Acceptability of a Pain History Assessment and Education Chatbot (Dolores) Across Age Groups in Populations With Chronic Pain: Development and Pilot Testing.

BACKGROUND: The delivery of education on pain neuroscience and the evidence for different treatment approaches has become a key component of contemporary persistent pain management. Chatbots, or more formally conversation agents, are increasingly being used in health care settings due to their versatility in providing interactive and individualized approaches to both capture and deliver information. Research focused on the acceptability of diverse chatbot formats can assist in developing a better understanding of the educational needs of target populations. OBJECTIVE: This study aims to detail the development and initial pilot testing of a multimodality pain education chatbot (Dolores) that can be used across different age groups and investigate whether acceptability and feedback were comparable across age groups following pilot testing. METHODS: Following an initial design phase involving software engineers (n=2) and expert clinicians (n=6), a total of 60 individuals with chronic pain who attended an outpatient clinic at 1 of 2 pain centers in Australia were recruited for pilot testing. The 60 individuals consisted of 20 (33%) adolescents (aged 10-18 years), 20 (33%) young adults (aged 19-35 years), and 20 (33%) adults (aged >35 years) with persistent pain. Participants spent 20 to 30 minutes completing interactive chatbot activities that enabled the Dolores app to gather a pain history and provide education about pain and pain treatments. After the chatbot activities, participants completed a custom-made feedback questionnaire measuring the acceptability constructs pertaining to health education chatbots. To determine the effect of age group on the acceptability ratings and feedback provided, a series of binomial logistic regression models and cumulative odds ordinal logistic regression models with proportional odds were generated. RESULTS: Overall, acceptability was high for the following constructs: engagement, perceived value, usability, accuracy, responsiveness, adoption intention, esthetics, and overall quality. The effect of age group on all acceptability ratings was small and not statistically significant. An analysis of open-ended question responses revealed that major frustrations with the app were related to Dolores' speech, which was explored further through a comparative analysis. With respect to providing negative feedback about Dolores' speech, a logistic regression model showed that the effect of age group was statistically significant (χ22=11.7; P=.003) and explained 27.1% of the variance (Nagelkerke R2). Adults and young adults were less likely to comment on Dolores' speech compared with adolescent participants (odds ratio 0.20, 95% CI 0.05-0.84 and odds ratio 0.05, 95% CI 0.01-0.43, respectively). Comments were related to both speech rate (too slow) and quality (unpleasant and robotic). CONCLUSIONS: This study provides support for the acceptability of pain history and education chatbots across different age groups. Chatbot acceptability for adolescent cohorts may be improved by enabling the self-selection of speech characteristics such as rate and personable tone.

Context-dependant enhancers as a reservoir of functional polymorphisms and epigenetic markers linked to alcohol use disorders and comorbidities.

Alcohol use disorder (AUD) is one of the major causes of mortality and morbidity world-wide. It is estimated that 50% of the causes of AUD are heritable. Efforts to determine the genetic determinants governing AUD using genome wide association studies (GWAS) show that the most strongly associated SNPs occur within, or in the vicinity of, genes encoding enzymes that metabolise ethanol. However, these studies were not so conclusive in identifying the genes that influenced the choice to drink ethanol or why a proportion of the population become addicted. Most importantly, these studies also found that over 98% of the 1292 SNPs associated with AUD (p<1 × 10-6) were found outside of coding regions and within the poorly understood non-coding genome. Many years of study have shown that functional components of the non-coding genome include enigmatic enhancer elements whose biological role is to modulate levels of gene expression in specific cells, in specific amounts and in response to the correct stimuli. The current short review introduces the functional components of the non-coding genome, such as promoters and enhancers, and critically assesses the latest methods of identifying and characterising their context dependant roles in AUD and mental health disorders. We then go on to examine what is known about the roles of enhancers, such as the GAL5.1 enhancer, in alcohol intake and explore how enhancers are affected by polymorphic variation and epigenetic markers such as DNA-methylation and may influence susceptibility to AUD. The review finishes by discussing the future of AUD genetics and what technologies will need to be brought to bear to understand how genetic and environmentally induced changes in enhancer structure may contribute to the need to drink alcohol to excess.

RetINal Toxicity And HydroxyChloroquine Therapy (INTACT): protocol for a prospective population-based cohort study.

