, rs1983891, and rs339331) were significantly associated with prostate cancer risk (P values ranging from 0.01 to 1.1 × 10(-5)). Allele frequencies and ORs were overall lower in our population of European descent than in the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (P = 0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (P = 0.62).
Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent.
This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups.
Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very ...large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.
Abstract Objectives Individuals who die by suicide often consult their general practitioners (GPs) in their final weeks of life. The aim of this study was to gain a deeper knowledge of the clinical ...characteristics and GP assessments and treatments among individuals who consulted their GPs during the month preceding suicide. Further, we compared these features in those with and without contact with psychiatric services (PC and NPC, respectively) during the two years that preceded the suicide. Design A nationwide retrospective explorative study investigating medical records. Setting Primary care in Sweden. Participants Individuals who died by suicide in Sweden in 2015 with a GP visit within 30 days of death. Results The study cohort corresponds to one fifth ( n = 238) of all suicides that occurred in Sweden in 2015 ( n = 1179), representing all those with available primary care records showing contact with a GP during the final 30 days of life (NPC: n = 125; PC: n = 113). The mean age was 58 years ± 19. Patients in the NPC group were older (NPC: 63 years ± 19 vs. PC: 53 years ± 18, p < 0.0001) and presented psychiatric symptoms less often (NPC: 50% vs. PC: 67%, p < 0.006). Somatic symptoms were as common as psychiatric symptoms for the whole sample, being present in more than half of individuals. Suicide risk was noted in only 6% of all individuals. Referral to psychiatric services occurred in 14%, less commonly for the NPC group (NPC: 6% vs. PC: 22%, p < 0.001). Cardiovascular or respiratory symptoms were noted in 19%, more often in the NPC group (NPC: 30% vs. PC: 6%, p < 0.001), as were diagnoses involving the circulatory system (all 10%, NPC:14% vs. PC: 5%, p < 0.020). Conclusion A high level of somatic symptoms was observed in primary care patients both with and without psychiatric contact, and this might have influenced GPs’ management decisions. Psychiatric symptoms were noted in two thirds of those with psychiatric contact but only half of those without. While GPs noted psychiatric symptoms in over half of all individuals included in the study, they seldom noted suicide risk. These findings highlight the need for increased attention to psychiatric symptoms and suicide risk assessment, particularly among middle-aged and older individuals presenting with somatic symptoms. Strengths and limitations of this study The National Cause of Death Register has excellent coverage of suicide deaths and access to medical records was very good. The medical record review provided detailed information regarding primary care utilization before death by suicide. Because of the lack of statistical power, due to the limited number of persons with GP contact during the last month of life, we chose not to correct for multiple comparisons. Our study approach did not capture the reasons behind GPs’ documentation of elevated suicide risk. No systematic inter-rater reliability (IRR) testing was made, however, reviewers received training and continuous support from the research group.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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