Olaparib-induced Adaptive Response Is Disrupted by FOXM1 Targeting that Enhances Sensitivity to PARP Inhibition

FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair. FOXM1 knockdown by RNAi or inhibition by thiostrepton decreases FOXM1 expression, decreases the expression of HR repair genes, such as BRCA1 and RAD51, and enhances sensitivity to olaparib. Comet and PARP trapping assays revealed increases in DNA damage and PARP trapping in FOXM1-inhibited cells treated with olaparib. Finally, thiostrepton decreases the expression of BRCA1 in rucaparib-resistant cells and enhances sensitivity to rucaparib. Collectively, these results identify that FOXM1 plays an important role in the adaptive response induced by olaparib and FOXM1 inhibition by thiostrepton induces “BRCAness” and enhances sensitivity to PARP inhibitors

Linked Lives: Exploring Gender and Sedentary Behaviors in Older Adult Couples

Objectives: We explored associations between co-habiting partners for sedentary behavior (type and time, via accelerometry and self-report), gender, and a surrogate health measure (inflammatory biomarker: C-reactive protein, CRP). Methods: Participants completed activity questionnaires and the Timed Up and Go (mobility), wore an accelerometer for 7 days, and provided samples for high-sensitivity (hs) CRP. We used multilevel modeling (partners within couples) to investigate associations between independent variables and (a) sedentary behavior and (b) hsCRP. Results: 112 couples (50% women) provided sedentary data and hsCRP. Sedentary behavior was significantly correlated (r = .440, p men). Gender, moderate to vigorous physical activity (MVPA), and mobility estimated 37% of the modeled variance in sedentary time, while body mass index (BMI) and MVPA estimated 10% of the modeled variance in hsCRP. Discussion: Despite differences in how activity was accumulated, there were no significant differences between women’s and men’s health biomarker.Canadian Institutes of Health Research https://doi.org/10.13039/501100000024michael smith foundation for health research https://doi.org/10.13039/501100000245social sciences and humanities research council of canada https://doi.org/10.13039/501100000155university of british columbia https://doi.org/10.13039/501100005247Peer Reviewe

Daily Affect and Daily Prospective Memory in People after Stroke and Their Partners: The Moderating Role of Resting Heart Rate

Introduction: Experimental research suggests that affect may influence prospective memory performance, but real-life evidence on affect-prospective memory associations is limited. Moreover, most studies have examined the valence dimension of affect in understanding the influence of affect on cognitive performance in daily life, with insufficient consideration of the arousal dimension. To maximize ecological validity, the current study examined the relationships between daily affect and daily prospective memory using repeated daily assessments and the role of resting heart rate on these relationships. We examined both valence and arousal of daily affect by categorizing affect into four dimensions: high-arousal positive affect, low-arousal positive affect, high-arousal negative affect, and low-arousal negative affect. Method: We examined existing data collected from community-dwelling couples, of which at least one partner had a stroke history. The analytic sample included 111 adults (Mage = 67.46 years, SD = 9.64; 50% women) who provided 1,274 days of data. Among the participants, 58 were living with the effects of a stroke and 53 were partners. Participants completed daily event-based prospective memory tasks (in morning and/or evening questionnaires), reported daily affect in the evening, and wore a wrist-based Fitbit device to monitor resting heart rate over 14 consecutive days. Results: Results from multilevel models show that, within persons, elevated high-arousal negative affect was associated with worse daily prospective memory performance. In addition, lower resting heart rate attenuated the inverse association between high-arousal negative affect and lowered prospective memory performance. We did not find significant associations of high- or low-arousal positive affect and low-arousal negative affect with daily prospective memory. Discussion: Our findings are in line with the resource allocation model and the cue-utilization hypothesis in that high-arousal negative affect is detrimental to daily prospective memory performance. Lower resting heart rate may buffer individuals’ prospective memory performance from the influence of high-arousal negative affect. These findings are consistent with the neurovisceral integration model on heart-brain connections, highlighting the possibility that cardiovascular fitness may help maintain prospective memory into older adulthood

Let’s Enjoy an Evening on the Couch? A Daily Life Investigation of Shared Problematic Behaviors in Three Couple Studies

Symptom-system fit theory proposes that problematic behaviors are maintained by the social system (e.g., the couple relationship) in which they occur because they help promote positive relationship functioning in the short-term. Across three daily life studies, we examined whether mixed-gender couples reported more positive relationship functioning on days in which they engaged in more shared problematic behaviors. In two studies (Study 1: 82 couples who smoke; Study 2: 117 couples who are inactive), days of more shared problematic behavior were accompanied by higher daily closeness and relationship satisfaction. A third study with 79 couples post-stroke investigating unhealthy eating failed to provide evidence for symptom-system fit. In exploratory lagged analyses, we found more support for prior-day problematic behavior being associated with next-day daily relationship functioning than vice-versa. Together, findings point to the importance of a systems perspective when studying interpersonal dynamics that might be involved in the maintenance of problematic behaviors