PURPOSE: Hydroxychloroquine (HCQ) is an important medication for patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other rheumatic diseases. Although it is well-tolerated and cost-effective, the risk of HCQ retinal toxicity is of increasing concern. The aim of this study is to re-examine the HCQ retinal toxicity incidence rate, risk factors and clinical course after discontinuation. METHODS: We designed a prospective population-based cohort study in adult patients with SLE or RA, currently receiving HCQ for five or more years, who are residents of British Columbia (BC), Canada. Based on administrative data, we identified 5508 eligible participants (1346 SLE and 4162 RA). They will participate in annual or biannual retinal screening over 5 years in alignment with the recently revised American Academy of Ophthalmology guidelines. To standardise procedures for retinal screening, imaging, diagnostic criteria, severity staging and data transfer, a consensus meeting was convened in December 2019 with participation of BC retinal specialists and the research team. Agreement was attained on: use of spectral domain-optical coherence tomography as the primary objective screening modality; classification of images into categories of normal, equivocal or abnormal; and transferring the equivocal and abnormal images plus corresponding subjective test results via cloud-based server from each clinic to a reading centre. Confirmation of HCQ retinal toxicity diagnoses and severity staging will be performed by three independent and masked reviewers. The incidence of HCQ retinal toxicity will be calculated, accounting for the competing risk of death. Hazard ratios for each risk factor will be calculated for the risk of HCQ retinopathy, after adjusting for confounders. We will also estimate the risk of HCQ retinal toxicity progression over 5 years. ETHICS AND DISSEMINATION: This study has received approval from the University of British Columbia Clinical Research Ethics Board (H20-00736) and the Vancouver Coastal Health Research Institute.

Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis.

OBJECTIVE: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction. METHODS: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap-Tead reporter cells and Yap-Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells. RESULTS: Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen-), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1ß, Jak-dependently activated Yap and induced Yap-Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA. CONCLUSIONS: Our findings uncover the IL-6-Yap-Snail signalling axis in pathogenic SF in inflammatory arthritis.

CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake.

Excessive alcohol intake is associated with 5.9% of global deaths. However, this figure is especially acute in men such that 7.6% of deaths can be attributed to alcohol intake. Previous studies identified a significant interaction between genotypes of the galanin (GAL) gene with anxiety and alcohol abuse in different male populations but were unable to define a mechanism. To address these issues the current study analysed the human UK Biobank cohort and identified a significant interaction (n = 115,865; p = 0.0007) between allelic variation (GG or CA genotypes) in the highly conserved human GAL5.1 enhancer, alcohol intake (AUDIT questionnaire scores) and anxiety in men. Critically, disruption of GAL5.1 in mice using CRISPR genome editing significantly reduced GAL expression in the amygdala and hypothalamus whilst producing a corresponding reduction in ethanol intake in KO mice. Intriguingly, we also found the evidence of reduced anxiety-like behaviour in male GAL5.1KO animals mirroring that seen in humans from our UK Biobank studies. Using bioinformatic analysis and co-transfection studies we further identified the EGR1 transcription factor, that is co-expressed with GAL in amygdala and hypothalamus, as being important in the protein kinase C (PKC) supported activity of the GG genotype of GAL5.1 but less so in the CA genotype. Our unique study uses a novel combination of human association analysis, CRISPR genome editing in mice, animal behavioural analysis and cell culture studies to identify a highly conserved regulatory mechanism linking anxiety and alcohol intake that might contribute to increased susceptibility to anxiety and alcohol abuse in men.

Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4.

A high-fat diet induces hypothalamic inflammation in rodents which, in turn, contributes to the development of obesity by eliciting both insulin and leptin resistance. However, the mechanism by which long-chain saturated fatty acids trigger inflammation is still contentious. To elucidate this mechanism, the effect of fatty acids on the expression of the pro-inflammatory cytokines IL-6 and TNFα was investigated in the mHypoE-N42 hypothalamic cell line (N42). N42 cells were treated with lauric acid (LA) and palmitic acid (PA). PA challenge was carried out in the presence of either a TLR4 inhibitor, a ceramide synthesis inhibitor (L-cycloserine), oleic acid (OA) or eicosapentaenoic acid (EPA). Intracellular ceramide accumulation was quantified using LC-ESI-MS/MS. PA but not LA upregulated IL-6 and TNFα. L-cycloserine, OA and EPA all counteracted PA-induced intracellular ceramide accumulation leading to a downregulation of IL-6 and TNFα. However, a TLR4 inhibitor failed to inhibit PA-induced upregulation of pro-inflammatory cytokines.In conclusion, PA induced the expression of IL-6 and TNFα in N42 neuronal cells independently of TLR4 but, partially, via ceramide synthesis with OA and EPA being anti-inflammatory by decreasing PA-induced intracellular ceramide build-up. Thus, ceramide accumulation represents one on the mechanisms by which PA induces inflammation in neurons.

