The role of genetic breast cancer susceptibility variants as prognostic factors

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.     

Workplace social capital and all-cause mortality: a prospective cohort study of 28,043 public-sector employees in Finland

Objectives. We examined the association between workplace social capital and all-cause mortality in a large occupational cohort from Finland.Methods. We linked responses of 28 043 participants to surveys in 2000 to 2002 and in 2004 to national mortality registers through 2009. We used repeated measurements of self- and coworker-assessed social capital. We carried out Cox proportional hazard and fixed-effects logistic regressions.Results. During the 5-year follow-up, 196 employees died. A 1-unit increase in the mean of repeat measurements of self-assessed workplace social capital (range 1–5) was associated with a 19% decrease in the risk of all-cause mortality (age- and gender-adjusted hazard ratio [HR] = 0.81; 95% confidence interval [CI] = 0.66, 0.99). The corresponding point estimate for the mean of coworker-assessed social capital was similar, although the association was less precisely estimated (age- and gender-adjusted HR = 0.77; 95% CI = 0.50, 1.20). In fixed-effects analysis, a 1-unit increase in self-assessed social capital across the 2 time points was associated with a lower mortality risk (odds ratio = 0.81; 95% CI = 0.55, 1.19).Conclusions. Workplace social capital appears to be associated with lowered mortality in the working-aged population.In the past 2 decades, interest has grown in the health effects of social capital, defined as the features of social structures, such as levels of interpersonal trust and norms of reciprocity and mutual aid, that act as resources for individuals and facilitate collective action.^1–3 In the literature, social capital has been conceptualized (and measured) both at the individual level and at the group level.^4,5 At the individual level, the most common approach has been to measure individual perceptions of the level of cohesion or solidarity in the group to which the individual belongs. At the group level, the focus is on the collective (e.g., neighborhood or workplace). Thus, a common practice has been to aggregate the individual responses from surveys to the collective. Some authors have also measured social capital through objective indicators that are not dependent on respondent perceptions, such as density of civic associations within a community.⁶ Another approach derives measures of social capital from social network analysis.⁷Adding to cross-sectional ecological analyses,⁸ at least 7 prospective studies in nonoccupational settings have examined the association between social capital and mortality among the working-aged population through at least 1 indicator of social capital.^9–15 Findings from those studies have been mixed, although the preponderance of evidence favors a weak inverse association.Several factors may have contributed to inconsistent evidence. For example, previous studies on mortality have focused on social capital in residential or geographical areas rather than in occupational settings, although recent research has emphasized the importance of the evaluation of workplace social capital to explain variations in employees'' health.^16–19 Indeed, for working populations, sources of variation in social capital are likely to be found in settings where people spend an increasing portion of their daily lives: workplaces.^20,21 Furthermore, because all these studies assessed social capital at only 1 time point, further data with repeated measurements of social capital are needed to strengthen the evidence.The Finnish Public Sector Study had at least 3 strengths that addressed the question of workplace social capital and mortality. First, it provided unique individual- and workplace-level survey data from a large occupational cohort linked to comprehensive national mortality registers. The linkage was complete, minimizing any bias related to selective sample retention. Second, the data included repeated assessments of workplace social capital, which enabled the determination of both repeated exposure and change in workplace social capital. Third, both self- and coworker-assessed social capital were available. This information helped to address reporting bias. We used these data to examine the hypothesis that repeated exposure to low workplace social capital and adverse changes in social capital are associated with increased mortality, corresponding to previous findings on workplace social capital and self-rated health and depression,²² important correlates of all-cause mortality.²³     

Insomnia symptoms as a predictor of incident treatment for depression: prospective cohort study of 40,791 men and women

ObjectiveTo examine the quantity and quality of insomnia symptoms as predictors of treatment for depression in the largest cohort study to date.MethodsForty thousand seven hundred and ninety-one Finnish public sector employees (mean age 43.9 years, 81% female), free of depression at baseline, participated in this prospective observational cohort study. Participants responded to the survey in 2000–2002 or 2004 and the mean follow-up was 3.3 years. Self-reported sleep was linked to comprehensive individual-level health registers to assess treatment for depression (antidepressant medication, commencements of psychotherapy or hospitalization due to depression).ResultsOne thousand seven hundred and three participants fulfilled any of our set criteria for depression-related treatment. After adjustments for baseline characteristics, insomnia symptoms five to seven nights/week were associated with an increased risk of incident treatment for depression, hazard ratio 1.64 (95% confidence interval 1.44–1.86). Hazard ratio for symptoms two to four nights/week was 1.46 (1.29–1.64). Difficulties initiating or maintaining sleep and non-refreshing sleep increased the risk when analyzed separately. Those reporting all four symptoms at least twice a week had 2.09-fold (1.75–2.49) risk. The findings did not materially change after excluding depression cases within the first two years of the follow-up.ConclusionsThese data suggest an association between insomnia symptoms and moderately increased risk of clinically significant depression outcomes. Insomnia should be considered as a component in prediction models for new-onset depression.     

Human ROBO1 regulates interaural interaction in auditory pathways

In rodents, the Robo1 gene regulates midline crossing of major nerve tracts, a fundamental property of the mammalian CNS. However, the neurodevelopmental function of the human ROBO1 gene remains unknown, apart from a suggested role in dyslexia. We therefore studied axonal crossing with a functional approach, based on magnetoencephalography, in 10 dyslexic individuals who all share the same rare, weakly expressing haplotype of the ROBO1 gene. Auditory-cortex responses were recorded separately to left- and right-ear sounds that were amplitude modulated at different frequencies. We found impaired interaural interaction that depended on the ROBO1 in a dose-dependent manner. Our results indicate that normal crossing of the auditory pathways requires an adequate ROBO1 expression level.     

Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3–4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.     

Ameloblastoma: a retrospective single institute study of 34 subjects

Objective: This study aims to clarify demographic and clinical aspects of patients with ameloblastoma treated at a single Finnish institute during 1985–2016. Associations between predictor variables (gender and age) and outcome variables (location, tumour type, growth patterns and average tumour size) were sought.

Materials and methods: A retrospective cohort study was designed and implemented including 34 patients diagnosed with primary ameloblastoma and treated at the Helsinki University Central Hospital. Patient records were investigated, and tissue samples re-evaluated. The chi-square test was used on all categorized variables and t-test for continuous ones. A p value equal to or under .05 was considered significant.

Results: Males were slightly more predominant among the Finnish patients with ameloblastoma. Maxillary tumours were seen exclusively in male patients (p?=?.034). Additionally, these patients were older than patients with mandibular tumours (p?=?.007). A mixture in histological growth patterns was more common than originally anticipated. The study revealed a wide range of clinical signs and subjective symptoms, of which pain or other sensations were experienced most often.

Conclusions: This study of 34 subjects shows that southern Finnish patients with ameloblastoma do not substantially differ from patients in similar study designs.