Structural divergence creates new functional features in alphavirus genomes

Alphaviruses are mosquito-borne pathogens that cause human diseases ranging from debilitating arthritis to lethal encephalitis. Studies with Sindbis virus (SINV), which causes fever, rash, and arthralgia in humans, and Venezuelan equine encephalitis virus (VEEV), which causes encephalitis, have identified RNA structural elements that play key roles in replication and pathogenesis. However, a complete genomic structural profile has not been established for these viruses. We used the structural probing technique SHAPE-MaP to identify structured elements within the SINV and VEEV genomes. Our SHAPE-directed structural models recapitulate known RNA structures, while also identifying novel structural elements, including a new functional element in the nsP1 region of SINV whose disruption causes a defect in infectivity. Although RNA structural elements are important for multiple aspects of alphavirus biology, we found the majority of RNA structures were not conserved between SINV and VEEV. Our data suggest that alphavirus RNA genomes are highly divergent structurally despite similar genomic architecture and sequence conservation; still, RNA structural elements are critical to the viral life cycle. These findings reframe traditional assumptions about RNA structure and evolution: rather than structures being conserved, alphaviruses frequently evolve new structures that may shape interactions with host immune systems or co-evolve with viral proteins

Unexpected Consequences: Women’s experiences of a self-hypnosis intervention to help with pain relief during labour.

Background Self-hypnosis is becoming increasingly popular as a means of labour pain management. Previous studies have produced mixed results. There are very few data on women’s views and experiences of using hypnosis in this context. As part of a randomized controlled trial of self-hypnosis for intra-partum pain relief (the SHIP Trial) we conducted qualitative interviews with women randomized to the intervention arm to explore their views and experiences of using self-hypnosis during labour and birth. Methods Participants were randomly selected from the intervention arm of the study, which consisted of two antenatal self-hypnosis training sessions and a supporting CD that women were encouraged to listen to daily from 32 weeks gestation until the birth of their baby. Those who consented were interviewed in their own homes 8-12 weeks after birth. Following transcription, the interviews were analysed iteratively and emerging concepts were discussed amongst the authors to generate organizing themes. These were then used to develop a principal organizing metaphor or global theme, in a process known as thematic networks analysis. Results Of the 343 women in the intervention group, 48 were invited to interview, and 16 were interviewed over a 12 month period from February 2012 to January 2013. Coding of the data and subsequent analysis revealed a global theme of ‘unexpected consequences’, supported by 5 organising themes, ‘calmness in a climate of fear’, ‘from sceptic to believer’, ‘finding my space’, ‘delays and disappointments’ and ‘personal preferences’. Most respondents reported positive experiences of self-hypnosis and highlighted feelings of calmness, confidence and empowerment. They found the intervention to be beneficial and used a range of novel strategies to personalize their self-hypnosis practice. Occasionally women reported feeling frustrated or disappointed when their relaxed state was misinterpreted by midwives on admission or when their labour and birth experiences did not match their expectations. Conclusion The women in this study generally appreciated antenatal self-hypnosis training and found it to be beneficial during labour and birth. The state of focused relaxation experienced by women using the technique needs to be recognized by providers if the intervention is to be implemented into the maternity service

Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network

PURPOSE: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. METHODS: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. RESULTS: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. CONCLUSION: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs

Factors Influencing Cost-Related Nonadherence to Medication in Older Adults: A Conceptually Based Approach

Although multiple noncost factors likely influence a patient's propensity to forego treatment in the face of cost pressures, little is known about how patients' sociodemographic characteristics, physical and behavioral health comorbidities, and prescription regimens influence cost-related nonadherence (CRN) to medications. We sought to determine both financial and nonfinancial factors associated with CRN in a nationally representative sample of older adults.We used a conceptual model developed by Piette and colleagues that describes financial and nonfinancial factors that could increase someone's risk of CRN, including income, comorbidities, and medication regimen complexity. We used data from the 2004 wave of the Health and Retirement Study and the 2005 HRS Prescription Drug Study to examine the influence of factors within each of these domains on measures of CRN (including not filling, stopping, or skipping doses) in a nationally representative sample of Americans age 65+ in 2005.Of the 3071 respondents who met study criteria, 20% reported some form of CRN in 2005. As in prior studies, indicators of financial stress such as higher out-of-pocket payments for medications and lower net worth were significantly associated with CRN in multivariable analyses. Controlling for these economic pressures, relatively younger respondents (ages 65–74) and depressive symptoms were consistent independent risk factors for CRN.Noncost factors influenced patients' propensity to forego treatment even in the context of cost concerns. Future research encompassing clinician and health system factors should identify additional determinants of CRN beyond patients' cost pressures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78680/1/j.1524-4733.2009.00679.x.pd

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network

The original version of this Article contained an error in the spelling of the author Geoffrey S. Ginsburg, which was incorrectly given as Geoffrey Ginsburg. This has now been corrected in both the PDF and HTML versions of the Article. Erratum for Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network. [Genet Med. 2019