Disease-associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue-specific activity of the cannabinoid-1 receptor gene promoter; implications for cannabinoid pharmacogenetics.

Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Toward addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterized the effects of disease-associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake, and anxiety-like behavior. We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human-specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t-allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding of the roles of noncoding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics.

Early and reversible changes to the hippocampal proteome in mice on a high-fat diet.

BACKGROUND: The rise in global obesity makes it crucial to understand how diet drives obesity-related health conditions, such as premature cognitive decline and Alzheimer's disease (AD). In AD hippocampal-dependent episodic memory is one of the first types of memory to be impaired. Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired. METHODS: In this study we use hippocampal proteomics to investigate the effects of HFD in the hippocampus. Mice were fed either a low-fat diet (LFD) or HFD containing either 10% or 60% (Kcal) from fat for 3 days, 1 week or 2 weeks. One group of mice were fed the HFD for 1 week and then returned to the LFD for a further week. Primary hippocampal cultures were challenged with palmitic acid (PA), the most common long-chain saturated FA in the Western diet, and with the anti-inflammatory, n-3 polyunsaturated FA, docosahexaenoic acid (DHA), or a combination of the two to ascertain effects of these fatty acids on dendritic structure. RESULTS: HFD-induced changes occur in hippocampal proteins involved in metabolism, inflammation, cell stress, cell signalling, and the cytoskeleton after 3 days, 1 week and 2 weeks of HFD. Replacement of the HFD after 1 week by a low-fat diet (LFD) for a further week resulted in partial recovery of the hippocampal proteome. Microtubule-associated protein 2 (MAP2), one of the earliest proteins changed, was used to investigate the impact of fatty acids (FAs) on hippocampal neuronal morphology. PA challenge resulted in shorter and less arborised dendrites while DHA had no effect when applied alone but counteracted the effects of PA when FAs were used in combination. Dendritic morphology recovered when PA was removed from the cell culture media. CONCLUSION: This study provides evidence for the rapid and reversible effects of diet on the hippocampal proteome and the impact of PA and DHA on dendritic structure.

Disruption of an enhancer associated with addictive behaviour within the cannabinoid receptor-1 gene suggests a possible role in alcohol intake, cannabinoid response and anxiety-related behaviour.

The cannabinoid-1 receptor (CB1) plays a critical role in a number of biological processes including nutrient intake, addiction and anxiety-related behaviour. Numerous studies have shown that expression of the gene encoding CB1 (CNR1) is highly dynamic with changes in the tissue specific expression of CNR1 associated with brain homeostasis and disease progression. However, little is known of the mechanisms regulating this dynamic expression. To gain a better understanding of the genomic mechanisms modulating the expression of CNR1 in health and disease we characterised the role of a highly conserved regulatory sequence (ECR1) in CNR1 intron 2 that contained a polymorphism in linkage disequilibrium with disease associated SNPs. We used CRISPR/CAS9 technology to disrupt ECR1 within the mouse genome. Disruption of ECR1 significantly reduced CNR1 expression in the hippocampus but not in the hypothalamus. These mice also displayed an altered sex-specific anxiety-related behavioural profile (open field test), reduced ethanol intake and a reduced hypothermic response following CB1 agonism. However, no significant changes in feeding patterns were detected. These data suggest that, whilst not all of the expression of CNR1 is modulated by ECR1, this highly conserved enhancer is required for appropriate physiological responses to a number of stimuli. The combination of comparative genomics and CRISPR/CAS9 disruption used in our study to determine the functional effects of genetic and epigenetic changes on the activity of tissue-specific regulatory elements at the CNR1 locus represent an important first step in gaining a mechanistic understanding of cannabinoid regulatory pharmacogenetics.

Using the CRISPR/Cas9 system to understand neuropeptide biology and regulation.

Neuropeptides and their receptors play a role in physiological responses such as appetite, stress and inflammatory pain. With neuropeptides having such diverse and important physiological roles, knocking-out the genes encoding them, their receptors, parts of their regulatory sequences, or reproducing disease associated polymorphic variants are important steps in studying neuropeptides and how they may contribute to disease. Previously, knock-outs were generated using methods such as targeted homologous recombination in embryonic stem cells but this method is costly and time-consuming. The CRISPR/Cas9 system has rapidly taken over the genome editing field and will advance our understanding of neuropeptide genes and their regulation. With CRISPR/Cas9 technology, the time and costs involved in producing transgenic animal models, is greatly reduced. In this review, we describe how the system can be used to manipulate genomic sequences by "knock-out" or "knock-in" mutations in cell lines or in animal models. We also discuss the specificity of the system and methods to limit off-target effects. When combined with the availability of genome sequences, CRISPR/Cas9 directed genome editing in vitro and in vivo, promises to provide a deeper understanding of the biology of the neuropeptides in health and disease than has ever been available before.

Determining Epigenetic Targets: A Beginner's Guide to Identifying Genome Functionality Through Database Analysis.

There can now be little doubt that the cis-regulatory genome represents the largest information source within the human genome essential for health. In addition to containing up to five times more information than the coding genome, the cis-regulatory genome also acts as a major reservoir of disease-associated polymorphic variation. The cis-regulatory genome, which is comprised of enhancers, silencers, promoters, and insulators, also acts as a major functional target for epigenetic modification including DNA methylation and chromatin modifications. These epigenetic modifications impact the ability of cis-regulatory sequences to maintain tissue-specific and inducible expression of genes that preserve health. There has been limited ability to identify and characterize the functional components of this huge and largely misunderstood part of the human genome that, for decades, was ignored as "Junk" DNA. In an attempt to address this deficit, the current chapter will first describe methods of identifying and characterizing functional elements of the cis-regulatory genome at a genome-wide level using databases such as ENCODE, the UCSC browser, and NCBI. We will then explore the databases on the UCSC genome browser, which provides access to DNA methylation and chromatin modification datasets. Finally, we will describe how we can superimpose the huge volume of study data contained in the NCBI archives onto that contained within the UCSC browser in order to glean relevant in vivo study data for any locus within the genome. An ability to access and utilize these information sources will become essential to informing the future design of experiments and subsequent determination of the role of epigenetics in health and disease and will form a critical step in our development of personalized medicine.

A seasonal switch in histone deacetylase gene expression in the hypothalamus and their capacity to modulate nuclear signaling pathways.

Seasonal animals undergo changes in physiology and behavior between summer and winter conditions. These changes are in part driven by a switch in a series of hypothalamic genes under transcriptional control by hormones and, of recent interest, inflammatory factors. Crucial to the control of transcription are histone deacetylases (HDACs), generally acting to repress transcription by local histone modification. Seasonal changes in hypothalamic HDAC transcripts were investigated in photoperiod-sensitive F344 rats by altering the day-length (photoperiod). HDAC4, 6 and 9 were found to change in expression. The potential influence of HDACs on two hypothalamic signaling pathways that regulate transcription, inflammatory and nuclear receptor signaling, was investigated. For inflammatory signaling the focus was on NF-κB because of the novel finding made that its expression is seasonally regulated in the rat hypothalamus. For nuclear receptor signaling it was discovered that expression of retinoic acid receptor beta was regulated seasonally. HDAC modulation of NF-κB-induced pathways was examined in a hypothalamic neuronal cell line and primary hypothalamic tanycytes. HDAC4/5/6 inhibition altered the control of gene expression (Fos, Prkca, Prkcd and Ptp1b) by inducers of NF-κB that activate inflammation. These inhibitors also modified the action of nuclear receptor ligands thyroid hormone and retinoic acid. Thus seasonal changes in HDAC4 and 6 have the potential to epigenetically modify multiple gene regulatory pathways in the hypothalamus that could act to limit inflammatory pathways in the hypothalamus during long-day summer-like conditions.

An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome.

We have successfully used comparative genomics to identify putative regulatory elements within the human genome that contribute to the tissue specific expression of neuropeptides such as galanin and receptors such as CB1. However, a previous inability to rapidly delete these elements from the mouse genome has prevented optimal assessment of their function in-vivo. This has been solved using CAS9/CRISPR genome editing technology which uses a bacterial endonuclease called CAS9 that, in combination with specifically designed guide RNA (gRNA) molecules, cuts specific regions of the mouse genome. However, reports of "off target" effects, whereby the CAS9 endonuclease is able to cut sites other than those targeted, limits the appeal of this technology. We used cytoplasmic microinjection of gRNA and CAS9 mRNA into 1-cell mouse embryos to rapidly generate enhancer knockout mouse lines. The current study describes our analysis of the genomes of these enhancer knockout lines to detect possible off-target effects. Bioinformatic analysis was used to identify the most likely putative off-target sites and to design PCR primers that would amplify these sequences from genomic DNA of founder enhancer deletion mouse lines. Amplified DNA was then sequenced and blasted against the mouse genome sequence to detect off-target effects. Using this approach we were unable to detect any evidence of off-target effects in the genomes of three founder lines using any of the four gRNAs used in the analysis. This study suggests that the problem of off-target effects in transgenic mice have been exaggerated and that CAS9/CRISPR represents a highly effective and accurate method of deleting putative neuropeptide gene enhancer sequences from the mouse genome.

A Longitudinal Study of Predictors of Housing Stability, Housing Quality, and Mental Health Functioning Among Single Homeless Individuals Staying in Emergency Shelters.

The current study examined risk and resilience factors at multiple levels that affect homeless individuals' ability to exit homelessness and achieve housing stability. It also examined the relationship between housing status, housing quality and mental health functioning. The methodology is a longitudinal study of single homeless individuals staying in emergency shelters in a medium-sized Canadian city who were followed for a 2 year period. Data were collected from participants at a baseline interview when they were homeless and at a 2-year follow-up. There were 329 participants interviewed at baseline and 197 (59.9%) participants interviewed at follow-up. Results from a structural equation modelling analysis found that having interpersonal and community resources were predictive of achieving housing stability. Specifically, having a larger social support network, access to subsidized housing, and greater income was related to achieving housing stability. On the other hand, having a substance use problem was a risk factor associated with a failure to achieving housing stability. Being female, feeling personally empowered, having housing that is perceived of being of higher quality were directly predictive of mental health functioning at follow-up. Findings are discussed in the context of previous research and their policy implications.

The noncoding human genome and the future of personalised medicine.

Non-coding cis-regulatory sequences act as the 'eyes' of the genome and their role is to perceive, organise and relay cellular communication information to RNA polymerase II at gene promoters. The evolution of these sequences, that include enhancers, silencers, insulators and promoters, has progressed in multicellular organisms to the extent that cis-regulatory sequences make up as much as 10% of the human genome. Parallel evidence suggests that 75% of polymorphisms associated with heritable disease occur within predicted cis-regulatory sequences that effectively alter the 'perception' of cis-regulatory sequences or render them blind to cell communication cues. Cis-regulatory sequences also act as major functional targets of epigenetic modification thus representing an important conduit through which changes in DNA-methylation affects disease susceptibility. The objectives of the current review are (1) to describe what has been learned about identifying and characterising cis-regulatory sequences since the sequencing of the human genome; (2) to discuss their role in interpreting cell signalling pathways pathways; and (3) outline how this role may be altered by polymorphisms and epigenetic changes. We argue that the importance of the cis-regulatory genome for the interpretation of cellular communication pathways cannot be overstated and understanding its role in health and disease will be critical for the future development of personalised medicine.

Change in coping and defense mechanisms across adulthood: longitudinal findings in a European American sample.

This study examined longitudinal changes in coping and defense mechanisms in an age- and gender-stratified sample of 392 European American adults. Nonlinear age-related changes were found for the coping mechanisms of sublimation and suppression and the defense mechanisms of intellectualization, doubt, displacement, and regression. The change trajectories for sublimation and suppression showed that their use increased from adolescence to late middle age and early old age and remained mostly stable into late old age. The change trajectory for intellectualization showed that the use of this defense mechanism increased from adolescence to middle age, remained stable until late midlife, and started to decline thereafter. The defense mechanisms of doubt, displacement, and regression showed decreases from adolescence until early old age, with increases occurring again after the age of 65. Linear age-related decreases were found for the coping mechanism of ego regression and the defense mechanisms of isolation and rationalization. Gender and socioeconomic status were associated with the mean levels of several coping and defense mechanisms but did not moderate age-related changes. Increases in ego level were associated with increased use of the defense mechanism intellectualization and decreased use of the defense mechanisms of doubt and displacement. Overall, these findings in a European American sample suggest that most individuals showed development in the direction of more adaptive and less maladaptive coping and defense strategies from adolescence until late middle age or early old age. However, in late old age this development was reversed, presenting potential challenges to the adaptive capacity of older adults.

Tannic Acid preferentially targets estrogen receptor-positive breast cancer.

Research efforts investigating the potential of natural compounds in the fight against cancer are growing. Tannic acid (TA) belongs to the class of hydrolysable tannins and is found in numerous plants and foods. TA is a potent collagen cross-linking agent; the purpose of this study was to generate TA-cross-linked beads and assess the effects on breast cancer cell growth. Collagen beads were stable at body temperature following crosslinking. Exposure to collagen beads with higher levels of TA inhibited proliferation and induced apoptosis in normal and cancer cells. TA-induced apoptosis involved activation of caspase 3/7 and caspase 9 but not caspase 8. Breast cancer cells expressing the estrogen receptor were more susceptible to the effects of TA. Taken together the results suggest that TA has the potential to become an anti-ER(+) breast cancer treatment or preventative agent.

Personality-Related Risk and Resilience Factors in Coping with Daily Stress among Adult Cancer Patients.

We employed a diary design to study personality-related risk and resilience factors in adult cancer patients coping with daily stress. We focused on individuals' self-concept incoherence (SCI) as a personality-related risk factor and on psychological well-being (PWB) at baseline and daily beliefs of control as resilience factors. Reactivity to daily stress was assessed in terms of negative daily mood. Multilevel modeling analyses yielded significant main effects of daily stress, PWB at baseline, and daily control. These main effects were qualified by significant two- and three-way interactions. The significant Stress X Control interaction indicated that individuals reported more negative mood in response to daily stress on low-control days compared to high-control days. Similarly, a significant SCI X Control interaction suggested that individuals with a more coherent self-concept benefited more from feeling in control in terms of experiencing less increase in negative mood compared to individuals with a more incoherent self-concept. Significant three-way interactions also indicated that the associations between stress, control and negative daily mood differed by level of SCI and level of PWB at the beginning of the study. Overall, the findings from this study show the complex associations between risk and resilience factors and daily emotional well-being in a sample of adults who were affected by a life-threatening illness.

Personal Risk and Resilience Factors in the Context of Daily Stress.

This chapter focuses on the role that personal risk and resilience factors play as adults of all ages cope with the stressors encountered in everyday life. Theorists have suggested that researchers should focus on the effects of daily stress and coping rather than focusing exclusively on major life events and chronic stress and have proposed that understanding how adults cope with daily stress is a key aspect of understanding long-term well-being and adaptation in adulthood. After presenting a conceptual model outlining the major components of the daily stress process, the chapter reviews the existing empirical literature on personal risk and resilience factors in the context of daily stress. This research clearly suggests that there is no universal generalization that can be made regarding whether chronological age, in and of itself, confers greater vulnerability or resilience onto adults. Instead, we argue that researchers should ask when and under what conditions is age associated with greater vulnerability to daily stress and when and under what conditions is age associated with greater resilience to daily stress. Age differences in reactivity to daily stress are clearly embedded within a complex system of factors-structural, individual, and situational-that influence stress reactivity and stress recovery in several ways. This complexity should not be taken to mean that stress reactivity and recovery cannot be charted or understood. Researchers, however, will need to approach this complexity with a great deal of theoretical, methodological, and statistical rigor to move our understanding of the importance of age in shaping risk and resilience to daily stress forward. The final section of the chapter outlines several directions for future research in the area of aging and resilience. In particular, we argue that a focus on personal risk and resilience factors in the context of daily stress, in combination with the application of sophisticated statistical methods (e.g., dynamic systems modeling), will contribute to a more dynamic and person-centered understanding of processes of resilience.

Self-concept differentiation and self-concept clarity across adulthood: associations with age and psychological well-being.

This study focused on the identification of conceptually meaningful groups of individuals based on their joint self-concept differentiation (SCD) and self-concept clarity (SCC) scores. Notably, we examined whether membership in different SCD-SCC groups differed by age and also was associated with differences in psychological well-being (PWB). Cluster analysis revealed five distinct SCD-SCC groups: a self-assured, unencumbered, fragmented-only, confused-only, and fragmented and confused group. Individuals in the self-assured group had the highest mean scores for positive PWB and the lowest mean scores for negative PWB, whereas individuals in the fragmented and confused group showed the inverse pattern. Findings showed that it was psychologically advantageous to belong to the self-assured group at all ages. As hypothesized, older adults were more likely than young adults to be in the self-assured cluster, whereas young adults were more likely to be in the fragmented and confused cluster. Thus, consistent with extant theorizing, age was positively associated with psychologically adaptive self-concept profiles.